Carboline alkaloids yohimbines

Cleavage of the hetero ring in a number of extended tetrahydro-j8-carboline systems was observed in the course of structural elucidation of tetrahydro-jS-carboline alkaloids. A few examples only will be given. The indole derivative 287 was isolated as one of the products of the selenium dehydrogenation of yohimbine (358 R = and... 

A number of alkaloids are known whose structures are more or less similar to those of endogenous neurotransmitters. Targets can be the receptor itself, the enzymes which deactivate neurotransmitters, or transport processes, which are important for the storage of the neurotransmitters in synaptic vesicles. Alkaloids relevant here include (Table IV) brucine, ergot alkaloids, eseridine, serotonin, physostigmine, gelsemine, j8-carboline alkaloids, strychnine, yohimbine, berberine, bicuculline, bul-bocapnine, columbamine, coptisine, coralyne, corlumine, ephedrine, ga-... 

Yohimbine is a major carboline alkaloid in the bark of Pausinystalia species, such as Pausinystalia yohimbe (Corynanthe yohimbe), Pausinystalia macrocerus, Pausinystalia paniculata, and Pausinystalia trillesi. It is also found in Pseudocinchona africana and Rauwolfia canescens. 

The simplest of the group is the base (13), isolated from Dracontomelum mangiferum and was shown to be in partially racemic form by the synthesis and resolution of the compound. The ( —)-isomer (13) slightly predominates in the natural mixture the absolute configuration was assigned by o.r.d. comparison " with yohimbine and i/ -yohimbine. In fact this is the only simple tetrahydro-jS-carboline alkaloid yet obtained which is not completely racemic. 

Systematic structure activity relationships (SARs) around the scaffold of the natural alkaloid yohimbine led to the discovery of 1,2,3,4-tetrahydro-p-carboline (THpC) derivatives that have been shown to be very potent and highly selective 5HT2b receptor antagonists. Of particular interest are 1-substituted-THpC compounds (1 to 4) that were selected for further development (Figure 6.1). 

Most jS-carboline alkaloids are toxic to animals and may repel potential predators (E 5.5.3). Reserpine, rescinnamine, yohimbine, vinblastine, vincristine and strychnine are used in the materia medica (F 2). 2-Methyl- and l,2-dimethyl-6-methoxytetrahydro-jS-carboline, harmine, harmaline and tetrahydroharmine as well as ibogaine are constituents of hallucinogenic preparations used by American and African.natives (F 3). 

As shown in Chart 5.1, a wide variety of alkaloid skeleta are derivable from Type I precursor and tryptamine by further ring closures. It is worth pointing out that in so far as they have been investigated, they all have had the same stereochemistry for the carbon equivalent to C-15 of yohimbine. In this chapter, certain tetrahydro-j8-carboline alkaloids, viz., the yohimbines, their ring E seco equivalents and ring E oxygen heterocycles will be discussed since they show much chemistry in common. Over the years most of their degradation products have been synthesized, they have been interrelated, their absolute stereochemistries derived, and some have been synthesized. For these reasons they have become valuable reference compounds. 

Nicotine boldine and other aporphine alkaloids C-toxiferine coniine and other piperidine alkaloids cytisine and other quinohzidine alkaloids epibatidine tubocurarine Berbamine, berberine, and other isoquinoline alkaloids cinchonidine and other quinoline alkaloids corynanthine, yohimbine, and other indole alkaloids emetine ephedrine ergometiine and related ergot alkaloids Ergocornine and related ergot alkaloids bulbocapnine and related aporphine alkaloids anisocycline, stylopine, and related protoberberine alkaloids salsolinol and related isoquinohnes BicuculUne, cryptopine, hydrastine, and related isoquinoline alkaloids securinine harmaline and related beta-carboline alkaloids Corymine, strychnine, and related indole alkaloids Histrionicotoxin and related piperidines ibogaine and related indole alkaloids nuciferine and related aporphine alkaloids... 

The second approach (224-226) employs O-methylhexadehydroyohimbine (420), prepared from spiroindeno-2-(l -tetrahydro-0-carboline)-l-onederivative 416 by photolysis and subsequent reduction, as the key intermediate. The side product (418) of the photolysis was also utilized for the preparation of 420 via subsequent phosphoryl chloride treatment and sodium borohydride reduction. Birch reduction of 420 resulted in enol ether 421, which could be transformed to 15,16-didehydroyohimbinone (410), prepared previously by Szantay et al. (74, 221) as a universal precursor of the synthesis of yohimbine-type alkaloids. 

Several other groups of alkaloids have pyrrolopyridine or carboline nuclei. Of the harmala group, apoharmine (110), harman (189) and harmine (7-methoxyharman) are typical. The important tranquilizer and antihypertensive alkaloids of the reserpine group are pentacycles based on 13- carboline, as is yohimbine. 

The most commonly used MAO inhibitors include hydrazines, such as iproniazid, Marsilid, Marplan, Niamid, Nardil, Catron also nonhydrazines such as propargylamines, cyclopropylamines, aminopyrazine derivatives, indolealkylamines, and carbolines. MAO-inhibiting materials discussed in this book include yohimbine various tryptamines, especially 5-MeO-DMT and the alpha-methyltryptamines and the various harmala alkaloids. The latter are especially potent inhibitors, but, like yohimibine and the tryptamines, are short-lasting in action (30 minutes to several hours). Some of the commercial MAO inhibitors listed above are effective for several days to several weeks. 

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