New approaches to Pictet–Spengler-type cyclisation reactions

A modified Pictet–Spengler synthesis has been developed, which alleviates the problems associated with the classical synthesis. A-methoxyurethanes were used as precursors, and cyclisation initiated under mild Lewis acid conditions in non-aqueous media at room temperature. Precursors with unactivated aromatic ring systems could be cyclised. The presence of various substituents at the C-1 position of the new compound was made possible by investigating different methods of synthesising the α-methoxyurethane precursors. Two general routes were used; the first utilising the reaction between imines and chloroformates and the second using the anion of secondary urethanes. The generality of the methodology was explored. The use of different cyclising reagents was investigated; it was found that the counter-ion involved in these reagents was of great significance in these reactions. Studies on the effect of substituents on the aromatic rings in the N-(α-methoxy-α-phenylmethyl)-N-methoxycarbonylamide precursors were also undertaken with interesting results. Attempts to carry out the cyclisation of related precursors—trifluoroacetamides and tosylates—were unsuccessful. Protected 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acids, novel α-amino acid systems, were synthesised; and the methodology was also applied to the syntheses of isoindoline and 2,3,4,5-tetrahydro-1H-2-benzazepine ring systems with partial success. A preliminary examination of the diastereoselective and enantioselective synthesis has also been undertaken.