Stereoselective construction of the tetrahydrofuran nucleus by alkoxyl radical cyclizations

Whereas carbon radical cyclizations have been applied for many years in the stereoselective synthesis of carbocyclic compounds, intramolecular C-O bon d formations using alkoxyl radical reactions are less well understood. Sinc e the discovery of N-alkoxypyridine-2( 1 H)-thiones 8 as efficient sources of oxygen-centered radicals, and the marked progress in the synthesis of th ese and related compounds which has been made in the last five years, howev er, a systematic study of O-radical cyclizations under neutral conditions h as 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) x 10(8) s(-1) (30 degreesC)] which, aft er hydrogen trapping, selectively affords 2-methyltetrahydrofuran (50). Tet rahydro pyran (56), which originates from the slower 6-endo-trig cyclizatio n, was observed in minor amounts. This observation pointed to a more divers e regioselectivity of O-radicals in intramolecular addition reactions to ol efinic double bonds than had been predicted from earlier experiments. A mec hanistic 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-subst ituted 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 pare-substituted 1 -aryl-4penten-1-oxyl radicals 51e-m. These intermediates cyclize regioselec tively, but not 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 ra dical 51u cyclizes 6-endo-trig-selectively to afford, after hydrogen trappi ng, 2-phenyltetrahydropyran (59u) as the major product (5-exo:6endo = 5:95) . Results from mechanistic and theoretical studies have been combined in or der to derive a general model for predicting alkoxyl radical selectivities in ring closure reactions. The utility of this predictive device has recent ly been confirmed in the course of a new stereoselective synthesis of the c entral ring in muscarine alkaloid 72.