B-Carboline derivatives

Biochemistry and pharmacology of tryptamine and B-carboline derivatives A minireview." Journal of Psychoactiv Drugs 16 (1984) 347-58. 

N. Ide, M. Ichikawa, K. Ryu, K. Ogasawara, J. Yoshida, S. Yoshida, T. Sasaoka, S.-I. Sumi, and H. Sumiyoshi, Antioxidants in processed garlic. II. Tetrahydro-b-carboline derivatives identified in aged garlic extract, in G, 2002, 449 150. 

The B-carboline derivative 85 was isolated as a natural product from a hybrid plant cell culture. It was synthesized from tryptamine and (E)-4,5,6-tri-0-acetyl-2,3-dideoxy-D-erythro-hex-2-enose. Condensation of tryptamine with 1,2-0-cyclohexyMene o-xylo-pentodialdose gave tetra-hydro analogue 85a [143-145]. 

Mannich reaction, and this method has recently been extended and repeatedly applied (see Section IV, B, 2). It involves treating a 1-m-hydroxybenzyl-1,2,3,4-tetrahydro-jS-carboline derivative (389) with formaldehyde at pH 4.4. When the aqueous solution of the hydrochloride of the hydroxymethyl derivative so formed is made basic with sodium carbonate, the pentacyclic base (390) precipitates. 

Interaction of substituted dienediamines with ethylenediamine yields im-idazo[3,2-n]pyridine derivatives (95JHC477). 3-Arylaminoindoles, with distinct enamine properties, are the starting materials for the synthesis of indolo[3,2-b]quinoline derivatives [96KFZ(7)42]. a-Carboline derivatives can be obtained from enamine-based 3-dimethylamino-2-indolinones [96KFZ(9)35, 96KFZ(10)32], The synthesis and transformation of enamines based on the pyrido[l,2-n]pyrazine ring system into imidazo[l,2-n]pyridine and imidazo[l,2-a]pyrimidine derivatives have been reported... 

The Wittig-type reactions of iminophosphoranes with isocyanates and related compounds have also been extensively used in heterocyclic synthesis. Examples include the preparations of the mesoionic [l,3,4]thiadiazolo[2,3-c][l,2,4]triazines (210) from (209), 0 bicyclic guanidines, e.g. (212), from (211), naphthypyridines (215), (216), and (217) from (213) and (214), 2 pyrido[l,2-f]pyrimido-[4,5-d)pyrimidines (218), 7H-pyrido-[4,3-c]- (219) and 10H-pyrido[3,4-b]- (220) carbazoles, tricyclic fused 2,4-diimino-l,3-diazetidines (222) from the bisiminophosphorane (221), benzotriazepines (225) from (223) and (224), 6 and mesoionic thiazolo-[2,3-b]-1,3,4-thiadiazoles (227) and N,N-bisheteroarylamines from the iminophosphorane (226), derived from 3-amino-4-phenylthiazole-2(3H)-thione. The carbodiimides (229), prepared from the iminophosphorane (228), can be converted into quinolines or a-carboline derivatives depending on the nature of the isocyanate used in the reaction with (228) and the reactions of iminophosphoranes (230) and (231) with aryl and styryl isocyanates provide one-pot syntheses of quinoline, a-carboline, and quinindoline derivatives. 9... 

In contrast, the orange base euxylophorine B (33) is stable in acetonitrile solution, but in methanol suffers nucleophilic attack at C-5 with formation of the colourless jS-carboline derivative (34). Treatment of (34) with trifluoroacetic acid results in slow conversion into the trifluoroacetate of euxylophorine B on the other hand, thermolysis of (34) does not regenerate (33), but gives instead the benzodiazepine derivative (35). 

Ganesan et al. reported the total synthesis of the cell cycle inhibitor (-)-spirotryprostatin B (622) in 2000 (411). Their synthesis started with L-tryptophan methyl ester 616, which was treated with senecialdehyde to give imine 617. The indole derivative reacted in a iV-acyl-iminium Pictet-Spengler condensation to yield the tetrahydro-p-carboline derivative 618 (412) (Scheme 10.2). 

