Merging lithium carbenoid homologation and enzymatic reduction: A combinative approach to the HIV-protease inhibitor Nelfinavir

被引：22

作者：

Castoldi, Laura ^{[1
]}

Ielo, Laura ^{[1
,2
]}

Hoyos, Pilar ^{[3
]}

Hernaiz, Maria J. ^{[3
]}

De Luca, Laura ^{[2
]}

Alcantara, Andres R. ^{[3
]}

Holzer, Wolfgang ^{[1
]}

Pace, Vittorio ^{[1
]}

机构：

[1] Univ Vienna, Dept Pharmaceut Chem, Althanstr 14, A-1090 Vienna, Austria

[2] Univ Messina, Dept Chem Biol Pharmaceut & Environm Sci, Viale Annunziata, I-98168 Messina, Italy

[3] Univ Complutense Madrid, Dept Chem Pharmaceut Sci QUIMCIFARM, Pza Ramon y Cajal S-N, Madrid 28040, Spain

来源：

TETRAHEDRON | 2018年 / 74卷 / 18期

关键词：

Homologation; Lithium carbenoids; Enzymatic reductions; Drug Synthesis; a-haloketones; Halohydrins; Selectivity; ALPHA'-CHLOROMETHYLKETONE DERIVATIVES; CONTINUOUS-FLOW SYNTHESIS; CYCLOPENTYL METHYL-ETHER; WEINREB AMIDES; ORGANIC-SYNTHESIS; ORGANOMETALLIC CHEMISTRY; CHEMOSELECTIVE ADDITION; DIAZOCARBONYL COMPOUNDS; ANHYDROUS DIAZOMETHANE; STRAIGHTFORWARD ACCESS;

D O I：

10.1016/j.tet.2018.03.034

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

An effective stereocontrolled synthesis of the HIV protease inhibitor Nelfinavir is reported. Two transformations were identified crucial for achieving success: the formation of a densely functionalized alpha-chloroketone via the homologation of a Weinreb amide with chloromethyllithium (LiCH2Cl), followed by its erythro selective reduction into the corresponding chiral chlorohydrin. A commercially available enzyme P2-CO2 was particularly well suited for this purpose, affording the key alcohol (in an excellent 99% de), which was then smoothly converted into the active biologically active agent. Published by Elsevier Ltd.

引用

页码：2211 / 2217

页数：7