Chemoenzymatic Synthesis of α-Hydroxy-β-methyl-γ-hydroxy Esters: Role of the Keto−Enol Equilibrium To Control the Stereoselective Hydrogenation in a Key Step

• Published in: Journal of organic chemistry 2010-03, Vol.75 (5), p.1410-1418
• Main Authors: Milagre, Cíntia D. F, Milagre, Humberto M. S, Moran, Paulo J. S, Rodrigues, J. Augusto R
• Format: Article
• Language: English
• Subjects: Alkenes - chemical synthesis; Alkenes - chemistry; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Catalysis; Chemistry; Crystallography, X-Ray; Cyclization; Esters; Exact sciences and technology; Fundamental and applied biological sciences. Psychology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Hydrogen-Ion Concentration; Hydrogenation; Magnetic Resonance Spectroscopy; Methods. Procedures. Technologies; Molecular Structure; Noncondensed benzenic compounds; Organic chemistry; Phenylpropionates - chemical synthesis; Phenylpropionates - chemistry; Preparations and properties; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo902227f

α-Hydroxy-β-methyl-γ-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).