Division of Clinical Pharmacology and Experimental Therapeutlcs of the Department of Medicine San man&sco General Hospital Medical Center and the Department of Medicine and Langley Porter Psychiatric Institute untversity of CaKOmia. san Francisco san Francisco. California 94143 We descrlbe methods for the synthesis of enantiom-pure (S)-nicotIne-S,3'-d2. (S)-nornicotine8'.3'-d2. and (S)coUnlne-S'.C-d2. The key intermediate was 5-bromomyosmine, which underwent base catalyzed exchange with deuterium oxide to give 5-bromomyosmtne-3.3'dz with > 99% incorporation of label. This intermediate was reduced to [f)-5-bromo- nomicotined'.S-d2 with sodium borohydrlde. resolved. and converted to (S)-nornicotine-3'.3'-d2 by reductive debromination with hydrogen and a palladium catalyst. Reductive alkylation with formaldehyde and sodium borohydrlde provided (S)-nicotine-S,3'-d2. which was converted to (S)-cotinine-C.C-d2 by reaction with bromine followed by zinc reduction The deuterium label is located at positions that are not attacked in the major routes of marmnallan metabolism of these alkaloids. Syntheses of tetradeuterated analogs of nicotine and cotlnine and a pentadcuterated analog of nicotine. in which additional deuterium atoms are incorporated in the methyl groups, are also reported. Key W e Nicotine. cotintnc. nomicotine. deuterium. enantiomem Nicotine [3-(l-methyl-2-pyrrolidinyl)-pyridine] occurring in tobacco is largely, if not entirely, the levorotatory (S)-enanUomer 111. Tobacco smoke contains a small amount (about 2-10% of the total nicotine) uf (R)-nicotine. presumably formed by racemization during the combustion process I2.31. Nornicotine [3-(2-pyr~olidinyl)-pyTidinel, a minor tobacco alkaloid, exists in the plant as an appmdmately 40:60 ratio (R):(S) enantiomers 141. Nornicotine fs also a mammalian metabolite of nicotine 151. Presumably. the nornicotine formed metabolically from (S)-nicotine also has the (S)-confIguration. but this remains to be verlfied experimentally. Metabolic formation of cotinfnc I1-methyl-5-(3-~dyl)-2-pyrrolidinone], a major metabolite of nicotine, has been shown to occur without significant racemization IS].