Synthesis of optically pure deuterium-labelled nicotine, nornicotine and cotinine

We describe methods for the synthesis of enantiomerically pure (S)-nicotine-3′,3′-d2. (S)-nornicotine-3′,3′-d2, and (S)-cotinine-4′,4′-d2. The key intermediate was 5-bromomyosmine, which underwent base catalyzed exchange with deuterium oxide to give 5-bromomyosmine-3′,3′-d2 with > 99% incorporation of label. This intermediate was reduced to (±)-5-bromonornicotine-3′,3′-d2 with sodium borohydride, resolved, and converted to (S)-nornicotine-3′,3′-d2 by reductive debromination with hydrogen and a palladium catalyst. Reductive alkylation with formaldehyde and sodium borohydride provided (S)-nicotine-3′,3′-d2. which was converted to (S)-cotinine-4′,4′-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 mammalian metabolism of these alkaloids. Syntheses of tetradeuterated analogs of nicotine and cotinine and a pentadeuterated analog of nicotine, in which additional deuterium atoms are incorporated in the methyl groups, are also reported.