NONOXIDATIVE COUPLING METHODOLOGY FOR THE SYNTHESIS OF THE ANTITUMOR BISINDOLE ALKALOID VINBLASTINE AND A LOWER-HALF ANALOG - SOLVENT EFFECT ON THE STEREOCHEMISTRY OF THE CRUCIAL C-15/C-18' BOND

The overall strategy for the synthesis of vinblastine (1) is based upon the nonoxidative cleavage of the tertiary amine (+)-18 to generate the intermediate delocalized cation 18a, which in the presence of an electron-rich aromatic nucleophile can be trapped at C-18' to give the bisalkaloid analogues 19, 20, and 2 1. To ascertain the effect on C-18' stereochemistry with respect to C-2' and C-4' stereochemistry, we have made a number of stereoisomers of the tetracyclic amine 30. Treatment of (-)-30 with ClCO2CH2C6H4NO2-p/vindoline/CH2Cl2/25-degrees-C gave two compounds (40 and 41) and none of the correct C-18'S isomer 57, whereas treatment of (-)-30 with ClCO2CH2C6H4NO2-p/vindoline/CH3NO2 at -20-degrees-C gave the correct 18'S stereoisomer 57 (46%), along with 40 (33%) and traces of 41. Hydrolysis of 57 gave the diol 59 (85%), which was oxidized using pyridine/SO3 to the alpha-hydroxy aldehyde 60 (77%). Hydrogenolysis of 60 (Pd/C/MeOH) gave vinblastine (1) (89%). A shorter and more stereoselective synthesis of (-)-30 is described, and the synthesis of the non-vindolinyl analogue 73 is given. This study establishes that of all the various stereoisomers of the top-half precursors to vinblastine, only the (-)-(9R,2S,2'S)-30 diastereomer couples to vindoline to give the correct C-18'S stereochemistry for conversion into vinblastine.