Efficient solution phase parallel synthesis of norstatine analogs

doi:10.1016/j.tet.2004.07.085

Tetrahedron

Volume 60, Issue 41, 4 October 2004, Pages 9043-9048

https://doi.org/10.1016/j.tet.2004.07.085 Get rights and content

Abstract

The reaction of glycidic amides with various functionalized nitriles to afford norstatine analogs in a regio- and diastereoselective fashion (43–99% yield) is described. Utilizing this chemistry, a 20 membered solution phase library was prepared in two steps featuring three points of diversity.

Graphical Abstract

Introduction

Since the discovery of the inhibitory activity of (hydroxymethyl)carbonyl isosteres against aspartyl proteases, the norstatine analogs 1 have become a popular target for medicinal chemists.1, 2 Amongst the various synthetic approaches to these analogs, the reaction of glycidic esters 3 with acetonitrile to afford the desired 3-N-acylamino-2-hydroxy compounds 2 via the oxazoline intermediate 4, appears to be the most straightforward (Fig. 1).³ Surprisingly, the scope of this reaction has been largely unexplored: glycidic esters have been reported to react with only a few simple unfunctionalized nitriles (i.e. acetonitrile and propionitrile), and only a single glycidic amide^3c has been described as an alternative to the ester. However, in all of the published examples, the transformation proceeds with remarkably high regio- and diastereoselectivity, which would be a crucial feature for the efficient preparation of a diverse solution phase library. Herein, we present our investigations into expanding the reaction scope and describe the preparation of a small library of norstatine analogs.⁴

Section snippets

Chemical approaches

Our initial approach to the library synthesis was based on the results published by Zvonkova and others.³ For our initial synthetic studies, we used racemic glycidic acid 5a available via a simple mCPBA epoxidation of the commercially available olefin.⁵ When the epoxy-acid 5a reacted with acetonitrile in the presence of an excess of BF₃·OEt₂, the corresponding 3-N-acyl-2-hydroxyacid 6a was isolated upon base hydrolysis of the oxazoline 4a (Fig. 2). We found that this transformation can be

General comments

NMR experiments were conducted with a Bruker ARX300 spectrometer at 75 MHz for ¹³C and 300 MHz for ¹H spectra. Samples were dissolved in CDCl₃ with TMS as the internal reference. Affinity chromatography was carried out using Bondesil (SCX 40 μm). Reactions were carried out under dry nitrogen with magnetic stirring. LC/MS analysis was conducted on HP1100 with Polaris C18 A-5μ column. Thin layer chromatographic (TLC) analyses were performed using 10×20 cm Analtech Silica Gel GF plates (25 mm thick).

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Efficient solution phase parallel synthesis of norstatine analogs

Abstract

Introduction

Section snippets

Chemical approaches

General comments

ChemBiochem

J. Med. Chem.

Chem. Pharm. Bull.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

Eur. J. Org. Chem.

Bioorg. Med. Chem.

Org. Lett.

J. Org. Chem. USSR

Recl. Trav. Chim. Pays-Bas

Tetrahedron Lett.