P-Carbolines, derivatives

Other examples of deuterium incorporation at the epimeric centre have also been reported. When treated with a deuterated acid (DCl/MeOD and TFA-d, respectively), both P-carboline derivative 18 [20] and vinylogous urethane 19 [21] resulted in deuterium incorporation at C-l and C-12b (both correspond to C-3), respectively, Fig. (2). Mechanisms similar to that of Mechanism 1 were suggested to explain the epimerization. It should be noted, however, that, as pointed out above, mere deuterium incorporation is not sufficient evidence for Mechanism 1. Were Mechanism 1 alone responsible for the epimerization, both deuterium incorporation and epimerization would have to happen at the same rate. 

Structural features, reaction conditions and acid strength also influence the acid-catalysed epimerization reaction. For example, Mechanism 1 requires protonation at C-7, which seems to occur under strongly acidic conditions. When a P-carboline derivative was treated with a weakly acidic solution (TFA-d, 2.9 equiv., rt), deuterium incorporation did not occur, whereas refluxing of a similar compound in a DCl/MeOH solution resulted in deuterium incorporation at the epimeric centre. Therefore, it is impossible to define one universal mechanism to explain the epimerization reaction for any given compound. On the contrary, each compound type must be separately investigated under different conditions. Clearly, then, the acid-catalysed epimerization reaction of indole alkaloids is a fruitful research area. 

Japanese workers reported in 1956 (J. Pharm. Soc. Jpn., 76, 966 (1956)) that phosphorus trichloride-catalysed cyclisation of A-(3,4-dimethoxyphenylacetyl)tryptamine in boiling benzene gave the expected dihydro-p-carboline derivative. A recent reinvestigation of this reaction, however, showed that the major product, formed in 46% yield, is in fact the spirocyclic indoline derivative 1. When TFAA in benzene was used for the cyclisation, the indoline 2 was obtained in quantitative yield. 

The ethyl aluminum dichloride-catalyzed Michael alkylations of some indoles with N-(diphcnylmethylcnc)-a,()-didehydroamino acid esters allowed successful short synthesis of the tryptophan derivative and the 1,1-diphenyl-p-carboline derivatives, as well as compounds 253 and 252 (Scheme 55) [ 178]. 

Scheme 8.3 depicts an efficient and stereospecific synthesis of tadalafil (1) as well as 12a-epf-tadalafil (11). Pictet-Spengler reaction of D-trypto-phan methyl ester hydrochloride 9 with equal molar piperonal by refluxing for 4 h in nitromethane afforded cfs-lO-HCl in 98% ee and 94% yield. The hydrochloride salt of cis tetrahydro-p-carboline derivative a s-10-HCl was directly treated with 1.5 equiv of chloroacetyl chloride in dichloromethane at 0°C in the presence of 3 equiv of triethylamine to form N-chloroacetyl tetrahydro-p-carboline derivative 5 in 92% yield. Then compoimd 5 reacted with 5 equiv of methylamine overnight in DMF at room temperature to furnish tadalafil 1 in 95% yields. 

Tsuji, R., Nakagawa, M., Nishida, A. An efficient synthetic approach to optically active P-carboline derivatives via Pictet-Spengler reaction promoted by trimethylchlorosilane. Tetrahedron Asymmetry 2003, 14,177-180. 

Pictet-Spengler cyclization. 1,2,3,4-Tetrahydro-P-carboline derivatives result from CAN oxidation of carbamates of N-trimethylsilylmethyltryptamine. 

A collection of tetrahydro-P-carbolines has been prepared [401] by first attaching various tryptamines to Novabiochem s vinylsulfonytmethyl resin (560) by Michael addition involving the tryptamine amino groups. Subsequent reaction with various aromatic aldehydes in the presence of catalytic p-TSA in toluene at 80 °C afforded the desired tetrahydro-P-carboline derivatives (563) in excellent yields (Scheme 117). 

The 2-cyclohexylacetaldehyde is too air sensitive and needs to be protected to be further handled and stored. The aldehyde was protected either as a dimethylacetal or as a sodium bisulfite adduct. However, we discovered that the dimethylacetal derivative was unreactive in the reaction conditions (acidic) in the Pictet-Spengler reaction generating the tetrahydro-p-carboline derivative. In addition, the dimethylacetal derivative is an oil, making its isolation difficult on the plant scale. Therefore, we choose to isolate the 2-cyclohexylacetaldehyde as a bisulfite adduct, yielding a white crystalline solid. 

Oxidation of the tetrahydro-p-carboline derivative obtained by Pictet-Spengler reaction (vide supra, 75 to 80%)... 

Tetrahydro-p-carbolines, important structural elements of many tryptophan-derived natural alkaloids, showed a broad spectrum of pharmacological activities. One-pot cyclocondensation of polymer-bound tryptophan 399 with different aldehydes and ketones in CHCI3 in the presence of/>-toluenesulfonic acid (PTSA) as catalyst were carried out under MWI to give polymer-bound 1,2,3,4-tetrahydro-p-carboline derivatives within 15 min. Subsequent reaction with KCN in MeOH at room temperature gave 400 in 87-96% yields (Scheme 80). When cyclization was carried out under reflux in CHCI3 for 15 min using identical stoichiometry, no... 

