Asymmetric catalytic racemization

Similar arguments apply to the asymmetric catalytic racemization of amygdalin, recorded by Smith (133). Amygdalin is the gentiobioside of (-l-)-mandelonitrile. The extreme optical lability of the latter is reflected in the great precautions which have to be taken to avoid its racemization, for the pure crystalline (-b) nitrile is readily racemized by the presence of even a trace of water, probably by a mechanism of the type suggested by Fischer and Bergmann (40) ... 

Optically active trialkylphosphines are known to be configurationally stable toward racemization, and ligands of type 3 have been synthesized and applied in the asymmetric catalytic hydrogenation of amidoacrylic acids (Scheme 6 5). 

This article provides a brief overview of several recent total syntheses of natural and unnatural products that have benefited from the use of catalytic asymmetric processes. The article is divided by the type of bond formation that the catalytic enan-tioselective reaction accomplishes (e.g C-C or C-0 bond formation). Emphasis is made on instances where a catalytic asymmetric reaction is utilized at a critical step (or steps) within a total synthesis however, cases where catalytic enantioselective transformations are used to prepare the requisite chiral non-racemic starting materials are also discussed. At the close of the article, two recent total syntheses are examined, where asymmetric catalytic reactions along with a number of other catalyzed processes are the significant driving force behind the successful completion of these efforts (Catalysis-Based Total Syntheses). 

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. 

As shown in Table 14, starting with the enantioface of an achiral olefin hydro-formylated with an asymmetric catalytic system, a correct prediction of the antipode of a racemic substrate mainly hydroformylated with the same catalytic system has been made in the few cases examined up to now. 

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... 

Asymmetric hydrolysis has several specific advantages to offer. First of all it uses water as one of the reagents. Water is cheap, safe, and environmentally benign Second, chiral 1,2 diols are versatile building blocks for complex organic molecules. Finally, asymmetric catalytic epoxidation does not work for alkenes such as propylene. However, by this method a racemic mixture of... 

The aldol reaction of a silyl enol ether proceeds in a double and two-directional fashion, upon addition of an excess amount of an aldehyde, to give the silyl enol ether in 77 % isolated yield and more than 99 % ee and 99 % de (Sch. 33) [92]. This asymmetric catalytic aldol reaction is characterized by kinetic amplification of product chirality on going from the one-directional aldol intermediate to the two-directional product. Further transformation of the pseudo C2 symmetric product still protected as the silyl enol ether leads to a potent analog of an HIV protease inhibitor. Kinetic resolution of racemic silyl enol ethers by the BINOL-Ti catalyst (1) has been reported by French chemists [93]. 

Asymmetric catalysis encompasses the use of both biocatalysts (e.g., enzymes) and chemical catalysts that possess an element of chirality (e.g., a transition metal complex bearing a chiral ligand). From a commercial perspective, the interest in asymmetric catalysis emanates from inherent economic and ecological benefits that are associated with the capacity to produce a large volume of valuable enantiomerically enriched material through the agency of a negligible quantity of a chiral catalyst. Asymmetric catalytic processes may involve kinetic resolution of a racemic substrate, or preferably, direct transformation of a prochiral substrate into the desired chiral molecule. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

Concerning future work, an improvement might be the extension of the asymmetric catalytic nitroaldol reaction to the field of solid-support synthesis. An interesting contribution concerning the use of dendritic catalysts in the Henry reaction was reported very recently by Cossio et al. [48], who demonstrated that dendrimers based on achiral triethanolamine exhibit catalytic properties. Several nitroalkanols were synthesized with syn/anti ratio up to 2 1 (racemic syn- and anti-products). The design of enantiomerically pure dendrimers and their application to the field of asymmetric catalytic nitroaldol reaction should be of high interest. 

In 2005 the use of trans-12 in the intramolecular asymmetric catalytic aldol cyclodehydration of /neso-3,4-disubstituted-l,6-dialdehydes was reported. While (5 )-proline 1 was a very efficient catalyst for this transformation, it afforded the desired product as a racemic mixture. On the contrary both hydro y-prolines trans-4 and trans-12 exerted a certain degree of stereocontrol, with trans-12 being less stereoselective but more active than trans-4 (Scheme 11.10). 

Asymmetric BV oxidations can also be used in PKR, where the two different enantiomers of a racemic cyclic ketone lead selectively to the two regioisomeric lactones. For example, in 2004, the BV oxidation of racemic bicyclobutanones was successfully realized by the Katsuld group using Zr(salen) complex 116. In this study, the authors demonstrated that Zr(salen) complex 116 exhibits asymmetric catalytic activity in the BV oxidation of racemic bicyclo[3.2.0]alkan-5-ones 113, in which one enantiomer of 113 led to the normal lactone (NL) 114 and the other enantiomer led to the abnormal lactone (AL) 115, both with excellent ee values fScheme 2.2R1. 

Allyl acetates 1/ent-l that possess identical R groups undergo aUyUc substitution via an achiral intermediate 2. Both enantiomers of starting material proceed via the same intermediate. In the absence of any controlling influence, approach of the nucleophile via pathways a and b is equally likely, and a racemic product 3/ent-3 will be formed (Scheme 1). However, the opportunity for an asymmetric catalytic reaction exists if the reaction can be channeled through one pathway selectively. Overall, the process represents a dynamic resolution, since a racemic starting material is converted into an enan-tiomericaUy emiched product. 

It is therefore possible to design asymmetric catalytic reactions that proceed through such rapidly racemizing complexes. However, for most palladiumdigand combinations, reaction of the acetate 108 affords mainly the linear products 110 and 112. But, some Ug-ands can afford a catalytic system that is selective for the branched isomers 109 and 111 as shown in Scheme... 

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