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

Version 2 2024-06-03, 10:51
Version 1 2017-04-05, 09:59
journal contribution
posted on 2024-06-03, 10:51 authored by WA Loughlin, SS Schweiker, ID Jenkins, Luke HendersonLuke Henderson
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 Bucherer–Bergs reaction conditions to give hydantoin 26, which was opened to the corresponding amino acid 30 using di-tert-butyl 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 μM.

History

Journal

Tetrahedron

Volume

69

Pagination

1576-1582

Location

Amsterdam, The Netherlands

ISSN

0040-4020

eISSN

1464-5416

Language

eng

Publication classification

C1.1 Refereed article in a scholarly journal

Copyright notice

2012, Elsevier

Issue

5

Publisher

Elsevier B.V.