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

Wendy A. Loughlin, Stephanie S. Schweiker, Ian D. Jenkins, Luke C. Henderson

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1576-1582
Number of pages7
JournalTetrahedron
Volume69
Issue number5
DOIs
Publication statusPublished - 4 Feb 2013
Externally publishedYes

Fingerprint

Phosphorylase a
Glycogen Phosphorylase
Lactams
Aldehydes
Hydantoins
Boranes
Amino Acids
Inhibitory Concentration 50
Methanol
Hydrolysis
Alcohols
Oxidation

Cite this

Loughlin, Wendy A. ; Schweiker, Stephanie S. ; Jenkins, Ian D. ; Henderson, Luke C. / Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors. In: Tetrahedron. 2013 ; Vol. 69, No. 5. pp. 1576-1582.
@article{f13e46861e1e4044a1ddc519d379e8a6,
title = "Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors",
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 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.",
author = "Loughlin, {Wendy A.} and Schweiker, {Stephanie S.} and Jenkins, {Ian D.} and Henderson, {Luke C.}",
year = "2013",
month = "2",
day = "4",
doi = "10.1016/j.tet.2012.12.004",
language = "English",
volume = "69",
pages = "1576--1582",
journal = "Tetrahedron",
issn = "0040-4020",
publisher = "Elsevier",
number = "5",

}

Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors. / Loughlin, Wendy A.; Schweiker, Stephanie S.; Jenkins, Ian D.; Henderson, Luke C.

In: Tetrahedron, Vol. 69, No. 5, 04.02.2013, p. 1576-1582.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors

AU - Loughlin, Wendy A.

AU - Schweiker, Stephanie S.

AU - Jenkins, Ian D.

AU - Henderson, Luke C.

PY - 2013/2/4

Y1 - 2013/2/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84872106708&partnerID=8YFLogxK

U2 - 10.1016/j.tet.2012.12.004

DO - 10.1016/j.tet.2012.12.004

M3 - Article

VL - 69

SP - 1576

EP - 1582

JO - Tetrahedron

JF - Tetrahedron

SN - 0040-4020

IS - 5

ER -