The synthesis of 1-hydroxy phosphonates of high enantiomeric excess using sequential asymmetric reactions: titanium alkoxide-catalyzed P-C bond formation and kinetic resolution

Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to good enantiomeric excess (e.e.s similar to 70%). The hydroxy phosphonates were acetylated and the acetates were subjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the enriched (R)-configured acetate with improved e.e. (> 90%). The moderate enantio selectivities obtained in the catalytic P-C bond formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials. (C) 2001 Elsevier Science Ltd. All rights reserved.