Ex Parte 7417170 et al

Patent Trial and Appeal Board

Aug 29, 2014

95002077 (P.T.A.B. Aug. 29, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 95/002,077 08/16/2012 7417170 80911.000500 4567 21967 7590 08/29/2014 HUNTON & WILLIAMS LLP INTELLECTUAL PROPERTY DEPARTMENT 2200 Pennsylvania Avenue, N.W. WASHINGTON, DC 20037 EXAMINER HUANG, EVELYN MEI ART UNIT PAPER NUMBER 3991 MAIL DATE DELIVERY MODE 08/29/2014 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ SYMED LABS LIMITED Requester and Respondent v. GRÜNENTHAL GMBH Patent Owner and Appellant ____________ Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 Technology Center 3900 ____________ Before ROMULO H. DELMENDO, JAMES T. MOORE, and RICHARD M. LEBOVITZ, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This is a decision on the appeal by the Patent Owner from the Patent Examiner’s decision to reject claims 59-115 in the above-identified inter partes reexamination of US 7,417,170 B2. The Board’s jurisdiction for this appeal is under 35 U.S.C. §§ 6(b), 134, and 315. We affirm-in-part. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 2 I. BACKGROUND The patent in dispute in this appeal is US 7,417,170 B2 (“the ’170 patent) which issued Aug. 26, 2008. The Patent Owner and real party in interest is “Grünenthal GmBH.” Appeal Br. 3 (January 22, 2014). A request for inter partes reexamination of ’170 patent was filed August 16, 2012 under 35 U.S.C. §§ 311-318 1 and 37 C.F.R. §§ 1.902-1.997. The Requester is Symed Labs Limited. Respondent Br. 1. (February 19, 2014). The claims of the ’170 patent are directed to methods of preparing substituted 3-arylbutyl-amine compounds corresponding to formula I. According to the patent, the compounds have analgesic properties. ’170 patent, col. 1, ll. 25- 31. II. CLAIMS Claim 59 is the only independent claim on appeal. Claim 59 reads as follows: A method for the preparation of a substituted 3-aryl-butyl dimethylamine compound corresponding to formula I, 1 This date is prior to the effective date of the America Invents Act (“AIA”) as regards the Inter Partes Reexamination statutes. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 3 wherein R l is Cl -3-alkyl, which is branched or unbranched, R 2 is Cl - 4-alkyl, which is branched or unbranched, R 3 is H, R 4 is H, R 7 is CH3, R 8 is CH3, R 9 to R 13 in each case independently of one another are chosen from H, OH, and OR 14 , where R 14 is chosen from branched or unbranched Cl - 6-alkyl and benzyl in each case in the form of one of its stereoisomers, or in the form of a mixture of stereoisomers, or in each case in the form of a physiologically acceptable salt, or in each case in the form of a solvate, said method comprising: (a) reacting a 1-dimethylamino-3-aryl-butan-3-ol compound corresponding to formula II with an acid, to produce a substituted 3-aryl-but-3-enyl-dimethylamine compound corresponding to formula III, Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 4 wherein the stereochemistry at position 2 according to formulas II and III remains unchanged, and (b) hydrogenating the substituted 3-aryl-but-3-enyl-dimethylamine compound corresponding to formula III in the presence of a platinum or palladium catalyst and hydrogen to produce the substituted 3-aryl-butyl-dimethylamine compound corresponding to formula I. III. REJECTIONS The Examiner set forth the rejections in the Right of Appeal Notice dated October 23, 2013 (“RAN”). An Examiner’s Answer, entered April 9, 2014, incorporates by reference the rejections in the RAN. The rejections in the RAN are as follows: 1. Claims 59-71, 73-87, 90, 93-105, 107-111, and 113-115 under 35 U.S.C. § 103(a) (pre-AIA) as obvious in view of Buschmann 2 and Puetz I. 3 RAN 12. 2 Helmut Buschmann et al., US Patent 5,811,582 issued September 22, 1998. 3 Claudia Pütz et al., WO 01/49651 A2 published July 12, 2001. References are to Clautia Puetz et al., US 6,890,959 issued May 10, 2005, an English Language equivalent. RAN 7. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 5 2. Claims 59-71, 73-84, 87, 90, 93-105, 107-111, and 113-115 under 35 U.S.C. § 103(a) (pre-AIA) as obvious in view of Buschmann, Welstead, 4 and admissions in the ’170 patent specification. RAN 18. 3. Claims 59-62, 67-115 under 35 U.S.C. § 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. RAN 23. 4. Claims 59-62 and 67-115 under 35 U.S.C. § 112 (pre-AIA), second paragraph, as indefinite for failing to particularly point out and distinctly claim the subject matter which the applicant regards as the invention. RAN 24. 5. Claims 59-62 and 67-115 under 35 U.S.C. § 314(a) as enlarging the scope of the claim of the patent being reexamined. RAN 24. 6. Claim 88 under 35 U.S.C. § 112 (pre-AIA), second paragraph, as improperly dependent. RAN 24. IV. CLAIM INTERPRETATION Claim 59 is directed to a method for the preparation of substituted 3-aryl- butyl-dimethylamine compounds corresponding to formula I. The compounds of formula I comprise substituents R 1 to R 4 and R 7 to R 14 , which are specifically defined in the claim. The formula I compound is recited in the claim preamble to be “in each case in the form of one of its stereoisomers, or in the form of a mixture of stereoisomers.” The claimed method comprises two recited steps, (a) and (b). Step (a), which is the first step, comprises reacting a formula II compound with an acid to form a formula III compound. This step is also referred to as “acid dehydration” or “dehydration.” The formula II compound is also described in this Decision as the 4 William Welstead, Jr., US 3,978,129 issued August 31, 1976. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 6 starting material. Step (b) comprises hydrogenating the formula III compound in the presence of a platinum or palladium catalyst and hydrogen to produce the formula I compound. According to step (a), “the stereochemistry at position 2 according to formulas II and III remains unchanged” when the compound of formula II is converted into the compound of formula III. The meaning of this phrase is in dispute. The Examiner construed the phrase to mean that the product compound of formula III must end up with the same configuration at position 2 as the starting compound of formula II. RAN 3-4. In other words, if the formula II compound is in the form of a mixture of stereoisomers, it must produce a mixture of the same stereoisomers of formula III after reacting the formula II compound with the acid in step (a). Respondent Br. 6. Patent Owner contends that the claimed requirement that “the stereochemistry at position 2 according to formulas II and III remains unchanged” precludes “reading the method claim on a reaction carried out on a racemic starting material” of formula II. Appeal Br. 7. Patent Owner argues: Because a racemic starting material will result in a racemic intermediate having varied stereochemistry (i.e., not preserving the stereochemistry of position 2), and the specification makes abundantly clear and those of skill in the art understand that preserving selectivity (i.e., stereochemistry remains unchanged) requires the use of nonracemic mixtures or optically-pure starting materials. Id. First, we begin with the definition. The term “stereoisomer,” as it appears in the preamble of claim 59, refers to molecules that have the same connectivity Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 7 between atoms, but a different arrangement of the atoms in space. Anslyn 5 298. Based on this definition, the requirement of step (a) that “the stereochemistry at position 2 according to formulas II and III remains unchanged” means that the spatial arrangement of atoms around position 2 is not changed when the formula II compound is converted into the formula II compound. The formula II and III compounds are depicted below: Position 2 is shown in the formula II and III compounds reproduced above. The arrangement of the atoms in space around position 2 is unchanged, according to claim 59, when the formula II compound is reacted with an acid to form the formula III compound. The compound of formula III has a “but-3-enyl” bond. Patent Owner argues that the formula II compound can not be a “racemate” because starting with a racemate would end up with “a racemic intermediate having varied stereochemistry (i.e., not preserving the stereochemistry of position 2).” Appeal Br. 7. A “racemate” is a 50:50 mixture of enantiomers, where each enantiomer has a different arrangement of atoms in space. Anslyn 343. 5 E.V. Anslyn and D.A. Dougherty, Modern Physical Organic Chemistry, Chapter 6, University Science Books (2006). eISBN 978-1-938787-63-8 (eBook) (attached). Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 8 Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Id. at 299. One nomenclature used to name enantiomers is the R,S system in which there is a center carbon atom and the atoms are arranged around it in a clockwise R configuration or a counterclockwise S configuration. Id. at 304. Another nomenclature uses the E,Z system when an alkene double bond is present. Id. Patent Owner’s argument does not follow the plain languge of the claim. The claim requires that the arrangement of the atoms in space (“stereochemistry”) “remains unchanged” when step (a) converts the formula II compound to the formula III compound. If a steroisomer of the R or S configuration were the starting compound formula II, then - as Patent Owner contends - the formula II compound would be required by the claim to have either the R or S configuration of the starting material. However, Patent Owner has not identified any language in the claim that would prohibit starting with a mixture of enantiomers (R and S) of formula II and ending up with the same mixture (R and S) of formula II. The sterochemistry would still be “unchanged” because the same arrangement of atoms in space at position 2 would occur in both the formula II and II compounds. There was additional discussion by the Requester concerning the language in claim 59 that the formula I compound produced by the method can be “in the form of one of its stereoisomers, or in the form of a mixture of stereoisomers.” Respondent Br. 5. Requester argues that since the formula I compound can be a mixture of stereoisomers, so can the starting compound formula II and intermediate compound formula III. Id. at 5-6. The formula I compound is produced by hydrogenating the formula III compound in step (b) of the claim. We have not been directed to evidence in the Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 9 record that it is necessary for the formula III compound to comprise a mixture of stereoisomers in order to produce a mixture of stereoisomers of formula I upon carrying out the hydrogenation step (b). Consequently, Requester’s argument is not supported by objective evidence or scientific reasoning. V. PRIOR ART REJECTIONS The claims stand rejected as obvious in view of Buschmann and Puetz I or Bushchmann and Welstead. In each rejection, Buschmann is cited for describing dehydrating a compound of formula II with an acid to produce a compound of formula III, a reaction that corresponds to step (a) of claim 59. RAN 12-13 and 18-19. It is acknowledged by the Examiner that Buschman does not describe hydrogenating the formula III compound to produce a compound of formula I, as recited in step (b) of the clam. Id. at 13 and 19. However, the Examiner found that hydrogenation is described in Puetz I and Welstead. Id. The Examiner determined it would have been obvious to one of ordinary skill in the art to hydrogenate Buschmann’s formula III compound to have made a formula I compound. Id. at 14 and 20. Patent Owner contends that Buschmann “fails to teach a method of dehydrating a tertiary alcohol [formula II] with an acid to form a but-3-enyl [formula III] compound, wherein the stereochemistry at position 2 remains unchanged” as required by claim 59. Appeal Br. 10 (emphasis added). According to Patent Owner, Buschmann descibes starting with a racemate of formula II compounds as reactants in the dehydration reaction which “would result in the formation of the more thermodynamically favored, but undesirable, but-2-enyl by- product over the but-3-enyl compound.” Id. Patent Owner contends that both the Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 10 but-3-enyl and but 2-enyl intermediates are formed by the dehydration reaction carried out by Buschmann when starting with a racemate. Id. at 11. Patent Owner takes the position that Buschmann’s acid dehydration reaction, starting with a racemate, produces 2-enyl compounds of formula III in which the sterochemistry is lost at the 2-position when converted to a formula III compound. In contrast, claim 59 comprises production of a 3-enyl compound of formula III after dehydration of the formula II compound with an acid, preserving the steeochemistry. Patent Owner’s argument appears to be based on a declaration by co- inventor Wolfgang Hell, Ph.D (“Hell Decl.”), in which Dr. Hell indicated that the following configurations would have been expected after acid dehydration of the formula II compound: Hell Decl. ¶10. The figure reproduced above shows the formula III compound in two enantiomer configurations - E and Z - which could be produced after acid dehydration. Id. According to Dr. Hell, the stereochemistry at position 2 of the formula II compound would have been expected to have been lost when treated with acid in step (a) to produce the formula III compound in the E- and Z- configurations. Id. Patent Owner’s argument is not supported by adequate persuasive evidence. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 11 First, the starting material of formula II appears to be a stereoisomer and not the racemate said to have been described in Buschmann. See Hell Decl. ¶6 showing chiral centers in the formula II compound. Second, and more significantly, Dr. Hell did not testify that the 2-enyl configuration reproduced in the figure above actually resulted. Rather, Dr. Hell stated: “Upon considering the starting material of general formula II, a skilled chemist would expect that predominantly the (undesired) but-2-enyl compounds would be formed.” Id. at ¶10. Thus, there is insufficient evidence that Buschmann’s acid dehydration reaction, which corresponds to step (a) of claim 59, results in a change in the stereochemistry at position 2 when a racemate is the formula II starting material. Third, evidence was not identified in the record of what stereochemistry would result when a racemate of the formula II compound was treated with acid in accordance with step (a) of claim 59. Because the claim requires “wherein the stereochemistry at position 2 according to formulas II and III remains unchanged,” the stereochemistry of both formula II and formula III compounds must be determined in order to ascertain whether the sterochemistry changed or did not change in Buschmann after acid dehydration. However, Dr. Hell did not provide evidence in his declaration of the stereochemistry of Buschmann’s formula II racemate nor of the formula III that is produced by acid dehydration of the racemate. In sum, Patent Owner has not provided sufficient persuasive evidence that the Examiner erred in finding that the sterochemistry would be unchanged if a formula II compound of Buschmann were used as a starting material for the dehydration reaction. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 12 A. Unexpected results Dr. Hell testified in his declaration that “the efficiency and high diastereoselectivity of the claimed process could not have been expected or predicted in any way by a skilled pharmaceutical or organic chemist, and can only be regarded as an unexpected and surprising superior result.” Hell Decl. ¶8. According to Dr. Hell, the claimed process begins with a stereoisomer of formula II (chiral centers shown as positions 2 and 3). Id. at ¶6. Dr. Hell testified that the skilled chemist would have expected predomnantly 2-enyl compounds. Id. at ¶10. However, Dr. Hell stated that “[s]urprisingly, in contrast to what would be expected by a person skilled in the art, mainly the desired but-3-enyl compound is prepared, as shown by the several examples in the ’170 Patent.” Id. at ¶12. Dr. Hell further testified that such unexpected reuslts were obtained whether the starting material compound of formula II was in the 2R or 2S configuration. Id. at ¶14. The Examiner did not consider these results persuasive because they were not commensurate in scope with the claims. RAN 25-26. The Examiner found that the claim covered using a mixture of enanatiomers for the starting material of the formula II compound, but the results described in the Hell declaration were obtained using an optically pure stereoisomer. Id. at 25. Respondent Br. 13-14. When “unexpected results” are a basis for patentability of the claims, the Patent Owner has the burden to show that the results have a “nexus” to the claimed subject matter and are reasonably commensurate with its scope. In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). “If an applicant demonstrates that an embodiment has an unexpected result and provides an adequate basis to support the conclusion that other embodiments falling within the claim will behave in the Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 13 same manner, this will generally establish that the evidence is commensurate with scope of the claims.” Id. In this case, the results described as “unexpected” by Dr. Hell were obtained with R- and S-enantiomers as starting materials. However, Patent Owner did not establish that the claims are limited to these starting materials. As explained above, Patent Owner did not provide persuasive evidence that, when a racemate of formula II is used as the starting compound, the stereochemistry would change upon reacting it with an acid as in step (a), and would therefore be excluded by the claims. Thus, the claim is reasonably interpreted to include racemates as starting materials. Dr. Hell did not establish that, when racemates of formula II are used, unexpected results were obtained. Nor did Dr. Hell demonstrate that formula II racemates would have been expected to behave as did the R- and S-enantiomers. Consequently, the Examiner’s determination that the results described in the Hell Declaration are not commensurate with the full scope of claim 59 is supported by a preponderance of the evidence. In addition to lacking results for the full scope of the claim, the Examiner also found the results deficient because “Buschmann describes the same elimination step (a) as recited in claim 59, and exemplifies the use of hydrochloric acid (Example 1) and formic acid (Example 5).” RAN 26. As such, the Examiner found that “Buschmann’s process would also lead to the same selective reaction as argued by the Patent Owner.” Id. The Examiner’s reasoning is logical. Buschmann is not limited to racemates of formula II, but discloses enantiomers, as well. Buschmann, col. 2, ll. 38-39; Respondent Br. 7-8. When a specific enantiomer is used in Buschmann’s process, it would have been reasonable to expect the same results described in the Hell Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 14 Declaration because the same starting materials and reaction conditions are used. In re Best, 562 F.2d 1252, 1255 (CCPA 1977) (“Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product.”). Although Buschmann may not have recognized that, when starting with a specific stereoisomer, the results described in the Hell declaration would have been obtained, such results are not a basis for patentability. “Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991). VI. § 112 AND BROADENING REJECTIONS A. R 1 and R 2 Original claim 1 defined R 1 as “chosen from H, C1-3-alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted”; and R 2 as “H or C1-4-alkyl, which is branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted.” Claim 59, which was added during the reexamination proceeding, changed the wording of R 1 and R 2 : R 1 is C1-3-alkyl, which is branched or unbranched, R 2 is C1-4-alkyl, which is branched or unbranched, The Examiner contends that the definitions of R 1 and R 2 as recited in claim 59 are not described in the ’170 patent specification or in the original claims, and further constitutes a broadening amendment in contravention of 35 U.S.C. § 314(a). RAN 23-25. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 15 During reexamination of an unexpired patent, claim terms are given their broadest reasonable interpretation consistent with the patent specification. In re Suitco Surface, Inc., 603 F.3d 1255, 1259 (Fed. Cir. 2010); In re Abbott Diabetes Care Inc., 696 F.3d 1142 (Fed. Cir. 2012). The ’170 patent defines the term “alkyl” which is recited in the description of R 1 and R 2 . In the context of this invention, alkyl . . . radicals are understood as meaning saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which can be unsubstituted or mono- or polysubstituted. Here, C1-2 -alkyl represents C1- or C2-alkyl, C1-3-alkyl represents C1-, C2- or C3-alkyl, C1-4-alkyl represents C1-, C2-, C3- or C4-alkyl. ’170 patent, col. 3, ll. 56-62. The patent thus defines “alkyl” to mean saturated, unsaturated, branched, unbranched, unsubstituted, monosubstituted, and polysubstituted alkyls. The recitation in original claim 1 that the C1-3-alkyl of R 1 and the C1-4 alkyl of R 2 “is branched or unbranched, saturated or unsaturated, unsubstituted or mono- or polysubstituted” is redundant since “alkyl” is already expressly defined in the ’170 patent to include these modifications. While it is unclear why Patent Owner chose to subsequently change the wording of R 1 and R 2 in claim 59 by deleting “saturated or unsaturated, unsubstituted or mono- or polysubstituted,” the deletion does not alter the scope of the claim since “alkyl” is expressly defined in the patent to include these modifications. Accordingly, we conclude that R 1 and R 2 as recited in claim 59 are described in the ’170 patent and do not broaden the scope of the claim. The claims are also rejected as indefinite under § 112, second paragraph, because the definitions of that R 1 and R 2 as recited in claim 59 are said to be Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 16 unclear. RAN 24. In view of the definition of “alkyl” in the ‘170 patent, we shall reverse this rejection, as well. B. “in any desired mixing ratio” Original claim 1 defined the formula I compound in claim 1 to be “in each case in the form of one of its stereoisomers, its racemates or in the form of a mixture of stereoisomers, in any desired mixing ratio. Claim 59 deletes the phrase “in any desired mixing ratio.” The Examiner contends that formula I lacking such phrase is not described in the patent specification and constitutes a broadening amendment. RAN 23-25. Requester contends that the claim is broadened because “the claims would theoretically encompass any mixing ratio, whether the mixing ratio was desired or not.” Respondent Br. 19. This argument is unpersuasive. It is unclear how the mental process of desiring a mixing ratio further limits the claim when the claim already recites a “mixture of stereoisomers” which would encompass any mixing ratio. The rejection is reversed. C. Claim 61 Claim 61 stands rejected as indefinite because “there is no explanation regarding the line protruding from the phenyl ring.” RAN 24. Patent Owner responds that “the protruding line is an artifact of attempting to ‘strike out’ subject matter, which is an inadvertent formatting error. . . . [which] does not rise to the level of an indefiniteness rejection and should be addressed as a minor informality.” Appeal Br. 21. We agree with Patent Owner and reverse the rejection. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 17 D. Claim 88 Claim 88 is said by the Examiner to be improperly dependent on later claim 110. Patent Owner acknowledges this is an error. Appeal Br. 21-22. The rejection is therefore affirmed. VII. SUMMARY The obviousness rejections of claims 59-71, 73-87, 90, 93-105, 107-111, and 113-115 in view of Buschmann and Puetz I, and of claims 59-71, 73-84, 87, 90, 93-105, 107-111, and 113-115 in view of Buschmann, Welstead, and admissions in the ’170 patent specification are AFFIRMED. The dependent claims were not argued separately and thus fall with independent claim 59. The §112 written description rejection of claim 59-62 and 67-115 is REVERSED. The §112 second paragraph rejection of claims 59-62 and 67-115 is REVERSED. The § 314(a) rejection of 59-62 and 67-115 is REVERSED. The §112 second paragraph rejection of claim 88 is AFFIRMED. TIME PERIOD FOR RESPONSE In accordance with 37 C.F.R. § 41.79(a)(1), the “[p]arties to the appeal may file a request for rehearing of the decision within one month of the date of: . . . [t]he original decision of the Board under § 41.77(a).” A request for rehearing must be in compliance with 37 C.F.R. § 41.79(b). Comments in opposition to the request and additional requests for rehearing must be in accordance with 37 C.F.R. § 41.79(c) & (d), respectively. Under 37 C.F.R. § 41.79(e), the times for requesting rehearing under paragraph (a) of this section, for requesting further rehearing under paragraph (d) of this section, and for submitting comments under paragraph (c) of this section may not be extended. Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 18 An appeal to the United States Court of Appeals for the Federal Circuit under 35 U.S.C. §§ 141-144 and 315 and 37 C.F.R. § 1.983 for an inter partes reexamination proceeding “commenced” on or after November 2, 2002 may not be taken “until all parties’ rights to request rehearing have been exhausted, at which time the decision of the Board is final and appealable by any party to the appeal to the Board.” 37 C.F.R. § 41.81. See also MPEP § 2682 (8th ed., Rev. 7, July 2008). In the event neither party files a request for rehearing within the time provided in 37 C.F.R. § 41.79, and this decision becomes final and appealable under 37 C.F.R. § 41.81, a party seeking judicial review must timely serve notice on the Director of the United States Patent and Trademark Office. See 37 C.F.R. §§ 90.1 and 1.983. AFFIRMED-IN-PART Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 19 Patent Owner and Third Party Requester: HUNTON & WILLIAMS LLP INTELLECTUAL PROPERTY DEPARTMENT 2200 PENNSYLVANIA AVENUE, N.W. WASHINGTON, DC 20037 ack Appeal 2014-007435 Reexamination Control 95/002,077 Patent 7,417,170 B2 20 ATTACHMENT 297 CHAPTER 6 Stereochemistry Intent and Purpose Stereochemistry is the study of the static and dynamic aspects of the three-dimensional shapes of molecules. It has long provided a foundation for understanding structure and re- activity. At the same time, stereochemistry constitutes an intrinsically interesting research field in its own right.Many chemists find this area of study fascinatingdue simply to the aes- thetic beauty associated with chemical structures, and the intriguing ability to combine the fields of geometry, topology, and chemistry in the study of three-dimensional shapes. In ad- dition, there are extremely important practical ramifications of stereochemistry. Nature is inherently chiral because the buildingblocks of life (
