3,4-Dihydro-p-carboline

In 1969, Szantay and co-workers published a linear synthesis of (+)-yohimbine and (—)-P-yohimbine (75) in full detail (220). Tetracyclic key intermediate 400, obtained from 3,4-dihydro-p-carboline and a properly substituted a,p-unsatu-rated ketone (173), was treated with a proper phosphonoacetic acid derivative to give unsaturated nitrile 401 or unsaturated ester 402. Catalytic reduction of the latter resulted almost exclusively in 404 with normal stereo arrangement, while reduction of 401 supplied a mixture of normal and epialloindolo[2,3-a] quinolizines 403 and 405, respectively. Dieckmann ring closure of diester 404 gave 18a-methoxycarbonylyohimbone (407) as the thermodynamically favored... 

DehydrogenationThe tetrahydro-P-carboline 2 can be dehydrogenated directly to the dihydro-p-carboline 4 by two equiv. of 1, but the conversion is effected... 

A. Synthesis and Reactions of 3,4-Dihydro-P-carboline Reissert Compounds... 

The Reissert reaction of 3,4-dihydro-p-carboline (213) has also been studied 47,48). It has been shown that 3,4-dihydro-p-carboline (213) afforded 1-cyano-2,9-dibenzoyl-l,2,3,4-tetrahydro-P-carboline (214) with a phase-transfer catalyst and trimethylsilyl cyanide (Scheme 27). However, the normal Reissert product 2-benzoyl-l-cyano-l,2,3,4-tetrahydro-p-carboline (215) was obtained when a catalytic amount of anhydrous aluminum chloride was used in addition to the trimethylsilyl cyanide reagent. Reaction of 214 with sodium... 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Imino Diels-Alder reactions.1 The cycloaddition of dihydro-p-carbolines with... 

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. 

Kang H, Fenical W (1996) New Isoeudistomin Class Dihydro-P-carbolines from an Undescribed Ascidian of the Genus Eudistoma. Nat Prod Lett 9 7... 

Harmaline (= 3,4-Dihydroharmine Harmidine) (dihydro P-carboline, indole) Harman (= l-Methyl-p5-carboline)... 

Addition of the propargyl Grignard reagent to 3,4-dihydro-p-carboline followed by silver(I)-mediated oxidative cyclization to the dihydroindolizino[8,7-fo]indole and chemoselective hydrogenation provide racemic harmicine (three steps, 46 % overall yield). 

Finally, it might be noted that several brominated tetrahydro- and dihydro-p-carbolines are known, for example woodinine (64) [52,53] and 19-bromoisoeudisto-min U (65) [54], both from Eudistoma spp. The tunicate Pseudodistoma arborescens has yielded arboresddine A (66) a brominated derivative of the well-known indolo[2,3-a]quinolizidine alkaloid ring system [55]. 

The quatemization of imines to form mote reactive iminium salts has had limited synthetic utility since the activating substituents are often not easily removed. For this reason Lewis acids have been utilized to activate imines. MacLean and cowotkers have also addressed this problem and found that si-lylation of 3,4-dihydroisoquinolines and 3,4-dihydro-P-carbolines with trimethylsilyl triflate (TMS-OTf) provides a reactive, yet labile, silyl iminium salt which undergoes nucleophilic addition (Scheme 9). With this procedure, 3,4-dihydro-6,7-dialkoxyisoquinoline (54) was converted to amidine (56) in 98% yield. In the absence of TMS-OTf no addition occurred. 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

In the preparation of (3-carbolines such as 165, aromatization of ring C has proved much more difficult from the PS tetrahydro-p-carboline intermediate than the BN dihydro-P-carboline intermediate (129, 123). Coupling 165 with macrocycle 166 yielded an amide which was reduced to the tertiary amine, manzamine C. 

We developed two highly efficient approaches toward the 5HT2b receptor antagonist LY414197. The first route utilized a Pictet-Spengler reaction to construct the racemic THpC derivative. Access to the most active (5)-enantiomer was then achieved in up to 70% yield through a one-pot resolu-tion-racemization process. The second approach is based on the chiral Af-arenesulfonylated-1,2-diamine/ruthenium(II)-catalyzed asymmetric reduction of a 3,4-dihydro-p-carboline precursor, obtained from a Bischler-Napieralski or related Friedel-Crafts methodology. 

There are only two reported examples of dihydro-P-carbolines. The first was isoeudistomin U which was initially reported to be a 4-substituted dihydro-a-carboline derivative [95], but whose structure was revised after total synthesis to 3,4-dihydroeudistomin U (165) [114]. Recently, the dihydro—3-carboline (166) was reported from an imdescribed ascidian of the genus Eudistoma [115]. 

Activity of P-Carbolines, Tetrahydro-P-Carbolines and Dihydro-P-Carbolines... 

The bioactivity of the dihydro-P-carboline isoeudistomin U (165) was reported to be similar to that of eudistomin U it was not cytotoxic to CEM human leukemia lymphoblasts, nor did it exhibit antimicrobial activity against marine bacterial strains, although it exhibited strong activity against Agrobacterium tumefaciens [95]. No activity data was reported for (166) [115]. 

