Alkaloids tryptamine-derived

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). 

We became particularly interested in strychnine when we noticed that the tetracycle 21 (Scheme 4.6), which might be readily available by an intramolecular Diels-Alder cycloaddition of a tryptamine-derived aminodiene, contains much of the complexity of this popular alkaloid target. In fact, this tetracycle is common to many indole monoterpene alkaloids including members of the Strychnos, Aspidosperma, and... 

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

Thomas (23) predicted that the non-tryptamine moiety of the indole alkaloids is derived from a cyclopentanoid monoterpene precursor. Wenkert (2k) independently reached to the same conclusion. 

Another substrate class, for which the outcomes of a radical and a carbocationic process are opposite, are indoles (Fig. 85) [418], Indeed, when oxaziridines 315a or 315c were treated with indoles 314c in the presence of 2 or 10 mol% of C11CI2/ TBAC oxazolidinoindolines 316c were obtained as the exclusive products in 53-90% yield. The reaction is applicable to 2-, 3-, and 2,3-disubstituted indoles. Chiral indole derivatives acylated with (S)-proline units at nitrogen underwent asymmetric diastereoselective aminohydroxylation reactions with 86-91% de. Tricyclic hemiaminals derived from tryptamine derivatives could be transformed to pyrrolidinoindolines, which are core structures of a number of alkaloids. 

Trost s synthesis138 of desethylibogamine (233) illustrates the application of a new approach to alkaloid synthesis, in which the two vital cyclization processes involve catalysis by palladium complexes protection of the nitrogen by formation of an amide, so often necessary in conventional syntheses, is here unnecessary. The first of the cyclization processes, (234)—>(235), results in a very neat formation of the isoquinuclidine ring system via a palladium-catalysed SN2 cyclization of the tryptamine derivative (234) (Scheme 24). 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

The majority of alkaloids have been found to be derived from amino acids, such as tyrosine, phenylalanine, anthranilic acid, tryptophan/tryptamine, ornithine/arginine, lysine, histidine and nicotinic acid (Fig. 2.1). However, alkaloids maybe derived from other precursors such as purines in case of caffeine, terpenoids, which become aminated after the main skeleton has been synthesized i.e. aconitine or the steroidal alkaloids, are found in the Solanaceae and Liliaceae. Alkaloids may also be formed from acetate-derived polyketides, where the amino nitrogen is introduced as in the hemlock alkaloid, coniine. 

All terpenoid indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Fig. 2b). Tryptophan decarboxylase, a pyridoxal-dependent enzyme, converts tryptophan to tryptamine (62, 63). The enzyme strictosidine synthase catalyzes a stereoselective Pictet-Spengler condensation between tryptamine and secologanin to yield strictosidine. Strictosidine synthase (64) has been cloned from the plants C. roseus (65), Rauwolfla serpentine (66), and, recently, Ophiorrhiza pumila (67). A crystal structure of strictosidine synthase from R. serpentina has been reported (68, 69), and the substrate specificity of the enzyme can be modulated (70). 

Yohimbine, a compound with aphrodisiac properties, has been synthesised (ref.58) in an elegant six-step route from tryptamine derivable in theory from tryptophan a major constituent amino acid from casein, other alkaloids of the indole group such as vincamine... 

Quadrigemine B (28). The alkaloid gives fragment ions mje 172,173, 516, and 517 in the mass spectrometer. This is strongly indicative of the presence of a chimonanthine-type unit situated at one end of a tetrameric tryptamine derivative. 

Ergot Alkaloids.—The tryptophan and tryptamine derivatives (30) and (31) respectively, labelled in each case with 14C at the carbinol carbon, have been shown20 to be precursors of the alkaloids agroclavine (32) and elymoclavine (33). These results throw further light on the sequence of intermediates leading from tryptophan to the ergoline system. 

Roxburghines constitute a group of octacyclic sesquimeric indole alkaloids conceptually derived from two tryptamine molecules and a monoter-pene moiety of the corynanthe type. Roxburghine D (171) and the new analog, roxburghine X (172), C31H32N4O2, mp 215°C, [a]D27 -29°,... 

Since its discovery the Pictet-Spengler cyclization has formed the basis of numerous syntheses of alkaloids containing aromatic subunits. This high-yielding reaction involves, in its broadest sense, nucleophilic attack on an iminium ion by the Tr-electrons of a tethered aromatic moiety. In the classical reaction a substituted P-phenethylamine is condensed with an aldehyde under acidic conditions to produce a te-trahydroisoquinoline (Scheme 16). A useful variant of the Pictet-Spengler reaction, which provides tetr ydro-(3-carbolines and their derivatives, involves the condensation of a tryptamine derivative and an aldehyde (Scheme 16). Whether nucleophilic attack on the resulting iminium ion occurs initially at the a- or -indole carbon is a topic of current debate and, indeed, there is evidence to suggest that the mechanistic pathway could be substrate dependent. ... 

