Chemoenzymatic synthesis of alpha-hydroxy-beta-methyl-gamma-hydroxy esters: role of the keto-enol equilibrium to control the stereoselective hydrogenation in a key step.

Abstract

Alpha-hydroxy-beta-methyl-gamma-hydroxy esters not only are found in many natural products and potent drugs but also are useful intermediates in organic synthesis due to their highly functionalized skeleton that can be further manipulated and applied in the synthesis of many compounds with remarkable biological activities. This work was based on a chemoenzymatic approach to obtain these molecules with three contiguous stereogenic centers in a highly enantio- and diastereoselective way. Two distinct linear routes were proposed in which the key steps in both routes consisted of initial stereocontrolled ketoester bioreduction followed by unsaturated carbonyl bioreduction or reduction with Pd-C. Other key reactions in the synthesis include a Wasserman protocol for chain homologation and a Mannich-type olefination with maintenance of enantiomeric excess for all intermediates during the sequence. Whereas route A gave exclusively the skeleton with 3R,4R,5S configuration (99% ee and 11.5% global yield after 7 steps), route B gave the skeleton with 3R,4R,5S and 3R,4S,5R configurations (dr 1:12, 98% ee and 20% global yield after 5 steps).

DOI: 10.1021/jo902227f

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Cite this paper

@article{Milagre2010ChemoenzymaticSO, title={Chemoenzymatic synthesis of alpha-hydroxy-beta-methyl-gamma-hydroxy esters: role of the keto-enol equilibrium to control the stereoselective hydrogenation in a key step.}, author={Cintia D F Milagre and Humberto M. S. Milagre and Paulo Jos{\'e} Samenho Moran and Jos{\'e} Augusto Ros{\'a}rio Rodrigues}, journal={The Journal of organic chemistry}, year={2010}, volume={75 5}, pages={1410-8} }