-amino acids, nucleotides, and sugars) are chiral and appear in nature in enantiomerically pure forms. Hence, any substances cre- ated by humankind to interact with or modify nature are interacting with a chiral environ- ment. This is an important issue for bioorganic chemists, and a practical issue for pharma- ceutical chemists. The Food and Drug Administration (FDA) now requires that drugs be produced in enantiomerically pure forms, or that rigorous tests be performed to ensure that both enantiomers are safe. In addition, stereochemistry is highly relevant to unnatural systems. As we will de- scribeherein, theproperties of synthetic polymers are extremelydependent upon the stereo- chemistry of the repeating units. Finally, the study of stereochemistry can be used to probe reactionmechanisms, andwewill explore the stereochemical outcomeof reactions through- out the chapters in parts II and III of this text. Hence, understanding stereochemistry is nec- essary formost fields of chemistry, making this chapter one of paramount importance. All introductory organic chemistry courses teach the fundamentals of stereoisomerism, and wewill only briefly review that information here. We also take a slightly more modern viewpoint, emphasizingnewer terminology andconcepts. The goal is for the student to gain a fundamental understanding of the basic principles of stereochemistry and the associated terminology, and then to present some of the modern problems and research topics in this area. 6.1 Stereogenicity and Stereoisomerism Stereochemistry is a field that has often been especially challenging for students. No doubt one reason for this is the difficulty of visualizing three-dimensional objects, given two- dimensional representations on paper. Physical models and 3-D computermodels can be of great help here, and the student is encouraged to use them asmuch as possible whenwork- ing through this chapter. However, only simplewedges and dashes are given inmost of our drawings. It is these kinds of simple representations that one must master, because attrac- tive, computer generated pictures are not routinely available at the work bench. The most common convention is the familiar ‘‘wedge-and-dash’’ notation. Note that there is some variability in the symbolism used in the literature. Commonly, a dashed wedge that gets larger as it emanates from the point of attachment is used for a receding group. However, considering the art of perspective drawing, it makes no sense that the wedge gets bigger as 298 CHAPTER 6 : STEREOCHEMISTRY Projecting away from the viewer Projecting toward the viewer Hydrogens projecting toward the viewer The convention used in this book it moves further away. Yet, this is the most common convention used, and it is the con- vention we adopt in this book. Many workers have turned to a simple dashed line instead (see above), or a dash that does get smaller. Similarly, both a bold wedge and a bold line are used to represent forward-projecting substituents. Another common convention is the bold ‘‘dot’’ on a carbon at a ring junction, representing a hydrogen that projects toward the viewer. The challenge of seeing, thinking, anddrawing in three dimensions is not the only cause for confusion in the study of stereochemistry. Anothermajor cause is the terminology used. Hence, we start this chapter off with a review of basic terminology, the problems associated with this terminology, and then an extension intomoremodern terminology. 6.1.1 Basic Concepts and Terminology Therewas considerable ambiguity and imprecision in the terminology of stereochemis- try as it developed during the 20th century. In recent years, stereochemical terminology has clarified.We present here a discussion of the basics, not focused solely on carbon. However, in Section 6.2.4wewill examine carbon specifically.Whilemost of this shouldbe review,per- haps the perspective and some of the terminologywill be new. Let’s start by delineating the difference between a stereoisomer and other kinds of iso- mers. Recall that stereoisomers are molecules that have the same connectivity but differ in the arrangement of atoms in space, such as cis- and trans-2-butene. Even gauche andanti bu- tane are therefore stereoisomers. This is in contrast to constitutional isomers, which are molecules with the same molecular formula but different connectivity between the atoms, such as 1-bromo- and2-bromobutane. The constitution of amolecule is definedby thenum- ber and types of atoms and their connectivity, including bondmultiplicity. These definitions are straightforward and clear (as long aswe can agree on the definition of connectivity-see the GoingDeeper highlight on page 300). An historical distinction, but one that is not entirely clear cut, is that between configura- tional isomers and conformational isomers. Conformational isomers are interconvertible by rotations about single bonds, and the conformation of a molecule concerns features re- lated to rotations about single bonds (see Chapter 2). There is some fuzziness to this distinc- tion, attendant with the definition of a ‘‘single’’ bond. Is the C-N bond of an amide a single bond, even though resonance arguments imply a significant amount of double bond charac- ter and the rotation barrier is fairly large?Also, some olefinic ‘‘double’’ bonds canhave quite low rotation barriers if the appropriatemix of substituents if present. Because of these exam- ples, aswell as other issues concerning stereochemistry,we simplyhave to livewith a certain amount of terminological ambiguity. A related term is atropisomers, which are stereoiso- mers that can be interconverted by rotation about single bonds but for which the barrier to rotation is large enough that the stereoisomers can be separated and do not interconvert readily at room temperature (examples are given in Section 6.5). The term configurational isomer is a historic one that has no real value in modern ste- reochemistry. It is generally used to encompass enantiomers and disastereomers as isomers (see definitions for these below), but stereochemical isomers is a better term. The term con- 2996 .1 STEREOGENICITY AND STEREOISOMER ISM Figure 6.1 Simple flowchart for classifying various kinds of isomers. Two structures with the same formula Same connectivity ? Constitutional isomers Stereoisomers Non- congruent mirror images ? Diastereomers Enantiomers yes yes no no figuration is still useful. Mislow defines configuration as ‘‘the relative position or order of the arrangement of atoms in space which characterizes a particular stereoisomer’’. A re- lated term is absolute configuration, which relates the configuration of a structure to an agreed upon stereochemical standard. For example, later in this chapter we discuss the d and l nomenclature system, where the arrangement of atoms in space is related to that of ()-glyceraldehyde. If the arrangement of atoms in space in a molecule can be related to ()-glyceraldehyde, or some other standard, we state that we know that molecule’s abso- lute configuration. When two stereoisomers are nonsuperposable mirror images of each other, they are known as enantiomers (see the schematic examples in the margin). To achieve the mirror image of amolecule, simply imagine a sheet of glass placed alongside themolecule of inter- est, then pass each atom through the glass such that each atom ends up the same distance fromthe sheet of glass as in theoriginal structure. Stereoisomers that are not enantiomers are known as diastereomers. Figure 6.1 shows a simple flow chart for classifying isomers. Any object that is nonsuperposable (noncongruent)with itsmirror image is chiral. If an object is not chiral-that is, if its mirror image is congruentwith the original-it is achiral. Classic Terminology There are a series of termsused in the context of stereochemistry that are ingrained in the literature, and several you are likely familiarwith frombeginningorganic chemistry.Wede- finemany of these terms here, and examine how they can bemisleading. After a look at this classic terminology,moremodern and concise terms are given. Confusion with respect to terminology arises with terms such as ‘‘optically active’’ and ‘‘chiral center’’, which often mislead as much as they inform.Optically active refers to the ability of a collection ofmolecules to rotate plane polarized light (a phenomenon thatwe ex- plore indetail in Section 6.1.3). In order for a sample to be optically active, itmust have an ex- cess of one enantiomer. Now comes the confusion. Optically active was generally used as a synonym for chiral in the earlier literature, and unfortunately this usage continues at times even today.Wediscourage thisuse. Theproblem is that there aremanyexamples of chemical W X Z Y W Sheet of glass X Z Y Z W X Y Z Enantiomers: non-superimposable mirror images V V W X Y 300 CHAPTER 6 : STEREOCHEMISTRY OH Chiral molecules without a “chiral center” CH3 H H H3C C HO CC Connections Stereoisomerism and Connectivity Further, what aboutmetal coordination?We are comfortablewith a clear connectivity pattern in inorganicA crucial concept in the definition of stereoisomers complexes such as ironpentacarbonyl or a porphyrin com-given above is ‘‘connectivity’’. Inmethane or 2,3- plex. Butwhat aboutMg2+ ions complexing a carbonyl?dichlorobutane, there is no doubt as to the connectivity of When is a bond tooweak to be considered relevant forthe system.However, there is an innate arbitrariness to the stereoisomerism?term, and this can lead to some ambiguity about stereo- isomerism. For example, do hydrogen bonds count in our list of connectivity?No, but consider the implications of this. If hydrogen bonds ‘‘don’t count’’, then howdowe think about isomerism in double-helical DNA?Dowe just ignore the interaction of the two strands? As a simpler example, in a solution of a racemic carboxylic acid, does O Mg2 + Mg2 + Stereoisomers? O dimerization create true diastereomers? Finally, there has been amodern emphasis on ‘‘topo- logical isomerism’’, structureswith loops or interlocking rings inwhich large parts of themolecule are not con- nected to each other in any conventional way. This can produce novel stereochemical situations, aswewill see in Section 6.6. In the end, there is no universally agreed upon con- vention for connectivity as it relates to stereoisomerism. Usually, the connectivity of a system is clear.When there is the potential for ambiguity, though, a clear statement of the ground rules should bemade. H H Do diastereomers exist in a solution of enantiomeric carboxylic acids? O H O O H O H H O H O O H O samples that contain chiralmolecules, but the samples themselves are not optically active.A racemicmixture, a 50:50 mixture of enantiomers, is not optically active, but every molecule in the sample is chiral. It is important to distinguish between a sample that is optically inac- tive because it contains a racemic mixture and a sample that is optically inactive because it contains achiral molecules, and the earlier terminologymade this difficult. Also, it is easy to imaginemolecules, evenwhen enantiomerically pure, that would not rotate plane polarized light to any measurable extent. The extent of rotation of plane polar- ized light dependsupondifferences in the refractive indiceswith respect to right and left cir- cularly polarized light as it passes through the sample. Enantiomers that do not have dra- matically different refractive indices would not result in measurable rotations. Examples would be a carbon with four different n-alkyl chains attached, with chain lengths of maybe 10, 11, 12, and 13 carbons; or one with four C10 chains, but terminating in -CH3, -CH2D, -CHD2, and -CD3. In each case the molecule is chiral, but any rotation of plane polarized light would be immeasurably small. Operationally, they are optically inactive. Finally, even an enantiomerically pure sample of a chiral molecule will show zero rotation at certain wavelengths of light, aswemove from () rotation to () rotation in the optical rotatorydis- persion (ORD) curve (see Section 6.1.3). ‘‘Optically active’’ is an ambiguous description. More confusion arises with terms that are meant to focus on the chirality at a particular point in a molecule. The prototype is the chiral center or chiral carbon, which is defined as an atom or specifically carbon, respectively, that has four different ligands attached. Here, the term ‘‘ligand’’ refers to any group attached to the carbon, such as H, R, Ar, OH, etc. The particular case of a carbon with four different ligands has also been termed an asymmetric carbon. One problemwith such terms, aswewill showbelow, is that ‘‘asymmetric carbons’’ and ‘‘chiral centers/carbons’’ exist in molecules that are neither asymmetric nor chiral. In addition,manymolecules can exist in enantiomeric formswithout having a ‘‘chiral center’’. Classic examples include dimethylallene and the twisted biphenyl shown in the margin- we’ll seemore below.Given all this, although the termsmay already be part of your vocabu- lary, we discourage their use. 3016 .1 STEREOGENICITY AND STEREOISOMER ISM CH3H H Cl H3C C C Swap two ligands C H HO NH2 CO2H Swap two ligands Swap two ligands Swap two ligands Swap two ligands Ru ClH2O Cl Cl OH2 H2O Cl Cl P F F Ru ClCl Cl H2O OH2 H2O F Cl Cl P Cl F CH3H3C HH C C C H2N HO H CO2H H Figure 6.2 Moleculeswith stereogenic centers. The stereogenic centers aremarkedwith colored arrows, and a curved black arrow is used to showhow ligand interchange at a stereogenic center produces a new stereoisomer. More Modern Terminology Muchof the confusion that can be generatedwith the terms given abovewas eliminated with the introduction of the stereogenic center (or, equivalently, stereocenter) as an orga- nizing principle in stereochemistry. An atom, or a grouping of atoms, is considered to be a stereogenic center if the interchange of two ligands attached to it can produce a new stereo- isomer. Not all interchanges have to give a new stereoisomer, but if one does, then the center is stereogenic. The center therefore ‘‘generates’’ stereochemistry. A non-stereogenic center is one in which exchange of any pair of ligands does not produce a stereoisomer. The term ‘‘stereogenic center’’ is, in a sense, broader than the term ‘‘chiral center’’. It implies nothing about themolecule being chiral, only that stereoisomerism is possible. The structures in Fig- ure 6.2 show several stereogenic centers. Note that in more complex geometries, such as pentacoordinate or hexacoordinate atoms, we do not need all the ligands to be inequivalent in order to have a stereogenic center. Given these new terms, we strongly encourage stu- dents to abandon the term ‘‘chiral center’’ and to reserve ‘‘optically active’’ as a description of an experimental measurement. A related and more encompassing concept is that of a stereogenic unit. A stereogenic unit is an atomor grouping of atoms such that interchange of a pair of ligands attached to an atom of the grouping produces a new stereoisomer. For example, the CC group of trans-2- butene is a stereogenic unit because swapping a CH3/H pair at one carbon produces cis-2- butene.A tetrahedral atom is a stereogenic unit,where swapping the positions of any twoof four different ligands gives a stereoisomer (see below). In the examples of chiral molecules without ‘‘chiral centers’’ noted above, the CCC unit of the allene and the biphenyl itself are stereogenic units. Many workers have adopted terms such asplanar chirality and axial chirality todescribe systems such as chiral biphenyl and allene based structures, respectively. The justification for these terms is that suchmole- cules do not have stereogenic centers, but rather stereogenic units. Admittedly, terms that address chirality without stereogenic centers could be useful. However, since a molecule that is truly planar (i.e., has a plane of symmetry) must be achiral, planar chirality is an odd use of the word ‘‘planar’’. Developing precise, unambiguous definitions of these terms is a challenge that, in our view, has not yet been met. Currently, the best term is ‘‘stereogenic unit’’, where the biphenyl or allene groups have the ability to create chirality, just as a tetra- hedral atom has the ability to generate chirality. 302 CHAPTER 6 : STEREOCHEMISTRY Figure 6.3 Illustration of the concept of the stereogenic center in the context of carbon.Whether in a chiral molecule like 2-butanol or an achiral molecule likemeso-tartaric acid, interconversion of two ligands at a stereocenter produces a new stereoisomer. (R )-2-Butanol (S )-2-Butanol Stereogenic center Interconverting two ligands produces a new stereoisomer H CH3 H OH HH3C H CH3 H H OHH3C meso -Tartaric acid (R,R )-Tartaric acid Stereogenic center Interconverting two ligands produces a new stereoisomer HO CO2H H OH HHO2C HO CO2H H H OHHO2C To illustrate the value of the newer terminology, let’s review two prototypes of organic stereochemistry. First, consider a molecule that has a carbon with four different ligands, a carbonwewill describe as CWXYZ. A specific example is 2-butanol (Figure 6.3). If we inter- change any two ligands at carbon 2,we obtain a stereoisomer-the enantiomer-of the orig- inal structure. Thus, C2 of 2-butanol is a stereogenic center. The analysis can get more com- plicated in systemswithmore than one CWXYZ center. Let’s consider such a case. Figure 6.3 also shows tartaric acid. Beginning with the structure labeled ‘‘meso’’, if we interchange two ligands at either C2 or C3, we obtain a new structure, such as (R,R)-tartaric acid. (If youdonot recall theR andSnotation, look ahead to Section 6.1.2.) This structure has the same connectivity as meso-tartaric acid, but the two are not congruent (verify for your- self), and so the new structure is a stereoisomer of the original. However, (R,R)- and meso- tartaric acid are notmirror images, so they are not enantiomers. They are diastereomers. Note that themeso form of tartaric acid is achiral; verify for yourself that it is congruent with itsmirror image. However, C2 andC3 ofmeso-tartaric acid are stereogenic centers; that is, swapping any two ligands at either center produces a new stereoisomer. This is one value of the stereogenic center concept. As we noted above, in earlier literature a CWXYZ center such asC2 or C3was called a chiral center, but it seems odd to saywe have two chiral centers in an achiral molecule! A CWXYZ center does not guarantee a chiral molecule. However, a CWXYZ group is always a stereogenic center. Tartaric acid has two stereogenic centers and exists as three possible stereoisomers. This is an exception to the norm. Typically, a molecule with n stereogenic, tetracoordinate car- bons will have 2n stereoisomers-2n-1 diastereomers that each exist as a pair of enantiomers. For example, a structurewith two stereogenic centerswill exist asRR, SS,RS, and SR forms. In tartaric acid theRS andSR forms are identical-they are both themeso form-becauseC2 andC3 have the same ligands. The2n rule quickly creates complexity inmoleculeswithmultiple stereogenic centers. In complex natural products that are often targets of total synthesis efforts, it is conventional to note the number of possible stereoisomers (for example, 10 stereogenic centers implies 1024 stereoisomers), with only one combination defining the proper target (see the Following Connections highlight). Polymers, both natural and synthetic, can produce extraordinary stereochemical diversity when each monomer carries a stereogenic center. We’ll return to this issue below. Whenmany stereogenic centers are present in amolecule, it becomes difficult to refer to all the possible stereoisomers. It is often useful to consider only two different isomers, called epimers. Epimers are diastereomers that differ in configuration at only one of the several stereogenic centers. Imagine taking any one of themany stereogenic centers in everninomi- cin (shown in the next Connections highlight) and changing the stereochemistry at only that one stereogenic center. This creates an epimer of the original structure. Another example is the difference between the
- and -anomers of glucose, which are epimeric forms of the sugar (look ahead to Figure 6.18 for definitions of
