Development of Enzymatic Method for Asymmetric Induction and Its Application for Natural Products Synthesis

1. 利用面包酵母合成手性内酯面包酵母还原3-烷基化-丁烯内酯得到光学纯度高、收率高的手性丁烯内酯。面包师酵母还原3-苯基硫甲基丁烯内酯得到(R)-3-苯基硫甲基- γ -丁烯内酯（99%ee），一种用于萜合成的通用手性构建块。3-苄基氧甲基- γ -丁烯内酯的类似反应生成(S)-3-苄基氧甲基丁烯内酯（95%ee），并将其转化为S.病毒色素基因的自调节因子- 1。不对称合成天然α -生育酚采用化学酶法合成(2R,4'R,8'R)- α -生育酚。通过脂肪酶催化前手性1,3-二乙酸酯水解合成了色素部分，得到的单酯光学纯度为67%ee。另一方面，通过脂肪酶催化C_5前手性1,3-二醇的酯交换反应，在95%的收率下得到了C_<15>侧链。采用脂肪酶催化前手性1,3-二醇的不对称酯交换反应，通过两条途径首次合成了从鸢尾菌（Ircinia variabilis）中分离得到的抗菌菌(S)-变异菌素。2-羟基甲基-4-苯基硫代-1-丁醇是变异物苷合成的关键中间体，不对称诱导的光学纯度为99%。采用化学酶法合成了维吉尼亚链霉菌维吉尼亚霉素诱导因子维吉尼亚丁内酯C。在研究过程中发现，脂肪酶催化2-氨基乙基-1,3-丙二醇的前手性酯交换反应使单酯具有较高的光学纯度，单酯的绝对构型依赖于酰胺基团。

1. Synthesis of chiral lactones using bakers' yeast Bakers' yeast reduction of 3-alkylated-gamma-butenolides gave chiral gamma-butanolides with high optical purity in good yield. Bakers' yeast reduction of 3-phenylthiomethylbutenolide afforded (R)-3-phenylthio-methyl-gamma-butanolide (99%ee), a versatile chiral building block for terpene synthesis. Similar reaction of 3-benzyloxymethyl-gamma-butenolide gave (S)-3-benzyloxymethylbutanolide (95%ee), and its transformation to factor-I, the autoregulator of S. viridocchromogenes, was also examined.2. Asymmetric synthesis of natural alpha-tocopherol The formal synthesis of (2R,4'R,8'R)-alpha-tocopherol was achieved using chemoenzymatic process. The chroman part was synthesized via lipase-catalyzed hydrolysis of prochiral 1,3-diacetate and the optical purity of the monoester obtained was 67%ee. On the other hand, the C_<15> side chain was obtained in 95%ee via lipase-catalyzed transesterification of C_5 prochiral 1,3-diol.3. Asymmetric synthesis of variabilin, furanosesterterpene in sponge The first synthesis of antibacterial (S)-variabilin, isolated from Ircinia variabilis was accomplished via two routes by lipase-catalyzed asymmetric transesterification of prochiral 1,3-diols. The optical purity in asymmetric induction to 2-hydroxymethyl-4-phenylthio-1-butanol, the key intermediate of variabilin synthesis, was 99%ee.4. Asymmetric synthesis of the autoregulator of antibiotics in Streptomyces Virginia butanolide C, virginiamycin inducing factor of S. virgiae, was accomplished via chemoenzymatic process. In the course of this work, it was found that lipase-catalyzed transesterification of prochiral 2-amidoethyl-1,3-propanediols gave the chiral monoesters with high optical purity and the absolute configuration of the monoester was dependent on the amide group.