Asymmetric Synthesis of Highly Functionalized Tetrahydropyran DPP-4 Inhibitor

被引：29

作者：

Xu, Feng ^{[1
]}

Zacuto, Michael J. ^{[1
]}

Kohmura, Yoshinori ^{[1
]}

Rosen, Jon ^{[1
]}

Gibb, Andrew ^{[2
]}

Alam, Mahbub ^{[2
]}

Scott, Jeremy ^{[2
]}

Tschaen, David ^{[1
]}

机构：

[1] Merck Res Labs, Rahway, NJ 07065 USA

[2] Merck Sharp & Dohme Res Labs, Proc Res Preparat Lab, Hoddesdon EN11 9BU, Herts, England

来源：

ORGANIC LETTERS | 2014年 / 16卷 / 20期

关键词：

ALKYNOL CYCLOISOMERIZATION; HYDROGENATION; MECHANISM; CATALYSIS; ALCOHOLS; GLYCALS; PHASE;

D O I：

10.1021/ol502661g

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization. Hydroboration followed by a Ru-catalyzed oxidation affords the desired functionalized pyranone core scaffold. Finally, stereoselective reductive amination and subsequent acidic deprotection afford the desired, potent DPP-4 inhibitor in 25% overall yield.

引用

页码：5422 / 5425

页数：4

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