- and -anomers). 3036 .1 STEREOGENICITY AND STEREOISOMER ISM Connections Total Synthesis of an Antibiotic with these techniques havebecome is the total synthesis of ever- a Staggering Number of Stereocenters ninomicin 13,384-1. This compound contains 13 rings and 35 stereocenters (3.4 1010 possible stereoisomers).Synthetic chemists are continually in search of newmeth- Althoughmany of the stereocenters were derived fromods to control the stereochemical outcome of synthetic the ‘‘chiral pool’’ (see Section 6.8.3), several stereocenterstransformations. Although the exactmethods used are associatedwith the ring connections and ring-fusionsbest described in textbookswith a focus upon asymmetric were set with reactions that proceedwith varying degreessynthesis, it is worthmentioning here how sophisticated of stereoselectivity and specificity.the field is becoming. By analyzing how the topicity rela- tionshipswithin reactants will influence enantiomeric and Nicolaou, K.C.,Mitchell, H. J., Suzuki, H., Rodriguez, R.M., Baudoin, disastereomeric selectivities, amultitude of reactionswith O., and Fylaktakidou, C. ‘‘Total Synthesis or Everninomicin 13,384-1-Part 1: Synthesis of A1B(A)C Fragment.’’Angew. Chem. Int. Ed. Eng., 38, 3334-good stereochemical control have been developed. One 3339 (1999), and subsequent communications.particular example that highlights just how far advanced OMe OMe OMe OH HO OH Me HO OH OMe O MeO O O HO Me Me Cl Cl O O O O Me Me Me Me Me OH O O O Me OHHO Everninomicin 13,384-1 NO2 O O OH O O O O O O 6.1.2 Stereochemical Descriptors All introductory organic chemistry texts provide a detailed presentation of the various rules for assigning descriptors to stereocenters. Herewe provide a brief review of the termi- nology to remind the student of the basics. Many of the descriptors for stereogenic units begin with assigning priorities to the attached ligands. Higher atomic number gets higher priority. If two atoms under compari- son are isotopes, the one with higher mass is assigned the higher priority. Ties are settled by moving out from the stereocenter until a distinction is made. In other words, when two attached atoms are the same, one examines the next atoms in the group, only looking for a winner by examining individual atomic numbers (do not add atomic numbers of several atoms). Multiple bonds are treated as multiple ligands; that is, CO is treated as a C that is sin- gly bonded to twooxygenswith one oxygenbound to aC. For example, thepriorities shown below for the substituted alkene are obtained, giving an E-stereochemistry. O An E-alkene Higher Priority OCH2CH3 Lower Priority O Considered as C C N Considered as CR NC N N R R H C C R H O O C Br Highest priority Lowest priority CH3Cl Cl CH3 H3C H Higher priority Lower priority Lower priority Higher priority O O F 304 CHAPTER 6 : STEREOCHEMISTRY HHO Turn molecule over OH 11 22 33 OH H OH (S)-2-Butanol (R)-2-Butanol O Higher priority Lower priority Higher priority (Z )-3-Chloromethyl-3-penten-2-one Lower priority CH3H H3C Cl R,S System For tetracoordinate carbon and related structures we use the Cahn-Ingold-Prelog sys- tem. The highest priority group is given number 1, whereas the lowest priority group is given number 4. Sight down the bond from the stereocenter to the ligand of lowest priority behind. Ifmoving from thehighest (#1), to the second (#2), to the third (#3) priority ligand in- volves a clockwise direction, the center is termedR. A counterclockwise direction implies S. E,Z System For olefins and related structureswe use the same priority rules, butwe divide the dou- ble bond in half and compare the two sides. For each carbon of an olefin, assign one ligand high priority and one low priority according to the rules above. If the two high priority li- gands lie on the same side of the double bond, the system isZ (zusammen); if they are on op- posite sides, the system is E (entgegen). If an H atom is on each carbon of the double bond, however, we can also use the traditional ‘‘cis’’ and ‘‘trans’’ descriptors. d and l The descriptors d and l represent an older system for distinguishing enantiomers, relating the sense of chirality of any molecule to that of d- and l-glyceraldehyde. d- and l-glyceraldehyde are shown below in Fischer projection form. In a Fischer projection, the horizontal lines represent bonds comingout of theplane of thepaper,while the vertical lines represent bonds projecting behind the plane of the paper. Youmaywant to review an intro- ductory text if you are unfamiliar with Fischer projections. The isomer of glyceraldehyde that rotates plane polarized light to the right (d) was labelledd, while the isomer that rotates plane polarized light to the left (l) was labelled l. To namemore complex carbohydrates or amino acids, one draws a similar Fischer pro- jectionwhere theCH2OHorR is on the bottomand the carbonyl group (aldehyde, ketone, or carboxylic acid) is on the top. The d descriptor is used when the OH or NH2 on the penulti- mate (second from the bottom) carbon points to the right, as in d-glyceraldehyde, and l is usedwhen theOHorNH2 points to the left. See the following examples. HO H H OH H OH CH2OH D-Arabinose CHO O HO H H OH H OH CH2OH D-Fructose CH2OH H OH HO H H OH HO H CH2OH L-Idose H NH2 CH2PH D-Phenylalanine CO2H H OH CH2OH CHO H2N H CH2OH L-Serine CO2H CHO L-Glyceraldehyde OH =H CH2OH D-Glyceraldehyde CHO HO H CH2OH CHO H =HO CH2OH CHO The d and l nomenclature system is fundamentally different than the R/S or E/Z sys- tems. The d and l descriptors derive from only one stereogenic center in the molecule and are used to name the entire molecule. The name of the sugar defines the stereochemistry of all the other stereogenic centers. Each sugar has a different arrangement of the stereogenic centers along the carbon backbone. In contrast, normally a separate R/S or E/Z descriptor is used to name each individual stereogenic unit in a molecule. The d/l nomenclature is a carry over from very early carbohydrate chemistry. The terms are now reserved primarily for sugars and amino acids. Thus, it is commonly stated that all natural amino acids are l, while natural sugars are d. 3056 .1 STEREOGENICITY AND STEREOISOMER ISM Erythro and Threo Another set of terms that derive from the stereochemistry of saccharides are erythro and threo. The sugars shown below are d-erythrose and d-threose, which are the basis of a no- menclature system for compoundswith two stereogenic centers. If the two stereogenic cen- ters have two groups in common, we can assign the terms erythro and threo. To determine theuse of the erythro and threodescriptors, draw the compound in a Fischer projectionwith the distinguishing groups on the top and bottom. If the groups that are the same are both on the right or left side, the compound is called erythro; if they are on opposite sides, the com- pound is called threo. See the examples given below.Note that these structures have enanti- omers, and hence require R and S descriptors to distinguish the specific enantiomer. The erythro/threo systemdistinguishes diastereomers. H2N H H NH2 Ph Threo CO2H H NH2 H NH2 Ph Erythro CO2H HO H H OH CH2OH D-Threose CHO H OH H OH CH2OH D-Erythrose CHO Br H Br H t -Bu Erythro CH3 Br H H Br t -Bu Threo CH3 Helical Descriptors-M and P Many chiral molecules lack a conventional center that can be described by the R/S or E/Z nomenclature system. Typically these molecules can be viewed as helical, and may have propeller, or screw-shaped structures. To assign a descriptor to the sense of twist of such structures, we sight down an axis that can be associated with the helix, and consider separately the ‘‘near’’ and ‘‘far’’ substituents, with the near groups taking priority. We then determine the highest priority near group and the highest priority far group. Sighting down the axis, ifmoving from the near group of highest priority to the corresponding far group re- quires a clockwise rotation, the helix is a right-handedhelix and is described asP (or plus).A counterclockwise rotation implies a left-handed helix and is designated asM (orminus). As in all issues related to helicity, it does not matter what direction we sight down the axis, be- causewewill arrive at the same descriptor. Three examples ofmoleculeswithM/Pdescrip- tors are shown below. CH3 CH3 NO2 O2N H3C H3C H Sight Cl H C H3C HC CH3 HH C H Cl Counterclockwise M Sight O2N CH3 NO2 CH3 Clockwise P Sight H CH3 CH3 H Clockwise P As another example, consider triphenylborane (Eq. 6.1, where a, b, and c are just labels of hydrogens so that you can keep track of the rotations shown). Triphenylborane cannot be fully planar because of steric crowding, and so it adopts a conformationwith all three rings twisted in the same direction, making a right- or left-handed propeller. TheM or P descrip- 306 CHAPTER 6 : STEREOCHEMISTRY tors are most easily assigned by making an analogy to a common screw or bolt. Common screws or bolts are right-handed (‘‘reverse thread’’ screws and bolts are left-handed). If the sense of twist is the same as a screw or bolt, it is assigned thePdescriptor (check theP andM descriptors for yourself in Eq. 6.1). a bc B a B c B b P M ‡ (Eq. 6.1) Rotation about the C-B bonds of triphenylborane is relatively facile, and the motions of the rings are correlated in the sense shown (Eq. 6.1). In Eq. 6.1 the arrows denote the direction of bond rotation, not the helical direction. Two rings rotate through a perpen- dicular conformation while one moves in the opposite way. This ‘‘two-ring flip’’ reverses helicity and, in a substituted case (now a, b, and c in Eq. 6.1 are substituents), creates a new diastereomer. Ent and Epi Because of the stereochemical complexity of many natural products, short and simple descriptors have come into common use to relate various stereochemical relationships. For example, the enantiomer of a structure with many stereogenic centers has the prefix ent-. Ent-everninomicin is a trivial name that can be given to the enantiomer of everninomicin. Similarly, due to the stereochemical complexityofmanynatural products, theprefix epi- has become a convenient way to name structures where only one stereogenic center has under- gone a change in configuration. For example, any epimer of everninomicin can be called epi- everninomicin. Usually, a number precedes ‘‘epi-’’ to distinguishwhich center has changed configuration. Using Descriptors to Compare Structures Compounds that have the same sense of chirality at their individual stereogenic centers are called homochiral. Homochiral molecules are not identical-they just have the same senseof chirality,much like all people’s right handsaredistinct but of the samechirality.As a chemical example, the amino acids l-alanine and l-leucine are homochiral. Thosemolecules with a differing sense of chirality at their stereogenic centers are called heterochiral. The same sense of chirality can often, but not always, be analyzed by examining whether the different kinds of stereochemical descriptors at the stereogenic centers are the same. For example, (R)-2-butanol and (R)-2-aminobutane are homochiral. Further, all the naturally oc- curring amino acids are l, so they are all homochiral (see the next Connections highlight). Homochiral has been used by some as a synonym for ‘‘enantiomerically pure’’. This is another usage of a term that should be discouraged, as homochiral already had a clear and useful definition, and using the same term to signify two completely different concepts can only lead to confusion.Abetter term for designating an enantiomerically pure sample is simply enantiopure. 6.1.3 Distinguishing Enantiomers Enantiomers are distinguishable if and only if they are placed in a chiral environment, and all methods to separate or characterize enantiomers are based on this principle. Sup- pose, for example, thatwe have a collection of right- and left-handedgloves, andwewant to retrieve only the right-handed ones. Using a simple hook to reach into the pile cannot suc- ceed because a hook is achiral-it cannot distinguish handedness. A chiral object, however, like a right hand, can distinguish between the gloves just by trying them on. 3076 .1 STEREOGENICITY AND STEREOISOMER ISM Connections The Descriptors for the Amino Acids have a higher priority than the carbonyl carbon. In addi- Can Lead to Confusion tion, the amino acids threonine and isoleucine have two stereocenters and can exist as diastereomers. In the nat-As just noted, all amino acids have the same sense of chi- ural amino acids, the sidechain isR for threonine and Srality in that they are all l in the d/l terminology system. for isoleucine. The diastereomers obtained by reversingYet, in themoremodern Cahn-Ingold-Prelog system, the stereocenter at the sidechain only are termed allo-they do not all have the same designators. All have the S threonine and allo-isoleucine.stereochemisty, except cysteine, which has the same sense of chirality but isR because the sulfurmakes the sidechain HSCH2 H2N H R S R L-Cysteine CO2H L-Threonine H3C H2N H S L-Alanine CO2H CO2HH2N OH H3C H H S S L-Allo-threonine CO2HH2N CH3HO H H S S L-Isoleucine CO2HH2N CH2CH3H3C H H S R L-Allo-isoleucine CO2HH2N CH3CH3CH2 H H Figure 6.4 shows some chemical examples of this. If a racemicmixture of 2-aminobutane is allowed to react with an enantiomerically pure sample of mandelic acid, the two amides that are produced are diastereomers. The two diastereomers can be separated by any con- ventional method (such as crystallization or chromatography), and subsequent hydrolysis of a pure diastereomer gives enantiomerically pure 2-aminobutane. The interaction that creates diastereomers out of enantiomers need not be covalent. Weaker, non-covalent complexes are often discriminating enough to allow separation of en- antiomers. The most classical way to separate enantiomeric amines is to form salts with a OH Enantiomers Stationary phase NH2 NH2 OH NH2 OH NH2 OH NH3 OH Diastereomers separable by any conventional technique Diastereomeric salts separable by crystallization (S )-(+)-Mandelic acid Transient diastereomeric interactions NH3 OH HO HN O HO HN O CO2H CO2 CO2CO2CO2CO2 Figure 6.4 Strategies for separating enantiomers, using 2-aminobutane as an example. Left: Forming diastereomeric derivatives-in this case, amides ofmandelic acid. Center: Forming diastereomeric salts that can be separated by crystallization. Right: Chiral chromatography,making use of transient, diastereomeric interactions between the enantiomers of 2-aminobutane and the chiral stationary phase. 308 CHAPTER 6 : STEREOCHEMISTRY chiral acid anduse crystallization to separate the diastereomeric salts. There aremanyvaria- tions on this theme, and this traditional approach is still very commonly used, especially for large scale, industrial applications. For the smaller scales associatedwith the research laboratory, chiral chromatography is increasingly becoming the method of choice for analyzing and separating mixtures of en- antiomers.We show in Figure 6.4 a hypothetical system inwhich themandelic acidwe have used in the previous examples is attached to a stationary phase. Now, transient, diastereo- meric interactions between the 2-aminobutane and the stationary phase lead to different re- tention times and thus to separation of the enantiomers. Both gas chromatography and liq- uid chromatography are commonly used to separate enantiomers. With a tool to discriminate enantiomers in hand,we candetermine the enantiomeric ex- cess (ee) of a sample. This commonly usedmetric is defined asXa -Xb, whereXa andXb rep- resent the mole fraction of enantiomers a and b, respectively. Usually ee is expressed as a percentage,which is 100%(Xa -Xb). Analogous terms such asdiastereomeric excess (de) are also used. The traditional tools for evaluating ee are the chiroptical methods discussed be- low.However, methods such as high fieldNMR spectroscopywith chiral shift reagents (see the Going Deeper highlight below), NMR spectroscopy of derivatives that are diastereo- meric, and chromatography (HPLC and GC) with chiral stationary phases, are becoming evermore powerful and popular. Going Deeper Chiral Shift Reagents A convenient technique tomeasure the ratio of enantiom- ers in a solution is to differentiate them in theNMR spec- trumusingwhat is known as a chiral shift reagent. These reagents are typically paramagnetic, enantiomerically puremetal compounds that associatewith the enantio- mers to form complexes. The complexes formed between the chiral shift reagent and the enantiomers are diastereo- meric, and thus can be resolved inNMR spectroscopy. The paramagnetic nature of the reagents induces large chemi- cal shifts, further assistingwith the resolution of the spec- 11.6 11.4 11.2 11.0 10.8 10.6 10.4 ppmtral peaks associatedwith the diastereomeric complexes. For example, the enantiomeric forms of 2-deuterio- McCreary,M.D., Lewis, D.W.,Wernick, D. L., andWhitesides, G.M. 2-phenylethanol can be readily distinguished in theNMR ‘‘Determination of Enantiomeric Purity Using Chiral Lanthanide Shift using a complex known as Eu(dcm). Coordination of the Reagents.’’ J. Am. Chem. Soc., 96, 1038 (1974). Buchwald, S. L., Anslyn, E.V., andGrubbs, R.H. ‘‘Reaction of Dicyclopentadienylmethylenetitaniumalcohol to the Eu center leads to diastereomers. The 1H withOrganicHalides: Evidence for a RadicalMechanism.’’ J. Am. Chem.NMR spectrum shown to the side of theH on the ste- Soc., 107, 1766 (1985).reogenic center of 2-deuterio-2-phenylethanol indicates that the two enantiomers (in a 50:50 ratio) are easily distinguished. O O DH + Eu 50/50Eu(dcm) OH OH HD 3 3096 .1 STEREOGENICITY AND STEREOISOMER ISM Optical Activity and Chirality Historically, themost common technique used to detect chirality and to distinguish en- antiomers has been to determinewhether a sample rotates plane polarized light.Optical ac- tivity and other chiroptical properties that canbemeasuredusingORDandCD (see below) have long been essential for characterizing enantiomers. Their importance has lessened somewhat with the development of powerful NMR methods and chiral chromatographic methods, but their historical importance justifies a brief discussion of themethodology. All introductory organic chemistry textbooks cover the notion of optical activity-the ability of a sample to rotate a plane of polarized light. We check to see if the plane in which the polarized light is oscillating has changed by some angle relative to the original plane of oscillation onpassing through the sample.A solution consisting of amixture of enantiomers at a ratio other than50:50 can rotateplanepolarized light to either the right (clockwise) or the left (counterclockwise).A rotation to the right is designated (); a rotation to the left is desig- nated (-). Earlier nomenclature used dextrorotatory (designated as d) or levorotatory (des- ignated as l) instead of () or (-), respectively. Typically, light of one particular wavelength, the Na ‘‘D-line’’ emission, is used in such studies. However, we can in principle use any wavelength, and a plot of optical rotation vs. wavelength is called an optical rotatory dis- persion (ORD) curve. Note that as we scan over a range of wavelengths, any sample will have somewavelength regionswith rotation and otherswith - rotation. Since the rotation must pass throughzero rotation as it changes from to -, any chiral samplewill be optically inactive at somewavelengths. If one of those uniquewavelengths happens to be at (or near) the Na D line, we could be seriously misled by simple optical activity measurements. Fur- thermore, at theNaD line, rotation is often small for conventional organicmolecules. In ad- dition, we previously discussed instances inwhich a chiral samplemight be expected to fail to rotate plane polarized light. Thus, optical activity establishes that a sample is chiral, but a lack of optical activity does not prove a lack of chirality. Why is Plane Polarized Light Rotated by a Chiral Medium? We have said that we need a chiral environment to distinguish enantiomers, and so it may seem odd that plane polarized light can do so. To understand this, wemust recall that electromagnetic radiation consists of electric and magnetic fields that oscillate at right angles to each other and to the direction of propagation (see Figure 6.5 A). In normal light (such as that coming from a light bulb or the sun), the electric fields are oscillating at all pos- sible angleswhenviewing the radiationpropagating towardyou (Figure 6.5B). Planepolar- ized light has all the electric fields oscillating in the same plane (Figure 6.5B andC), and can be viewed as the single oscillation shown in Figure 6.5A. The representation in Figure 6.5A B Direction of propagation Viewing the oscillating electric fields of normal light down the axis of propagation Viewing the oscillating electric fields of plane polarized light down the axis of propagation A. B. C. E Left circularly polarized + = Right circularly polarized Plane polarized D. Faster rotating + = Slower rotating Plane is rotated Figure 6.5 The phenomenon of optical activity.A.Oscillating electric andmagnetic fields.B. The difference between normal (non-polarized) light and plane polarized light, viewing the oscillating electric fields down the axis of propagation.C. Plane polarized light is a combination of right and left circularly polarized light.D. If the differential index of refraction causes one form to ‘‘rotate’’ faster than the other, the effect is to rotate the plane of polarization. 