Diastereodirected Synthesis of 1-Aryl-4-phenyl-β-carbolines

Abstract

A diastereodirected Pictet-Spengler reaction has been carried out to give the previously unknown 1-aryl(alkyl)-4-phenyl-β-carbolines and it has been found that all of the β-carbolines diastereomers obtained have predominantly the R*,R*-configuration. The diastereoselectivity of the given reaction is 44-70%.We have demonstrated a high diastereoselectivity of α-phenyl-nor-gramine in the Michael reaction with cyclic ketones and acetoacetic ester [1,2]. The present work is concerned with a study of the diastereoselectivity of the reaction of β-phenyltryptamine (1) with aromatic and aliphatic aldehydes (the Pictet-Spengler reaction [3]).Two routes are possible for the reaction studied, i.e. at the phenyl ring to give a tetrahydroquinoline [3] or at the pyrrole ring of the indole to give a β-carboline [4,5]. We propose that the reaction will involve the participation of the indole ring as a result of its π-excessive nature. In [4], the synthesis of 1-unsubstituted 4-phenyl-β-carbolines was described and it was shown that they possess marked biological activity.The previously proposed mechanism for the Pictet-Spengler reaction includes a stage of formation of a spiro[3H-indole-3,2'-pyrrolidine] derivative which subsequently rearranges to a β-carboline [6-8]. On this basis we propose that the reaction in our case using differently structured aldehydes and β-phenyltryptamine as starting materials occurs via the formation of intermediate 2. It is known that the diastereoselectivity is determined by stereoelectronic or spatial factors [9]. In this connection, in the intermediate the substituents in position 2 and 4 of the pyrrolidine ring must be maximally removed from one another, i.e. they have a trans arrangement. The rearrangement of compound 2 to the β-carboline system is evidently influenced by the same steric factors to form mainly the (R*,R*)-1-aryl(alkyl)-4-phenyl-β-carbolines 3 (here, and subsequently, the * indicates the relative configuration).The structures of the compounds prepared were investigated using one-and two-dimensional NMR spectroscopy. The 1 H and 13 C NMR one-dimensional spectra show two sets of signals of differing intensity which correspond to two diastereomers (the signals were assigned by analysing two-dimensional COSY, HSQC, and HMBC spectra). The spatial structure of each of the diastereomers was revealed using two-dimensional H-H NOE (NOESY) spectroscopy which allows one to identify the close positioned protons.We have studied the configuration of both diastereomers in the case of compounds 3a,b. In all of the compounds studied the H-3 protons have a clear equatorial or axial nature as shown by the shape of the H-3 and H-3a proton signals in the 1 H NMR spectra. This makes easier the identification of the configuration of the __________________________________________________________________________________________ 1 D. I. Mendeleev

Synthesis of 4-phenyl-1-(2-thienyl)-2,3,4,9-tetrahydro-1H-β-carboline

“…We demonstrated that the Pictet-Spengler reaction can be made diastereospecific by using β-phenyltryptamine (1) and various carbonyl compounds as starting materials [7][8][9][10][11]. Herein the possibility of forming and preparing a diastereomeric excess of (1R * ,4R * )-4-phenyl-1-(2-thienyl)-2,3,4,9-tetrahydro-1H-β-carboline using the Pictet-Spengler reaction and β-phenyltryptamine (1) and 2-thiophenecarbaldehyde (2) as starting materials was studied [12].…”