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Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors
journal contribution
posted on 2013-02-04, 00:00 authored by W A Loughlin, S S Schweiker, I D Jenkins, Luke HendersonLuke HendersonAn 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
TetrahedronVolume
69Issue
5Pagination
1576 - 1582Publisher
Elsevier B.V.Location
Amsterdam, The NetherlandsPublisher DOI
ISSN
0040-4020eISSN
1464-5416Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2012, ElsevierUsage metrics
Keywords
Diazaspiro[4.5]decanehydantoinlactammimeticGlycogen Phosphorylase aScience & TechnologyPhysical SciencesChemistry, OrganicChemistryX=Y-ZH SYSTEMSRESTRICTED TRH ANALOGSPROTEIN PHOSPHATASE-1POTENTIAL 1,3-DIPOLESTARGETING SUBUNITCONFORMATIONAL-ANALYSISPYROGLUTAMATE REGIONDOPAMINE-RECEPTORDESIGNACIDOrganic Chemistry
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