The total synthesis of the {\it Cephalotaxus\/} alkaloids: d1-demethylcephalotaxinone, d1-cephalotaxinone, d1-cephalotaxine, d1-11-hydroxycephalotaxine, and d1-drupacine

Timothy Paul Burkholder, Purdue University

Abstract

An efficient total synthesis of dl-cephalotaxine is described. Key steps include: (1) conjugate-addition of an aryl lithium moiety to a vinyl sulfone moiety followed by alkylation of the resulting $\alpha$-sulfonyl anion with allyl bromide to afford an adduct bearing the entire carbon assemblage of the Cephalotaxus alkoloids; (2) self-immolative elimination of homoallyl sulfone through treatment with t -butyl lithium; (3) establishment of the tetracyclic array by intramolecular (4+2) cycloaddition of an acyl nitroso moiety to an exocyclic E-diene. This latter reaction features the first example of a stereochemical outcome which violates the implicit rule of syn -tether specifically for intramolecular cycloaddition reactions. The overall yield of dl-cephalotaxine from the vinyl sulfone is 14-17% considering that both isomers from the cycloaddition reaction are utilized. The first total synthesis of dl-11-hydroxycephalotaxine and dl-drupacine are described. The tetracyclic lactam used in the cephalotaxine synthesis is converted to dl-11-hydroxycephalotaxine by an eight-step sequence in 16% overall yield. Oxidative functionalism is effected by a two-step procedure involving sulfenylation of the lactam followed by oxygenation of the enolate derived from the monosulfenylated lactam with molecular oxygen. Stereoselective reduction of the resulting $\alpha$-ketolactam with borane-tetrahydrofuran complex affords the required $\beta$-hydroxyl moiety. Isomerization of the $\Delta\sp{3,4}$ enol ether to the $\Delta\sp{1,2}$ methyl enol ether proceeds with partial fragmentation of the Cephalotaxus nucleus presumably due to increased steric interactions of the C-11 acetoxy moiety. dl-11-Hydroxycephalotaxine is converted to dl-drupacine under acidic conditions by the method of Powell. A model study for a possible alternative synthesis of the active esters of cephalotaxine through an intramolecular acyl transfer is outlined.

Degree

Ph.D.

Advisors

Fuchs, Purdue University.

Subject Area

Organic chemistry

COinS