Ban s general entry to the Strychnos and Aspidospema alkaloids makes ingenious use of a novel photoisomerization of 1-acylindole derivatives to 3-acylindolenines. When applied to the tryptamine derivative (132), the derived indolenine (133) spontaneously rearranged, with formation of the indole-amide (134) in 80% yield (Scheme 22). Obvious stages then led to (135), which... 

Studies on known alkaloids include one on the AA BB system and the conformational populations of tryptamine and some N-substituted derivatives, and X-ray crystal structure analyses of psilocybin " and psilocin. " In connection with the separation and identification of tryptamine derivatives in the cerebrospinal fluid of schizophrenic patients the g.l.c. analysis of the heptafluorobutyroyl derivatives is recommended success is claimed on picogram quantities of material. ... 

In principle there appears no reason why a condensation product of secologanin with tryptophan instead of tryptamine should not occur in nature to give a new series of carboxy terpenoid indole alkaloids parallel to the known tryptamine derivatives. A few representatives have been isolated in recent years, and probably more will follow with the adoption of isolation techniques suited to amino acids. 

Since tryptophan is recognized as a main constituent of plant proteins and as a common biogenetic precursor of the complex indole alkaloids, the wide occurrence of tryptamine derivatives in the plant kingdom is not unexpected. The presently known cases of these simple indole alkaloids have been ones in which a tryptamine unit formally appears as a slightly modified structure (e.g., by oxidation or methylation), as a cyclized form or a dimeric variation thereof, or as a modification which incorporates short carbon chains (e.g., C4, C2) or a simple aromatic structure (anthranilic acid) respectively. The great majority of the simple indole alkaloids are confined to the dicotyledon plants. 

Table I is a compilation of plant species which contain the simple indole alkaloid types of Fig. 1. As mentioned earlier, the main requirement for the inclusion of a certain simple indole alkaloid into Table I is that it contain a tryptamine unit as a readily distinguishable feature in its structure. That tryptamine is a precursor in the biosynthesis of many of the b, c, d, and e type simple indole bases is yet to be shown although it is felt that future work will prove the correctness of such a view. Gramine, the simplest indole alkaloid, has been included in the tryptamine classification a because it is biosynthetically related to tryptophan cryptole-pine has been likewise included therein although its structural relationship to tryptophan appears more obscure (Volume VIII, Chapter 1, pp. 4, 19). The calycanthine type does not possess a tryptamine structure but it is included in the simple indole alkaloid b classification since most of its congeners are tryptamine derivatives and since it exhibits a close biogenetic relationship to this latter (chimonanthine) type (Volume VIII, Chapter 16). Type d is represented by the small number of the so-called canthin-6-one alkaloids (Volume VIII, pp. 260-252, 497-498). The most recent variation of the simple indole alkaloids is found in the Anacardiaceae family. Its indoloquinolizidine nucleus suggests inclusion with type d on the basis of structural and biogenetic similarity. Finally, simple indole alkaloid type e is composed of the well-defined evodiamine (rutaecarpine) structural form (Volume VIII, Chapter 4).

SSS is highly specific for both substrates (198)-, for example, tryptophan was not accepted as substrate, nor was any substituted tryptamine derivative. Indole alkaloids such as ajmalicine, vindoline, and catharanthine did... 

More recently, Kalaus and Szantay have made use of a similar approach to synthesize a variety of pentacyclic indole alkaloids containing the aspidospermane, ibophyUidine, and iboxyphylline core structures. In one approach, featured in the formal total synthesis of ( )-12-demethoxy-N(l)-acetylcylindrocarine (188) [73], a benzyl-protected tryptamine derivative 183 was treated with an appropriately substituted aldehyde (184) to form the enamine species 185a-b, which then underwent... 

In an alternative approach to the synthesis of similar alkaloids, Kalaus and Szantay chose to construct the D-rings first, before the pivotal Diels-Alder reactions (Scheme 45). Thus, deprotection of the trityl-protected tryptamine derivative... 

Quadrigemine C (254) [96] and 11,11 -dideoxyvertillin A (255) [97] are representative of a remarkable series of tryptamine-derived plant alkaloids that link together two to eight pyrrolidinoindoline units, such as the monomer okaramine N (256) [98], dimer ditryptophenaline (257) [99,100] and 11,11 -dideoxyverticillin A (255) [97], trimer idiospermuline (258) [101], and tetramer psycholeine (259) [96], together with an exceptional member of this family psychotrimine (260) [102-104] (Fig. 10). 

We did discuss the status of the upcoming book for a while. For those who don t know, it was leaked on the Net a while back that Sasha is working on TiHKAL (Tryptamines I Have Known and Loved). This book will do the same job for all of the indole or tryptamine-derived psychoactives that PiHKAL did for the phenethylamines. Thus it would cover DMT and all the di-alkyl-tryptamines mentioned above, DMT analogues and derivatives like 5MDMT, psilocybin and psilocin, the beta-carbolines such as harmine and harmaline, everyone s favorite problem child LSD and its related ergot alkaloids, and doubtless many compounds which the rest of us have never heard of. There will also be an appendix on new phenethylamines which have been reported to him during the last year. Apparently the publication of PiHKAL has brought a number of researchers "out of the closet" with more material for him to publish. 

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