Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

Abstract

Whereas carbon radical cyclizations have been applied for many years in the stereoselective synthesis of carbocyclic compounds, intramolecular C−O bond formations using alkoxyl radical reactions are less well understood. Since the discovery of N-alkoxypyridine-2(1H)-thiones 8 as efficient sources of oxygen-centered radicals, and the marked progress in the synthesis of these and related compounds which has been made in the last five years, however, a systematic study of O-radical cyclizations under neutral conditions has become available. Kinetic experiments using the radical clock technique found that the parent 4-penten-1-oxyl radical 1 undergoes an extremely fast 5-exo-trig ring-closure [(4 ± 2) × 108 s−1 (30 °C)] which, after hydrogen trapping, selectively affords 2-methyltetrahydrofuran (50). Tetrahydropyran (56), which originates from the slower 6-endo-trig cyclization, was observed in minor amounts. This observation pointed to a more diverse regioselectivity of O-radicals in intramolecular addition reactions to olefinic double bonds than had been predicted from earlier experiments. A mechanistic study of ring-closure reactions of the substituted 4-penten-1-oxyl radicals 51 led to two major conclusions. Firstly, 1-, 2-, 3-, and 5-substituted radicals cyclize stereoselectively and 5-exo-trig-regioselectively. The degree of stereoselectivity is governed by steric effects. To date, the only exceptions to this rule remain cyclizations of the para-substituted 1-aryl-4-penten-1-oxyl radicals 51e−m. These intermediates cyclize regioselectively, butnot stereoselectively. Secondly, substituents at position 4 of the 4-penten-1-oxyl radical are the key for controlling regioselectivities in O-radical ring-closure reactions. Thus, the 4-phenyl-4-penten-1-oxyl radical 51u cyclizes 6-endo-trig-selectively to afford, after hydrogen trapping, 2-phenyltetrahydropyran (59u) as the major product (5-exo:6-endo = 5:95). Results from mechanistic and theoretical studies have been combined in order to derive a general model for predicting alkoxyl radical selectivities in ring closure reactions. The utility of this predictive device has recently been confirmed in the course of a new stereoselective synthesis of the central ring in muscarine alkaloid 72.