Title

Synthesis and evaluation of C8- substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors

Date of this Version

1-1-2013

Document Type

Journal Article

Publication Details

Citation only

Loughlin, W., Schweiker, S.S., Jenkins, I.D., & Henderson, L.C.(2013). Synthesis and evaluation of C8- substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors. Tetrahedron, 69(5), 1576-1582.

Access the journal

2013 HERDC submission. FoR code: 030503

© Copyright, Elsevier Ltd, 2013

ISSN

0040-4020

Abstract

An effective synthesis of 4.5-spiro lactams 28/29, has been completed in nine steps with an overall yield of 5.8%. The 4.5-spiro lactams were made from 2-allyl-Cbz-Pro-OMe 21, which was converted into the corresponding alcohol 22 via a hindered borane reaction with (2-methylbutyl)2borane. Subsequent Swern oxidation of 22 gave novel aldehyde 23. Aldehyde 23 was treated under BucherereBergs reaction conditions to give hydantoin 26, which was opened to the corresponding amino acid 30 using di-tertbutyl dicarbonate and DMAP followed by hydrolysis. Treatment of amino acid 30 with acidic methanol gave 4.5-spiro lactams 28/29. Only 4.5-spiro lactam 29 displayed moderate activity against GPa with an IC50 of 241 mM

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This document has been peer reviewed.