Acyl asymmetric desymmetrization

The preparation of stereochemically enriched compounds by asymmetric acyl transfer in a stoichiometric sense can be divided into two broad classes [1] (1) those in which a racemic or achiral /weso nucleophile reacts diastereoselectively with an enantiomerically highly enriched acyl donor (Type I, see below) and (2) those in which an enantiomerically highly enriched nucleophile reacts diastereoselectively with a racemic or achiral/meso acyl donor (Type II, see below). When a racemic component is involved, the process constitutes a kinetic resolution (KR) and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoeselectivity - is 50%. When an achiral/meso component is involved, the process can constitute a site-selective asymmetric desymmetrization (ASD) or, in the case of 7r-nucleophiles and reactions involving ketenes, a face-selective addition process and the maximum theoretical yield of diastereomerically pure product - given perfect diastereoselectivity - is 100% (Scheme 8.1). 

Scheme 8.1 Classification of stoichiometric asymmetric acyl transfer processes. ASD = asymmetric desymmetrization.

Other reactions not described here are formal [3 -i- 2] cycloadditions of a,p-unsaturated acyl-fluorides with allylsilanes [116], or the desymmetrization of meso epoxides [117]. For many of the reactions shown above, the planar chiral Fe-sandwich complexes are the first catalysts allowing for broad substrate scope in combination with high enantioselectivities and yields. Clearly, these milestones in asymmetric Lewis-base catalysis are stimulating the still ongoing design of improved catalysts. 

A few interesting variants of the Pd-catalyzed acylation of organozincs have been developed. In one such variant, thiol esters are employed in place of acyl chlorides214. Another is the Ni-catalyzed reaction of organozincs with cyclic anhydrides215 shown in Scheme 82. this desymmetrization reaction can be made highly enantioselective, it would become a significant tool for asymmetric synthesis. 

Most of the inherently chiral calix[5]arenes described up to now, owe their chirality, however, to the asymmetric substitution pattern at the narrow rim, and due to the lack of other general, selective derivatization reactions are derived from 1,2-or 1,3-crown ethers. Both compounds possess a symmetry plane and can be desymmetrized by a single O-alkyl or O-acyl residue in position 3 (=5) or 4 (=5).151,152,153 In practice, 1,2-crown ethers 79 were prepared from mono-O-alkyl derivatives by reaction with the appropriate ditosylates, while 80 was obtained from the 1,3-crown-ether by subsequent O-alkylation or O-acylation using a weak base to benefit from the fact, that the first deprotonation leads to a hydrogen-bonded (4/5)monoanion. The picolyl derivatives 79 (n = 2) were resolved by HPLC... 

Asymmetric Acylation of me o-Diols. Both cyclic and acyclic me o-1,2-diols are desymmetrized by acylation in the presence of a stoichiometric amount of this ligand with modest-to-excellent enantioselectivity (eq 4). In a special case, cis-5,5-dimethyl-2-cyclopentene-l,4-dior was monobenzoylated in the presence of a catalytic amount of this ligand in good yield and with perfect enantioselection (87%, >99.5% ee). 

Desymmetrization of AT-Boc-protected serinol has been achieved in good yield and high enantiomeric excess (ee > 99%) by acylation with PPL in vinyl acetate (Fig. 19) (26). The product has been exploited as an intermediate in different ways to prepare (4R)- and (4S)-substituted oxazolidinones known as Evans auxiliaries. These compounds have important tasks as asymmetric inductors for synthesis. 

On the basis of their previous work utilizing oligopeptides containing alkylimidazoles in asymmetric acylation reactions. Miller has reported the successful desymmetrization of bisphenol 171. Treatment of diol 171 with peptide 172 (5 mol%) and acetic anhydride gave ester 173 in 80% yield and 95% ee. This unprecedented desymmetrization represents a particularly challenging and impressive case as the desired site of functionalization is >5.7 A from the prochiral stereogenic center of the substrate (Scheme 29). ... 

Asymmetric synthesis of unnatural j8-amino acids derivatives based on azide chemistry is known. Enantioselective desymmetrization of mera-anhydride 293 mediated by cinchona alkaloids gives optically active monomethylester 294. This compound was converted into the acyl azide, which underwent Curtius degradation followed by alcoholysis of the intermediate isocyanate affording 8-amino acid derivative 295 in high enantiomeric excess. The authors observed that Grubbs catalyst was able to polymerize norbomene-type monomer 295 affording the corresponding polymer 296 in quantitative yield (Scheme 3.45). 

Hydrolases and mainly lipases have appeared as valuable biocatalysts for the development of asymmetric transformations. Several strategies have been carried out involving the classical KR and DKR of racemic alcohols and the desymmetrization of meso- and prochiral diols. Taking into account the reversibility of this type of process in complementary hydrolysis pathway and adequate conditions must be established to favor synthetic acylation reactions. 

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