Abstract

Auxiliary-controlled diastereoselective synthesis of a syn C-6-epimer of the ADAM 10 inhibitor GI254023X

Highlights

  • The cell surface-expressed metalloprotease, ADAM10 (A Disintegrin and Metalloproteinase Domain-containing protein 10), is a member of the ADAM metalloprotease family and plays a vital role in cell adhesion and proteolytic processes of the ectodomain of various cell surface receptors and signalling molecules.[1,2]Disruption of ADAM10 activity can lead to the development of various diseases such as Alzheimer’s, asthma, cardiovascular disease, inflammatory diseases, and cancer, and drugs that modulate this protein are desirable.[1]

  • Future work will assess the influence of the C-5/C-6 relative stereochemistry on the biological activity against ADAM10

  • Reaction progress were monitored by thin layer chromatography (TLC) using aluminium backed silica-gel 60 F254 plates and was observed using both ultraviolet and fluorescent light or spraying with a 2.5% solution of anisaldehyde in a mixture of sulfuric acid and ethanol (1:10 v/v)

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Summary

Introduction

The cell surface-expressed metalloprotease, ADAM10 (A Disintegrin and Metalloproteinase Domain-containing protein 10), is a member of the ADAM metalloprotease family and plays a vital role in cell adhesion and proteolytic processes of the ectodomain of various cell surface receptors and signalling molecules.[1,2]Disruption of ADAM10 activity can lead to the development of various diseases such as Alzheimer’s, asthma, cardiovascular disease, inflammatory diseases, and cancer, and drugs that modulate this protein are desirable.[1]. The step involved the attachment of the Evans’ auxiliary (Scheme 3) via its anion to 5phenylpentanoyl chloride, 2, (produced from the reaction of 5-phenylpentanoic acid with thionyl chloride), to produce 3, which was reacted with dibutylboron triflate and triethylamine, followed by acetaldehyde to generate the diastereomerically pure secondary alcohol in chiral, non-racemic form, 4, in a 90% isolated yield by chromatography.

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