Enantioselective synthesis of 1-substituted tetrahydroisoquinolines.

Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2014.Many organic compounds are chiral and they are useful because of the biological activities associated with them. The biological activities of chiral compounds are often linked to absolute configuration, i.e. a compound and its mirror image can have different biological activities. For example, one enantiomer can be toxic whereas the other enantiomer is non-toxic. Enantioselective synthesis plays a significant role in the synthesis of biologically active compounds. The activity of tetrahydroisoquinolines prompted us to investigate the stereoselective synthesis of selected 1-substituted tetrahydroisoquinolines. The objectives of this project were to investigate stereoselective synthesis of some 1- substituted tetrahydroisoquinolines and compare different chiral auxiliaries used in the Bischler-Napieralski and Pictet-Spengler reactions and finally to optimize the number of steps needed to prepare the target compounds. The main challenge encountered in the Pictet-Spengler method was the decomposition of the phenylacetaldehyde. The successfully used method was the Bischler-Napieralski reaction because it does not involve the use of a phenylacetaldehyde. Using the Bischler-Napieralski method, non-stereoselective and stereoselective syntheses of tetrahydroisoquinolines have been achieved. The racemic tetrahydroisoquinolines have been synthesized in a three-step procedure starting from 3,4-dimethoxyphenylethylamine whereas the chiral tetrahydroisoquinolines were synthesized from vanillin in a seven-step reaction procedure. The R and S enantiomers of α-methylbenzylamine were successfully employed in the synthesis of 1-benzyltetrahydroisoquinolines. However, the Renantiomer of 1,2,3,4-tetrahydro-1-naphthylamine could be used to form a chiral phenylethylamine, while ring closure in a Biscler-Napieralski reaction was not successful under similar reaction conditions. The diastereoselectivity of the reactions to form the chiral tetrahydroisoquinolines was determined using NMR spectroscopy and was found to be 96% and 90% de for the (R)- and (S)-1-benzyl-6,7-dimethoxy-N-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinoline, respectively. The stereochemistry of the final products was found to be similar to that of the chiral auxiliary starting material for each of the synthesized chiral tetrahydroisoquinolines. Yields for the precursors were good to moderate, especially on the final stages of the synthesis