I. The total synthesis of thiarubrine C, a DNA-cleaving natural 1,2-dithiin. II. Application of (alkoxycarbonylamino)methyl radical cyclization to the total synthesis of (plus/minus)-sibirine.

Abstract

An efficient and generally applicable method for the synthesis of 3,6-disubstituted 1,2-dithiins has been developed. The method involves the use of tert-butyl mercaptan for its regio- and stereoselective 1,4-bis-addition to 1,4-disubstituted 1,3-butadiynes. Deprotection of the tert-butyl group and formation of the 1,2-dithiin ring are accomplished in a single operational step by treatment of the thiol adducts with iodine, N-iodosuccinimide, or N-bromosuccinimide, providing a variety of 3,6-disubstituted 1,2-dithiin compounds in good to excellent yields. A mild and efficient procedure for the reduction of sulfoxides to thioethers has also been established. Activation of the sulfoxides in situ by treatment with acetic anhydride followed by reduction with zinc metal affords their corresponding thioethers in high yields. The first total synthesis of thiarubrine C, a DNA-cleaving natural 1,2-dithiin, has been realized in 9 steps from readily available 2,4-hexadiyne-1,6-diol. Preliminary studies on its DNA-cleavage have revealed its ability to cleave DNA in the presence of a thiol, oxygen, and trace of a metal ion, thus suggesting the generation of hydroxyl radical and its involvement as part of the mechanism for DNA-cleavage. A method to achieve (alkoxycarbonylamino)methyl radical cyclization using phenyl selenides as precursors has been established. The preparation of phenyl selenides involves the efficient formation of a carbon-nitrogen bond from the corresponding alcohol by the use of the Mitsunobu reaction and the tin-lithium exchange of the organostannane intermediate followed by quenching with diphenyl diselenide. The above radical cyclization has been applied to the total synthesis of a Nitraria alkaloid, sibirine. The preparation of the phenyl selenide precursor, 3-(t-butyldimethylsiloxy)-2-$\{3\sp\prime$- (N-(carbomethoxy)-N-phenylselanylmethylamino) $\}$propyl-1-phenylsulfonylcyclohexene, involves the use of the Suzuki coupling reaction of an alkenyl bromide and a protected amine-containing alkylborane as a key step. The radical cyclization directly provides the 2-azaspiro (5.5) undecane skeleton of sibirine with high regio-and stereoselectivity when a vinyl sulfone is used as the radical acceptor. This total synthesis of sibirine is achieved in 12 steps from 1,3-cyclohexanedione.