An efficient, stereocontrolled synthesis of a potent omuralide-salinosporin hybrid for selective proteasome inhibition
An efficient, stereocontrolled synthesis of a potent omuralide-salinosporin hybrid for selective proteasome inhibition
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DOI：
10.1021/ja052376o
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发表时间：
2005-06-29
影响因子：
15
通讯作者：
Corey, EJ
中科院分区：
文献类型：
--
作者：
Reddy, LR;Fournier, JF;Corey, EJ
一个短的和高度立体控制的合成有效的蛋白酶体的？3从（S）-苏氨酸衍生的恶唑啉4已开发。合成顺序总结于方案1中。4的烯醇化锌与异丁醛的羟醛缩合反应和随后的甲硅烷基化反应提供了TBS醚5的非对映选择性（10：1）。5的恶唑啉环经还原断裂，氨基醇经Swern氧化得到氨基酮6，再经N-酰化反应得到丙烯酰胺7，其结构经X-射线晶体学分析证实。丙烯酰胺7通过Kulinkovich Ti（II）−环戊烯配合物的新应用环化成8。8的甲硅烷基化和9的自由基环化反应在低温下产生的双环内酰胺10的所有立体中心的完全控制。10经羟基脱硅和N-脱保护得到二羟基酯11，该酯通过一种新的三步序列转化为3：（1）用[Me 2AlTeMe]2脱甲基，（2）结合β-内酯化和氯化，（3）脱硅以实现TBS醚的裂解。
A short and highly stereocontrolled synthesis of the potent proteasome inhibitor3from the (S)-threonine-derived oxazoline4has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of4with isobutyraldehyde and subsequent silylation provided the TBS ether5diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of5followed by Swern oxidation of the resulting amino alcohol afforded amino ketone6, converted further by N-acylation to the acrylamide7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide7was cyclized to8by a novel application of the Kulinkovich Ti(II)−cyclopentene complex. Silylation of8to9and radical cyclization at low temperature produced the bicyclic lactam10with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of10gave the dihydroxy ester11, which was converted to3by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined β-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether.