Practical asymmetric catalytic

The use of epoxides has expanded dramatically with the advent of practical asymmetric catalytic methods for their synthesis. Besides the enantioselective epoxida-tion of prochiral olefins, approaches for the use of epoxides in the synthesis of enantiomerically enriched compounds include the resolution of racemic epoxides. 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

The first catalytic 1,4-addition of diethylzinc to 2-cyclopentenone with over 90% ee was described by Pfaltz and Escher, who used phosphite 54 with biaryl groups at the 3,3 -positions of the BINOL backbone.46 Chan and co-workers achieved high enantioselectivity in the same reaction (up to 94% ee) by using chiral copper diphosphite catalyst (R,R,R)-41 48,48a 48d Hoveyda and co-workers used ligand 46 to realize excellent enantiocontrol (97% ee) in the 1,4-additions of 2-cyclopentenones,52 which may be used in the practical asymmetric synthesis of some substituted cyclopentanes (including prostaglandins). 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

We have been gratified to see that the Comprehensive Asymmetric Catalysis three volume set has been received with enthusiasm by the chemical community since its publication in 1999. As was easily anticipated, advances in asymmetric catalysis have continued at an explosive pace since then. Recognition of the impact of this field on chemistry has been evidenced both in practical terms by the application of asymmetric catalytic methods in a variety of new laboratory and industrial contexts, and quite visibly through the lofty recognition of to three of the pioneers of the field in the 2001 Nobel Prize. 

To summarise, the development of novel enantioselective fluorination methods with the aid of either chiral N-fluoro ammonium salts or transition metal catalysts has established truely practical routes towards chiral fluorinated compounds. Despite the current mechanistic uncertaincies it appears that a door has been opened for exciting and promising further development of asymmetric (catalytic) fluorination reactions in the near future [31, 32]. 

Until recently, syntheses of enantiopure r/v-aminoindanols relied either on starting materials from the chiral pool or on chemical or enzymatic resolution of racemic intermediates.7 36 1 Advances in catalytic asymmetric epoxidation (AE) and asymmetric dihydroxylation (AD) of prochiral olefins42-48 enabled the development of truly practical asymmetric syntheses of cis-1 -amino-2-indanols (see Chapter 9).49-54... 

A recent discovery that has significantly extended the scope of asymmetric catalytic reactions for practical applications is the metal-complex-catalyzed hydrolysis of a racemic mixture of epoxides. The basic principle behind this is kinetic resolution. In practice this means that under a given set of conditions the two enantiomers of the racemic mixture undergo hydrolysis at different rates. The different rates of reactions are presumably caused by the diastereo-meric interaction between the chiral metal catalyst and the two enantiomers of the epoxide. Diastereomeric intermediates and/or transition states that differ in the energies of activation are presumably generated. The result is the formation of the product, a diol, with high enantioselectivity. One of the enantiomers of... 

The continuing development of efficient and practical asymmetric processes will be one of the major driving forces in the future of drug discovery and development. In particular, the design of new general and practical catalytic processes will help explore the link between chirality and biological activity. 

The most interesting and practical asymmetric induction process that involves enamines is the proline-catalyzed conversion of the prochiral triketone in Scheme 15 to the cyclic aldol condensation product" or to the aldol product. The course of the reaction is determined by the presence (or absence) of a strong acid such as hydrochloric acid as a cocatalyst. As a result of both the practical significance of the product(s) as synthetic intermediate(s) and the catalytic nature of this process, there has been a high level of interest directed at establishing the mechanistic pathway for these reactions. 

Because most olefins are prochiral starting materials, the dihydroxylation reaction creates one or two new stereogenic centers in the products. Since the discovery of the first stoichiometric asymmetric dihydroxylations [7], catalytic versions with considerable improvements in both scope and enantioselectivity have been developed [8]. From the standpoint of general applicability, scope, and limitations, the osmium-catalyzed asymmetric dihydroxylation (AD) of alkenes has reached a level of effectiveness which is unique among asymmetric catalytic methods. As there are recent reviews in this field [9], this section is primarily oriented toward a summary of aspects of fundamental understanding and interesting practical application of catalytic dihydroxylations. 

Asymmetric catalysis is heralded for the potential advantages it can bestow in the production of chiral molecules. Ultimately, however, asymmetric catalysis is vindicated only through practical application. Commercialization of asymmetric catalytic processes relies on economical large-scale production of the requisite chiral ligands and/or catalysts. To realize the capabilities inherent in the DuPHOS/BPE technology, it was vital that we develop a practicable procedure for manufacture of these ligands. 

This innovation has the verisimilitude of great practical worth. To date, attainment of high enantioselectivities in the hydrogenation of a-arylenamides is singularly associated with the Me-DuPHOS-Rh and Me-BPE-Rh catalysts. However, there remained a major obstacle to the establishment of a commercially practicable process for the production of a-1 -arylalkylamines—no viable synthesis of a-arylenamides existed. In asymmetric catalysis, the actual catalytic step is only one aspect of the entire process. A muted yet crucial facet of industrial asymmetric catalysis deals with substrate synthesis. The great emphasis placed on the catalytic step often obscures the need for economical production of the substrate. Many potential asymmetric catalytic reactions have been rendered impractical because of inaccessibility of the requisite substrates. 

In 1995, Bolm and Bienewald introduced a new, very practical method for the asymmetric catalytic oxidation of sulfides [44]. In the presence of vanadium complex prepared in situ from VO(acac)2 and 23 reactions of various sulfides or dithianes fike 24 with aqueous hydrogen peroxide afforded the corresponding sulfoxides with enantiomeric excesses of up to 85% (Eq. 2). Only traces of the corresponding sulfones were observed. The transformation can easily be carried out in open vessels at room temperature using inexpensive H2O2 as oxidant. 

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