Synthesis of left-hand segment began with 7-benzyloxyindole 197. A Vilsmeier-Haack formylation followed by condensation afforded nitroalkene 198. Reduction, acylation with succinic anhydride, and subsequent Bischler-Napieralski cyclization provided dihydro-p-carboline 199. Noyori asymmetric reduction of 199, further treatment with A-iodosuccinimide, followed by activation with silver triflate in the presence of dimethoxy-N,N-diallylaniline furnished the desired coupling product 200. Subsequent saponification and cyclization via a ketene intermediate gave the rearrangement precursor 201. Oxidative skeletal rearrangement initiated by m-CPBA followed by removal of the Fmoc group and conversion of the aniline to the hydrazine furnished Fischer indole precursor 202 (Scheme 35). 

Conducted in an intramolecular sense, both Mannich and Vilsmeier reactions have been much used for the construction of tetrahydro-p-carbolines (dihydro-P-carbolines), such as are found in many indole alkaloids (p-carboline is the widely used, trivial name for the pyrido[3,4-Z ]indole nucleus). 

The action of a solution of potash in amyl alcohol on rutaecarpine produces anthranilic acid and a second acid which, when boiled with hydrochloric acid, is readily decarboxylated to tryptamine (6, 25, 94, 134, 135, 169). A close relationship between rutaecarpine and evodiamine was demonstrated by fusion of isoevodiamine hydrochloride. Rutaecarpine was formed with liberation of chloromethane. A number of syntheses of (63) have been reported 101, 135, 161), including some under so-called physiological conditions. Some of the more recent examples will be mentioned. Kametani et al. 102,108) obtained (63) in 80% yield through a regiospecificH s+n s cycloaddition of a keteneimine (generated in situ by extrusion of sulfur dioxide from the sulfmamide anhydride of anthranilic acid) with 3,4-dihydro-p-carboline or with 1,2,3,4-tetrahydro-l-keto-P-carboline 109) (also called 1,2,3,4-tetrahydronorharman-l-one or, as in Chemical Abstracts, 2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-one) ac-... 

H-nmr 5 2.53 (3H, s, NMe) and 5.90 (IH, s, C3-H). The structure of (67) was partially revealed by alkaline hydrolysis which yields N-methyl-anthranilic acid and 3,4-dihydro-p-carboline. Boiling alcoholic potassium hydroxide degrades (67) to N-methylanthranilic acid, carbon dioxide and tryptamine. When boiled with alcoholic hydrochloric acid (67) yields optically inactive isoevodiamine [evodiamine hydrate (74)] which can be recyclized with acetic anhydride or oxalic acid to optically inactive evodiamine. (67) can be converted to rutaecarpine via the dry hydrochloride of (74), which, on heating, yields (63). The chemistry of evodiamine has been reviewed by Armarego (6) see also (25, 94, 134, 169). 

Semenov BB, Krasnov KA (2004) Synthesis of 4-phenyl-3,4-dihydro-P-carboline. Chem Nat Comp 40 591-592... 

Small amount of water (10-50 equiv.) are able to affect the stereoselectivity of the products between 9-tosyl-3,4-dihydro-P-carboline and ketones in the presence of L-proline as a catalyst in DMSO (Scheme 24.5a) [131]. This effect was also observed in CH2CI2 and acetone, although it cannot be fully rationalized. Later, proline gave rise to high stereoselectivities in the catalytic reaction of aqueous tetrahydro-2H-pyran-2,6-diol with N-(p-methoxyphenyl) (PMP) aldimines in DMSO to afford the corresponding tetrahydropyridines via a Mannich-type/ intramolecular cycUzation cascade reaction (Scheme 24.5b) [132]. 

The enamine (/dienamine)-iminium cycle-specific cascade catalysis is an important constituent of amine-catalyzed cascade reactions [10]. This strategy has been explored extensively and also applied to natural product synthesis. One such example is the total synthesis of dihydrocorynantheol, which was first isolated from the bark of Aspidosperma marcgravianum in 1967 [29]. This indole alkaloid is a member of the corynantheine and was found to exhibit antiparasitic, antiviral, or analgetic activities, which have attracted considerable attention from the synthetic community. Among those reported total syntheses, Itoh et al. developed a Mannich-Michael cascade reaction catalyzed by L-proline 52 for the total synthesis of ent-dihydrocorynantheol 54 (Scheme 3.8) [30], The cascade reaction of 3-ethyl-3-buten-2-one 51 with dihydro-P-carboline 50 catalyzed by 30mol% of (S)-proline afforded the tetracyclic core structure 53 in 85% yield. Excellent stereoselectivity was achieved in this cascade reaction (99% enantiomeric excess and almost complete diastereomeric control). Therefore, this organocascade reaction could lead expeditiously to construction of the core structure, which enabled the authors to accomplish the total synthesis of enl-dihydrocorynantheol 54 in just five steps. 

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