310 CHAPTER 6 : STEREOCHEMISTRY does not look chiral, yet planepolarized light canbeused todistinguish enantiomers. To rec- oncile this, wemust appreciate that plane polarized light can be considered to be created by two circularly polarized beams of light, one rotating clockwise and one counterclockwise. Circular polarizationmeans that the plane of the oscillating electric field does not remain steady, but instead twists to the right or the left, referred to as right or left circularly polar- ized light. In other words, the linear vector that traces out the plane polarized wave is formed from two circularly polarizedwaves, one rotating clockwise and one rotating coun- terclockwise (Figure 6.5D). Taken separately, these circularly polarized beams are rotating in ahelical fashion, andhence are chiral. The right and left polarizedbeamsof light are there- fore enantiomers of each other. So, indeed,we again find that it takes chiral entities to distin- guish between chiral chemical structures. As theplanepolarized light passes througha chiral sample, several different kindsof in- teractions between the light and the material are possible. One is actual absorption of the light, which we explore below when circular dichroism is discussed. However, another is simple refraction. The indices of refraction of the chiral material for the right and left polar- ized light are expected to be different, which means that the speed of light through the medium is different for the two polarizations, a phenomena called circular birefringence. Therefore, one of the light componentswill lag behind the other. ‘‘Lagging behind’’ means a slower rate of propagation due to a different refractive index for that form of light (Figure 6.5D). The result is that right- and left-handed twists no longer have the same phasematch- ing to cancel along the original plane, but instead they cancel alonga slightlydifferent plane, rotated away from the original plane. Circular Dichroism In the discussion above, plane polarized light was described as a combination of right and left circularly polarized light. Just as a chiral medium must refract left and right circu- larly polarized light differently, chiral molecules must have different absorptions of the left and right circularly polarized light. Circular dichroism (CD) spectroscopy measures this differential absorption. This technique involves the same absorption phenomenon that oc- curs in UV/vis spectroscopy, which is discussed in Chapter 16. One collects a CD spectrum bymeasuring the difference in absorption of right and left circularly polarized light as a function of thewavelength of the light.At certainwavelengths of circularly polarized light, the right-handed form is absorbed more (defined as a positive value) than the left-handed form, and vice versa at other wavelengths. There are specific rules related to exciton coupling (coupling of electronic states between two or more chro- mophores) that dictate which form of light is absorbed the most at various wavelengths. This is beyond the scope of this chapter, but extensive discussions of this phenomenon are available in themore specialized texts cited at the end of this chapter. Because of thepredictability of CD spectra, in earlier times, CDwas frequently used as a means of establishing the absolute configuration of chiral molecules, and extensive correla- tions of CD spectra with molecular structure were developed based upon empirical rules. The shapes of the curves, called either plain curves or curves possessing positive and/or negativeCotton effects, can be correlatedwith structure. Inmore recent times, x-ray crystal- lographyhas become themost commonway to establish absolute configuration (see below). One area in which CD has remained quite a powerful and commonly used tool is in studies of protein secondary structure.Wewill discuss this application of CD later in this chapter. X-Ray Crystallography Ifwehave a crystal of an enantiomerically pure compound, andwedetermine its crystal structure, you might think that we would then know its absolute configuration. Actually, this is typically not the case. Nothing in the data collection or analysis of x-ray crystallogra- phy is inherently chiral, and sowe cannot tell which enantiomerwe are imaging in a typical crystallography study. There are twoways around this.One is an advanced crystallographic technique called anomalous dispersion. Anomalous dispersion occurs when the x-ray wavelength is very close to the absorption edge of one of the atoms in the structure. This 3116 .2 SYMMETRY AND STEREOCHEMISTRY leads to an unusual scattering interaction that contains the necessary phase information to allow enantiomer discrimination. Originally a somewhat exotic technique, the method has become more common as more diverse and brighter x-ray sources have become available. The alternative approach to determine absolute configuration by x-ray crystallography is to functionalize the molecule of interest with a chiral reagent of known absolute configu- ration. Returning to the example of Figure 6.4, if we determine the crystal structure of one of the separated amide diastereomers, crystallography will unambiguously establish the rela- tive configurations of the original molecule and the appended carboxylic acid. Since we in- dependently know the absolute configuration of the the (S)-()-mandelic acid thatweused, we know the absolute configuration of the 2-aminobutane. 6.2 Symmetry and Stereochemistry Stereochemistry and symmetry are intimately connected, and in developing somemore ad- vanced aspects ofmodern stereochemistry, it is convenient to be able to invoke certain sym- metry operations.Aproper understandingof symmetry cangreatly clarify a number of con- cepts in stereochemistry that can sometimes seem confusing. One operation that we have already used extensively is that of reflection through a mirror plane, and simple guidelines using imaginary sheets of glasswere given.Wewill not need todevelop the entire concept of point group symmetries in this textbook. For those who are familiar with point groups and irreducible representations,wewill occasionallymention themwhere appropriate, but they are not required. However, for those students not well versed in symmetry operations, we now give a very short summary of some of the basics. 6.2.1 Basic Symmetry Operations A symmetry operation is a transformation of a system that leaves an object in an indis- tinguishable position. Formolecular systems, we need be concernedwith only two types of symmetry operations: proper rotations (Cn) and improper rotations (Sn). A Cn is a rotation around an axis by (360/n) that has the net effect of leaving the position of the object unchanged. Thus, a C2 is a 180 rotation, a C3 a 120 rotation, and so on. These are termed ‘‘proper’’ rotations, because it is actually physically possible to rotate an object by 180 or 120. Some examples are shown below, with the atoms labeled only to highlight the operation. C2CRotate 180° Hb Ha Clb Cla C Ha Hb Clc Cla C3 Clb HRotate 120° C Clb Clc Cla H Cla Clb C In contrast, improper rotations are not physically possible. An Sn involves a rotation of (360/n), combined with a reflection across a mirror plane that is perpendicular to the rota- tion axis (see examples on the next page). Note that S1 is equivalent to just amirror reflection (denotedwith a ), while S2 is equivalent to a center of inversion (denotedwith an i). TheC1 operation also exists. It leaves anobject completely unmovedand is also termed the identity operation, sometimes symbolized as E. An internal  plane that includes a C2 axis is desig- nated a v, while a  plane perpendicular to aC2 axis is designated h. 6.2.2 Chirality and Symmetry Nowwe can further refine the connection between symmetry and chirality. Quite sim- ply, for a rigidmolecule (or object of any sort), a necessary and sufficient criterion for chirality is 312 CHAPTER 6 : STEREOCHEMISTRY Ha Hb Hd Hc C4 C CC Hd Hc Hb Ha C CC Hd Hc Hb Ha C CC S4 σ-Plane reflection S6 σ-Plane reflection He Hf Hd Hc Hb Ha He Hf Hd Ha Hc Hb Hb Ha Hc Hf Hd He C6 S2 = i σ-Plane reflection He Hf Hd Hc Hb Ha Hd He Hf Hb Ha Hc Hc Hb Ha He Hf Hd C2 an absence of Sn axes; the existence of any Sn axis renders an object achiral. For example, con- sider the two structures shown below. The first object has an S2 axis and is not chiral, while the second object does not have an S2 axis, let alone any Sn axis, and so the structure is chiral. C C2 B A C S2 operation σ-Plane reflection defined by a plane perpendicular to the C2 Not chiral because the S2 axis returns the same structure C B A C C A B C C A B C D C2 B A C S2 operation σ-Plane reflection defined by a plane perpendicular to the C2 Chiral because there is no Sn axis that returns the same structure C A B D C A B D In addition,when a chiralmolecule is subjected to any improper rotation, it is converted into its enantiomer. Since the simplest improper axis to use is an S1, the  plane (seemany of our examples above), most chemists first look for an internal mirror plane in a molecule to decide if it is chiral or not. If the molecule possesses an internal mirror plane in any readily accessible conformation, then the molecule is achiral. For those familiar with point groups, it is a simplematter to show that all chiralmolecules fall into one of five point groups:Cn,Dn, T,O, or I. All other point groups contain an Sn axis. Chiral molecules need not be asymmetric. Asymmetric is defined as the complete ab- sence of symmetry. However, many chiral molecules have one or more proper rotation axes -just no improper axes are present. These compounds can be referred to as dissymmetric, essentially a synonym for chiral. Thus, while all asymmetric (point group C1) molecules are 3136 .2 SYMMETRY AND STEREOCHEMISTRY chiral, not all chiral molecules are asymmetric. Importantly, high symmetry chiral mole- cules play a special role inmany processes, especially in efforts to influence the stereochem- istry of synthetic reactions (see the following Connections highlight). Connections C2 Ligands in Asymmetric Synthesis meric excess. Since themetal is non-stereogenic in aC2 symmetric complex, coordination of the Diels-AlderThe use ofC2 symmetric ligands in catalytic asymmetric reactants to either face of themetal produces identicalinduction is a common designmotif. Below are shown a complexes.We ask that you show this in an Exercise atseries of chiral Lewis acid catalysts that have been used the end of the chapter. The environment around themetalfor Diels-Alder reactions. In every case aC2 axis exists is still chiral, however, and so asymmetric induction is pos-in the structures. Also, in every case themetal is non- sible. This samemotif will be seen in aGoingDeeper high-stereogenic.Most catalytic processes involveweak interac- light on polymerization reactions given in Section 6.7.tions between substrate and catalyst, and this often leads to a situation inwhich several different binding interac- Evans, D.A.,Miller, S. J., Lectka, T., and vonMatt, P. ‘‘Chiral Bis(oxazo- tions between substrate and catalyst are possible. Each line)copper(II) Complexes as Lewis Acid Catalysts for the Enantioselective Diels-Alder Reaction.’’ J. Am. Chem. Soc., 121, 7559-7573 (1999).different binding interactionmight produce different ster- eoselectivity, making it difficult to achieve high enantio- O Ni (OH2)3 NN O O Ti Ph Ph Ph I I PhPh Ph C2 symmetric catalysts O O Cl ClO O O ON N Fe 6.2.3 Symmetry Arguments We argued above that any rigid molecule lacking an Sn axis is chiral. We don’t need to know anything else about the molecule to reach this conclusion with confidence. This is an example of a symmetry argument-a statement from first principles that depends only on the symmetry, not on the precise nature, of the system under consideration. Two important features of symmetry argumentsmust always be remembered. First, the most compelling symmetry arguments are based on an absence of symmetry. If we can be sure that a certain kind of symmetry is lacking, then firm conclusions can be reached. Stated differently, two objects (molecules or parts ofmolecules in our context) are equivalent if and only if they are interconvertable by a symmetry operation of the system. On the other hand, if two objects are not interconvertable by a symmetry operation, they are expected to be dif- ferent, and they are different in essentially all ways.We cannot rule out the possibility of ac- cidental equivalence. However, we expect that, in most instances, if the precision of our measurement is high, objects that are not symmetry equivalentwill bemeasurablydifferent. We will generally use a phrase such as ‘‘are expected to be different’’ to acknowledge the possibility that in some systems thedifferences between two symmetry inequivalent objects may be too small to be detected at the present level of precision. For example, consider the C1-C2 vs. the C2-C3 bonds of n-butane. We can be certain that there can never be a symmetry operation of butane that will interconvert these two bonds.As such, they are different, and they aredifferent in allways. Theywill havedifferent bond lengths, different IR stretching frequencies, and different reactivities. The absence of symmetry can be unambiguous-we know for sure that the two C-C bonds discussed above cannot be interconverted by symmetry. On the other hand, wemust be careful about usinga symmetry argument todeclare twoobjects to be equivalent, because that canbe a cyclic argument. For example, consider aCH2group in cyclobutane. It is tempt- 314 CHAPTER 6 : STEREOCHEMISTRY H really Cyclobutane H H H ing to conclude that the two hydrogens are equivalent. If we draw the molecule as square and planar, there are symmetry operations that interconvert them (a C2 axis and a  plane). Wehad to assume a structure for the system, andwe chose ahigh symmetry structure.How- ever, there is no law thatmoleculeswill adopt the highest possible symmetry, and in the par- ticular case of cyclobutane, the molecule indeed adopts a lower symmetry form, as we saw in Section 2.3.2. Cyclobutane is nonplanar, and the hydrogens of a given CH2 are inequiva- lent (the time scale is of importance in this argument, as we discuss later in the chapter). Thus, in the absence of independent information about the symmetry of a system, it is risky to simply look at a structure and say two parts are equivalent. On the other hand, ifwehave independent evidence that amolecule has certain symme- try elements-for example, from an x-ray structure-then we can use those symmetry ele- ments to make statements about equivalence. Restating, two objects are equivalent if and only if they are interconverted by a symmetry operation of the system, and if they are not in- terconverted by a symmetry operation of the system, they are expected to be different. Another important aspect of symmetry arguments is that they tell us nothing about mag- nitudes. We can conclude that two angles are expected to be different, but theymay differ by 10 or by 0.0000000001. Symmetry arguments are oblivious to such distinctions. Objects are either different or not; that is all we can conclude. 6.2.4 Focusing on Carbon Whilemost chemists are justifiably enamored of symmetry, in a sense it is the absence of symmetry that makes things happen. Let’s illustrate this by considering the desymmetriza- tion of methane. The carbon in methane is not a stereogenic center-that is, interchanging the positions of two hydrogens does not produce a new stereoisomer in this high symmetry structure.Weoften say that a carbonatomwith four covalent ligandshas ‘‘tetrahedral’’ sym- metry.What does that mean? It means that in CH4 the four hydrogens lie at the vertices of a regular tetrahedron, with the C at the center (Figure 6.6). Every H-C-H angle is arc cos(-1⁄3) 109.47, and every bond length is the same. These two descriptors (one length, one an- gle) are enough to fully describe such a system, and the same geometry holds for most CX4 systems. H H H H 109.5° C X θ1 θ2 Y Y Y C Figure 6.6 Left: The ‘‘tetrahedral’’ carbon atom. Right: Differing angles in a CXY3molecule. Things get more interesting when all four ligands are different. As first appreciated by Pierre Curie, it is the lack of symmetry that gives rise to observable phenomena. For exam- ple, in CXY3, a desymmetrized CX4, there are now two different valence angles (X-C-Y and Y-C-Y) (Figure 6.6) and twobond lengths, so therewas an increase in the number of observ- ables on lowering the symmetry. Desymmetrization to produce a CXY3 structure also leads to anewmolecular property that is notpossible forCX4-adipolemoment (Chapter 2).With further desymmetrization toCX2Y2, three angles are nowpossible, and so on. These systems no longer correspond to a perfect, regular tetrahedron, but we still tend to refer to them as ‘‘tetrahedral’’. They just happen to be irregular tetrahedrons. Full desymmetrization to produce CWXYZ gives four different bond lengths and six different angles. As already discussed, this complete desymmetrization also leads to chiral- ity.Wenoted inChapters 1 and2 thatmost organicmolecules donothaveperfect tetrahedral angles, and that all C-C bonds lengths are not the same. In that context, we focused on the quantitative deviations from the standard norms, and how specific bonding theories could rationalize them. Here, we are arriving at similar conclusions, but from a different perspec- tive. Our argument that a CXY3 molecule has two different angles can be made with confi- dence and without any knowledge of what X and Y are, as long as they are different. It is a symmetry argument, and so it is incontrovertible, but qualitative in nature. 3156 .3 TOPIC ITY RELATIONSHIPS 6.3 Topicity Relationships Thus far we have focused on terminology appropriate for describing the stereochemical re- lationships betweenmolecules. Aswewill see, it is also convenient to describe relationships between regions of molecules such as two different methyl groups or two faces of a sys- tem. In such cases we are considering the topicity of the system. The topicity nomenclature is derived from the same roots as topography and topology, relating to the spatial position of an object. 6.3.1 Homotopic, Enantiotopic, and Diastereotopic If twoobjects cannot be interconvertedbya symmetry operation, they are expected tobe different. This reasoning applies not only to entire molecules, but also to differing regions within a molecule. When the groups can be interconverted by a symmetry operation, they are chemically identical. Yet, depending upon the symmetry operation, they can act differ- ently. The terms we introduce here have the suffix -topic, which is Greek for ‘‘place’’. When identical groups or atoms are in inequivalent environments, they are termed heterotopic. They canbe either constitutionally heterotopic or stereoheterotopic.Constitutionally heter- otopicmeans that the connectivity of the groups or atoms is different in the molecule. Ste- reoheterotopic means the groups or atoms have different stereochemical relationships in themolecule under analysis. Consider the CH2 group of 2-butanol. There are no symmetry operations in 2-butanol, and as such the two hydrogens of the CH2 cannot be interconverted by a symmetry opera- tion. Therefore, these two hydrogens are expected to be different from one another in all meaningful ways, such as NMR shift, acidity, C-H bond length, bond dissociation energy, reactivity, etc. They have the same connectivity, but there is no symmetry operation that in- terconverts them in any conformation. They are stereoheterotopic, and defined specifically as diastereotopic. Now consider the CH2 group of propane. There is, or more properly can be, a C2 opera- tion that interconverts the two hydrogens, and so they are considered to be equivalent. The modern terminology is homotopic, and is defined as interconvertable by a Cn axis of the molecule. These hydrogens are equivalent in all ways. We have one more case to consider, exemplified by the CH2 group in ethyl chloride. There is a symmetry element that interconverts the two hydrogens-amirror plane. Here is where the distinction between proper and improper symmetry elements becomes impor- tant. These hydrogens are equivalent because they are interconverted by a symmetry ele- ment. However, just as with two enantiomers, such an equivalence based upon a mirror plane will be destroyed by any chiral influence. As such, these hydrogens are termed enan- tiotopic-that is, interconverted by an Sn axis of the molecule. Enantiotopic groups, when exposed to a chiral influence, becomedistinguishable, as if theywere diastereotopic. The ex- ample of the use of a chiral shift reagent given on page 308 illustrates this point. Homotopic groups remain equivalent even in the presence of a chiral influence. Since chiral molecules need not be asymmetric (they can have Cn axes), groups can be homotopic even though they are part of a chiral molecule. Consider the chiral acetal shown in themar- gin. The methyl groups are homotopic because they are interconvertable by a C2 operation. A chiral influence cannot distinguish thesemethyl groups. Another common situation where topicity issues become important is at trigonal centers, such as carbonyls and alkenes. As some examples, let’s focus on carbonyl groups. The two faces of the carbonyl are homotopic in a ketone substituted by the same groups [R(CO)R], such as acetone, because the molecule contains a C2 axis (see below). The faces are enantiotopic in an unsymmetrically substituted ketone, such as 2-butanone, because they are interconverted by aplane. The faces arediastereotopic in a structure such as either enantiomer of 3-chloro-2-butanone, because there are no symmetry elements that intercon- vert the faces. H Different in all ways Diastereotopic hydrogens Ha Hb HO Equivalent in all ways Homotopic hydrogens Ha Hb Enantiotopic hydrogens Equivalent unless within a chiral environment Ha Hb Cl CH3 CH3 O C O Ph Ph Chiral molecule with homotopic methyl groups 316 CHAPTER 6 : STEREOCHEMISTRY The other hydrogen would be pro-S Assigning this H, the result is pro-R D 1 3 2 H H Cl D H Cl Cl H3C H3C O H3C H3C O Top face Structure is the same upon rotation; homotopic faces Bottom face H3CH2C H3C O H3C H3CH2C O Top face Structure is not the same upon rotation; mirror plane exists; enantiotopic faces Bottom face H3C H3C Cl O H Top face No symmetry element; diastereotopic faces Bottom face 6.3.2 Topicity Descriptors-Pro-R/ Pro-S and Re/Si Just as it was convenient to have descriptors to distinguish enantiomericmolecules, it is also useful to be able to identify enantiotopic hydrogens. To do so,weuse something similar to theR/Snotation. For aCH2group,first take thehydrogen that is beingassigned adescrip- tor and mentally promote it to a deuterium. Now assign priorities in the normal way. If the result is that the newly formed stereogenic center is R, the hydrogen that we mentally re- placed by deuterium is denoted pro-R, and if the new stereocenter is S, the hydrogen is de- notedpro-S. An exampleusing chloroethane is given in themargin. The samenomenclature convention can be usedwith diastereotopic hydrogens. The ‘‘pro’’ terminology ismeant to imply that the centerwouldbecomestereogenic (and henceworthyof anR/Sdescriptor) if the substitutionweremade. For this reason, the carbon containing the enantiotopic hydrogens is also referred to as a prochiral center. While some find this term useful, it can lead to confusion, and as such, describing the situation in terms of enantiotopic groups is preferable. It shouldbe apparent that the enantiotopic groupsneed not be hydrogens. For example, two methyl groups or two chlorines can be enantiotopic. The pro-R/S distinction would be made by converting the methyl to be named to a CD3 group, and the Cl to be named to a higher isotope (see below). CD3 1 3 2 The other methyl would be pro-S 3 Put lowest priority methyl group behind the page Assigning this CH3, the result is pro-R H3C CH3 Cl D3C CH3 Cl Cl Cl 1 2 The other chlorine would be pro-R Put the methyl group behind the page because it is lowest priority Assigning this Cl, the result is pro-S Cl Cl CH3 Cl* Cl CH3 Cl* 3176 .4 REACTION STEREOCHEMISTRY: STEREOSELECTIV ITY AND STEREOSPEC IF IC ITY When assigning a descriptor to the enantiotopic faces of a trigonal structure, start by simplyplacing themolecule in theplaneof thepaper.Next assignpriorities to the groupsus- ing the same methods for R/S and E/Z. If the result is a clockwise rotation, the face we are looking at is referred to as Re; if it is a counterclockwise rotation, the face is Si. An example using 2-butanone is given in the margin. Once again, it is common to refer to the carbon of the carbonyl as prochiral, because attachment of a different fourth ligand will create a ste- reogenic center and possibly a chiral molecule. 6.3.3 Chirotopicity The terms enantiotopic and diastereotopic describe the relationship between a pair of atoms or groups in amolecule. Sometimes it is also useful to describe the local environment of a single atom, group, or location in amolecule (even if it does not coincidewith an atomic center) as chiral or not.A chirotopic atomor point in amolecule is one that resides in a chiral environment, whereas an achirotopic atom or point does not. All atoms and all points as- sociated with a chiral molecule are chirotopic. In achiral molecules, achirotopic points are those that remain unchanged (are invariant) upon execution of an Sn that is a symmetry op- eration of themolecule. For most situations, this means that the point either lies on amirror plane or is coincident with the center of inversion of the molecule. Importantly, there will generally be chirotopic points even in achiral molecules. These terms can be clarified by looking at some specific examples. In the following ro- tamers ofmeso-1,2-dichloro-1,2-dibromoethane, the only achirotopic site in rotamer A is the point of inversion in the middle of the structure. Every atom is in a locally chiral environ- ment, and so is chirotopic. For rotamer B, all points in themirror plane (a plane perpendicu- lar to the page of the paper) are achirotopic. All other points in these conformers are chiro- topic, existing at sites of no symmetry. In other words, all other points in these conformers feel a chiral environment, even though themolecule is achiral. As another example, consider once again the chiral acetal shown in the margin. The C atom indicated resides on aC2 axis but not on any type ofSn axis, and so it is chirotopic.Note, however, that theC isnon-stereogenic.Hence, non-stereogenic atoms can reside in chiral en- vironments. Refer back to the firstConnections highlight in Section 6.2.2. In this highlight all themetals are chirotopic but nonstereogenic. The term ‘‘chirotopic’’ focuses us on the points in a molecule that are under a chiral influence, which is the most important factor for using stereochemical principles to understand spectroscopy and reactivity. 