A new strategy for the synthesis of Woodward's densely functionalized carbocyclic precursor to reserpine (2) that is based upon serial radical 5-exo/6-exo cyclizations of readily prepared dienic hexopyranose derivatives has been examined. The substrates 4, 7, 9, and 12, which are obtainable in simple steps from commercially available triacetylglucal, have their unsaturations on-template at C2 and off-template at C7, and the cyclization sequence is triggered by use of a silicon tether appendage placed at C-4 in the pyran ring. The first radical cyclization takes place onto the s Delta(2,3) unsaturation and serves the dual purpose of introducing a carbon branch at C-3 in a complete regio- and stereocontrolled manner as well as generating a radical at C-2 that experiences the 6-exo-trig ring closure to form the actual cyclohexane ring in which all but one of the required stereocenters have been established. Electron-withdrawing substituents that accelerate the 6-exo-trig ring closure, as in substrates 4(a and b), were found to be necessary for the second cyclization to take place in good yields. Nevertheless, some cyclohexane formation was also obtained in the radical cyclization of substrates 9(a and b) in which an allylic phenyl sulfide was used as the C-7 trap. The presence of an acetate substituent at C-6 in the latter cases resulted in a high degree of stereocontrol for the 6-exo cyclization process based in a stereochemical model that invokes release of 1,3 allylic strain in the transition state for the radical cyclization. The compounds resulting from the radical cyclizations of 4a,b and 9a,b were transformed to the same [2.2.2]oxabicyclic intermediate 34 that was correlated with Woodward's carbocyclic intermediate after opening of the glycosidic bond.
