Yohimbine-type alkaloids

Two important books on the biogenesis of indole alkaloids have been published (5, 6), therefore we do not intend to cover the literature of the biogenesis of corynantheine- and yohimbine-type alkaloids. Our chapter begins with the structure elucidation of the alkaloids isolated during the past two decades and proceeds with the synthesis, transformation, as well as spectroscopy of the alkaloids in question. 

New normal yohimbine-type alkaloids, isolated or characterized, together with their primary sources, are listed in Table I. Note that aspexcine, isolated from Aspidosperma excelsum Benth., has earlier been characterized as a 10-methoxyisositsirikine. This alkaloid, however, proved to be identical with excel-sinine (81) (53) (see Section II.B. 14.). 

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. 

A series of publications by Albright et al. report the investigation of methods for the oxidation of hydroxy groups in yohimbine-type alkaloids and the functionalization of yohimbone (305) at the C-18 position (293-297). 

Diagram 26. Emetine and biosjmthesis of yohimbine-type alkaloids. 

Three alkaloids, gambirtannine, dihydrogambirtannine, and oxogambirtan-nine, have been isolated from gambir (110). These alkaloids are considered to be generated from yohimbine-type alkaloids by dehydration and aromatization. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Similarly to the corynantheine-type alkaloids, yohimbines could also be divided into four groups according to the relative configurations of the stereo centers C-3, C-15, and C-20. 

Active Constituents Yohimbine, yohimbiline, ajmaline (indole-type alkaloids). 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

So far, reductive photocyclization has been successfully applied to the synthesis of yohimbine-type compounds (54), benzo[/]quinolines, and ergot alkaloids including lysergic acid (55-57) (Scheme 19). 

The hydrogen abstraction, in this instance, presumably occurs at the P-carbon of the enone (139). The resultant biradical ring closes to afford the observed products. The ic-ic excited triplet state is involved in the conversion of the enone (141) into the spiroketone (142). The reaction again involves hydrogen abstraction by the ft-carbon followed by cyclization within the biradical. Photocyclization of enamides such as (143) has led to a new synthetic approach to the yohimbine anreserpine type alkaloids. " The photocyclization of the enone (144) provides a route for the synthesis of 3.10-dimethoxyprotoberberines. ... 

The stem bark of P. yohimbe (= P. johimbe Corynanthe yohimbe), "yohimbe as it is known in Cameroon, Gabon and Congo is used traditionally as an aphrodisiac and stimulant to prevent sleep (41). The bark contains 1-6% of indole alkaloids, most of which are yohimbane-type alkaloids, the main one being yohimbine [7], which is structurally related to reserpine [8] (89). Yohimbine is a selective inhibitor of a-2- adrenergic receptors and, while at low dose it has hypertensive activity, at high dose it is hypotensive (vasodilation of peripheral vessels). It is the vasodilation of peripheral vessels, and especially vasodilation of the corpus cavemosum, which is the cause of the reputation of yohimbine as an aphrodisiac (90). Tests have shown, indeed, that increased... 

Until recently only monomeric indole and oxindole alkaloids had been isolated from the bark and leaves of Uncaria gambir Roxb. (Rubiaceae). Amongst these were alkaloids of the corynantheine and yohimbine types."" However, from a different batch of plant material five new isomeric alkaloids, the roxburghines A—E, C31H32O2N4, have been isolated in 0.0005—0.005 % yield. ... 

The ability of plants to utilize both the major biogenetic routes (to CCLXIX and CCLXX) is amply demonstrated by the various Stryehnos species, some of which elaborate the strychnine family of alkaloids, some of which (the South American Stryehnos) elaborate yohimbine types (curare alkaloids). Even more striking is the biosynthesis in the one plant Gdsemium sempervirens (not a Stryehnos) of both gelsemine... 

Calabash-C. Thick syrupy mass, packed in gourds, the alkaloids present are mostly of the strychnine type, rarely of the yohimbine type. Individual compounds are C- toxiferine 1, C-dihydrotoxiferine, C-curarine 1, and C-calebassine (see toxiferines) (C stands for calabash). 

Yohimbine (obsolete synonyms johimbine, quebra-chine, aphrodine). C21H26N2O3, Mk 3S4.4S. The parent indole alkaloid of the yohimbine type occurring in nature as the (-t-l-form, the racemate is accessible by synthesis. Other, naturally occurring stereoisomers of Y. have been isolated a-Y. (rauwolscine, corynanthidine, isoyohimbine, mesoyohimbine, 16/3,17ct, 20a-Y.), allo-Y. (16a,17a,20a-Y), 3-epi-a-Y. (isorauhim-bine), /3-Y. (amsonine), and corynanthine (rauhimbine, 16, 17a-Y). 

Calabash curare, prepared from plants of the genus Strychnos, is packed in hollow gourds. It contains a large number of alkaloids and is extremely poisonous. The alkaloids contain an indole ring system and can be divided into 3 types the yohimbine type (e.g. mavacur-ine), the strychnine type (e.g. Wieland-Gumlich aldehyde) andthehfrindole type (e. g. calabash toxiferin-I). 

Strictosidine was experimentally incorporated into a series of different alkaloids, including yohimbine-, strychnine- and gelsemine-type alkaloids (151). 

Alio Series. Only three alkaloids belonging to the allo-type yohimbines, that... 

Several semisynthetic derivatives of yohimbine alkaloids show interesting pharmacological activity. For example, 17-methylthiomethoxyyohimbane stereoisomers (612 and 613) are valuable central nervous system depressants (349) and several hydrazides of yohimbinecarboxylic acid (614 and 615-type compounds) are useful cardiac stimulants, respiratory analeptics, and antihypertensives (350-353). 

The four major stereochemical types of yohimbine alkaloids are illustrated by yohimbine (normal) [368], pseudoyohimbine (pseudo) [369], cr-yohimbine (alio) [370], and 3-ep/-a-yohimbine (epiallo) [371]. Of particular diagnostic importance are the C(3), C(6), and C(15) shifts... 

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