PREPARATION AND CHARACTERIZATION OF ALKYL(3,5,6-TRIMETHYLBENZIMIDAZOLYL)COBAMIDES, ANALOGS OF BASE-OFF ALKYLCOBALAMINS - PRODUCTS WITH DEFINED STEREOCHEMISTRY VIA DIRECT METHYLATION OF ALKYLCOBALAMINS

Reductive alkylation of cyano(3,5,6-trimethylbenzimidazolyl)cobamide (CNMe3BzmCba), an analog of cyanocobalamin in which the pendant axial 5,6-dimethylbenzimidazole ligand is uncoordinated and N-methylated, in zinc/aqueous methanol with various alkylating agents (CH3I, CH3CH2I, NCCH2Br, CF3CH2I, and CF3Br) has been shown to lead to pairs of diastereomeric alpha- and beta-alkyl(3,5,6-trimethylbenzimidazolyl)cobamides (RMe3BzmCba's), in which the organic ligand occupies the ''lower'' or ''upper'' axial ligand position, respectively. In the case of CF3Br, reductive alkylation of CNMe3BzmCba in zinc/aqueous acetic acid also leads to a pair of diastereomeric alpha- and beta-CF2HMe3BzmCba's due to the reductive defluorination of the CF3Me3BzmCba's formed in situ. The ratio of the diastereomers formed varies widely with R from 2:98 (alpha:beta) for R = CH3CH2 to 93:7 for R = CF3. In order to provide a stereocontrolled route to the beta-RMe3BzmCba's, which serve as convenient models of the base-off species of beta-alkylcobalamins (beta-RCbl's), direct N-methylation of beta-RCbl's with dimethyl sulfate in excess cyanide has been investigated. For those organocobalt corrinoids which are stable in excess cyanide (R = CH3CH2, NCCH2, CF3, and CF2H) this route provides uniquely the beta-RMe3-BzmCba in yields of 76-86%. For beta-CH3Cbl, which undergoes partial decomposition in cyanide, the yield was only 20%, while for beta-CF3CH2Cbl, which undergoes massive decomposition in cyanide, no beta-CF3CH2Me3BzmCba could be obtained by this route. The latter compound, as well as beta-CH3CH2Me3BzmCba, was obtained, in 20% yield, by N-methylation of beta-CF3CH2Cbl or beta-CH3CH2Cbl in the absence of cyanide in refluxing methanol.