A novel and efficient synthesis of a highly active analogue of clasto-lactacystin β-lactone

被引：99

作者：

Soucy, F ^{[1
]}

Grenier, L ^{[1
]}

Behnke, ML ^{[1
]}

Destree, AT ^{[1
]}

McCormack, TA ^{[1
]}

Adams, J ^{[1
]}

Plamondon, L ^{[1
]}

机构：

[1] LeukoSite Inc, Dept Chem, Cambridge, MA 02139 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 1999年 / 121卷 / 43期

关键词：

D O I：

10.1021/ja991175f

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Herein, we describe a new convergent synthesis of a more potent analogue of clasto-lactacystin beta-lactone (2), PS-519 compound 4, which is currently in preclinical development for the treatment of ischemia-reperfusion injury in stroke and myocardial infarction. The synthetic strategy relies on building two intermediates (an oxazoline and an aldehyde) which are joined through a doubly diastereoselective aldol reaction, setting up the requisite unichiral centers in the final product (4). The facial selectivity and ultimate stereocontrol are achieved by employing a trivalent aluminum Lewis acid, Me2AlCl, in a chelation-induced reaction which yields a single aldol adduct. The efficiency of the synthetic approach has allowed for the preparation of multigram quantities of clinical grade material, which will support Phase I studies.

引用

页码：9967 / 9976

页数：10

共 90 条

[21]

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[22] The structural requirements for inhibition of proteasome function by the lactacystin-derived β-lactone and synthetic analogs [J].