TOTAL SYNTHESIS OF THE CEPHALOTAXUS ALKALOIDS DL-CEPHALOTAXINE, DL-11-HYDROXYCEPHALOTAXINE, AND DL-DRUPACINE

This paper reports the chemical details of our total synthesis of dl-cephalotaxine (1) and the completion of the first total synthesis of dl-1 1-hydroxycephalotaxine (3) and dl-dupracine (4). Key steps in the synthesis of dl-cephalotaxine include: (1) conjugate addition/alkylation of aryllithium 23C to vinyl sulfone 21 to afford adduct 24C, bearing the entire carbon assemblage; (2) self-immoliative elimination of homoallyl sulfone 24C to exocyclic diene 25 via treatment with t-BuLi; (3) establishment of the tetracyclic array by an intramolecular Diels-Alder reaction of an acylnitroso moiety to the exocyclic diene of 16. This latter reaction features the first example of a regiochemical outcome which violates the implicit rule of syn-tether specificity in an intramolecular [4 + 2] cycloaddition. The first total syntheses of dl-1 1-hydroxycephalotaxine (3) and dl-drupacine (4) features a reductive 1,2-carbonyl transposition strategy on lactam 28ac involving: (1) sulfenylation of the enolate derived from 28ac with S-phenyl benzenethiosulfonate, (b) oxidation of the enolate derived from 33-beta with molecular oxygen; and (c) reduction with BH-3/THF to give the requisite 11-beta-hydroxy amine 36-beta as the major product (56% overall). The equilibrating methylation conditions utilized to convert 38 to 40 also resulted in the formation of macrocyclic amine 41. This result has substantial negative implications with regard to the use of diketone intermediates related to 3 and 38 for synthesis of enantiomerically pure materials in the cephalotaxine area.