Environmentally benign diastereoselective synthesis of granatane and tropane aldol derivatives

Direct aldol reactions of tropinone and granatanone (pseudopelletierine) with aromatic aldehydes were promoted by the presence of water. The anti-syn-diastereoselectivity depended on the amount of water used or on the possibility of product precipitation from the reaction mixture. Some of the reactions showed excellent atom economy, a low E factor, and high diastereoselectivity (up to 98%). In several cases 'seeding' with the anti isomer, used to induce the deposition of solid products, improved the conversion (up to 1.8 times) and the anti-syn ratio (up to 98 : 2). The applicability of spontaneous direct aldol reactions in the presence of water was also extended to N-alkyl nortropanones or norgranatanones using an aqueous-organic medium. However, under these conditions only the exo, syn isomers of the N-substituted aldols were obtained. The syn- selectivity for the tropane- and granatane-related aldols is specific for water-promoted reactions and results from thermodynamic control.