Asymmetric Synthesis and Stereochemistry

Asymmetric synthesis is any synthesis that produces enantiomerically or diastereomeri-cally enriched products. This is the expected result if enantiomerically enriched chiral substrates are employed. Of interest here are asymmetric syntheses where the reactants are either achiral or chiral but racemic. Many examples of this type are collected in volumes edited by Morrison [33]. The first example of an asymmetric synthesis involved use of the chiral, optically pure base brucine in a stereoselective decarboxylation of a diacid with enantiotopic carboxyl groups [34]  

Both the ally lie alcohol and tert-hutyX hydroperoxide are achiral, but the product epoxide is formed in high optical purity. This is possible because the catalyst, titanium tetraiso-propoxide, forms a chiral (possibly dimeric [36]) complex with resolved diethyl tartrate [(+)-DET] which binds the two achiral reagents together in the reactive complex. The two enantiotopic faces of the allylic double bond become diastereotopic in the chiral complex and react at different rates with the tert-butyl hydroperoxide. Many other examples may be found in recent reviews [31, 37-39]. 

The field of organoboron chemistry pioneered by Brown [40] also provides a wealth of excellent transformations. Consider the asymmetric reduction of carbonyl compounds by Alpine-Borane [41]. Alpine-Borane is prepared by the following sequence  

In the second step, achiral 9-borabicyclo[3.3.1]nonane (9-BBN) adds to the less hindered diastereotopic face of a-pinene to yield the chiral reducing agent Alpine-Borane. Aldehydes are rapidly reduced to alcohols. The reaction with deuterio-Alpine-Borane, which yields (R)-a-d-henzy alcohol in 98% enantiomeric excess ( ) reveals a very high degree of selectivity of the enantiotopic faces of the aldehyde group in a crowded transition state  

As a consequence of steric congestion in the transition state, ketones generally require high pressures to increase the reaction rate but yield optically active secondary alcohols in high . Thus, acetophenone yields 100% . of (S -l-phenylethanol at 2000 atm  

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SOME COMMON DEFINITIONS IN ASYMMETRIC SYNTHESIS AND STEREOCHEMISTRY... 

ORGANIC STEREOCHEMISTRY - covers conformation and configurational analysis, asymmetric synthesis, and stereochemistry and steric factors in organic reactions. 

William R. Roush is Warner Lambert/Parke Davis Professor of Chemistry at the University of Michigan. He received his B.S. from the University of California, Los Angeles, in 1974 and his Ph.D. from Harvard University in 1977. His research area is organic chemistry, with specialized interests in organic synthesis and natural products chemistry, stereochemistry of organic reactions, development of new methods and regents, asymmetric synthesis, and oligosaccharide synthesis. 

Aaron, H.S., Uyeda, R.T., Frack, H.F., and Miller, J.I., The stereochemistry of asymmetric phosphorus compounds. IV. The synthesis and stereochemistry of displacement reactions of optically active isopropyl methylphosphonochlo-ridate, /. Am. Chem. Soc., 84, 617, 1962. 

Organosulfur chemistry is presently a particularly dynamic subject area. The stereochemical aspects of this field are surveyed by M. Mikojajczyk and J. Drabowicz. in the fifth chapter, entitled Qural Organosulfur Compounds. The synthesis, resolution, and application of a wide range of chiral sulfur compounds are described as are the determination of absolute configuration and of enantiomeric purity of these substances. A discussion of the dynamic stereochemistry of chiral sulfur compounds including racemization processes follows. Finally, nucleophilic substitution on and reaction of such compounds with electrophiles, their use in asymmetric synthesis, and asymmetric induction in the transfer of chirality from sulfur to other centers is discussed in a chapter that should be of interest to chemists in several disciplines, in particular synthetic and natural product chemistry. 

A full paper describing the synthesis and stereochemistry of the four pinane-2,3-diols, summarizing all the earlier work, has appeared. A reagent for the asymmetric reduction of ketones has been prepared from lithium aluminium hydride and two of these diols, (289a) and (289b). ... 

