Stereocontrol in radical Mannich equivalents for aminosugar synthesis: haloacetal and 2-(phenylthio)vinyl tethered radical additions to α-hydroxyhydrazones

Abstract

Studies of stereocontrol in two types of radical equivalents of Mannich addition reactions offer new insights for application to aminosugar synthesis. In the first method, haloacetal addition (Ueno–Stork reaction) is extended to dihydroxyhydrazones, leading to an adduct with the unexpected 3- epi- l-daunosamine configuration. A neighboring α-benzyloxy substituent causes a dramatic reversal of stereocontrol compared with hydrazones where this substituent is absent; vicinal dipole repulsion is proposed to account for the diastereoselectivity. In the second method, radical addition–cyclization with thiophenol and treatment with fluoride leads to diastereoselective group transfer from a silicon-tethered ethynyl group to the C N bond of hydrazones, affording anti-hydrazino alcohols with a trans-2-(phenylthio)vinyl substituent. The one-pot process occurs under neutral, tin-free radical conditions, and offers stereocontrol which is complementary to the haloacetal method. Synthetic utility of the radical Mannich concept is demonstrated in a brief asymmetric synthesis of N-trifluoroacetyl- l-daunosamine from achiral precursors.