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Synthesis and Highly Stereoselective Hydrogenation of the Statin Precursor Ethyl (5 S )‐5,6‐Isopropylidenedioxy‐3‐oxohexanoate
Author(s) -
Tararov Vitali I.,
König Gerd,
Börner Armin
Publication year - 2006
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.200600291
Subject(s) - chemistry , catalysis , stereoselectivity , asymmetric hydrogenation , medicinal chemistry , stereochemistry , organic chemistry , enantioselective synthesis
A search for the large‐scale preparation of (5 S )‐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 (3 S )‐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 (5 S )‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate ( 2a ) is unstable during distillation. Ethyl (5 S )‐5,6‐(isopropylidenedioxy)‐3‐oxohexanoate ( 2b ) was prepared alternatively on a multigram scale from (3 S )‐3,4‐(isopropylidenedioxy)butanoic acid ( 7 ) by activation with N,N′ ‐carbonyldiimidazole and subsequent reaction with Mg(OOCCH 2 COOEt) 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 (5 S )‐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 (Ph 3 P) 3 RuCl 2 catalyst. Ru[( R )‐Tol‐BINAP]Cl 2 neutralized with one equivalent of AcONa afforded the most efficient catalytic system for the production of optically pure syn ‐(5 S )‐5,6‐isopropylidenedioxy‐3‐hydroxyhexanoate ( syn ‐ 6 ) at a preparative substrate/catalyst ratio of 1000:1.