6.4 Reaction Stereochemistry: Stereoselectivity and Stereospecificity Topicity relationships and symmetry arguments provide a powerful approach to anticipat- ing reactivity patterns. Whether by habit, intuition, or full realization, it is the topicity rela- tionships discussed above that synthetic chemists use to develop chemical transformations that yield asymmetric induction. 6.4.1 Simple Guidelines for Reaction Stereochemistry Consider the three ketones in Figure 6.7 and the topicities of their carbonyl faces. In acetone, the two faces of the carbonyl are homotopic-interconverted by a C2 rotation. In 2-butanone, the faces are enantiotopic (prochiral)-interconverted only by a mirror plane. In (R)-3-chloro-2-butanone, the two faces are diastereotopic. This molecule is asymmetric, and so there can be no symmetry operation that interconverts the two faces of the carbonyl. A consequence of this lack of symmetry in (R)-3-chloro-2-butanone is that the carbonyl group is expected to be nonplanar-that is, O, C2, C1, and C3 will not all lie in a plane. The point is that because the two faces of the carbonyl are inequivalent, the carbonyl cannot be planar. This is a symmetry argument of the sort mentioned previously, and as with all sym- metry arguments, we cannot predict how large the deviation from planarity must be, only that it is expected to be there. As such, if we obtain a crystal structure of (R)-3-chloro-2-buta- none, we should not be surprised to find a nonplanar carbonyl. O 2 1 3 O The Re face The Si face 1 32 Br Br ClB. Cl HH Achirotopic plane Br H ClA. Cl BrH Achirotopic point C2 Carbon is chirotopic CH3 CH3 O C O Ph Ph 318 CHAPTER 6 : STEREOCHEMISTRY H3CC2 axis Homotopic faces H3C O Reaction with top face Reaction with bottom face H H3C H3C H Equivalent products (homomeric) OH H3CMirror plane only (plane of the carbonyl) Enantiotopic faces CH3CH2 O Reaction with top face Reaction with bottom face H Enantiomeric products H3C H3C No symmetry (asymmetric) Diastereotopic faces Cl O H Diastereomeric products H3C H3C Cl H Reaction with top face Reaction with bottom face H3C H3C H OH H3C CH3CH2 H OH H OH H3C CH3CH2 H OH H3C H3C Cl H OH H H Figure 6.7 Stereochemical consequences of reacting three different types of carbonylswith a hydride reducing agent. Let’s consider the reactivity of the three carbonyls shown inFigure 6.7. For acetone, reac- tion with an achiral reagent such as LiAlH4 produces the same product regardless of which carbonyl face reacts. This will always be the case for homotopic faces. For 2-butanone, reac- tion with LiAlH4 at enantiotopic faces gives enantiomeric products, (R)- and (S)-2-butanol. For (R)-3-chloro-2-butanone, the two carbonyl faces are different. They will give differ- ent products from the reaction with LiAlH4-namely, (R,S)- and (R,R)-2-chloro-3-butanol, which are diastereomers. As we can anticipate the stereochemical relationships among the products, we can also evaluate the symmetry properties of the transition states of the hydride addition reactions. For acetone, there is only onepossible transition state andonly oneproduct. For 2-butanone, the transition states derived from ‘‘top’’ and ‘‘bottom’’ attack are enantiomeric. As such they will have equal energies, and so G‡ will be the same for the formation of the two enan- tiomeric products. As a result, a racemic mixture must form. Finally, in the reduction of (R)-3-chloro-2-butanone, the two transition states are diastereomeric, and so they are ex- pected to have different energies (diastereomers differ in all ways). Since the starting point for the two reactions is the same, G‡ is expected to bedifferent for the two, and therefore the rates for formation of the two diastereomeric products cannot be the same. Since the rates of formation of the two products are not the same, we can state with certainty that the reduc- tion of (R)-3-chloro-2-butanone is expected to not produce a 50:50 mixture of the two products in the initial reaction. This can be anticipated fromfirst principles.Whenwe start from a single reactant and produce two diastereomeric products, we do not expect to get exactly a 50:50 mixture of products. However, as is always true of a symmetry argument, we cannot antici- pate how large thedeviation from50:50will be-itmaybe50.1:49.9 or 90:10.We canonly say that it is not 50:50. 3196 .4 REACTION STEREOCHEMISTRY: STEREOSELECTIV ITY AND STEREOSPEC IF IC ITY Let’s examine what happens if we use a single enantiomer of a chiral hydride reducing agent. Acetone still gives only one product-isopropanol. However, we would now expect the two enantiotopic faces of 2-butanone to be distinguished. The transition states corre- sponding to attack from opposite faces of the carbonyl are now diastereomeric, and some- thing other than a 50:50 mixture of the enantiomeric products (a non-racemic sample) is expected to result from such a reaction. Achieving asymmetric induction is therefore anti- cipated by simple symmetry arguments. The only issue is whether the magnitude of the ef- fect is small or large. To visualize how a chiral environment can distinguish enantiotopic groups, see the Connections highlight below that describes enzyme catalysis andmolecular imprints. Lastly, in the reduction of (R)-3-chloro-2-butanone, thedifferent faces of the ketonewere already diastereotopic due to the presence of the stereogenic center. Hence, even an achi- ral reducing agent such as LiAlH4 will give something other than a 50:50 ratio of R- and S-centers at the newly formed alcohol. Interestingly, switching from LiAlH4 to a chiral hy- dride agent has no impact (from a symmetry standpoint) on the reduction of (R)-3-chloro-2- butanone; we still expect something other than a 50:50mixture of two diastereomers. In summary: 1. Homotopic groups cannot be differentiated by chiral reagents. 2. Enantiotopic groups can be differentiated by chiral reagents. 3. Diastereotopic groups are differentiated by achiral and chiral reagents. 6.4.2 Stereospecific and Stereoselective Reactions The terms stereospecific and stereoselective describe the stereochemical outcomes of the sort we have been discussing. Even these terms, though, are sometimes used in confus- ing ways. Figure 6.8 illustrates the definitions of these terms as originally presented. In a stereospecific reaction, one stereoisomer of the reactant gives one stereoisomer of the prod- uct, while a different stereoisomer of the reactant gives a different stereoisomer of product. Hence, to determinewhether a reaction is stereospecific, one has to examine the product ra- tio from the different stereoisomers of the reactant. An examplewould be the epoxidation of 2-butene bymCPBA. The trans olefin gives the trans epoxide and the cis olefin gives the cis epoxide (Figure 6.8 A). SN2 reactions are also stereospecific, in that inversion of the stereo- mCPBA A. B. LiAIH4 O OH CH3 OH O mCPBA O CH3 CH3 Figure 6.8 A.An example of a stereospecific reaction (mCPBA ismeta- chloroperbenzoic acid).B.An example of a stereoselective reaction. If the enantiomerwere analyzed, the reactionwould also be stereospecific. 320 CHAPTER 6 : STEREOCHEMISTRY Connections Enzymatic Reactions, Molecular Imprints, synthetic receptors in Chapter 4. As a simplification of the and Enantiotopic Discrimination notion of complementarity, we can consider an enzyme binding site as an imprint of the substrate, similar to theThe general concept that enantiotopic groups can be dis- imprint of an object inwet sand. The analogy leads to atinguished chemically by a chiral environment is of para- very simple visual image of how an enzyme can distin-mount importance to enzymatic catalysis. Since enzymes guish enantiotopic groups. Consider the picture of theare constructed from chiral entities-
-amino acids-they molecularmodel of ethyl chloride sitting inwet sandare themselves chiral. Enzymes arewell known for their shown belowwith one enantiotopic hydrogen of the CH2stereoselectivity. The fact that enzymatic reactions are group embedded in the sand (A). After removing the plas-diastereoselective or enantioselective is not surprising; ticmodel, an impression is left in the sand (B).We cannotthis is expected to happenwhen the reagent (the enzyme) pick up and place the ethyl chloride back into the impres-is chiral and enantiomerically pure. The remarkable fea- sion in anyway besides the original placement (A).ture of enzymatic reactions is the high degree of stereo- Hence, this impression in the sand leads to only oneselectivity they generally display. of the two enantiotopic hydrogens buried in the sand,Enzymes possess binding sites that are comple- thus clearly differentiating among these two hydrogens.mentary to their substrates using the same principles of complementarity and preorganization introduced for A. B. C. chemistry on stereogenic centers is consistently observed, so that enantiomers of reactants must givedifferent enantiomers of theproducts. For a fewother examples, seeTable 6.1A. A reaction need not be perfectly stereospecific. If an 80:20 mixture of stereoisomers is pro- duced, we could call the reaction 80% stereospecific. Whether a reaction is or is not stereospecific has significant mechanistic implications, and wewill look at stereochemical analyses of this sort in future chapters. In essence, when a reaction is stereospecific, a common intermediate cannot be involved in themechanisms of reaction of the two stereoisomeric reactants. A stereoselective reaction is one inwhich a single reactant can give two ormore stereo- isomeric products, and one or more of these products is preferred over the others-even if the preference is very small. Nowwe only need to examine one stereoisomer of the reactant tomake thisdetermination for a reaction. In fact, the reactantmaynot evenexist as stereoiso- mers, yet the reaction can be stereoselective. See the example in Table 6.1B. A reaction is also stereoselective when two stereoisomers of the starting material give the same ratio of stereoisomeric products, as long as the ratio is not 50:50. This justmeans the reaction is not stereospecific. For example, this may occur if the mechanisms of reaction for 3216 .4 REACTION STEREOCHEMISTRY: STEREOSELECTIV ITY AND STEREOSPEC IF IC ITY Table 6.1 Stereospecific Reactions (A), a Stereoselective Reaction (B), and Stereoselective but Not Stereospecific Reactions (C) OTs OH + + + OH 90 10 60 20 20 A. B. SPh Substitution NaSPh OTs SPhNaSPh C. LiAIH4 Carbene addition CHBr3 Br Br CHBr3 KOC(CH3)3 KOC(CH3)3 Elimination Addition Br Br Ph Ph H3C H H Br O 67 33 KOC(CH3)3 KOC(CH3)3 DMSO DMSO + + 60 20 20 KOCH2CH3 HOCH2CH3 KOCH2CH3 HOCH2CH3 1) CH3Mgl 2) H2O PhPh Ph Ph Ph H CHO + H3C H Ph Br H H3C Ph H H H3C CH3 OH H CH3 H3C PhPh H OH 33 67 1) CH3Mgl 2) H2O CHO + H3C H Ph Br Br H3C H H H Ph CH3 OH H3C CH3Ph H OH the two stereoisomeric reactants proceed through a common intermediate, and that inter- mediate gives two stereoisomeric products with one in excess. However, there are also re- actions where the different stereoisomeric reactants give the same ratio of stereoisomeric products, even when a common intermediate is not formed (Table 6.1 C). All stereospecific reactions are stereoselective, but the converse is not true. Another example of a stereoselective reaction is the previously discussed reduction of (R)-3-chloro-2-butanone (see Figure 6.7). In this case the two products are diastereomers, and the reaction is referred to as diastereoselective. This reaction is also stereospecific, in that (S)-3-chloro-2-butanone will give a different ratio of products with the same reducing agent. If the two products are enantiomers [as in the reduction of 2-butanone (Figure 6.7)], the reaction is enantioselective if one enantiomer is formed preferentially. 322 CHAPTER 6 : STEREOCHEMISTRY HO H The H’s of the methyl group are actually inequivalent Hb Hc Ha CH3 Cl Cl Cl Cl H3C H H Slowed rotation in a methyl group H Unfortunately, an alternative usage of these terms exists. Often in the organic synthesis literature, stereospecific is taken to mean 100% stereoselective. This is a necessarily vague distinction, because it depends on the tools used to measure the product ratios. A reaction that appears ‘‘stereospecific’’ by a relatively crudemeasure such as optical activity,may turn into a ‘‘stereoselective’’ reaction when chiral HPLC reveals a 99:1 product ratio. Also, the mechanistic implications of stereospecificity are lost in this alternative usage. However, it seems likely that both usageswill exist side-by-side for some time, and the student needs to be aware of the distinction. Terminology aside, the reaction of a chemical sample composed of only achiral mole- cules (such as 2-butanone) cannot give rise to productswith any chiral bias (i.e., any enantio- meric excess) without the intervention of an external chiral influence. This observation has significant implications for discussions of such topics as the origin of chirality in natural sys- tems (see Section 6.8.3). A term similar to stereoselective is regioselective. ‘‘Regio’’ in this context is defined as a site in a molecule where a reaction can occur, and the difference in the reactivity of various sites is called regiochemistry. When more than one site reacts, a regioselective reaction is one where an excess of one of the possible products results. A common example is theMar- kovnikov addition of HCl to a double bond (see Chapter 10), where the chloride preferen- tially adds to the more substituted carbon (Eq. 6.2). Hence, this is a regioselective reaction. Here, the two carbons of the alkene are considered to be the two ‘‘regions’’ or sites in themol- ecule that can react. Once again, there are varying degrees of regioselectivity, ranging from 100% (completely selective) to 0% (completely unselective). HCI CI + Major Minor Cl (Eq. 6.2) 6.5 Symmetry and Time Scale 2-Butanol is asymmetric, so the two hydrogens of the CH2 group are diastereotopic. Shouldn’t the three hydrogens of the CH3 group at C1 (or C4) be diastereotopic also? It de- pends. In particular, it depends on the time scale of our observation of themolecule. When considering the symmetry of any system, wemust always include a time scale. In Section 6.2.2whenwe gave a symmetry argument for predicting chirality, we explicitly lim- ited ourselves to rigidmolecules. Symmetry arguments and stereochemistry aremuch sim- pler if we treat all molecules as rigid, geometric objects. However, real molecules are inmo- tion, and if the motion is fast compared to the time scale of observation, we have to include the motion in our analysis of symmetry. If we are considering 2-butanol at room tempera- ture, the rotation of the CH3 groupswill be fast undermost time scales of observation. Since that rotation interconverts the three hydrogens, they become equivalent; they are not dia- stereotopic under these conditions. However, there is no rotation that ever interconverts the hydrogens on the methylene group, and therefore the methylene hydrogens are always di- astereotopic, regardless of the time scale. If we lower the temperature or greatly increase our speed of observation, rotation will appear to be slow, and the hydrogens of the CH3 groups will be different. In practice this is difficult. However, computational methods typically produce static structures. Look care- fully at the output of a computed structure of even a simple asymmetricmolecule usingmo- lecularmechanics or quantummechanics. In the particular case of 2-butanol, there are three different C-H bond lengths calculated for both of themethyl groups. Alternatively, in very crowded systemswe can slowmethyl rotation enough to see indi- vidual hydrogens of aCH3. The structure shown in themargin, a triptycenederivative of the kindwehave seen before (Section 2.5.3, Figure 2.22), gives three uniqueNMRsignals for the coloredhydrogens at -90 C.Nevertheless, undermost experimental circumstances it is safe to treat the three hydrogens of amethyl group as equivalent. 3236 .5 SYMMETRY AND TIME SCALE Symmetry and time scale are always tightly coupled. For example, we discussed in Chapter 2 that cyclobutane is not planar, but rather adopts a lower symmetry, puckered ge- ometry. The methylene hydrogens are diastereotopic in this geometry. However, the inter- conversion of the puckered forms is rapid on most time scales, and so for most analyses of cyclobutane, all hydrogens appear equivalent. In fact, a planar representation (the time av- erage of two interconvertingpuckered forms) is acceptable formanyanalyses. Themolecule is only planarwhen the fleeting transition state between the puckered forms is achieved, but onmost time scales it behaves as if itwere planar. The same analysis can bemade for theCH2 groups in cyclohexane. However, the time scalemust be considerablymore leisurely for the averaging of the axial and equatorial hydrogens of cyclohexane to occur, because of the much higher barrier (and therefore slower rate) for ring inversion in cyclohexane compared to other cyclic hydrocarbons. Typically, if a flexible molecule can achieve a reasonable conformation that contains a symmetry element, the molecule will behave as if it has that symmetry element. The classic example is an aminewith three different substituents. The pyramidal form is chiral, but the two enantiomers interconvert rapidly bypyramidal inversion (Eq. 6.3). That rapid inversion leads to an effectively achiral system is appreciated when we consider that the transition state for inversion is a planar, achiral structure. R1 NR3 R2 NR3 R2 R1 (Eq. 6.3) Time scale is important for all stereochemical concepts. Even ourmost cherished stereo- chemical concept, the stereogenic tetracoordinate carbon, is undone ifwe are at high enough temperatures and long enough time scales that inversion of the center is possible through bond cleavage reactions. There aremany chiralmolecules forwhich enantiomeric forms canbe interconvertedby a rotation about a single bond. The enantiomeric conformations of gauche butane provide an example, where rapid rotation interconverts the two under most conditions. If the rota- tion that interconverts a pair of such enantiomers is slow at ambient temperature, however, the two enantiomers can be separated and used. Recall fromour first introduction of isomer terminology (Section 6.1) that stereoisomers that can be interconverted by rotation about single bonds, and for which the barrier to rotation about the bond is so large that the stereo- isomers do not interconvert readily at room temperature and can be separated, are called atropisomers. One example is the binaphthol derivative shown in the margin. It is a more sterically crowded derivative of the biphenyl compound discussed previously as an ex- ample of a chiral molecule with no ‘‘chiral center’’. A second example is trans-cyclooctene, where the hydrocarbon chain must loop over either face of the double bond (Eq. 6.4). This creates a chiral structure, and the enantiomers interconvert by moving the loop to the other side of the double bond. (Eq. 6.4) Facile rotation does not guarantee interconversion of conformational isomers. One of the most fascinating dynamic stereochemistry systems is exemplified by the triarylborane shown in Eq. 6.1. Correlated rotation of the rings, the ‘‘two-ring flip’’, is facile at room tem- perature. There are threedifferent two-ringflips possible, dependingonwhich ringdoes the ‘‘non-flip’’.All two-ringflips are fast, but in ahighly substituted system, not all possible con- formations can interconvert. As long as only two-ring flips can occur, we have two sets of rapidly interconverting isomers, but no way to go from one set to the other. This has been termed residual stereoisomerism. We have two separate stereoisomers, each of which is a collection of rapidly interconverting isomers. Clearly, stereoisomerismand time scale are in- timately coupled in such systems. Planar, achiral transition state R3 R2 R1N ‡ Binaphthol HO OH 324 CHAPTER 6 : STEREOCHEMISTRY 6.6 Topological and Supramolecular Stereochemistry One of the more interesting aspects of modern stereochemistry is the preparation and char- acterization of molecules with novel topological features. As we indicated in Chapter 4, su- pramolecular chemistry has produced a number of structureswith novel topologies such as catenanes and rotaxanes. ‘‘Simple’’ molecules (i.e., not supramolecules) can also have novel topological features such as knots or Möbius strips. Here we will introduce some current topics in this fascinating area, emphasizing the aspects that relate to stereoisomerism. But first, wemust agree upon a definition of ‘‘topology’’. Themathematical definition of topology, and the one that is best suited to stereochemis- try, concerns studies of the features of geometrical objects that derive solely from their con- nectivity patterns. Metric issues-that is, those associated with numerical values (such as bond lengths and bond angles)-are unimportant in topology. The easiest way to see this is to consider two-dimensional topology as the study of geometric figures that have been drawn on a rubber sheet. You can stretch and bend and flex the sheet as much as you like without changing the topology of a figure on the sheet (Figure 6.9A). Thus, a circle, a trian- gle, and a square are topologically equivalent becausewe can deformone to the other. Topo- logically, all three are just a closed loop. In three dimensions the same concept applies, with the additional requirements that you cannot break a line or allow any lines to cross, and you cannot destroy a vertex. In a dictionary, one will often see a second definition of topology that does include metric issues, so it is a synonym for topography. In topography (i.e., map making), itmattershowhigh themountain is, but in themathematical definition of topology wewill use here, it does not (in fact, themountain can be ‘‘stretched flat’’). With the very few special exceptions discussed below, all stereoisomers are, perhaps surprisingly, topologically equivalent. If you are allowed to stretch and bend bonds at will, it is a simple matter (Figure 6.9 B) to interconvert the enantiomers of 2-butanol without crossing any bonds (simple mathematically, but not chemically!). Similar distortions are possible with almost any molecule, allowing stereoisomers to interconvert. This is consis- tentwithourdefinition of stereoisomers asmoleculeswith the sameconnectivities (topolog- ies) but different arrangements of atoms in space. Since topology concerns only issues that derive from the connectivity of the system, structures with the same connectivity have the same topology. There are stereoisomers that have different topologies, however, and that is the topic of this section. We should firstmake explicit the natural connection