Conformationally biased selective alkylation of trans-cyclohexane-1,2-bis(sulfonamide) assisted by solvent-tuned protecting groups:: Applications to the synthesis of a large optically active polyazamacrocycle

The selective alkylation of (R,R)-cyclohexane-1,2-bis(sulfonamide) with trityl bromoalkyl ethers has been studied in detail. The major formation of either mono- or dialkylated compounds clearly depends on the right combination of protecting groups and the reaction solvent. An exhaustive study suggests that this effect can be reasonably explained by the conformational preferences of the monoalkylated compounds, which also depend on the reaction medium, solvophobic effects and weak intramolecular interactions. Structural analysis by NOE measurements showed the presence of folded conformations in solution for all the tested examples. Monte Carlo conformational searches supported this proposal, showing a very good correlation between the fraction of folded species and the selectivity towards monoalkylation. Finally, tuning of the reaction conditions, leading to either extended or folded conformations of the monoalkylated synthetic intermediates, was exploited for the efficient synthesis of a large optically active polyazamacrocycle. (c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006.