Institute of Chemistry, University of Campinas-UNICAMP, PO Box 6154, 13084-970 Campinas, SP, Brazil.
J Org Chem. 2010 Mar 5;75(5):1410-8. doi: 10.1021/jo902227f.
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).
α-羟基-β-甲基-γ-羟基酯不仅存在于许多天然产物和有效药物中，而且由于其高度官能化的骨架，在有机合成中也是有用的中间体，可以进一步进行操作，并应用于许多具有显著生物活性的化合物的合成中。这项工作基于一种化学酶促方法，以高度对映选择性和非对映选择性的方式获得具有三个连续立体中心的这些分子。提出了两种不同的线性路线，其中两条路线的关键步骤都包括初始立体控制酮酯生物还原，然后是不饱和羰基生物还原或用 Pd-C 还原。合成中的其他关键反应包括 Wasserman 链同系化方案和 Mannich 型烯烃化反应，在整个序列中所有中间体都保持对映体过量。虽然路线 A 仅给出具有 3R、4R、5S 构型的骨架（99%ee 和 7 步后 11.5%的总收率），但路线 B 给出具有 3R、4R、5S 和 3R、4S、5R 构型的骨架（dr 1:12，98%ee 和 5 步后 20%的总收率）。
