Practical asymmetric catalytic reactions

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. 

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. 

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... 

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. 

Yet, as noted in the introduction, the number of truly useful enantioselective catalysts is still limited, and there are only a handful of systems that have been used in a commercial context. With notable exceptions, even the number of asymmetric catalytic reactions that have seen appHcation in academic target-oriented synthesis research is relatively small. There is no doubt that a major emphasis in future research will be placed on rendering known reactions more practical. 

The nitroaldol reaction or Henry reaction is a powerful and highly versatile carbon-carbon bond-forming reaction, allowing a plethora of key molecular frameworks, such as p-hydroxynitroalkanes, 1,2-amino alcohols or a-hydroxy carboxylic acids to be synthesised in a straightforward manner. Therefore, the development of practical catalytic asymmetric versions of this reaction is still largely desirable. The first catalytic asymmetric nitroaldol reaction was reported in 1992, " but despite its long history, relatively few chiral ligands have... 

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). 

One active field of research involving the Heck reaction is asymmetric Heck reactions (AHR). The objective is to achieve enantiomerically-enriched Heck products from racemic substrates using a catalytic amount of chiral ligands, making the process more practical and economical Although intermolecular Heck reactions that occurred onto carbocyclic arenes are rare, they readily take place onto many heterocycles including thiophenes, furans, thiazoles, oxazoles,... 

B. HIGHLY PRACTICAL CATALYTIC ASYMMETRIC MICHAEL REACTION... 

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]. 

However, the development of cyclopropane synthesis through zirconocene chemistry is still in its infancy. The reactions presented in this chapter have only recently been reported for the most part, and not systematically studied. Further investigations appear to be desirable. Practical procedures involving optimized reaction conditions and simpler reagents would be welcomed. Advances should focus on the development of catalytic and asymmetric cyclopropanation reactions. 

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. 

---