P-Carboline system

Successful hydrogenation, which occurs only with the anhydronium base (or with the salt at pH 10) and not with its salt or with the unalkylated carboline, has been discussed on the basis of the canonical formula of the anhydronium base in the P-carboline system in which the / -quinoid structure might be responsible for the ease of hydrogenation (Scheme 12.17).126... 

Scheme 12.17 Canonical formula of the anhydronium base in the P-carboline system.

An impressive acyliminium ion initiated cyclization to the p-carboline system, combined with the simultaneous formation of an additional seven-membered ring, is found in the synthesis of the vasodilating alkaloid vincamine (80), as outlined in Scheme 39. ... 

Taylor, M. S., Jacobsen, E. N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558-10559. Kowalski, P., Mokrosz, J. L. Structure and spectral properties of P-carbolines. Part 9. New arguments against direct rearrangement of the spiroindolenine intermediate into P-carboline system in the Pictet-Spengler cyclization. An MNDO approach. Bull. Soc. Chim. Belg. 1997, 106, 147-149. 

The tricyclic P-carboline system itself is most conveniently prepared by one of two methods, both of which are conducive to substitution at C(l). The Pictet-Spengler (PS) reaction has been used in many of these syntheses, especially those requiring tetrahydro-ring C... 

The Bischler-Napieralski (BN) method has demonstrated great utility for fully aromatic P-carboline rings. Substitution on carbocyclic ring A of the p-carboline system requires suitably substituted tryptamine which can be prepared via the Fischer indole synthesis or one of several methods for synthesis of indole rings (28, 128). 

Apart from the biogenetic scheme described above, the only other useful piece of information that could direct the development of synthetic routes to manzamine A was provided by the Kobayashi group who demonstrated that the related natural product ircinal A (17, Scheme 3) could be converted into manzamine A (1) through initial condensation with tryptamine (16) and subsequent acid-induced Pictet—Spengler cyclization (see Chapter 5 for a discussion of this reaction), followed by DDQ-mediated oxidation to complete the fully aromatic P-carboline system. Although this discovery... 

The structure of guettardine (72), isolated from Guettarda heterosepala, suggests that this alkaloid may represent an intermediate between the Corynanthe and cinchonamine types of alkaloids (Herbert, 1986). If so, cleavage of the p-carboline system must precede the formation of the quin-uclidine ring (Fig. 34.20) (Herbert, 1986). 

A betaine containing the P-carboline system, of which there are examples in some ascidians and bryozoans, has been found in Lignopsis spongiosum, a deep-water (130-280 m) member of the Briareidae harvested in South Atlantic (Cabrera and Seldes, 1999). 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

Table 4 illustrates the use of the CAR technique to develop CL kinetic-based determinations for various analytes in different fields. As can be seen, the dynamic range, limit of detection, precision, and throughput (—80-100 samples/ h) are all quite good. All determinations are based on the use of the TCPO/ hydrogen peroxide system by exception, that for p-carboline alkaloids uses TCPO and DNPO. A comparison of the analytical figures of merit for these alkaloids reveals that DNPO results in better sensitivity and lower detection limits. However, it also leads to poorer precision as a result of its extremely fast reactions with the analytes. Finally, psychotropic indole derivatives with a chemical structure derived from tryptamines have also been determined, at very low concentrations, by CAR-CLS albeit following derivatization with dansyl chloride. 

The pyrrolo[3, 4 2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-P-carbolines did not occur under the conditions <00JHC1177>. 

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). 

Likewise, a wide range of complex polycyclic systems was constructed from suitable precursors. Compounds 269 and 270 were synthesized in 79% yield in a 1.6 1 ratio from tetrahydroisoquinoline-1-carboxylic acid, while 271 was obtained as a single stereoisomer in 87% yield from tetrahydro-p-carboline-l-carboxylic acid (Scheme 3.91). 

The direct condensation of unsaturated oxazolones with tryptamine in hydrochloric acid is an important and interesting case that deserves special attention. The reaction occurs via in situ hydrolysis of the oxazolone to a keto acid followed by a Pictet-Spengler-like reaction with tryptamine. This protocol affords a tetrahydro-p-carboline wherein the oxazolone is the synthetic equivalent of an arylacetalde-hyde. The reaction has been extended to substituted tryptamines 500 thus, allowing access to 1,3,4-trisubstituted tetrahydro-p-carbolines 501 as shown in Scheme 7.159. Some of these compounds have shown promising central nervous system activity. 

The principal reason that DMT must be administered parenterally is its rapid and efficient metabolism. It can be oxidized to the N-oxide. It can be cyclized to P-carbolines, both with and without an N-methyl group. It can be N-dealkylated to form NMT and simple tryptamine itself. Best known is its oxidative destruction, by the monoamine oxidase system, to the inactive indoleacetic acid. There is a wild biochemical conversion process known tor tryptophan that involves an enzymatic conversion to kynurenine by the removal of the indole-2-carbon. A similar product, N,N-dimethylkynurenine or DMK, has been seen with DMT, when it was added to whole human blood in vitro. 

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 asymmetric alkylation of the P-carboline ring system affords access to indole alkaloids. The simplest is tetrahydroharman, whose synthesis is mediated by asymmetric alkylation of a formamidine, as shown in Scheme 30. In the racemic series (c/. Scheme 16), the indole nitrogen may be protected simply by deprotonation with potassium hydride. However, in the chiral series the presence of a potassium ion lowers the selectivity. Thus, the methoxymethyl protecting group was used. 

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