Synthesis of 4-Substituted b-Carbolines

Various 4-subst~tuted D-carbolines are synthesized and further modified by electrophilic substitution reactions.The regioselectivity of electrophilic attack is demonstrated for a number of different reactions and strategies are outlined to achieve substitution at positions unaccessible by electrophilic attack.Ethyl B -c a r b o l i n e -3 -c a r b o x y l a t e , isolated from human urine by Braestrup and coworkers1), was found to exhiblt high affinity for benzodiazepine receptors.This observation has stimulated the search for new D-carboline derivat~ves with benzodiazepine-type activity , 3 ) .First results obtained in our synthetic programme revealed that introduction of 4-substituents into the carboline skeleton was often associated with a considerable increase in receptor binding affinities.Our report, therefore, concentrates upon synthetic methodology leading to 4-substituted D-carbolines and their further transformation. Table I listsup a number of characteristic compounds which were synthesized according to three general pathways: Path a 1. Path a represents the most convenient entry into the class of 4-substituted D-carbolines.The synthesis, outlined in the scheme below, employs standard methods of indole chemistry: aldimines were prepared by Campbell's procedure 4 and reacted with indoles in analogy to Snyder's reaction mode5).Condensation with nitroacetic acid ester was performed as described by Lyttle and ~r o f e e v ~) .Hydrogenation in the presence of Raney-Ni gave tryptophan derivatives I V , isolated