Abstract
AbstractA search for the large‐scale preparation of (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoates (2) – a key intermediate in the synthesis of pharmacologially important statins – starting from (S)‐malic acid is described. The synthesis of the required initial compound methyl (3S)‐3,4‐(isopropylidenedioxy)butanoate (1) by Moriwake’s reduction of dimethyl (S)‐malate (3) has been improved. Direct 2‐C chain elongation of ester 1 using the lithium enolate of tert‐butyl acetate has been shown to be successful at a 3‐ to 5‐fold excess of the enolate. Unfortunately, the product, tert‐butyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate (2a) is unstable during distillation. Ethyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate (2b) was prepared alternatively on a multigram scale from (3S)‐3,4‐(isopropylidenedioxy)butanoic acid (7) by activation with N,N′‐carbonyldiimidazole and subsequent reaction with Mg(OOCCH2COOEt)2. A convenient pathway for the in situ preparation of the latter is also described. Ethyl ester (2b) can be advantageously purified by distillation. The stereochemistry of the catalytic hydrogenation of β‐keto ester (2b) to ethyl (5S)‐5,6‐(isopropylidenedioxy)‐3‐hydrohyhexanoate (syn‐6 and anti‐6) has been studied using a number of homogeneous achiral and chiral Rh(I) and Ru(II) complexes with phosphine ligands. A comparison of Rh(I) and Ru(II) catalysts with (S)‐ and (R)‐BINAP as chiral ligands revealed opposite activity in dependence on the polarity of the solvent. No influence of the chiral backbone of substrate 2b on the enantioselectivity was noted. A ratio of syn‐6/anti‐6=2.3 was observed with an achiral (Ph3P)3RuCl2 catalyst. Ru[(R)‐Tol‐BINAP]Cl2 neutralized with one equivalent of AcONa afforded the most efficient catalytic system for the production of optically pure syn‐(5S)‐5,6‐isopropylidenedioxy‐3‐hydroxyhexanoate (syn‐6) at a preparative substrate/catalyst ratio of 1000:1.
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