between chemistry andmathemat- ics that allows us to discuss topology. Topology deals with graphs-objects that consist of edges and vertices (points where two or more edges meet). In considering chemical topol- ogy, we are considering a chemical graph, in which the edges are bonds and the vertices are atoms. The ambiguity concerning connectivity still applies (see the Going Deeper highlight in Section 6.1.1), but oncewe agree on a definitionwe can consider topological issues. Figure 6.9 The interconversion of topologically equivalent structures. A. Topologically, the triangle, circle, and square are all just closed loops (as long aswe do not consider the ‘‘corners’’ of the triangle and square to be vertices). B. Interconversion of the enantiomers of 2-butanol can be accomplished by flexing and bendingwithout crossing any bonds, and so the two enantiomers are topologically equivalent. Push back B. Pull forward Push Push Push Push H HHO HO A. Pull Pull Pull H OH 3256 .6 TOPOLOGICAL AND SUPRAMOLECULAR STEREOCHEMISTRY 6.6.1 Loops and Knots What are the simplest systems that can produce topological stereoisomers? Allwe need is a cyclic structure. Figure 6.10A shows a circle and a classic trefoil knot. Both structures are simply a single, closed loop (which is the definition of a knot,with a circle being the simplest knot or the ‘‘unknot’’). It is not possible to interconvert the two structures without crossing edges-they are topologically different. Molecular realizations of the circle and the trefoil knot would be examples of topological stereoisomers. Since they are not non-congruent mirror images, it is sensible to call them topological diastereomers. To create a chemical ver- sion of this situation, a structure as simple as (CH2)n could serve the purpose. Interestingly, knots are actually relatively common in biochemistry, as the next Connections highlight de- scribes. Figure 6.10 A. Topological stereoisomers-a circle and a trefoil knot. B. Enantiomorphous trefoil knots. A. B. How are these stereoisomers different from conventional diastereomers? The circle and the knot can be infinitely deformed-bent, twisted, stretched, and compressed-but they will never be interconverted (as long as we don’t cross any bonds). Conventional isomers can be interconverted bydeformation, as in the case of 2-butanol in Figure 6.9. Conventional stereoisomerism depends on the precise location of the atoms in space, leading to the terms geometric orEuclidian isomerism.With topological stereoisomers, we canmove the atoms all around, and retain our isomerism. Going Deeper Biological Knots-DNA and Proteins ducedwhen crosslinks occur between separate regions of the backbone,most typically via disulfide bonds.All we need tomake a knot is a cyclic structure. If the ring Rare examples of unique topologies in such systems areis large enough to allow the necessary twisting, a knotted known.However, it was recently realized that when thestructure could form.While it may seem fanciful to con- analysis includes cofactors and prosthetic groups such assider such structures, andwemight expect their prepa- seen in quinoproteins or iron-sulfur cluster proteins, inter-ration to depend on exotic syntheticmethods, knotted esting topologies including knots and catenanes are in factstructures turn out to be common in nature. Circular, more common thanpreviously realized. As always, in con-double-strandedDNAmolecules have been known for sidering stereochemical phenomena, our definition of con-some time, with very large ‘‘ring sizes’’ (thousands of nectivity is crucial. Earlier studies had counted only thenucleotides). Indeed, these large cycles do form knots, amino acids as contributing to the connectivity of the sys-which are in fact fairly common structures that can be tem.When cofactors are included,more complex connec-directly observed by electronmicroscopy. Catenated tivities result.circular DNAs have also been observed. What about proteins? Typically, naturally occurring Liang, C., andMislow, K. ‘‘Knots in Proteins.’’ J. Am. Chem. Soc., 116, proteins are not closed circles as in cyclic DNA; the C and 11189 (1994). N termini are not connected. However, cycles are intro- 326 CHAPTER 6 : STEREOCHEMISTRY 6.6.2 Topological Chirality If we can have topological diastereomers, can we have topological enantiomers-that is, is there topological chirality? There is, and the trefoil knot is a simple example. Figure 6.10 B shows two trefoil knots, and these two knots are enantiomorphs. The term enan- tiomers is reserved for molecules; enantiomorphs applies to geometrical objects. How do we know, however, that we could not just deform one structure into the other by stretching and pulling? If we could, the two formswould be topologically equivalent and thus not en- antiomers, and the trefoil knotwould be topologically achiral. Perhaps surprisingly, there is no generalway toprove a knot is chiral.One canprove it is achiral by just finding oneway to draw the knot (called a presentation) that is itself achiral. However, if you fail to find an achiral presentation, that doesn’t prove the knot is chiral; maybe you just weren’t able to find the achiral presentation. In the case of the trefoil knot, however, the structure is indeed chiral. 6.6.3 Nonplanar Graphs Wemention briefly here another topological issue that has fascinated chemists. For the overwhelming majority of organic molecules, we can draw a two-dimensional representa- tionwith no bonds crossing each other. This is called aplanar graph. If you cannot represent the connectivity of a system without some crossing lines, you have a nonplanar graph. It may seem surprising, butmostmolecules have planar graphs. Figure 6.11A shows some ex- amples that illustrate that this is so. Remember,we aredoing topology, sowe can stretch and bend bonds at will. Graph theory is a mature branch of mathematics, and graph theorists have established that all nonplanar graphs will conform to one of two prototypes, called K5 and K3,3 in graph theory terminology (Figure 6.11 B). K5 is simply five vertices, maximally connected. Every vertex is connected to every other. K3,3 contains two sets of three vertices, with every vertex of one set connected to every vertex of the other set. The fact that K3,3 is nonplanar is proof of Figure 6.11 A. Examples of howmost chemical structures can be represented as planar graphs. B.K5 andK3,3 nonplanar graphs. CH2A. B. K5 K3,3 3276 .6 TOPOLOGICAL AND SUPRAMOLECULAR STEREOCHEMISTRY the architectural conundrum, ‘‘three houses, three utilities’’. It is impossible to have three houses, each connected to three utilities (such as water, electric, and phone) without at least one instance of ‘‘lines’’ crossing. We will see molecular versions of these nonplanar graphs below. 6.6.4 Achievements in Topological and Supramolecular Stereochemistry Recent efforts have produced chemical structures that successfully realize many inter- esting and novel topologies. A landmark was certainly the synthesis of a trefoil knot using Sauvage’s Cu+/phenanthroline templating strategy described in Section 4.3.2. This nonpla- nar, topologically chiral structure is a benchmark for the field. Other more complicated knots havealso beenpreparedby this strategy.Vögtle andco-workers havedescribedan ‘‘all organic’’ approach to amide-containing trefoil knots, and have been able to separate the two enantiomeric knots using chiral chromatography. Another seminal advance in the field was the synthesis and characterization of a ‘‘Mö- bius strip’’ molecule (Figure 6.12). AMöbius strip can be thought of as a closed ribbonwith a twist, and it has long fascinatedmathematicians and the general public. Although the con- cept behind the Möbius strategy for preparing novel topologies was enunciated in the late 1950s, it was not chemically realized until the 1980s. A clever strategy based on tetrahy- droxymethylethylene (THYME) ethers was developed by Walba. Ring closure could pro- ceed with or without a twist, and when the reaction is performed, the two are formed in roughly equal amounts. An important design feature was that the ‘‘rungs’’ of the ladder system were olefins, which could be selectively cleaved by ozonolysis. Cleavage of the un- twisted product produced two small rings, but cleavage of the Möbius product gives a sin- gle, largermacrocycle, thereby differentiating the two topological stereoisomers. Figure 6.12 A. The synthetic strategy for the preparation of a molecularMöbius strip, and the results of rung cleavage. B.ATHYMEpolyether that can ring close tomake a Möbius strip.+ + = Cleave rungs A. B. Join x and y y y x x HO HO n OTsOOOOO O O O O O OTs Even without the twist, the three-rung Möbius ladder compound is a molecular reali- zation of an interesting topology. It is a simple example of a nonplanar graph with the K3,3 topology. Another example of a recently prepared molecule with a K3,3 topology is given in Figure 6.13 A. A structure with the K5 nonplanar graph has also been prepared, and it is shown in Figure 6.13B. As suggested in our discussion of supramolecular chemistry in Section 4.3, the facile preparation of complex catenanes and rotaxanes using the various preorganization strate- gies has led to the consideration of a number of novel stereochemical situations. Topolog- 328 CHAPTER 6 : STEREOCHEMISTRY A. B. O O O O O O O O A C D F E B A AB B C C D DE E F F O O O Figure 6.13 Examples of structureswith nonplanar graphs.A.AK3,3 molecule. To see this as a K3,3, beginwith the schematic graph as presented in Figure 6.11B, andmove the vertices B and E. This is topology, so that is legal because all the connectivities stay the same. The structure on the right, then, is labeled in the sameway. See also the three-rung laddermolecule of Figure 6.12A for another example of a K3,3 molecule. B.AK5molecule, and a schematic showing the sense that it has the K5 connectivity. ical stereoisomers have become commonplace. In addition, other types of isomerism that really do not fit any pre-existing categories are perhaps best regarded as supramolecular stereoisomerism. For example, rotaxanes and catenanes can often exist in different forms that are stereo- isomers, but with some unique properties. Figure 6.14 shows several examples. The rotax- ane of Figure 6.14A has been studied using electrochemistry, which drives the macrocycle from one ‘‘station’’ to the other. However, without oxidation or reduction of the paraquat, we expect an equilibriumbetween two forms that are differentiated solely by the position of the macrocycle along the rotaxane axle. Likewise, a catenane with two different building blocks in one of the rings will exist in two different forms (Figure 6.14 B). A similar form of supramolecular stereoisomerism arises in the ‘‘container compounds’’ discussed in Section 4.3.3. As shown in the schematic of Figure 6.14 C, when the container has two distinguish- able ‘‘poles’’, an unsymmetrical guest can lie in isomeric positions. Such isomerismhas been observed for both covalent and non-covalent container compounds. For each case in Figure 6.14, we have stereoisomers-structures with the same connec- tivities but differing arrangements of the atoms in space. They are not enantiomers, so they must be diastereomers. The novelty lies in the fact that these stereoisomers interconvert by a translation or reorientation of one component relative to the other. In some ways these struc- tures resemble conformers or atropisomers, which involve stereoisomers that interconvert by rotation about a bond. For the supramolecular stereoisomers, however, interconversion involves rotation or translation of an entire molecular unit, rather than rotation around a bond. Note that for none of the situations of Figure 6.14 do we have topological stereo- isomers. In each case we can interconvert stereoisomers without breaking and reforming bonds. 3296 .6 TOPOLOGICAL AND SUPRAMOLECULAR STEREOCHEMISTRY O N N NH NHR RO O O O RO R = -(CH2CH2O)3-Si(iPr)3 Paraquat A. B. C. NHNHR O O O O O O O O O O O O O O O OO O OO OO N N NN N N N N N NN N N N Figure 6.14 Supramolecular isomerism in rotaxanes, catenanes, and ‘‘container’’ compounds.A.Moving along a rotaxane axle can lead to isomerism if there are two different ‘‘docking stations’’.B. Similarly, catenanes can exist in isomeric forms if there is structural diversity in one of the rings.C.Aconceptualization of isomerism in a container compound. More complex catenanes can produce topological stereoisomers. Consider a [3]cate- nane with two types of rings, symbolized in Figure 6.15 A. Having the unique ring in the outer position vs. the inner position defines two stereochemical possibilities. These struc- tures are now topological diastereomers. They cannot be interconverted without breaking bonds. A large number of stereoisomers becomes possiblewith [n]catenanes as n gets larger and each ring is different. 330 CHAPTER 6 : STEREOCHEMISTRY I II B. C. A. vs. O OO O N O N R = C6H5 R = 4-methylphenyl OO O O R R OO N N O O OO O N O N O OO O O R O O O O OO O N O N OO O O R O O NNN N Figure 6.15 Topological isomerism in simple catenanes.A.Akind of ‘‘positional’’ isomerism that can occur in a [3]catenanewith two different kinds of ring.B.Amore subtle isomerism that involves ‘‘oriented’’ rings, and a chemical example.C. The ‘‘toplogical rubber glove’’, a pair of enantiomers that can interconvert readilywithout ever going through an achiral conformation. A more subtle case of topological isomerism arises in a [2]catenane in which the two rings are not simple, symmetrical circles, but rather have a sense of direction (Figure 6.15B). Now, topological enantiomers (I vs. II) are possible. This may be easier to see with a real chemical example (Figure 6.15 B). Again, the Sauvage Cu+/phenanthroline templating strategywas used to assemble two directional rings, producing a topologically chiral [2]cat- enane. You should convince yourself that the catenane shown can exist as a pair of enan- tiomers, and that no amount of spinning the rings can interconvert them. If one ringhas a senseof direction, but theother doesnot, an evenmore subtle phenome- non occurs. Figure 6.15 C shows such a case. The molecule is chiral. The two enantiomers, however, can interconvert readily by simply rotating the 1,5-dioxynaphthyl ring and trans- lating the othermacrocycle. Sauvage andMislow realized, however, that at no point during this process does an achiral conformation appear. In fact, it is impossible to create an achiral representation of this structure. The molecule has been referred to as a ‘‘topological rubber glove’’, referring to the fact that a rubber glove can be converted from right-handed to left- handed by pulling it inside out, but at no point in the process does an achiral form appear. 3316 .7 STEREOCHEMICAL IS SUES IN POLYMER CHEMISTRY 6.7 Stereochemical Issues in Polymer Chemistry Many unnatural polymers of considerable commercial importance have one stereocenter permonomer, such as inpolypropylene andpolystyrene (Figure 6.16).Unlike the ‘‘polymer- ization’’ involved in forming a protein or nucleic acid (see the next section), these unnatural systems typically start with a simple, achiral monomer (propene or styrene), and the poly- merization generates the stereogenic centers. Control over the sense of chirality for each polymerization step is often absent. As a result, considerable stereochemical complexity can be expected for synthetic polymers. For example, molecular weight 100,000 polypropylene has approximately 2400 monomers, and so 2400 stereogenic centers (look at the next Going Deeper highlight for an interesting ramification of this). There are thus 22400 or approxi- mately 10720 stereoisomers! The R,S system is not very useful here. Hence, polymer stereo- chemistry is denoted by a different criterion called tacticity. Tacticitydescribes only local, relative configurations of stereocenters. The termsarebest defined pictorially, as in Figure 6.16. Thus, isotactic polypropylene has the same configura- tion at all stereocenters. Recall the two faces of propylene are enantiotopic, and the isotactic polymer forms when all new bonds are formed on the same face of the olefin. If, instead, there is an alternation of reactive faces, the polymer stereocenters alternate, and a syndio- tactic polymer is produced. Finally, a random mixture of stereocenters produces atactic polymer. Control of polymer stereochemistry is amajor research area in academic and industrial laboratories. This is because polymers with different stereochemistries often have very dif- ferent properties. For example, atactic polypropylene is a gummy, sticky paste sometimes used as a binder, while isotactic polypropylene is a rugged plastic used for bottle caps. Re- cent advances (see the Going Deeper highlight on the next page and Chapter 13) have greatly improved the ability to control polymer stereochemistry, leading to commercial pro- duction of new families of polymerswith unprecedented properties. Another stereochemical issue is helicity, as some simple polymers can adopt a helical shape.We defer discussion of this to Section 6.8.2, inwhichwe discuss helicity in general. Figure 6.16 Different forms of polypropylene and polystyrene. R R Isotactic R R R = CH3, polypropylene R = C6H5, styrene R R R R R Syndiotactic R R R R R R Atactic R R R R Going Deeper Polypropylene Structure and youwill exceed the entiremass of the universe by a large the Mass of the Universe margin. In fact, even thoughmillions of tons of polypro- pylene aremade every year, every possible stereoisomerJust for fun, calculate themass of a sample ofmolecular of a polypropylene sample ofmolecular weight 100,000weight 100,000 polypropylene that has just onemolecule has never beenmade and neverwill be!of each of the 10720 possible stereoisomers. In doing so, 332 CHAPTER 6 : STEREOCHEMISTRY Going Deeper Controlling Polymer Tacticity-The Metallocenes Zr Cl Cl Si(Me)2 (Me)2Si Cl Si(Me)2 Cl Zr(Me)2Si Cl Si(Me)2 Cl C2-symmetric catalyst H3C Zr CH3 CH3 H3C Zr Zr TheC2-symmetric Zrmetallocene catalyst (top) and a highly schematic view of propylene complexing to it. Themid- dle two structures use the same face of the propylene, and lead to the same tacticity because of theC2 symmetry of the catalyst. The bottom two structures use the opposite face of the olefin. The adverse steric interaction of the CH3with the aromatic ring disfavors these structures. One of themost exciting recent advances in organic and stereogenic. Hence, the chlorines are homotopic and organometallic chemistry has been the development of either can be replacedwith propylene, giving identical new catalysts that produce polypropylenewith high ste- structures. Bymaking one side of the coordination site reochemical purity. Both isotactic and syndiotactic poly- muchmore bulky than the other, the propylenewill com- propylene are nowmade commerciallywith a new class plex to themetal (the first step in the reaction) with the ofmetallocene catalysts, prototypes of which are shown methyl group away from the crowded side. There are two below. Themechanism of the polymerization reaction is different ways to do this, but they are symmetry equiva- discussed in Chapter 17. Herewewill focus on the stereo- lent, and both involve the same face of the propylene. chemistry, because symmetry principles of the sort we dis- If the catalyst is enantiomerically pure, stereochemical cussed abovewere crucial in the design of this chemistry. control becomes possible. A key step inmetal-induced olefin polymerization The production of pure, syndiotactic polypropylene has the olefin face complexing to themetal center. The was evenmore challenging, but again symmetry notions two faces of the propylene double bond are enantiotopic. played a key role. Syndiotactic polypropylene requires an Isotactic polypropylene formswhen only one face of the alternation of stereochemistry at the catalyst center. For- propylenemonomer consistently reacts tomake polymer. mally, a syndiotactic polymer is like ameso compound, Thus, a chiral catalyst is needed to distinguish enantio- and so a chiral catalyst is not required. To achieve the topic faces of an olefin. But, howdowe ensure that only desired stereochemistry, a catalyst with amirror plane of one face reacts? It is a complicated problem, becausewhen symmetry (Cs) was developed (see next page). The idea an olefin like propylene complexes to ametal center in a was that the growing polymerwouldmove back and typical chiral environment, not onlywill both faces com- forth betweenmirror-image (enantiotopic) sites of the cat- plex to some extent, butmany orientations are possible for alyst (caused by steric influences of the growing chain), each complex. This leads tomany different reaction rates, and this alternating behaviorwould lead to an alternation and amixture of stereochemistries. A key to the solution, in the stereochemistry ofmonomer incorporation. This then, was to develop a catalyst that is chiral but not asym- was a bold suggestion, but this strategy has been success- metric. In particular, theC2-symmetricmetallocene shown fully implemented into commercially viable processes. belowwas prepared. Themetal is chirotopic but non- 3336 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY Zr Cl Cl C(Me)2 Zr Rn C(Me)2 CH3 CH3 Zr C(Me)2 Rn+1 Zr C(Me)2 Rn+2 Cs-symmetric catalyst CH3 Coates, G.W., ‘‘Precise Control of Polyolefin StereochemistryUsing Single-SiteMetal Catalysts.’’Chem. Rev., 100, 1223-1252 (2000); Resconi, L., Cavallo, L., Fait, A., and Piemontesi, F. ‘‘Selectivity in Propene PolymerizationwithMetallocene Catalysts.’’Chem. Rev., 100, 1253-1345 (2000). 6.8 Stereochemical Issues in Chemical Biology Molecular shape is a crucial concept in chemical biology. The ‘‘lock-and-key’’ metaphor of enzyme-substrate or antigen-antibody interactions is useful for understanding biological phenomena, and it depends crucially on molecular shape. Despite the marvelous diversity and apparent complexity of biomolecules, at a fundamental level, biopolymers are built up from really fairly simple monomers and connecting units. The structural complexity arises from an accumulation of a large number of individually straightforward interactions. As such, only a few basic stereochemical notions are necessary for dealing with biopolymers. Sincemanyof the complex chemical structures thatmakeup life (proteins, nucleic acids, and polysaccharides) are biopolymers, our current understanding of small molecule stereo- chemistry andpolymer topology allowsus to explore the stereochemistry of these biological structures. 6.8.1 The Linkages of Proteins, Nucleic Acids, and Polysaccharides As stated previously, polymer stereochemistry depends critically upon the structures of the monomers and how they are assembled. No new stereocenters are produced when amino acids are combined to make proteins, or nucleotides are combined to make nucleic acids. This is because the linkages created in forming the polymers are not stereogenic. The same is not true for polysaccharides, where the newly formed anomeric center is stereo- genic.Wewill consider these three types of biopolymers separately. Proteins Proteins are polymers built from a concatenation of
-amino acid monomers. There are twenty common amino acids, and all but one (glycine) are chiral. Thus, a protein-a poly(
