| In the past twenty years, interest in the asymmetric synthesis of 1,2,3,4-tetrahydroisoquinoline (THIQ) alkaloids has increased dramatically, due to their diverse biological activities; i.e., anticancer, antidepressant, and antibacterial activities. Conventional approaches for the construction of these alkaloids include the Bischler-Napieralski and Pictet-Spengler reactions. However, these procedures suffer from unreliable regio- and stereoselectivity as well as side reactions involving the iminium ion intermediates. An alternative method for the asymmetric construction of THIQs is the addition of laterally lithiated species to enantiopure sulfinimines (N-sulfinyl imines) to afford sulfinamides. Removal of the N-sulfinyl auxiliary and cyclization affords the corresponding optically active THIQs with substitution patterns not easily accessible by other methods.; This new method was applied to the asymmetric synthesis of cis - and trans-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline, which is the THIQ segment of the anti-malaria agents korupensamines and michellamines, which have shown pronounced anti-HIV activity. It was found that the N,N-diethylbenzamide directing metallation group resulted in the formation of a complex mixture of atropisomer sulfinamides, which was a result of restricted rotation around the acyl/aryl bond. These atropisomers made it impossible to determine the extent of asymmetric induction and to obtain a diastereomerically pure product. The use of laterally lithiated 2,4-dimethoxy-6-methyl-benzonitrile eliminated this problem and afforded a single diastereomer. In addition the sulfinamide that was produced from condensation with (S)-(+)-N-(acetylidene) p-toluenesulfinamide was easily converted to (3S)-(+)-1-methyl-3-phenyl-3,4-dihydroisoquinoline by treatment with methyl-lithium followed by acid hydrolysis. This accomplished three operations in one-pot.; The directing metallation groups N-tert-butyl- N-methylbenzainide, N-methylbenzamide, and benzonitrile were investigated in the synthesis of THIQs and it was found that all three groups afforded the corresponding sulfinamides in good yield (60–93%) and diastereoselectivity (40–>98% de). The utilization of the N-tert-butyl-N-methylbenzamide group was found to be advantageous when the laterally lithiated species was contiguously substituted and required an ortho-lithiation reaction to prepare. However, laterally lithiated o-tolunitriles afforded sulfinamides that were easily converted to THIQ derivatives.; The first asymmetric synthesis of the THIQ alkaloid (−)-canadine was accomplished in five steps from laterally lithiated 2,3-dimethoxy-6-methyl-benzonitrile and (S)-(+)-2-[(2-tert-butyldimethylsiloxyethyl)-4,5-methylene-dioxy-benzylidine]-1-methoxy-naphthalene-sulfinamide with an overall yield of 52% and >95% ee. (−)-Canadine is one of the active ingredients in Golden Seal, one of the top 25 selling herbs, and is being investigated as an antiturbercular agent. |
