Asymmetric synthesis with chiral auxiliaries

Based on the letrosynthetic analysis presented above, the first critical task on the way to testing the olefin metathesis-based strategy for the total synthesis of epothilone A (1) was the construction of the three key building blocks 61, 63, and 64. Focusing our attention first on the preparation of aldehyde 64, the Nicolaou group developed several approaches to this building block based on asymmetric synthesis with chiral auxiliaries one of these solutions is detailed in Scheme 19. 

Asymmetric synthesis with chiral cyclic phosphorus auxiliaries has been the subject of a review. ... 

Evans, D. A., Shaw, J. T. Recent advances in asymmetric synthesis with chiral imide auxiliaries. Acfr/aZ/fe Chimique 2002, 35-38. 

Evans has pioneered the use of carboximide-derived enolates in diastereo-selective enolate alkylation reactions [15, 82]. As discussed in subsequent chapters, N-acyl oxazolidinones (such as 114, 115, and 116) enjoy a unique position in asymmetric synthesis as chiral auxiliaries with wide applications in numerous mechanistically unrelated asymmetric transformations, among them aldol (Chapter 4), Diels-Alder (Chapter 17), enolate amination (Chapter 10), and conjugate addition (Chapter 12) reactions. Oxazolidinones 114 and 115 generally lead to Ca-substituted carboximide products in one dia-stereomeric series (cf 119, dr>99 1), while the complementary diastereo-meric adducts such as 122 dr =98 2) can be accessed through the use of oxazolidinone 116 (Scheme 3.18) [82]. 

Comparison of the Solid-State Ionic Chiral Auxiliary Method of Asymmetric Synthesis with the Pasteur Resolution Procedure... 

Fig. 4 Comparison of the solid-state ionic chiral auxiliary method of asymmetric synthesis with the Pasteur resolution procedure...

The enantiomeric synthesis of rranj-3,4-disubstituted tetrahydrothiophenes using a sulfur ylide cycloaddition has been reported <990L1667>. The sulfur ylide derived from the action of cesium fluoride on sulfide 111 underwent an asymmetric cycloaddition with chiral a,p-unsaturated camphorsultam amide 112 giving tetrahydrothiophene 113 (80% de). The configuration was confirmed by cleavage of the chiral auxiliary followed by reductive desulfurization with Raney-Ni which gave known carboxylic acid 114. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Such TT- TT interactions, which occur at approximately 3.5 A over an aromatic ring [98], are beneficial in selective synthesis. Specifically,asymmetric induction achieved with chiral auxiliaries and chiral catalysts can be enhanced by n-stacking effects [981. These are optimized under solvent-free conditions as there are no interactions able to interfere in such a system when compared to the solvent procedure. 

A number of highly enantioselective chiral allyl organometallic reagents have been described in the literature. These are of considerable interest both for the asymmetric synthesis of homoallyl alcohols as well as in double asymmetric reactions with chiral C=X electrophiles. - Two distinct groups of chiral allyl metal reagents can be identified those with conventional, easily introduced chiral auxiliaries and ones in which the center of chirality is a structural component of the reagent (e.g. allyl metal compounds with substituents at C-1). These are discussed separately in the sections that follow. 

Absolute asymmetric synthesis, a rapidly developing field, is a simple approach to the synthesis of enantiomerically pure compounds and has low environmental impact however, enantiomorphic crystals (with a chiral space group) are required, which are not necessarily formed by all compounds with prochiral centers. [2] Enantioselective syntheses with chiral auxiliaries and without biology have been fine-tuned most impressively and have a longer tradition, [3] but are still usually very costly and time-consuming. Several approaches to chemical synthesis may be outlined the synthesis is conducted in chiral media (recently inclusion compounds have been shown to be efficient [4]) or with... 

One of the reasons this reaction is so useful is that the products happen to be derivatives of the less readily available (J )-proline. But, as with chiral auxiliaries, if you use a chiral reagent you need a full equivalent of the source of enantiomeric purity (here, (-)-sparteine) which can get prohibitively expensive on a large scale. It is for this reason that the real pinnacles of achievement in asymmetric synthesis make use of asymmetric catalysis, which we turn to next. 

The first diastereoselective asymmetric synthesis with ee > 98% seems to be the asymmetric synthesis of aspartic acid of Korean et al in 1968. The chiral auxiliary was a chiral P>aminoalcohoL... 

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