Selected recent advances in the stereoselective synthesis of isoquinoline and p-carboline derivatives with the use of chiral auxiliaries of natural origin 05COS301. 

The initial success of the inverse electron demand [4 + 2]cycloaddition reaction of electron deficient, 1,2,4-triazine (61) with a-aryl enamine (60) to formulate the 4-arylpyridine forms the basis of a complementary approach to the CDE ring system of lavendamycin. In this strategy the oxidative insertion of aryl halide bond to provide the p-carboline derivative in the presence of palladium (0) was the notable feature. In a recently published article by Boger, a total synthesis of lavendamycin starting from the precursor 63 has been presented. The utility of... 

P-Carbolines are a class of indole alkaloids that are structurally similar to tryptophan, which has been shown to be useful for a variety of neuroscience applications The Baeyer pyridine synthesis was applied for the preparation of the P-carboline derivative ambocart) (346) ... 

Dimerization of 2-amino-3,4,6-tri-0-benzyl-2-deoxy-D-glucose with l.l -thionyl-or sulfonyl-di-imidazole gave the fructosazine and bis-tetrahydropyrano-piper-azine derivatives 73 and 74 in a ratio of 1 5, respectively a related compound appeared in Vol. 25, p.l32. The P-carboline derivative 75, isolated as a natural product from a hybrid plant cell culture product, was synthesized in six steps from tryptamine and ( )-4,5,6-tri-0-acetyl-2,3-dideoxy-D-ery/Aro-hex-2-enose. Thiazolo-triazoles such as 76, termed acyclo-C-nucleosides, were obtained on deacetylation of the product from condensation of peracetylated D-gluconic or galactaric acids with 4-araino-3-aryl-l,2,4-triazole-5-thiols in the presence of POCls. The related 1,2,4-triazole 77 and dihydroimidazole 78 were obtained by condensation of D-glucono-1,5-lactone with aminoguanidine and ethylenedia-mine, respectively, followed by acetylation then O-deacetylation. ... 

On the basis of the above mechanistic studies, the You group designed an Ir-catalyzed tandem dearomatization/migration protocol for asymmetric synthesis of enantioenriched tetrahydro-p-carboline derivatives 190 (Table 6.16). The migratory group in this reaction is methylene adjacent... 

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). 

Also, a large number of indole alkaloids are formed by Mannich reactions involving tryptophan or its decarboxylation product tryptamine with various aldehydes. Both the a- and p-position of the indole nucleus are electronegative, and a Mannich reaction with tryptamine can yield a p-carboline derivative or a 3,3-spiroindolenine [30]. A further example is provided by the tropinone biosynthesis (Figure 1.29) [31 ]. 

The bitter taste and blue fluorescence of the flesh of the toadstool Cortinarius infractus are due to P-carboline derivatives 613). From the methanolic extract of freeze dried fruit bodies have been isolated infractin (527) showing bright blue fluorescence under UV light, 6-hy-droxyinfractin (528) which fluoresces green-yellow, and a bitter principle, infractopicrin (529). The yellow pigment (528) [UV/vis. (methanol) max(log 8) = 214 (4.36), 231 (4.53), 246 (4.37), 258 (4.24), 290 (sh., 4.14), 296 (4.33), 360 (3.72)] has been synthesised according to the reactions depicted in Scheme 84 567). 

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... 

Fekete M, Kolonits P, Hien NT, Novak L (2005) Synthesis of novel tryptamine and P-carboline derivatives via palladium-catalyzed reaction of bromotryptamine with organic boronic acids. Cen Eur J Chem 3 792-802... 

Reactions of sugars with amino acids, which have more reactive functional groups (such as sulfur, hydroxy, aromatic and heterocyclic amino acids), also bypass the Amadori rearrangement and the reaction gives rise to various heterocycHc compounds. For example, glucose yields a thiazolidine derivative, 2-(d-gluco-l,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxyHc acid (4-213), with cysteine and a P-carboline derivative, 1,2,3,4-tetra hydro-1 - o-gluco-1,2,3,4,5-pentahydroxypentyl)-P-carboline (4-214), arises from tryptophan or tryptamine. 

Two new imidazole alkaloids and a P-carboline-derived alkaloid hyrtioreticulin F (73) were isolated from the marine sponge H. reticulatus and subsequently characterized [75]. No data were reported for the imidazole alkaloids characterized in the study, but the authors did report... 

Antioxidants in Processed Garlic Tetrahydro-P-carboline Derivatives in Aged Garlic Extract... 

This chapter discusses the antioxidant effects of 1,2,3,4-tetrahydro-P-carboline derivatives (THpCs) in AGE l-methyl-l,2,3,4-tetrahydro-P-carboline-... 

Figure 3, Effects oftetrahydro-p-carboline derivatives identified in aged garlic extract on LPS-induced nitrite production from macrophages. Data represent means SE of triplicate samples. Significant difference (p<0.01) compared with control without samples,...

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