Yohimbane derivatives

A series of publications appeared regarding the transformation of corynanthe-type alkaloids to yohimbane derivatives (285-287). The saponification of cory-nantheine (52) in methanol yielded a complex mixture of corynantheic acid (588), two C-16-epimer acetal acids (589), and demethoxycarbonylcory-nantheine (590). All four compounds upon hydrolysis in acid resulted in cory-... 

On the other hand, oxymercuration of demethylcorynantheine (593), followed by sodium borohydride reduction, gave 1 -abeo-( 17- 16)-yohimbane derivative 596 as the major product besides small quantities of ajmalicine (597) and 19-epiajmalicine (598) (287). 

Different Na-substituted normal as well as pseudo yohimbane derivatives have antiflammatory and analgesic activity (354, 355). 

The attempts by the same investigators to realize the synthesis of ajmalicine from corynantheine derivatives, previously reported" in brief, have now been published in detail " thus, while oxymercuration of demethylcorynantheine (115) followed by NaBHt reduction gave small quantities of ajmalicine (80) and 19-epiajmalicine, the major product was the IS-abeo (17 16) yohimbane derivative (116). 

Only a few of the known configurational types of these alkaloids are represented on pp. K8-K9. The yohimbane skeleton contains 3 asymmetric centres. All known yohimbane derivatives are homo-chirally analogous at C(i5), having the C(i5) configuration corresponding to (155) in yohimbane. There are thus 4 stereoisomeric types derived from the following 4 parent compounds ... 

Acid catalysed equilibration of certain yohimbane derivatives at C-3 is mediated by one or more of the following equilibria the driving force being toward the direction of greater thermodynamic stability. 

Lastly, Atta-ur-Rahman and Firdous were able to generate a 21-carbomethoxy yohimbane derivative by a one-step appendage of the DE-rings to a jS-carboline derivative (Scheme 3.77) (126). Methoxy substituted j8-carboline 391 was treated with bis-anhydride 441, prepared by condensation of cyclohexanone and oxalyl chloride, to afford pentacyclic zwitterionic substance 442 or 443, depending on the alcoholic solvent employed. Reduction of 442 afforded the pentacyclic enamine 444 in addition to 445, whereas reduction of the corresponding ethyl ester 443 provided 446 and 447. 

A related synthetic approach to yohimbine synthesis was utilized by Pandey and his coworkers (Scheme 3.91) (141,142). Thus, isochromanone 518 was converted to bromoester 519 which was then condensed with tryptamine to afford tetracyclic amide 520. Alternatively, 520 could be prepared by treatment of 518 with ammonia to provide 521 which was then AT-tryptophylated. Cyclization of 520 under standard conditions provided the dimethoxy-yohimbane derivative 522. 

The conversion of indole alkaloids to oxindole derivatives has been studied extensively. Since this review does not deal with the literature of oxindole alkaloids, only the most important transformations of the alkaloids having indo-loquinolizine as well as yohimbane skeletons are to be mentioned. 

As summarised here for the chemo-enzymatic approach of (—)-allo-yohimbane, synthon was once again the key lactone 1 (derived enzymatically from the above-mentioned meso-diacetate). Through condensation with tryptamine, a lactam was obtained which was then sequentially converted into (—)-allo-yohimban, indicating the high potential of this chemo-enzymatic approach for production of optically pure alkaloids of the terpenoid indoles. 

The process has been applied to the synthesis of derivatives of the yohimbane alkaloid... 

A number of syntheses of the yohimbane skeleton have been described. These include some leading to more or less unsaturated derivatives and finally to yohimbine by the timely introduction of the requisite five centers of asymmetry. 

YOHIMBAN-16-CARBOXYUC ACID derivative of BENZ(gJINDOLO(2,3-a)QUINOUZINE see RDKOOO YOHIMBAN-16-CARBOXYLIC ACID, 17-HYDROXY-, METHYL ESTER, MONOHYDROCHLORIDE, (16a,17P)-seeYBS500... 

