Reddy Leleti Rajender, Fournier Jean-François, Subba Reddy B V, Corey E J
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
J Am Chem Soc. 2005 Jun 29;127(25):8974-6. doi: 10.1021/ja052376o.
A short and highly stereocontrolled synthesis of the potent proteasome inhibitor 3 from the (S)-threonine-derived oxazoline 4 has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of 4 with isobutyraldehyde and subsequent silylation provided the TBS ether 5 diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of 5 followed by Swern oxidation of the resulting amino alcohol afforded amino ketone 6, converted further by N-acylation to the acrylamide 7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide 7 was cyclized to 8 by a novel application of the Kulinkovich Ti(II)-cyclopentene complex. Silylation of 8 to 9 and radical cyclization at low temperature produced the bicyclic lactam 10 with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of 10 gave the dihydroxy ester 11, which was converted to 3 by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined beta-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether.
已开发出一种从（S）-苏氨酸衍生的恶唑啉4高效立体选择性地合成强效蛋白酶体抑制剂3的方法。合成路线总结于方案1中。4的锌烯醇化物与异丁醛进行羟醛缩合反应，随后进行硅烷化反应，非对映选择性地得到TBS醚5（10:1）。5的恶唑啉环经还原裂解，所得氨基醇经Swern氧化得到氨基酮6，再通过N-酰化进一步转化为丙烯酰胺7，其结构经X射线晶体学分析确证。丙烯酰胺7通过Kulinkovich Ti（II）-环戊烯络合物的新应用环化得到8。8硅烷化得到9，并在低温下进行自由基环化反应，得到完全控制所有立体中心的双环内酰胺10。10的羟基脱硅烷化和N-脱保护得到二羟基酯11，通过一个新的三步序列将其转化为3：（1）用[Me2AlTeMe]2进行脱甲基反应，（2）β-内酯化和氯化反应相结合，（3）脱硅烷化以实现TBS醚的裂解。
