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有机化学
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有机化学 ›› 2008, Vol. 28 ›› Issue (06): 1102-1106. 上一篇    下一篇

研究简报

化学酶法合成(4R,6S)-6-羟甲基-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯

孙丰来，吴坚平，徐刚，杨立荣*   

  1. (浙江大学材料与化工学院 杭州 310027)
  • 收稿日期:2007-07-18 修回日期:2007-11-09 发布日期:2008-06-26
  • 通讯作者: 杨立荣

Chemoenzymatic Synthesis of (4R,6S)-4-t-Butoxycarbonylmethyl-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane

SUN Feng-Lai, WU Jian-Ping, XU Gang, YANG Li-Rong*

  

  1. (Institute of Bioengineering, College of Material Science and Chemical Engineering, Zhejiang Univer-sity, Hangzhou 310027)
  • Received:2007-07-18 Revised:2007-11-09 Published:2008-06-26
  • Contact: YANG Li-Rong

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设计了一种新的方法用于(4R,6S)-6-羟甲基-2,2-二甲基-1,3-二氧六环-4-乙酸叔丁酯(9)的合成. 以廉价、易得的消旋环氧氯丙烷为起始原料, 经过缩合和环氧开环得到消旋的4-(4-甲基苯甲氧基)-3-羟基丁腈(3). 在乙腈/正己烷(V∶V＝1∶4)的混合溶剂中, 脂肪酶Artgribacter sp.催化转酯化拆分消旋3得到(S)-4-(4-甲基苯甲氧基)-3-羟基丁腈(4), ee值98%, 收率47.0%. 再经过羟基保护, 与溴乙酸叔丁酯缩合得到(S)-6-(4-甲基苯甲氧基)-5-羟基-3-氧代已酸叔丁酯(6). 三乙基硼手性诱导还原6得到(3R,5S)-6-对甲基苄氧基-3,5-二羟基已酸叔丁酯(7), de值97%. 最后经过二羟基保护, 催化加氢脱去对甲苄基得到目标产物9.

关键词: 他汀药物, 化学酶法, 三乙基硼, 酶拆分

A new synthetic method for (4R,6S)-4-t-butoxycarbonylmethyl-6-hydroxymethyl-2,2-dimethyl- 1,3-dioxane was accomplished by a chemoenzymatic approach. Racemic 4-(4-methylbenzyloxy)-3-hydroxybutyronitrile (3) was firstly synthesized via condensation and epoxy opening reactions. (S)-4- (4-Methylbenzyloxy)-3-hydroxybutyronitrile (4) was obtained from resolution of racemic 3 by the lipase from Artgribacter sp. with a high enantiomeric excess (98% ee) in the mixture solvent of acetonitrile/hexane (V∶V＝1∶4). Dihydroxy ester 7 was synthesized by a syn-selective triethylborane mediated reduction with a de value of 97%. Af-ter acid-catalyzed protection of 7 and hydrogenolysis of the benzyl protecting group, the objective 9 was obtained with a high optical purity.

Key words: chemoenzymic synthesis, enzymatic resolution, triethylborane, statins