Monoterpene Bases.—Yohimbine-Corynantheine (and Related Oxindoles)-Pier aline Group. It is well known that 3,4-dehydroyohimbane (35a) is reduced by zinc-acetic acid to a mixture of yohimbane (35c) and i/ -yohimbane (35d) however, when 10-methoxy-3,4-dehydroyohimbane (35b) was similarly treated, a 2,3,4,7-tetrahydro-derivative (17 % yield) was formed as well as the corresponding 10-methoxy-yohimbanes. It was shown that this did not arise by further reduction of either of the methoxy-yohimbanes and no explanation is yet available for this interesting difference. Reserpine, a 6-methoxyindole, underwent C(3)-N(4) bond fission on reaction with zinc-acetic acid, as did indoles with no ring A methoxy-group. Cleavage of the C(3)-N(4) bond with the formation of N(4)-cyano-C(3)-alkoxy- or hydroxy-seco-derivatives was observed when yohimbine, i/ -yohimbine, and methyl reserpate were subjected to von Braun degradation conditions in alcohol or aqueous solution. 

Mannich base XL provided the tetracyclic ketoester XLI. Construction of ring E was then initiated by reacting compound XLI with the phos-phonic acid derivatives (XLIIa) or (XLIIb) to yield the unsaturated diester XLIIIa or the nitrile XLIIIb which were subsequently hydrogenated to XLIVa and XLIVb, respectively. Dieckmann condensation of XLIVa in homogeneous phase (NaH in dimethyl sulfoxide) effected its cyclization to the pentacyclic derivative XLV which was mostly in the enolic form. Structural and stereochemical proof of XLV was provided by its hydrolysis and decarboxylation to ( )-yohimbone (XLVI), further converted to (+ )-yohimbane (XLVII) by Wolff-Kishner... 

In this section are described the syntheses of some simple indolo-[2,3-a]quinolizine derivatives which bear a close relationship to the alkaloids of the yohimbane and corynane groups. 

Some interesting examples of levoglucosenone s application in the synthesis of natural products and rare carbohydrates have been reported (58-81). Indeed, levoglucosenone has been used in the synthesis of (+)-multistriatin (58,72-73), Prelog-Djerassi lactonic acid (58,59) md (-)-a//o-yohimbane (61) The synthesis of indole alkaloid reserpine (61), and serricomin (58), as well as tetrodotoxin (53,62) were also reported from levoglucosenone or its functionalized derivatives and was reviewed earlier by us (1). 

The Yohimbanes. The yohimbines (Table 5.1) take their names from their first isolated and most ubiquitous member, yohimbine. They are found in rubiaceous and apocynaceous plants. Now that their structures have been established, they could be named systematically as derivatives of the pentacyclic diazahydro-carbon,... 

Yet another example of a jS-carboline elaboration of the yohimbine skeleton is found in the work of Danishefsky (Scheme 3.72) (120). Diels-Alder reaction of jS-carbolines 255 or 415 with the readily prepared diene 416 afforded pentacyclic lactams 417 or 418, respectively. Amide reduction of 417 followed by enol ether hydrolysis afforded known yohimbane ketone 419 (114, 121). Attempts to isomerize the 7i-bond in 419 to give the a,j8-unsatu-rated ketone 401 were unsuccessful. Nevertheless, this chemistry demonstrates how Diels-Alder reactions of jS-carboline derivatives can be used to construct the pentacyclic skeleton of the yohimbines in an eflScient fashion. 

In the syntheses of 11-methoxynauclefine (433) (Scheme 3.75) and 11-methoxyrutaecarpine (440) (Scheme 3.76), Atta-ur-Rahman and Ghazala demonstrated how the pentacyclic yohimbine skeleton could be rapidly constructed from j8-carboline derivatives (125). Condensation of 391 with nicotinyl chloride (432) afforded the yohimbane 433 in addition to its seco-CD derivative 434 and pentacyclic analog 435. Thus, a one step synthesis of 11-methoxynauclefine (433) was achieved. 

The regioselectivity of the cychzation step was further studied with unsymmetrically substituted phthalimides and pyridinecarboximides resulting in divergent selectivity patterns. As an interesting application of the intramolecular photocycHzation, the synthesis of tetracyclic protoberine (Scheme 11) and yohimbane skeletons was reported. In both cases, PET cycHzation of compounds (as 32) was followed by Bronsted-acid catalyzed retro-Mannich reaction to give the corresponding isoquinoHne derivatives 34. 

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