-amino acid)-could have a huge number of stereoisomers. This is no way to build a living organism. As such, living systems contain only one enantiomer of each amino acid. Polymerization then produces only one stereoisomer, an isotactic polymer (Figure 6.17 A). The polymerization itself-the peptide bond formation-does not create a new stereogenic center. As a result, unlike polypropylene, the polymerization of amino acids does not re- quire any special stereochemical control of the bond forming reaction. The newly formed peptide bond is not a stereogenic unit, so amino acid polymerization is in some ways different than propylene polymerization. However, as we noted earlier in 334 CHAPTER 6 : STEREOCHEMISTRY O O OO P R OH Base Diastereotopic OO R R1 A. B. R3 R5 R2 R4 N H N H N H N H N H O OO O R R N H O X = C(O)NH s -ciss -trans O O R1 R4R2 R3 R5 N H X X X X O R H N R N O CON O CO Figure 6.17 Basic stereochemical issues in protein structures.A. The conventional representation of a protein chain, and an alternative representation that emphasizes the isotactic nature of the polymer.B. S-cis and s-trans geometries in a conventional peptide bond and in a peptide bond involving proline. Chapter 1, the peptide bond does have significant conformational preferences. The group is planar, and in secondary amides of the sort found in most peptide bonds, there is a signifi- cant preference for what is termed the s-trans or the Z stereochemistry (Figure 6.17 B). This preference is typically on the order of 4 kcal/mol, and it has a profound effect on the poten- tial shapes that proteins can adopt. The difference in this system from the polypropylene system is that the barrier separating the two forms of the peptide bond ( 19 kcal/mol) is such that they equilibrate readily at conventional temperatures. Thus, exerting stereochem- ical control over the formation of the peptide bond would be futile, because the system would quickly adjust to the thermodynamic equilibrium. Still, this highlights the inherent ambiguity of many stereochemical concepts. If the rotation barrier in amides was 29 kcal/ mol (or we lived at -78 C!), the peptide bond would be a stereogenic center, and tacticity would be a key issue in protein chemistry. The conformational preference of the peptide bond results from several factors, including adverse steric interactions in the s-cis and a fa- vorable alignment of bonddipoles in the s-trans form (Chapter 1). An exception ariseswhen proline contributes theN to an amide bond (Figure 6.17B). Now theNhas two alkyl substit- uents, and the cis-trans energy difference is much smaller. As such, proteins often adopt unique conformations in the vicinity of a proline. Nucleic Acids The only stereogenic centers of DNA and RNA are found at the sugar carbons, and be- cause the riboseordeoxyribose are enantiomericallypure, natural nucleic acids are isotactic. The P of the phosphodiester backbone of a nucleic acid is not a stereogenic center, but the twoO- groups of a connecting phosphate are diastereotopic. The phosphorus is thus prochi- ral. This has led to the use of labeled phosphates in mechanistic studies, as described with one example in a Connections highlight on the next page. Polysaccharides In contrast toproteins andnucleic acids, the linkages formedbetween saccharidemono- mers are made at stereogenic centers, and so stereochemical control of the polymerization step is critical. The crucial carbon, the anomeric center, is highlighted in Figure 6.18, which defines the nomenclature convention for this stereogenic center. This stereochemical distinc- 3356 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY Going Deeper CD Used to Distinguish a-Helices from b-Sheets tural type in black, and the experimental CD spectrum of myoglobin in color. Fitting the experimental spectrum as aThe twomost prominent secondary structural features linear combination of the three prototype curves leads toof protein chemistry are the
-helix and the -sheet (the an estimate of 80%
-helix, with the restmostly randombasic structures are described inAppendix 4). Asmen- coil. This is in good agreementwith the value of 77%tioned earlier, all helices have an inherent chirality. In con-
-helix derived from the x-ray structure ofmyoglobin.trast, sheets are in a sense flat, and therefore, they are not inherently chiral even though the peptide building blocks themselves are chiral. In addition to the
-helix and the -sheet, peptides and proteins can lack any defined shape, called a random coil. Once again, no inherent chirality would be associatedwith this structure, although the building blocks are chiral. This suggests that spectro- scopicmethods that probe chirality could be used to probe protein secondary structure. Circular dichroism is by far the onemost commonly employed. Themost useful region of the spectrum is from 190- 240 nm. Absorbances in this region are dominated by the amide backbone rather than the sidechains, making them more sensitive to secondary structure. In a CD spectrum, two negative peaks of similarmagnitude at 222 and 208 nm are indicative of an
-helix. A -sheet is revealed by a negative band at 216 nmand a positive one of similarmag- nitude near 195 nm. Lastly, a strong negative band near 200 nm and often a positive one at 218 nm is indicative of a lack ofwell-defined structure (the random coil). These are empirical observations that have been confirmed inmany 80000 60000 40000 20000 0 -20000 -40000 -60000 190 210 230 250 Wavelength (nm) E lli p ti ci ty β-sheet Random coil Myoglobin α-helix systems. The figure shows prototype spectra of each struc- tion is crucial. For example, when glucose is polymerized exclusively with
-1,4-glycoside bonds, a helical structure called amylose (a starch) is obtained. Conversely, all-1,4 linkages leads to a ‘‘rigid-rod’’ linear structure called cellulose. As with the stereoisomers of poly- propylene, these two stereoisomeric polymers have distinctly different properties. Starch is formed by animals and is primarily used for energy storage, while cellulose is a structural material found in plants. Thus, the enzymes thatmake glycosidic bonds arewell developed to control the stereochemistry of the coupling. Connections Creating Chiral Phosphates for Use to probemechanismsmany times in the context of organic as Mechanistic Probes reactions in part II of this book. When oneO- in a phosphodiester of DNAor RNA is replaced by, for example, a specific isotope or by S-, two stereoisomers are possible. This allows one to follow the stereochemistry of the reactions that take place at the phos- phorus center, potentially revealing themechanisms of these reactions. For example, RNaseA (an enzyme) cata- lyzes ring opening of the specific diastereomer of the cyclic phosphodiester shown to the right, giving only a single product inmethanol. This corresponds towhat is O Stereogenic phosphodiester group O S P Me H MeO O O O Base OHO S P O OH Base OHO known as an in-line attack, because the leaving group is Usher, D.A., Erenrich, E. S., and Eckstein, F. ‘‘Geometry of the First Stepin linewith the nucleophilic attack (similar to an SN2 reac- of Reaction of RibonucleaseA.’’ Proc. Natl. Acad. Sci. USA, 69, 116 (1972).tion).Wewill examine the use of stereochemical analyses 336 CHAPTER 6 : STEREOCHEMISTRY O H H HO H H H H OH OH O O H H H HO H H OH OH O Amylose Cellulose O H H HO H H H α -D-Glucose OH HO HO OH OH O H H HO H H OH β-D-Glucose OH OH H O H HO H H H OH OH O O O O O O O O O OOH OH OR R HO HO HO O H H HO H H O OH OH H O H H HO H H O OH OH H O H H HO H H O O OH OH H O O OH O HO O OH O O O O OH O HO O OH O Figure 6.18
- vs. -d-Glucosewith the key anomeric carbon highlighted, alongwith the structures of amylose and cellulose. For amylose and cellulose, the structures shown to the right of the arrows represent their structures in solution (withmany hydroxyls eliminated for clarity). 6.8.2 Helicity While helicity can be associatedwith many kinds of molecules, it is most frequently as- sociated with polymers (especially biopolymers). Here we briefly cover the helix as a gen- eral stereochemical element. All helices are chiral, as evidenced by the fact that we refer to helices as right- or left-handed. Typically, with molecular helices the right- and left-handed formsare topologically equivalent-that is,we can interconvert the twowithout breakingor crossingbonds.Ahelix is a stereogenic unit, but it is not the interchange of ligands that inter- converts opposite helices, but rather just the unwinding and rewinding of the helix. In structural biology helices are associatedwith bothDNAandproteins. Some polysac- charides adopt helical structures (see amylose in Figure 6.18), but this is not common. The double helix of DNA is right-handed. There is also a left-handed helical form of DNA termed Z-DNA. It is not the enantiomer of the much more common right-handed DNA. To make the enantiomer we would have to invert all the stereocenters of the deoxyribose sug- ars, which does not happen in nature. Z-DNA is a diastereomeric conformer, and it is fa- vored by certain sequences and salt conformations, although its relevance to biology is debated. Thus, while in simple, prototype helices the right- and left-handed forms are en- antiomers, in a system with enantiomerically pure, homochiral building blocks, reversing the sense of helicity produces a diastereomer. In proteins, the most common structural motif is the
-helix discussed in Chapter 3 and depicted in Appendix 4. Again, because the building blocks (amino acids) are chiral and enantiomerically pure, right- and left-handed
-helices are diastereomers. In nature only the right-handed form is seen. A second, much less common helix, termed 310 is also right-handed, and is just a conformer of the
-helix with different hydrogen bonding arrangements. 3376 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY Synthetic Helical Polymers Synthetic polymers that are isotactic are similar to biological building blocks in that all the stereocenters are homochiral. As such, it should not be surprising to learn that helical structures can show up in synthetic polymers, but usually not with the well-defined struc- tural integrity of DNA or protein
-helices. In nucleic acids and proteins, there are strong stereochemical biases built into the monomers, and these lead to strong preferences for one helical form over the other. In synthetic polymers, such strong biases are often absent. How- ever, in certain cases substantial helical biases canbe seen in synthetic polymers (see the next Connections highlight for an example). A truly remarkable example of a helical synthetic polymer is the series of polyisocya- nates studied byGreen and co-workers and summarized in Figure 6.19. The polyisocyanate backbone contains contiguous amide groupings reminiscent of a peptide or a nylon deriva- tive [nylon-6 is -C(O)(CH2)5NH-; polyisocyanates have been termed nylon-1; see Chapter 13 for further discussion of nylons]. The structure shown describes the basic layout of the backbone, but steric clashing between the carbonyl oxygen and the Rgroup precludes a pla- nar geometry. A trade-off between conjugation and sterics produces a helical structure, but in a simple polyisocyanatewe expect no particular bias for the right- or left-handed helix, as the two are enantiomers. One way to produce a helical bias is to convert the enantiomeric helices into diastereo- mers by incorporating stereogenic centers into the sidechains (R), much aswith natural bio- polymers. This strategyworks spectacularlywellwith polyisocyanates. As shown in Figure 6.19, making the sidechain stereogenic simply by virtue of isotopic substitution leads to a huge helical bias. That this is so is seen by the tremendous increase in optical activity and the reversal in sign on polymerizing the monomer. Both the magnitude and the change in sign establish that the inherent optical activity of the monomer is not responsible for the optical activity of thepolymer.With ahelical backbone, now the chromophoric amideunits contrib- ute to the optical rotation. Full CD studies support this analysis. What is the causeof this effect? It has beenestimated that the bias for onehelical handed- ness over the other induced by the isotopic substitution is on the order of 1 cal/mol per sub- unit-aminiscule amount. Thus,we are seeing an extreme example of cooperativity. Once a tiny bias is established, it propagates down the chain, each successivemonomer beingmore Figure 6.19 Examples of helicity in simple, non-natural polymers. Note that the optical rotation values given are on a per monomer basis, so the large increase in absolute value on polymerization ismeaningful. NCO NaCN [α]D = +0.65 (neat) [α]D = -444 (n -hexane) DMF, -58 °C D H H D RNCO N D H C
 H D NCO NaCN [α]D = -0.43 (neat) [α]D = +302 (n -hexane) DMF, -58 °C N NaCN DMF, -58 °C C n
 n C O R N CN N R O C O R N C N R O C O R N C R O O O 338 CHAPTER 6 : STEREOCHEMISTRY inclined to adopt the currently accepted chirality. It is truly amazing, though, that such a trivial inherent bias can ultimately lead to such an obvious effect. The detailed analysis of this sort of cooperativity involves some fairly complexmathandphysics, sowedirect the in- terested student to the references at the end of the chapter. The amplication of chirality inherent in the polyisocyanates described is an example of a phenomenon wherein a small initial chirality leads to a bias resulting in high enantio- meric excesses. This phenomenon has been termed the sergeants and soldiers principle, implying that the initial chiral influence is the ‘‘sergeant’’ that aligns all the ‘‘soldiers’’. This is a phenomenon that has been observed not only in polymer chemistry, but also with self-assembled supramolecular complexes driven by interactions and hydrogen-bonded systems. The optical rotations given in Figure 6.19 are extraordinarily large. The reason is not that these helical structures are somehow ‘‘more chiral’’ than typicalmolecules. Rather, the large rotations are due to the fact that with the polyisocyanates we are probing an intrinsically chiral chromophore. The feature of the molecule that is interacting most strongly with the light, the amide group, is itself distorted into a chiral shape.Amore typical situation is a chi- rally perturbed, intrinsically achiral chromophore, such as a carbonyl group (intrinsically achiral, as in acetone) with a nearby stereogenic carbon. In such cases, much smaller rota- tions and differential absorptions are typically seen. Connections A Molecular Helix Created from spectra reveal comparably large differential extinction Highly Twisted Building Blocks coefficients for right- and left-handed circular polarized light, confirming the helical nature of the polymers.The creation of helices using synthetic structures has attracted considerable attention due to the common heli- cal motif in peptides and nucleic acids. Achieving a syn- thetic polymerwith a complete right- or left-handed twist is difficult. One approach to helical molecules has been to make compounds known as helicenes, highly conjugated aromatic structures that naturally possess a twist due to the physical overlap of benzene rings. Convince yourself [6]Helicene that if the [6]helicene shownwere planar, unacceptable steric clasheswould occur. The shapes of these structures are akin to that which onewould get if one segment of a springwere cut off. Many helicenes have beenmade, including the [6]helicene shown and higher homologues. Not surprisingly, these structures showhigh optical rota- tions, because they are verymuch intrinsically chiral chromophores. More recently, a polymer based on the helicenemotif has been prepared. The key step in the synthesis of a heli- cal polymer based upon a helicene is the condensation of a chiral [6]helicene that has salicylaldehyde functionality at each endwith 1,2-phenylenediamine in the presence of a N Ni N O O MeO RO N Ni N O O OMe OR Ni salt. This gives the chemical structure shown to the right (bonds enormously stretched for clarity of presenta- tion). TheORD spectra of structures of this kind display Dai, Y., Katz, T. J., andNichols, D.A. ‘‘Synthesis of aHelical Conjugated Ladder Polymer.’’Angew. Chem. Int. Ed. Eng., 35, 2109 (1996).extraordinarily large rotations, and the circular dichroism 3396 .8 STEREOCHEMICAL IS SUES IN CHEMICAL BIOLOGY 6.8.3 The Origin of Chirality in Nature Themolecules of life are for themostpart chiral, and in living systems theyare almost al- ways enantiomerically pure. In addition, groups of biomolecules are generally homochiral -all amino acids have the same sense of chirality and all sugars have the same sense of chi- rality. As already discussed, the chirality of the amino acids leads to chiral enzymes, which in turn produce chiral natural products. All the chiral compounds found in nature that are readily accessible to synthetic chemists for the construction of more complex molecules are referred to as the chiral pool. What is theoriginof the chirality of themolecules of life, and the reason for thehomochi- rality?We cannot distinguish enantiomers unless we have a chiral environment. Further, in a reaction that forms a stereocenter, we cannot create an excess of one enantiomer over an- otherwithout some chirality to start with. In the laboratory today, all enantiomeric excesses that we exploit ultimately derive from natural materials. Whether it is the interaction with an enantiomerically pure amino acid fromanatural source, or an individualmanually sepa- rating enantiomorphous crystals (first achieved by Pasteur), the source of enantiomeric ex- cess in modern chemistry is always a living system. But how was this achieved in the ab- senceof life?This is a fascinating, complex, andcontroversial topic thatwe can touchononly briefly here. This question is often phrased as the quest for the origin of chirality in nature, butmore correctly it is the origin of enantiomeric excess and homochiralitywe seek. Models for the origin of life generally begin with simple chemical systems that, in time, evolve to more complex, self-organizing, and self-replicating systems. It is easy to imagine prebiotic conditions in which simple condensation reactions produce amino acids or mole- cules that closely resemble them, and indeed experiments intended tomodel conditions on the primitive earth verify such a possibility. However, it is difficult to imagine such condi- tions producing anything other than a racemicmixture. Essentially, there are two limiting models for the emergence of enantiomeric excess in biological systems. They differ by whether enantiomeric excess arose naturally out of the evolutionary process orwhether an abiotic, external influence created a (presumably slight) initial enantiomeric excess that was then amplified by evolutionary pressure (maybe a type of sergeant-soldier effect). The first scheme is a kind of selectionmodel. The building blocks (let’s consider only amino acids here) are initially racemic. However, there is considerable advantage for an early self-replicating chemical system to use only one enantiomer. For ex- ample, consider a simple polymer of a single amino acid. If both enantiomers are used, the likely result is an atactic polymer, which maywell have variable and ill-defined properties. However, if only a single enantiomer is used, only the isotactic polymer results. This kind of specificity could be self-reinforcing, such that eventually, only the single amino acid is used. The homochirality of nature could result because addition of a second amino acid to themix might be less disruptive if the new one has the same handedness as the original. The details of how all this could happen are unknown, but the basic concept seems plausible. Certainly, the remarkable cooperativity seen in polyisocyanates provides an interesting precedent. While we begin with racemicmaterials, there will never be exactly identical numbers of right- and left-handedmolecules in a sample of significant size. This is a simple statistical ar- gument. For example, earlier we considered the reduction of 2-butanone with lithium alu- minum hydride under strictly achiral conditions (Figure 6.7), and stated that we expect a racemic mixture without a significant enantiomeric excess. However, if we start with 1023 molecules of ketone, the probability thatwewill produce exactly 0.5 1023 molecules of (R)- and 0.5 1023molecules of (S)-alcohol is essentially nil. Therewill always be statistical fluc- tuations. For example, for a relatively small sample of 107 molecules there is an even chance that one will obtain a
0.021% excess of one enantiomer over the other (we cannot antici- pate which enantiomer will dominate in any given reaction). Perhaps such a small excess from a prebiotic reaction, or a significantly larger excess from a statistical fluke, got ampli- fied through selective pressure, and ultimately led to the chirality of the natural world. The alternative type ofmodel emphasizes thepossible role of an inherently chiral bias of external origin. One possibility for this bias is the inherent asymmetry of our universe re- 340 CHAPTER 6 : STEREOCHEMISTRY R1 R2 Syn Anti R3 flected in the charge-parity (CP) violation of the weak nuclear force. In particular,  decay of 60Co nuclei produces polarized electrons with a slight excess of the left- over the right- handed form. From this point, several mechanisms that translate the chirality of the emis- sion to a molecular enantiomeric excess can be envisioned. Unfortunately, all attempts to measure such enantiomeric enrichment in the laboratory have produced at best extremely small enrichments that have proven difficult to reproduce. An alternative proposal for an external chiral influence is an enantioselective photochemical process involving circularly polarized light, which is well established in the laboratory to give significant enantiomeric excesses. At present, however, no clear mechanism for creating circularly polarized light with an excess of one handedness in the prebiotic world has been convincingly demon- strated, although models have been proposed. Only further experimentation in the lab, or perhaps examination of the chirality of extraterrestrial life forms, will resolve this issue. 