Synthetic Strategy towards a Carbocyclic N‐Acetylneuraminic Acid

Abstract

In the study of glycosidases, a class of activity-based probes (ABPs), that are carbocyclic mimics of natural carbohydrates and can covalently bind the enzyme, have proven to be useful tools. This type of ABP has however not yet been reported for sialidases, glycosidases involved in various important biological processes in both health and disease, which hydrolyse terminal sialic acids. Here we present our study towards the synthesis of a carbocyclic sialic acid suitable for conversion into ABPs. We developed a route starting from a chiral furanone that includes a key early stage nitrone [3 + 2] cycloaddition to install most of the chiral centres present in N-acetylneuraminic acid. The final stereocentre is installed via a Barbier alkylation, after which a ring closing metathesis forms the pivotal carbocyclic intermediate. Due to challenges in the final stretch, we were not able to convert this intermediate into an N-acetylneuraminic acid ABP. However, the work presented here still represents a versatile route to potential future carbocyclic sialic acid derivatives.

Racemic Total Synthesis of Elmonin and Pratenone A, fromStreptomyces, Using a Common Intermediate Prepared byperi-Directed C–H Functionalization

“…This was achieved by converting 8 into the corresponding aryl lithium species, using standard bromo-lithium exchange conditions with n -BuLi/TMEDA in THF and subsequent reaction with 9 . The benzhydrol was conveniently oxidized to benzophenone 24 in 86% yield by Dess-Martin periodinane (DMP) in DCM. , A triple deallylation was then performed by treating 24 with catalytic Pd­(PPh 3 ) 4 and stoichiometric N,N- dimethylbarbituric acid, which gave the proposed biosynthetic precursor of 1 , compound 6 , quantitatively. 6 appeared to be stable; however, when 6 was dissolved in aged samples of (presumably slightly acidic) CDCl 3 , cyclization to elmonin 1 was observed serendipitously.…”