Asymmetric synthesis 440 Subject

Optically active drugs now occupy centre stage status and some agrochemicals like (S)-metolachlor, have also been introduced as optically pure isomers, so that the ballast of the unwanted isomer is avoided. Asymmetric synthesis is a topic of great interest in current research, and there is a steady flow of articles, reviews and books on almost every aspect of this subject. Table 4.8 lists examples of industrially important asymmetric synthesis. 

The subject of asymmetric synthesis generally (214, 215) gained new momentum with the potential use of transition metal complexes as catalysts. The use of a complex with chiral ligands to catalyze a synthesis asymmetrically from a prochiral substrate is advantageous in that resolution of a normally obtained racemate product may be avoided, for example,... 

Palladium-catalyzed bis-silylation of methyl vinyl ketone proceeds in a 1,4-fashion, leading to the formation of a silyl enol ether (Equation (47)).121 1,4-Bis-silylation of a wide variety of enones bearing /3-substituents has become possible by the use of unsymmetrical disilanes, such as 1,1-dichloro-l-phenyltrimethyldisilane and 1,1,1-trichloro-trimethyldisilane (Scheme 28).129 The trimethylsilyl enol ethers obtained by the 1,4-bis-silylation are treated with methyllithium, generating lithium enolates, which in turn are reacted with electrophiles. The a-substituted-/3-silyl ketones, thus obtained, are subjected to Tamao oxidation conditions, leading to the formation of /3-hydroxy ketones. This 1,4-bis-silylation reaction has been extended to the asymmetric synthesis of optically active /3-hydroxy ketones (Scheme 29).130 The key to the success of the asymmetric bis-silylation is to use BINAP as the chiral ligand on palladium. Enantiomeric excesses ranging from 74% to 92% have been attained in the 1,4-bis-silylation. 

Double asymmetric synthesis was pioneered by Horeau et al.,87 and the subject was reviewed by Masamune et al.88 in 1985. The idea involves the asymmetric reaction of an enantiomerically pure substrate and an enantiomerically pure reagent. There are also reagent-controlled reactions and substrate-controlled reactions in this category. Double asymmetric reaction is of practical significance in the synthesis of acyclic compounds. 

The general subject of asymmetric synthesis has been reviewed extensively (1-5). The term asymmetric synthesis has been defined in more than one way (1,4) however, a useful definition is the one given by Morrison and Mosher (1) a process which converts a prochiral unit [refs. 6 and 7] into a chiral unit so that unequal amounts of stereoisomeric products result. The stereoisomeric products may be enantiomeric or they may be diastereomeric. The substrate molecule must contain either enantiotopic or diastereotopic groups or faces (8,9), since the attack of a reagent at equivalent groups or faces cannot lead to isomeric products. 

The application of asymmetric synthesis through reaction of chiral enolates with aldehydes is commanding a great deal of current interest, and aspects of this topic have been the subject of a number of recent... 

In the last two decades optically active sulfur compounds have found wide application in asymmetric synthesis. This is mainly because organic sulfur compounds are quite readily available in optically active form. Moreover, the chiral sulfur groupings that induce optical activity can be removed from the molecule easily, under fairly mild conditions, thus presenting an additional advantage in the asymmetric synthesis of chiral compounds. This section deals with reactions in which asymmetric induction in transfer of chirality from sulfur to other centers was observed. This subject has been treated only in a cursory manner in recent reviews on asymmetric synthesis (290-292). 

We hope that this review of chiral sulfur compounds will be useful to chemists interested in various aspects of chemistry and stereochemistry. The facts and problems discussed provide numerous possibilities for the study of additional stereochemical phenomena at sulfur. As a consequence of the extent of recent research on the application of oiganosulfur compounds in synthesis, further developments in the field of sulfur stereochemistry and especially in the area of asymmetric synthesis may be expected. Looking to the future, it may be said that the static and dynamic stereochemistry of tetra- and pentacoordinate trigonal-bipyramidal sulfur compounds will be and should be the subject of further studies. Similarly, more investigations will be needed to clarify the complex nature of nucleophilic substitution at tri- and tetracoordinate sulfur. Finally, we note that this chapter was intended to be illustrative, not exhaustive therefore, we apologize to the authors whose important work could not be included. 

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. 

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

Tor a treatise on this subject, sec Morrison Asymmetric Synthesis, 5 vols. [vol. 4 co-cditcd by Scott] Academic Press New York, 1983-1985. For books, see N6gr4di Stereoselective Synthesis VCH New York, 1986 Eliel Olsuka Asymmetric Reactions and Processes in Chemistry American Chemical Society Washington, 1982 Morrison Mosher Asymmetric Organic Reactions Prentice-Hall Englewood Cliffs, NJ, 1971, paperback reprint, American Chemical Society Washington, 1976 Izumi Tai, Ref. I. For reviews, see Ward Chem. Soc. Rev. 1990, 19, 1-19 Whitesell Chem. Rev. 1989, 89, 1581-1590 Fujita Nagao Adv. Heterocycl. Chem. 1989, 45, 1-36 Kochetkov Belikov Russ. Chem. Rev. 1987, 56, 1045-1067 Oppolzer Tetrahedron 1987, 43, 1969-2004 Seebach Imwinkelried Weber Mod. Synth. Methods 1986, 4, 125-259 ApSimon Collier Tetrahedron 1986, 42, 5157-5254 Mukaiyama Asami Top. Curr. Chem. 1985, 127, 133-167 Martens Top. Curr. Chem. 1984, 125, 165-246 Duhamel Duhamel Launay Plaqucvcnt Bull. Soc.Chim. Fr. 1984,11-421-11-430 Mosher Morrison Science 1983,221, 1013-1019 Schollkopf Top. Curr. Chem. 

This book deals with the basic principles of asymmetric catalysis and places particular emphasis on its synthetic significance. The mechanisms of most of the chemical reactions that I will discuss are obscure and are therefore treated only briefly. My talks at Cornell relied heavily on chemistry developed in our laboratories at Nagoya University, and the materials in Chapters 2, 3, 5, and 6 are highly subjective. Because asymmetric synthesis with molecular catalysts is a very attractive and rich subject, many academic and industrial laboratories all over the world have contributed to its development. In an attempt to balance my coverage of the entire field, I have tried to include most of the major achievements recorded by the fall of 1992 within Chapter 4. 

There is no doubt that catalytic asymmetric synthesis has a significant advantage over the traditional diastereomeric resolution technology. However, it is important to note that for the asymmetric hydrogenation technology to be commercially useful, a low-cost route to the precursor olefins is just as crucial. The electrocarboxylation of methyl aryl ketone and the dehydration of the substituted lactic acids in Figures 5 and 6 are highly efficient. Excellent yields of the desired products can be achieved in each reaction. These processes are currently under active development. However, since the subjects of electrochemistry and catalytic dehydration are beyond the scope of this article, these reactions will be published later in a separate paper. 

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