O-Silylated C3-halohydrins as a novel class of protected building blocks for total, regio- and stereocontrolled synthesis of glycerolipid frameworks?

Organic & Biomolecular Chemistry Pub Date: 2009-11-26 DOI: 10.1039/B915533C

Abstract

We propose O-silylated C3-halohydrins [1(3)-O-silyl-2-O-acyl-, 1,2(2,3)-O-bis(silyl)-, and 1(3)-O-acyl-2-O-silyl-3(1)-halo-sn-glycerides] as new chirons in the total synthesis of glycerolipid constructs. These are efficiently producible via opening of the oxirane ring of the corresponding glycidyl derivatives and permit (i) displacement of the iodine by a requisite carboxylate in the presence of O-triisopropylsilyl (O-TIPS), O-tert-butyldimethylsilyl (O-TBDMS), and O-acyl substituents; (ii) selective acylation across an appropriate silyloxy system [e.g., O-TBDMS or O-triethylsilyl (O-TES)] of monoesterified haloglycerides; (iii) direct exchange of an O-silyl protection (e.g., O-TBDMS or O-TIPS) for a trichloroacetyl group; (iv) conversion of a terminal TBDMS group into the corresponding trifluoroacetate without affecting O-TIPS-, O-acyl- and iodo functions. The above transformations secure flexible routes to a variety of otherwise difficult-to-access key-intermediates [e.g., 1,2(2,3)-O-bis(acyl)-3(1)-trichloroacetyl-, 1,3-O-bis(acyl)-2-trichloroacetyl-, 1,2(2,3)-O-bis(acyl)-3(1)-O-TBDMS/TIPS-, 1,3-O-bis(acyl)-2-O-TIPS/TBDMS-, 1(3)-O-acyl-2-O-TIPS-, 1,2(2,3)-O-bis(acyl)-3(1)-iodo-sn-glycerols, etc.] and lend themselves to a powerful methodology for the preparation of di- and triacylglycerols as well as glycerol-based cationic lipids. The reactions involved are entirely regio- and stereospecific, avoid acyl migration, and can provide target compounds with a chosen absolute configuration from a single synthetic precursor.

Graphical abstract: O-Silylated C3-halohydrins as a novel class of protected building blocks for total, regio- and stereocontrolled synthesis of glycerolipid frameworks
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