FIGURE 11.59 1,2,3,4-Tetrahydro-P-carboline-derived diketopiperazines library. (From Kundu, B., Solid-phase strategies for the design and synthesis of heterocyclic molecules of medicinal interest, Curr. Opin. Drug... 

Li S, Yang B, Zhang Q, Zhang J, Wang J, Wu W (2010) Synthesis and bioactivity of beta-carboline derivatives. Nat Prod Commun 5 1591-1596... 

Gutsche B., Herderich M. High-performance liquid chromatography-electrospray ionisation-tandem mass spectrometry for the analysis of 1,2,3,4-tetrahydro-fi-carboline derivatives. Journal of Chromatography A, 767 101-106(1997). 

A protonated Schiff s base (11) is the presumed intermediate in the Mannich reaction. From the condensation of tryptamine with benzal-dehyde a Schiff s base (10 R = CgHg) has indeed been isolated, which on treatment with acid cyclizes to l-phenyl-l,2,3,4-tetrahydro-j8-carboline(14 R = CeHg). Condensation ofa tryptamine derivative with an aldehyde in the absence of acid leads to the corresponding Schiff s base (10), the structure of which has been proved by reduction to an Ajg-alkyltryptamine derivative (13) with sodium boro-hydride. Reconversion of a l,2,3,4-tetrahydro-j8-carboline (14 R = CH2C6H3-3,4- 0H)2) into the corresponding protonated SchifiF s base of tryptamine (11) has been postulated as a step in the rearrangement in strong acid of this 1,2,3,4-tetrahydro-jS-carboline derivative into an indolenine (see Section IV, B, 3). One instance of a Mannich-type condensation of an aldehyde with a modified tryptamine derivative into the jS-position, rather than into the a-position, of the indole... 

Following up this idea they synthesized )8-carboline and 1-methyl-/3-carboline by reaction of tryptophan with formaldehyde and acetaldehyde, respectively, under oxidizing conditions. The steps of this biogeneticaUy patterned synthesis have been repeatedly studied and are fuUy discussed in Sections III, A, l,aand III,E,2,a,i. The formation of l,2,3,4-tetrahydro-)8-carbolines as the initial step in the biogenesis of jS-carboline alkaloids, by reaction of tryptophan or trypta-mine or the corresponding hydroxylated derivatives with aldehydes or a-keto acids, derivable from a-amino acids, is a widely held concept. Two lines of circumstantial evidence favor this hypothesis. First, a number of simple l,2,3,4-tetrahydro-)8-carboline derivatives have been found to occur naturaUy. l-Methyl-l,2,3,4-tetrahydro-]8-carbo-line (461 = B = H eleagnine) has been isolated from Elaeagnus... 

The reduction of 2-methyl-1,2,3,4-tetrahydro-y-carboline (92) with zinc and hydrochloric acid in the presence of mercuric chloride gives the indolenine derivative, 2-methyl-l,2,3,4,4a,9b-hexahydro-y-carbo-line (93). A related compound, 4,9b-diethyl-2-methyl-l,2,3,4,4a,9b-hexahydro-y-carboline (96), was obtained by catalytic hydrogenation of 95, which was prepared by Fischer ring closure of the phenyl-hydrazone 94. The stereochemistry of the B/C ring junction in these... 

Alkylation at the ind-N of l,2,3,4-tetrahydro-j8-carbolines has been carried out with alkyl halide after treatment with sodamide in the usual manner. Cyanoethylation of a p /r-V-substituted tetrahydro-jS-carboline in the presence of Triton B yields the corresponding 9-cyanoethyl derivative. Similarly, treatment of p / -V-methyl-l,2,3,4,4a,9b-hexahydro-y-carboline with sodamide, followed by benzyl chloride, leads to the ind-A -benzyl-substituted derivatives. l-Oxo-l,2,3,4-tetrahydro-j8-carboline yields the ind-A -methyl derivative directly with dimethyl sulfate.Prolonged treatment with sodium hydride, followed by methyl iodide, yields the 2,9-dimethyl derivative. Heating with sodium hydride in acetone followed by the addition of dimethyl sulfate gives rise to the ind-V-methyl derivative. ... 

---