Relatively few applications of optically active tertiary arsines to asymmetric synthesis have been reported by comparison with the extensive work with phosphines . Authoritative accounts of the synthesis and stereochemistry of compounds of Group V elements are available other reviews cover the subject up until 1979 . For general treatments of organoarsenic chemistry up until 1976, including optically active compounds, two important works are available . Of related interest is an article on stereochemical aspects of phosphorus chemistry and another published in this series on optically active phosphines preparation, uses and chiroptical properties . On matters concerning the intricacies of resolutions work, the reader should consult Reference 21, especially Chapter 7, which is entitled Experimental Aspects and Art of Resolutions. 

The next ten chapters are all to do with stereochemistry. The next chapter and Chapter 30 concern relative stereochemistry and its control. All the other chapters are concerned with asymmetric synthesis and the different strategies that can be employed. The different strategies can be broadly divided into three groups. These are resolution, chiral pool and asymmetric induction. 

This book is intended for advanced undergraduate or graduate students, and other chemists needing a guide to the principles of asymmetric synthesis and stereoselectivity, and for experts who seek leading references to the primary literature. The book could be used for a course in organic mechanisms, stereochemistry, reactions, or synthesis. 

E. Asymmetric Synthesis and Absolute Stereochemistry of Dihydrofuroquinoline and Dihydropyranoquinoline Alkaloids... 

For an overview of the relationship between smell and stereochemistry, see R. Bentley, The Nose as a Stereochemist Enantiomers and Odour, Chem. Rev., 2006, 106, 4099. Interesting examples of the use of asymmetric methods in the large scale synthesis of drug molecules are given in M. Ikunaka, Chem. Eur. J. 2003, 9, 379. The prevalence of chiral drugs and the relative importance of asymmetric synthesis and resolution are discussed in B. Kasprzyk-Hordern, Chem. Soc. Rev., 2010, 39, 4466 and in J. S. Carey, D. Laffan, C. Thomson and M. T. Williams Org. Biomol. Chem. 2006, 2337. 

Grundon MF, Surgenor SA (1978) Asymmetric synthesis and absolute stereochemistry of the alkaloies araliopsine, isoplatydesmine, and ribalinine. Dual mechanism for a dihydrofuro-quinolone-dihydropyranoquinolone rearrangement J Chtan Soc Chem Commun 14 624-626... 

Mori, K. and Umemura, T. (1981) Stereochemistry of aplidiasphingosine as proposed by the asymmetric synthesis and C13 NMR study of sphingosine relatives. Tetrahedron Lett., 22, 4433-4436. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Scheme 5 details the asymmetric synthesis of dimethylhydrazone 14. The synthesis of this fragment commences with an Evans asymmetric aldol condensation between the boron enolate derived from 21 and trans-2-pentenal (20). Syn aldol adduct 29 is obtained in diastereomerically pure form through a process which defines both the relative and absolute stereochemistry of the newly generated stereogenic centers at carbons 29 and 30 (92 % yield). After reductive removal of the chiral auxiliary, selective silylation of the primary alcohol furnishes 30 in 71 % overall yield. The method employed to achieve the reduction of the C-28 carbonyl is interesting and worthy of comment. The reaction between tri-n-butylbor-... 

Throughout each chapter, clear structures, schemes, and figures accompany the text. Mechanism, reactivity, selectivity, and stereochemistry are especially addressed. Special emphasis is also placed on introducing both the logic of total synthesis and the rationale for the invention and use of important synthetic methods. In particular, we amplify the most important developments in asymmetric synthesis, catalysis, cyclization reactions, and organometallic chemistry. 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

Chiral sulphoxides are the most important group of compounds among a vast number of various types of chiral organosulphur compounds. In the first period of the development of sulphur stereochemistry, optically active sulphoxides were mainly used as model compounds in stereochemical studies2 5 6. At present, chiral sulphoxides play an important role in asymmetric synthesis, especially in an asymmetric C—C bond formation257. Therefore, much effort has been devoted to elaboration of convenient methods for their synthesis. Until now, optically active sulphoxides have been obtained in the following ways optical resolution, asymmetric synthesis, kinetic resolution and stereospecific synthesis. These methods are briefly discussed below. 

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