Majumdar Debatosh, Alexander Matthew D, Coward James K
Departments of Medicinal Chemistry and Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
J Org Chem. 2009 Jan 16;74(2):617-27. doi: 10.1021/jo801907p.
Two epoxide-containing peptidomimetics of the isopeptide, glutamyl-gamma-glutamate, have been synthesized via a route that should be generally applicable to the synthesis of isopeptide analogues in which an oxirane replaces the scissile peptide bond. Enzymes that catalyze the hydrolysis of peptides and isopeptides are often susceptible to inactivation by electrophilic substrate analogues. In this research, an epoxide was installed as an electrophilic replacement of the scissile isopeptide bond. The C-terminal glutamyl mimic was accessed by the stereospecific synthesis of suitably substituted cyclopentenes, 8 and 10, as surrogates for either the L- or D-enantiomer. The enantiomeric cyclopentenes were further elaborated to incorporate an appended sulfone that was reacted with a suitably protected glutamyl-gamma-semialdehyde in a Julia-Kocienski olefination reaction. This olefination afforded predominantly the desired E-olefin isosteres of L-glutamyl-gamma-D-glutamate and L-glutamyl-gamma-L-glutamate, following which peracid-mediated epoxidation and deprotection provided the epoxide-containing peptidomimetics, 4 and 5.
通过一条通常适用于合成异肽类似物的路线，合成了两种含环氧基的异肽模拟物——谷氨酰-γ-谷氨酸，其中环氧乙烷取代了可裂解的肽键。催化肽和异肽水解的酶通常易受亲电底物类似物的失活作用影响。在本研究中，安装了一个环氧基作为可裂解异肽键的亲电取代基。通过立体定向合成适当取代的环戊烯8和10作为L-或D-对映体的替代物，得到了C端谷氨酰模拟物。对映体环戊烯进一步进行修饰，引入一个附加的砜，该砜在Julia-Kocienski烯化反应中与适当保护的谷氨酰-γ-半醛反应。该烯化反应主要得到了L-谷氨酰-γ-D-谷氨酸和L-谷氨酰-γ-L-谷氨酸所需的E-烯烃电子等排体，随后通过过酸介导的环氧化和脱保护反应得到了含环氧基的肽模拟物4和5。