6.9 Stereochemical Terminology Stereochemistry has engendered a sometimes confusing terminology, with several terms that are frequently misused. Here we provide definitions of the most common terms. This collection is based in largemeasure on amuchmore extensive listing in the following book: Eliel, E. L.,Wilen, S.H., andMander, L.N. (1994). Stereochemistry ofOrganic Compounds, John Wiley& Sons, NewYork. Absolute configuration. Adesignation of the position or order of arrangement of the ligands of a stereogenic unit in reference to an agreed upon stereochemical standard. Achiral. Not chiral. A necessary and sufficient criterion for achirality in a rigid mole- cule is the presence of any improper symmetry element (Sn, including  and i). Achirotopic. The opposite of chirotopic. See ‘‘chirotopic’’ below. Anomers. Diastereomers of glycosides or related cyclic forms of sugars that are spe- cifically epimers at the anomeric carbon (C1 of an aldose, or C2, C3, etc., of a ketose). Anti. Modern usage is to describe relative configuration of two stereogenic centers along a chain. The chain is draw in zigzag form, and if two substituents are onopposite sides of the plane of the paper, they are designated anti. See also ‘‘syn’’, ‘‘antiperiplanar’’, and ‘‘anticlinal’’. Anticlinal. A term describing a conformation about a single bond. In A-B-C-D, A andDare anticlinal if the torsion angle between them is between 90 and 150 or -90 and -150. See Figure 2.7. Antiperiplanar. A term describing a conformation about a single bond. In A-B-C-D, A andD are antiperiplanar if the torsion angle between them is between150 to -150. See Figure 2.7. Apical, axial, basal, and equatorial. Terms associatedwith the bonds andpositions of ligands in trigonal bipyramidal structures. M Axial or apical Equatorial or basal L L L L L 3416 .9 STEREOCHEMICAL TERMINOLOGY Asymmetric. Lacking all symmetry elements (point group C1). All asymmetric mole- cules are chiral. Asymmetric carbon atom. Traditional term used to describe a carbon with four differ- ent ligands attached. Not recommended inmodern usage. Atactic. A termdescribing the relative configuration along a polymer backbone. In an atactic polymer, the stereochemistry is random-no particular pattern or bias is seen. Atropisomers. Stereoisomers (can be either enantiomers or diastereomers) that canbe interconverted by rotation about single bonds and for which the barrier to rotation is large enough that the stereoisomers can be separated and do not interconvert readily at room temperature. Chiral. Existing in two forms that are related as non-congruent mirror images. A nec- essary and sufficient criterion for chirality in a rigidmolecule is the absence of any improper symmetry elements (Sn, including  and i). Chiral center. Older term for a tetracoordinate carbonor similar atomwith fourdiffer- ent substituents. More modern, and preferable, terminology is ‘‘stereogenic center’’ (or ‘‘stereocenter’’). Chirotopic. The termused to denote that an atom, point, group, face, or line resides in a chiral environment. Cis. Describing the stereochemical relationship between two ligands that are on the same side of a double bond or a ring system. For alkenes only,Z is preferred. Configuration. The relative position or order of the arrangement of atoms in space that characterizes a particular stereoisomer. Conformers or conformational isomers. Stereoisomers that are interconverted by rapid rotation about a single bond. Constitutionally heterotopic. The samegroups or atomswith different connectivities. D and L. An older system for identifying enantiomers, relating all stereocenters to the sense of chirality of d- or l-glyceraldehyde. See discussion in the text. Generally not used anymore, except for biological structures such as amino acids and sugars. Diastereomers. Stereoisomers that are not enantiomers. Diastereomeric excess (de). In a reaction that produces two diastereomeric products in amounts A and B, de 100%( A- B )/(A B). Diastereotopic. The relationship between two regions of a molecule that have the same connectivity but are not related by any kind of symmetry operation. Dissymmetric. Lacking improper symmetry operations. A synonym for ‘‘chiral’’, but not the same as ‘‘asymmetric’’. Eclipsed. A term describing a conformation about a single bond. In A-B-C-D, A and D are eclipsed if the torsion angle between them is approximately 0. Enantiomers. Molecules that are related as non-congruentmirror images. 342 CHAPTER 6 : STEREOCHEMISTRY Enantiomeric excess (ee). In a reaction that produces two enantiomeric products in amounts A andA , ee 100%( A-A )/(AA ). Enantiotopic. The relationship between two regions of amolecule that are related only by an improper symmetry operation, typically amirror plane. Endo. In a bicyclic system, a substituent that is on a bridge is endo if it points toward the larger of the two remaining bridges. See also ‘‘exo’’. Epimerization. The interconversion of epimers. Epimers. Diastereomers that have the opposite configuration at only one of two or more stereogenic centers. Erythro and threo. Descriptors used to distinguish between diastereomers of an acy- clic structure having two stereogenic centers. When placed in a Fischer projection using the convention proper for carbohydrates, erythro has the higher priority groups on the same side of the Fischer projection, and threo has them on opposite sides. Exo. In a bicyclic system, a substituent that is on a bridge is exo if it points toward the smaller of the two remaining bridges. See also ‘‘endo’’. E,Z. Stereodescriptors for alkenes (see discussion in the text). Gauche. A term describing a conformation about a single bond. In A-B-C-D, A and D are gauche if the torsion angle between them is approximately 60 (or -60). See section 2.3.1. Geminal. Attached to the same atoms. The two chlorines of 1,1-dichloro-2,2- difluoroethane are geminal. See also ‘‘vicinal’’. Helicity. The sense of chirality of a helical or screw shaped entity; right (P) or left (M). Heterochiral. Having an opposite sense of chirality. For example,d-alanine and l-leu- cine are heterochiral. See also ‘‘homochiral’’. Heterotopic. The samegroups or atoms in inequivalent constitutional or stereochemi- cal environments. Homochiral. Having the same sense of chirality. For example, the 20 natural amino acids are homochiral-they have the same arrangement of amino, carboxylate, and side- chain groups. Has also been used as a synonym for ‘‘enantiomerically pure’’, but this is not recommended, because homochiral already was awell-defined term before this alternative usage became fashionable. Homotopic. The relationship between two regions of a molecule that are related by a proper symmetry operation. Isotactic. A term describing the relative configuration along a polymer backbone. In an isotactic polymer, all stereogenic centers of the polymer backbone have the same sense of chirality. Meso. A term describing an achiral member of a collection of diastereomers that also includes at least one chiral member. Optically active. Rotating plane polarized light. Formerly used as a synonym for ‘‘chiral’’, but this is not recommended. 3436 .9 STEREOCHEMICAL TERMINOLOGY Prochiral. A group is prochiral if it contains enantiotopic or diastereotopic ligands or faces, such that replacement of one ligand or addition to one face produces a stereocenter. See Section 6.3.2. R, S. The designations for absolute stereochemistry (see earlier discussion in the text). Racemic mixture or racemate. Comprised of a 50:50mixture of enantiomers. Relative configuration. This refers to the configuration of any stereogenic centerwith respect to another stereogenic center. If one center in a molecule is known as R, then other centers can be compared to it using the descriptorsR* or S*, indicating the same or opposite stereochemistry, respectively. Resolution. The separation of a racemic mixture into its individual component enan- tiomers. Scalemic. A synonym for ‘‘non-racemic’’ or ‘‘enantiomerically enriched’’. It has not found general acceptance, but is used occasionally. S-cis and s-trans. Descriptors for the conformation about a single bond, such as the C2-C3 bond in 1,3-butadiene, or the C-N bond of an amide. If the substituents are synperi- planar, they are termed s-cis (‘‘s’’ for ‘‘single’’); if they are antiperiplanar, they are termed s-trans. Stereocenter. See ‘‘stereogenic center’’. Stereogenic center. An atom atwhich interchange of any two ligands produces a new stereoisomer. A synonym for ‘‘stereocenter’’. Stereogenic unit. An atom or grouping of atoms at which interchange of any two li- gands produces a new stereoisomer. Stereoisomers. Molecules that have the same connectivity, but a different arrange- ment of atoms in space. Stereoselective. A term describing the stereochemical consequences of certain types of reactions. A stereoselective reaction is one for which reactant A can give two stereoiso- meric products, B and B’, and one product is preferred. There can be degrees of stereoselec- tivity. All stereospecific reactions are stereoselective, but the converse is not true. Stereospecific. A termdescribing the stereochemical consequences of certain types of reactions. A stereospecific reaction is one for which reactant A gives product B, and stereo- isomeric reactant A gives stereoisomeric product B’. There can be degrees of stereospecific- ity. Stereospecific does notmean 100% stereoselective. Syn. Modern usage is to describe the relative configuration of two stereogenic centers alonga chain. The chain isdrawn inzigzag form, and if two substituents are on the sameside of the plane of the paper, they are syn. See also ‘‘anti’’, ‘‘synperiplanar’’, and ‘‘synclinal’’. Synclinal. Atermdescribing a conformation about a single bond. InA-B-C-D,A and D are synclinal if the torsion angle between them is between 30 and 90 (or -30 and -90). See Figure 2.7. Syndiotactic. A termdescribing the relative configuration along a polymer backbone. In a syndiotactic polymer, the relative configurations of backbone stereogenic centers alter- nate along the chain. R1 R2 Syn Anti R3 344 CHAPTER 6 : STEREOCHEMISTRY Synperiplanar. A term describing a conformation about a single bond. In A-B-C-D, A and D are synperiplanar if the torsion angle between them is between30 and -30. See Figure 2.7. Tacticity. A generic term describing the stereochemistry along a polymer backbone. See ‘‘atactic’’, ‘‘isotactic’’, and ‘‘syndiotactic’’. Trans. Atermdescribing the stereochemical relationship between two ligands that are on opposite sides of a double bond or a ring system. For alkenes only, E is preferred. Vicinal. Attached to adjacent atoms. In 1,1-dichloro-2,2-difluoroethane, the relation- ship of either chlorine to either fluorine is vicinal. See also ‘‘geminal’’. Summary and Outlook The excitement that chemists feel for the area of stereochemistry has hopefully rubbed off during your reading of this chapter. From simple enantiomers and diastereomers, to rotax- anes, catenanes, and knots, stereochemistry continues to challenge organic chemists to cre- atemolecules of increasing complexity, which inevitably leads tomoleculeswith intriguing properties and simple aesthetic beauty. Furthermore, stereochemical concepts shed important light on the study of reaction mechanisms. It is this topic that we still need to develop further. In our analyses of reaction mechanisms we will rely heavily upon the concepts and terminology introduced in this chapter. Further, in textbooks and journal articles related to chemical synthesis, the control of stereochemistry during chemical transformations is a topic of paramount importance. Now that we have a firm background on the fundamentals of stereochemistry, it is time to launch into the practical applications. Exercises 1.Wehave stated that the stereogenic center in l-cysteine isR, while all other l-amino acids are S. Show this. 2. Statewhether the following sugars are l or d. O OH OH OHHO HO HO HO OH OH OH OH OHO HO HOOH OH OH HOHO O O HO OH HOHO O 3. Label the following alkenes as eitherZ or E. O O PhSe Br OEt 345EXERCISES 4.Wehave stated that the preferred conformation of a peptide bond isZ, also known as s-trans (referring to a trans arrange- ment of the single bond between C-N). Show thatZ is the appropriate descriptor. 5. Show that propylene and styrene are prochiral, and label the faces of propylene asRe or Si. 6.Howmany diastereomers are there for the following compound?Draw them all with chair cyclohexane representations. Also, draw themflat in the page as shown below, exceptwith solid dots on the bridgehead hydrogens to represent the caseswhere the hydrogens project up. 7.Draw enantiomers of the following compounds. Cl CH2CH3 H CH3 8. Identify the stereogenic centers or units in the following compounds. E C B D A A D E C B A D E B F C CH2CH3 H CH3 9. For each structure shown, label the pair ofmethyls as homotopic, enantiotopic, diastereotopic, or constitutionally heterotopic. CH3 CH3 CH3 CH3H3CCH3 CH3 CH3 10. Is the structure shown chiral? Is it asymmetric? 11. Find the achirotopic points in the following compounds. If there are no achirotopic points, state this. If all points are achiro- topic, state this also. CH3 CH2CH3 CH2CH2CH3 12. Label anyCn or Sn axes (includingmirror planes) in themolecules in Exercise 11. 13.Draw amolecule that contains aC3 axis and a singlemirror plane. 346 CHAPTER 6 : STEREOCHEMISTRY 14. Solutions of themolecule shown are optically active. However, upon reactionwith itself, all optical activity vanishes. Explain this phenomenon. In addition, generalize the result. That is, describe the stereochemical features necessary for such a situation to occur. SH Br 15.Draw a diastereomer of the followingmolecule that is not an epimer. 16. Find the prochiral hydrogens in the followingmolecules, and circle any pro-S hydrogens. If there are no prochiral hydro- gens, state this. 17. Predict whether the product ratio of the following reactionswill be 50:50 or a number other than 50:50. O CN MeOHO O O CN O CN MeOHOPh Ph O Ph Ph O O CN O Cu salt THF O O C C C C H CH2CH3 CH3 H CH2CH3 CH3 O O Cu salt THF O O C C C C 18. The following polymerization catalyst produces blocks of isotactic polypropylenewith alternating stereochemistry for each block. Explain how this happens. Ph Ph Zr Cl Aluminum reagent PropyleneCl mn 347EXERCISES 19. Show that the hydrogens of the CH2 groups of the followingmolecules are never equivalent in any conformation. 20. For eachmolecule shown, determinewhether the two faces of the olefin or carbonyl are homotopic, enantiotopic, or dia- stereotopic. For ethyl phenyl ketone, designate theRe and Si faces. CH3 CH3 O 21. Show that the hydrogens of the CH3 group of the followingmolecules are not equivalent in the conformation shown, but average due to bond rotation. C H H H H H H 22.Define the following reactions as stereoselective and/or stereospecific, and if so, determine the percent stereoselectivity and/or stereospecificity. The products inA,D, E, and F are as shown. The product ratios inB andC are hypothetical for purposes of this question. Br Br HHO2C H racemic H meso + HO2C Br Br CO2H Br2 CO2H H H Br Br CO2HH Br2 HO2C CO2HHO2C CO2H HO2C A. Br Br HHO2C H CO2H + HO2C Br Br CO2HH H + HO2C Br Br CO2HH Br2 CO2HH Br Br 30% 40%30% 30% CO2HH Br2 H H Br Br 30% HHO2C HO2C H Br Br 40% CO2HH HO2C CO2HHO2C CO2H HO2C B. Maleic acid Fumaric acid 348 CHAPTER 6 : STEREOCHEMISTRY Heat Ph Ph H O N(CH3)2 D. Heat PhH O N(CH3)2 Heat + 71% O N(CH3)2 E. F. Heat O N(CH3)2 PhOCH2Cl PhO OPh n -BuLi 29% + + 71% 29% 26% 14% Ph Br Br HHO2C H CO2H + HO2C Br Br CO2HH H + HO2C Br Br CO2HH Br2 CO2HH Br Br 30% 40%30% 40% CO2HH Br2 H H Br Br 40% HHO2C HO2C H Br Br 20% CO2HH HO2C CO2HHO2C CO2H HO2C C. 23.Draw anymolecule that contains an enantiotopic pair of hydrogens that are not attached to the same atom. 24.We showed that rapid rotation about the C1-C2 bond of 2-butanolmakes the three hydrogens at C1 symmetry eq Why is it that rapid rotation about the C2-C3 bond (or any other bond) does notmake the two hydrogens at C3 eq 25.Howmany stereoisomers are possible for a linear [3]catenane?Which of these are chiral (presume that the individ have amirror plane in the plane of the ring)? Consider separately three cases: a. all three rings are equivalent and tional, b. all three rings are different but not directional, and c. all three rings are inequivalent and directional. 26. Convince yourself that C60 has a planar graph. 349EXERCISES 27. The THYMEpolyether of Figure 6.12 could also closewith two twists. If it does, whatwould be the product of ozonolysis? 28. In the section on ‘‘Helical Descriptors’’ (part of Section 6.1.2), we showed an allene and two related structures and gave M/P assignments. Show that the same assignments are obtained if you sight down the opposite end of the axis shown. 29. Recall the [5]catenene olympiadane of Chapter 4. Howmany stereoisomerswould be possible if each ring of the system were different, whilemaintaining theOlympic ringmotif? Assume that all the rings are non-directional. 30. Ferrocene has two limiting conformations, an eclipsed form and a staggered form. Each has an Sn axis.What is n for each? Fe Eclipsed Fe Staggered 31.Wediscussed the ‘‘toplogical rubber glove’’, a system inwhich two enantiomers can interconvert without ever going through an achiral form. A related phenomenonwas observedmuch earlier with the biphenyl derivative shown, first pre- pared byMislow. The nitro groups are large enough that the biphenyls cannot rotate past one another on anymeaningful time scale. Convince yourself that a. thismolecule is chiral, b. the enantiomers can readily interconvert by rotations about single bonds, and c. at no time during the enantiomerization is a structure that is achiral involved. O O NO2 NO2 O2N O2NO O 32. For each structure shown, determinewhether the twomethyl groups are homotopic, enantiotopic, diastereotopic, or consti- tutionally heterotopic, both on a time scalewhere ring inversion is slow and on a time scalewhere ring inversion is fast. CH3 CH3 H3C H3C CH3 CH3 CH3 CH3 33.We saw in aGoingDeeper highlight in Section 2.5.3 that hexaisopropylbenzene adopts a geared conformation. Consider a structure inwhich two adjacent isopropyl groups are replaced by 1-bromoethyl groups (that is, one CH3 of an isopropyl is replaced by Br in two adjacent groups).Maintaining the rigorously geared structure, sketch all possible stereoisomers for this compound, and describe them as chiral or not and establish pair-wise relationships as enantiomeric or diastereo- meric. Consider especially the consequences of reversing the direction around the ring of the geared array. 34. Convince yourself that themetals in the complexes shown in the Connections highlight entitled ‘‘C2 Ligands inAsym- metric Synthesis’’ are indeed chirotopic but non-stereogenic. Also show that the coordination to either face of themetal in these complexes produces identical structures. 35. For themathematically inclined, calculate the probability of obtaining an exactly 50:50 ratio of enantiomers from the LAH reduction of 2-butanonewhen the amount of startingmaterial is a. 10molecules, b. 103molecules, and c. 1021 molecules. 36. In Section 6.8.1, a [6]helicene is shown in a Connections highlight. Assign anM or P descriptor to this helicene. Further- more, what is the appropriateM or P descriptor for the binaphthol compound show in themargin of Section 6.5? 37.Draw the stereoisomers of tris(o-tolyl)borane.What bond rotations are required to interconvert diastereomers, andwhich are required to inconvert enantiomers? B 3 38. The reaction of phenylacetylenewith Br2 only gives (Z)-1,2-dibromo-1-phenylethene, and therefore the reaction is 100% stereoselective. Is the reaction also stereospecific? Explain your answer. 350 CHAPTER 6 : STEREOCHEMISTRY 39.A famous topological construct is theBorromean rings, shown below. At first they appear to be just three interlocking rings, but lookmore closely. No two rings are interlocked. If we break any one ring, the entire construct falls apart. These rings hold together only if all three are intact. The symbolic significance of such a structure has been appreciated for centu- ries inmany diverse cultures. Chemically, the challenge is clear.We cannot build up the Borromean rings by first linking a pair of rings and then adding another, because there are no pairwise linkages. Alternative strategies are required, and sev- eral have been suggested. For the synthetically intrepid, design a synthesis of the Borromean rings using the generalmetal templating strategies that Sauvage applied to the creation of catenanes. Focus on strategic and topological issues rather than detailed chemical issues. Very recently, amolecular realization of the Borromean rings has been brilliantly synthe- sized by Stoddart and coworkers. See Chickak, K. S., Cantrill, S., Pease, A. R., Sheng-Hsien, C., Cave, G.W.C., Atwood, J. L., and Stoddart, J. F. ‘‘Molecular Borromean Ring.’’ Science, 304, 1308 (2004). Further Reading Classic Review Articles and Textbooks on Stereochemistry Mislow, K. (1966). Introduction to Stereochemistry, W.A. Benjamin, Inc., NewYork. Eliel, E. L.,Wilen, S.H., andMander, L.N. (1994). Stereochemistry of Organic Compounds, Wiley, New York. An extensive compilation of all topics related to organic stereochemistry. Also includes a comprehensive glossary of stereochemical terminology. Mislow, K. ‘‘Molecular Chirality.’’ Top. Stereochem., 22, 1 (1999). Juaristi, E. (1991). Introduction to Stereochemistry and Conformational Analysis, Wiley-Interscience, NewYork. Klyne,W., and Buckingham, J. (1978).Atlas of Stereochemistry, 2d ed., OxfordUniversity Press, NewYork. Three-Dimensional Drawing of Chemical Structures Hoffmann, R., and Laszlo, P. ‘‘Representation in Chemistry.’’Angew. Chem. Int. Ed. Eng., 30, 1 (1991). Chiral Molecules with High Symmetry Farina,M., andMorandi, C. ‘‘High Symmetry ChiralMolecules.’’ Tetrahedron, 30, 1819 (1974). Stereogenic and Chirotopic Mislow, K., and Siegel, J. ‘‘Stereoisomerism and Local Chirality.’’ J. Am. Chem. Soc., 106, 3319 (1984). Symmetry and Point Groups Cotton, F.A. (1971).Chemical Applications of Group Theory, 2nd ed.,Wiley-Interscience, NewYork. Heilbronner, E., andDunitz, J. D. (1993).Reflections on Symmetry, VerlagHelvetica Chimica Acta, Basel. Stereochemical Nomenclature and Terminology http://www.chem.qmw.ac.uk/iupac/stereo/ Cahn, R. S., Ingold, C.K., and Prelog, V. ‘‘Specification ofMolecular Chirality.’’Angew. Chem. Int. Ed. Eng., 5, 385 (1966). Rigaudy, J., andKlesney, S. (1979).Nomenclature of Organic Chemistry, Pergamon Press, Oxford, England. Hirschmann, H., andHanson, K. R. ‘‘On Factoring Chirality and Stereoisomerism.’’ Top. Stereochem., 14, 183 (1983). Mislow, K., and Raban,M. ‘‘Stereoisomeric Relations of Groups inMolecules.’’ Top. Stereochem., 1, 1 (1967). 351FURTHER READING Nicolaou, K.C., Boddy, C.N.C., and Siegel, J. S. ‘‘Does CIPNomenclature AdequatelyHandleMole- culeswithMultiple Stereoelements? ACase Study of Vancomycin andCognates.’’Angew. Chem. Int. Ed. Eng., 40, 701 (2001). Prochiral Nomenclature Hanson, K. R. ‘‘Applications of the Sequence Rule. I. Naming the Paired Ligands g,g at the Tetrahe- dral AtomXggij. II. Naming the Two Faces of a Trigonal AtomYghi.’’ J. Am. Chem. Soc., 88, 2731 (1996). Stereoselective and Stereospecific Reactions Zimmerman, H. E., Singer, L., and Thyagarajan, B. S. ‘‘Overlap Control of Carbanionoid Reactions. I. Stereoselectivity in Alkaline Epoxidation.’’ J. Am. Chem. Soc., 81, 108 (1959). Adams, D. L. ‘‘Toward the Consistent Use of Regiochemical and Stereochemical Terms in Introduc- toryOrganic Chemistry.’’ J. Chem. Educ., 69, 451 (1992). Optical Activity and Chiroptical Methods Hill, R. R., andWhatley, B.G. ‘‘Rotation of Plane-Polarized Light. A SimpleModel.’’ J. Chem. Educ., 57, 306 (1980). Brewster, J.H. ‘‘HelixModels of Optical Activity.’’ Top. Stereochem., 2, 1 (1967). Snatzke, E., ed. (1967).Optical Rotary Dispersion and Circular Dichroism inOrganic Chemistry, Heyden and Son, London. Crabbe, P. ‘‘Optical RotaryDispersion andOptical Circular Dichroism inOrganic Chemistry.’’ Top. Stereochem., 1, 93 (1967). Atropisomers Oki,M. (1993). The Chemistry of Rotational Isomers, Springer-Verlag, Berlin. Molecular Propellers and Residual Stereoisomerism Mislow, K.M. ‘‘Stereochemical Consequences of Correlated Rotation inMolecular Propellers.’’ Acc. Chem. Res., 9, 26 (1976). Polymer Stereochemistry Goodman,M. ‘‘Concepts of Polymer Stereochemistry.’’ Top. Stereochem., 2, 73 (1967). Helical Isocyanates Green,M.M., Park, J.-W., Sato, T., Teramoto, A., Lifson, S., Selinger, R. L. B., and Selinger, J. V. ‘‘The Macromolecular Route to Chiral Amplification.’’Angew. Chem. Int. Ed. Eng., 38, 3138 (1999). Topological Issues Schill, G. inCatenanes, Rotaxanes, and Knots, J. Boeckmann (ed.), Academic Press, NewYork, 1971. Sauvage, J. P. ‘‘InterlacingMolecular Threads on TransitionMetals: Catenands, Catenates, and Knots.’’Acc. Chem. Res., 23, 319 (1990). Liang, C., andMislow, K. ‘‘Topological Features of Protein Structures: Knots and Links.’’ J. Am. Chem. Soc., 117, 4201 (1995). Walba, D.M. ‘‘Topological Stereochemistry.’’ Tetrahedron, 41, 3161 (1985). Merrifield, R. E., and Simmons, H. E. (1989). TopologicalMethods in Chemistry, Wiley, NewYork. Chambron, J.-C., Sauvage, J.-P., andMislow, K. ‘‘A Chemically AchiralMoleculewithNoRigidly Achiral Presentations.’’ J. Am. Chem. Soc., 119, 9558 (1997). The ‘‘topological rubber glove’’. Life’s Handedness Sevice, R. F. ‘‘Does Life’s Handedness Come fromWithin?’’ Science, 286, 1282-1283 (1999). Bonner,W.A. ‘‘Origins of Chiral Homogeneity inNature.’’ Top. Stereochem., 18, 1 (1998).