GAMMA-BUTYROLACTONE NATURAL-PRODUCTS VIA TRIBUTYLTIN-HYDRIDE-MEDIATED RADICAL CYCLIZATIONS

A new synthetic methodology using tributyltin hydride generates complex gamma-butyrolactones via radical cyclization of alpha-bromo allylic esters with aryl or heteroaryl substituents at the distal position of the allylic double bond. Application of this chemistry has been made to two major families of natural products, the lignans (with racemic deoxypodorhizon as a target) and the Jaborandi alkaloids (with racemic pilocarpine/isopilocarpine as a target). For the lignan system, a highly convergent sequence provided for the efficient preparation of the cyclization precursor. The key cyclization gives a 46.4% yield of a 4:1 mixture of deoxypodorhizon and its cis epimer. Base isomerization of this mixture affords pure racemic deoxypodorhizon. For the alkaloid system, a slightly longer, but experimentally straightforward, route generates an imidazole derivative regiospecifically methylated on the alpha-nitrogen. From this allylic alcohol; the thermally unstable alpha-bromo allylic ester can easily be made. When this substrate is cyclized, a 4:1 mixture of isopilocarpine/pilocarpine results in 39.5% yield. This sequence provides an unusually direct route to pilocarpine via kinetic quench.