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 su bjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selec tive lipase, resulting predominantly in the hydrolysis of the (R)-isomer (a t 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydr olysis of the minor enantiomeric (S)-acetate to approximately 20% conversio n 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, re sulting in higher yields in comparison with the standard resolution of race mic materials. (C) 2001 Elsevier Science Ltd. All rights reserved.