Statine diastereoselective synthesis

In 2005, Kambourakis et al. reported the biocatalytic reduction of a-alkyl-1,3-diketones and a-alkyl-/l-ketoesters by employing isolated NADPH-dependent ketoreductases (KREDs). The corresponding optically pure single keto alcohols and hydroxy esters were obtained in quantitative yields (Scheme 3.9). The same group had previously reported the total synthesis of a new class of triterpene derivatives with anti-HIV activity, statin and statin analogues, based on a diastereoselective reduction of a 2-alkyl-substituted 3-ketoglutarate by a KRED. The results are summarised in Scheme 3.9. 

An early and typical synthesis shows the conversion of N-Boc-L-leucine methyl ester 6.98) to aldehyde 6.99. This aldehyde was condensed with the lithium enolate of ethyl acetate to give 6.100. Alcohol 6.100 was produced as a mixture of diastereomers and one of the important challenges of this strategy is to control the diastereoselectivity of the condensation. In this example, the 3S,4S diastereomer of 6.100 was separated and isolated (in 40% yield based on 6.99) and acid hydrolysis gave N-Boc statine 6.101)P ... 

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