547.759.3 V. N. Azev, 2 and V. V. Kachala 3A diastereotopic Pictet-Spengler reaction was performed to form previously unknown 1-and 1,1-substituted 4-phenyl-β-carbolines based on β-phenyltryptamine, aldehydes of various structure, and isatins. It has been demonstrated that the predominant diastereomers of the prepared β-carbolines have the (R*,R*) configuration. The diasteroselectivity (de) of the reaction varies from 44 to 88%.The Pictet-Spengler reaction, which occurs in plants and in humans, leads to the formation of various derivatives including isoquinoline and β-carboline.Some very simple alkaloids containing the β-carboline structural moiety and belonging to the harmane group are found in medicinal plants such as Passiflora fluidum [1], P. edulis, P. incarnata, Bansteriopsis caapi [2], and Peganum harmala [3], Zygophylaceae. They are used in traditional medicine to treat asthma, jaundice, and other diseases [3,4]. Harmaline is a known MAO inhibitor and powerful serotonin antagonist [5]. Harmane alkaloids have been detected in food plants [2] such as soy, rye, wheat, rice, barley, mushrooms, grape juice, wine [6], charred insects, and cigarette smoke. It has been reported that alcohol increases the harmane content in the brain and urine [7].Cytotoxic effects of harmane alkaloids have also been found [8]. These alkaloids are reported to affect the cardiovascular system [9, 10] and to have a hypotensive effect [10].The harmane alkaloids include also eleagnine [(1R)-1-methyl-2,3,4,9-tetrahydro-1H-β-carboline]. A synthesis of the racemate of eleagnine (1a) using the Pictet-Spengler reaction based on tryptamine (1) and acetaldehyde was previously proposed [11].Much later eleagnine was biosynthesized [12] and synthesized enantioselectively [13,14] and (1S)-1-methyl-2,3,4,9-tetrahydro-1H-β-carboline was synthesized enantioselectively (ee > 98%) [15]. The reaction proceeded through the formation of two diastereomers with subsequent fractional crystallization of one of them and removal of a sulfamide, which was known to be chiral.Recently the solid-phase chemistry of indole is rapidly developing with the Pictet-Spengler reaction being carried out on a polymeric support to synthesize 1,3-disubstituted β-carbolines. Diastereoselectivities (de) of 8-52% have been obtained from tryptophan [16][17][18][19][20][21][22][23][24][25]. It depended on the presence of a substituted nitrogen in the indole ring [20].Based on this, we carried out diastereotopic syntheses of previously unknown 4-phenyl-1-and 1,1-substituted β-carboline derivatives using the Pictet-Spengler reaction. The starting materials were β-phenyltryptamine (1) as the racemate and aliphatic, aromatic, and heterocyclic aldehydes.

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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

While continuing work on synthesis and study of novel β-carboline systems [1, 2], we obtained 4-phenyl-3,4-dihydro-β-carboline (2) (a representative of the previously undescribed group of 4-aryl-substituted 3,4-dihydro-β-carbolines) by formylation of β-phenyltryptamine (1) followed by cyclization under BischlerNapieralski reaction conditions. In contrast to known derivatives of this series, which are readily formed when the corresponding N-acyltryptamines are treated with phosphorus oxychloride [3], synthesis of compound 2 required considerably more vigorous conditions and was accompanied by secondary processes; the overall yield was only 20%.Since the diastereoselectivity is determined by either stereoelectronic factors or by steric factors [4], we hypothesized that if we used compound 2 in a Michael reaction and we used 1,3-dimethylbarbituric acid as the second component, then the reaction products would consist of two diastereomers with predominance of the R*,R*-isomer 3:

Fused pyridine derivatives R 0450 Diastereodirected Synthesis of 1-Aryl-4-phenyl-β-carbolines -[via Pictet-Spengler reaction]. -(SEMENOV, B. B.; NOVIKOV, K. A.; SMUSHKEVICH, Y. I.; AZEV, V. N.; KACHALA, V. V.; Chem. Heterocycl. Compd. (N. Y.) 41 (2005) 10, 1273-1279; Mendeleev Russ. Univ. Chem. Technol., Moscow 125190, Russia; Eng.) -R. Langenstrassen 24-150