Evans’ oxazolidinones Asymmetric alkylation with

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

A recently new designed Wang resin supported Evans chiral auxiliary (52) has been shown to perform Evans asymmetric alkylation on solid support (Scheme 12.19) [34, 35], Preparation of the auxiliary started with coupling of Fmoc-piperidine-4-carboxylic acid to Wang resin. Subsequent removal of the Fmoc protection was followed by coupling to N-protected (2J ,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid. After deprotection, the amino-alcohol moiety was converted into the oxazolidinone auxiliary 52 using carbonyldiimidazole (CDI). 

Atrasentan (58, Scheme 2.9), a potent and selective endothelin receptor antagonist developed by Abbott Laboratories (Abbott Park, IL), contains a substituted pyrroh-dine core that was initially accessed in optically pure form via a late-stage classic resolution." A more recent synthesis of atrasentan employs an Evans oxazolidinone in an asymmetric alkylation reaction to introduce the C3 stereocenter on the pyrrolidine ring. To this end, the mixed anhydride 53 was coupled with the L-valine-derived oxazolidinone 54... 

The first report of the use of N-acyl oxazolidinones in asymmetric alkylation was by Evans et al. in 1982. The reactions described were found to proceed with high levels of diastereoselectivity and with very good yields (Table 7.2). The primary factor in determining the stereochemical course of the reaction is the geometry of the enolate intermediate. Studies have shown the level of /Z-enolate control transfers directly to the level of diastereoselectivity of the alkylated product. Conveniently, it has also been established that the use of bulky bases (e.g., EDA and NaHMDS) for the deprotonation of A-acyl oxazolidinones strongly favors formation of the Z-(0)-enolate. Another factor influencing the stereochemical course of the reaction is the nature of the auxiliary itself. In particular, the ability of the... 

Excellent levels of asymmetric induction in various carbon-carbon bond-forming reactions, such as alkylation, conjugate addition and aldol reactions, are possible using a suitable chiral enolate and an achiral electrophile under appropriate reaction conditions. A variety of chiral enolates have been investigated, the most common and useful synthetically being those with a chiral auxiliary attached to the carbonyl group. The 2-oxazolidinone group, introduced by Evans, has proved to be an efficient and popular chiral auxiUary. Both enantiomers of the product are... 

The utility of the Al-acyl oxazolidinone alkylation has been demonstrated in the context of numerous total syntheses. For instance, in 2003, Evans and Connell used this method in the asymmetric total synthesis of the antifungal macrolide (-l-)-roxaticin 221. (+)-Roxaticin 221 is a pen-taene macrolide isolated from an unidentihed streptomycete similar to Strepfomyces ruber. Like similar compounds, it shows antifungal but not antibacterial activity. In the alkylation step (Scheme 7.32), 202 was treated with TiCLj and EtsN to provide the required Z-(0)-enolate, which was then treated with BOMCl to afford 209 in 99% yield and >200 1 diastereoselectivity. Removal of the auxiliary was... 

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]. 

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