Application of a modified Pictet–Spengler reaction to the synthesis of optically active tetrahydro-β-carbolines, key intermediates in the preparation of many indole alkaloids

Abstract

A recent modification of the Pictet–Spengler reaction has been applied to the synthesis of optically active tetrahydro-β-carbolines. The method was initially investigated by treating various Nⁱⁿ,N^α-substituted tryptophan methyl esters (10) with methyl propynoate or dimethyl butynedioate; cyclisation of the resulting enamines (13) was achieved by the addition of trifluoroacetic acid, to give the desired tetrahydro-β-carbolines as mixtures of diastereoisomers (11) and (12). Single crystal X-ray structure determinations were carried out on two of the isolated diastereoisomers (12b) and (11e); chemical modification of these compounds allowed an unambiguous assignment of stereochemistry to all of the products from the modified Pictet–Spengler reaction. It was thereby ascertained that Nⁱⁿ-methylation and/or N^α-benzylation of the tryptophan methyl esters led to an increase in the proportion of trans products after condensation/cyclisation with methyl propynoate. This observation was applied to the preparation of the cis-cyano ester (3), which was required as a key intermediate in the synthesis of alkaloids of the ajmaline group.