Yohimbane reaction

Wender and Aube have independently described the use of the Bischler-Napieralski reaction in the synthesis of Yohimban alkaloids. Aube s approach involved the cyclization of indole 50 followed by reduction of the resulting dihydroisoquinoline... 

The iron-mediated [2 + 2 + 1]-cycloaddition to cyclopentadienones has been successfully applied to the synthesis of corannulene [24] and the yohimbane alkaloid ( )-demethoxycarbonyldihydrogambirtannine [25]. A [2 + 2 + l]-cydoaddition of an alkene, an alkyne and carbon monoxide mediated by pentacarbonyliron, related to the well-known Pauson-Khand reaction [26], has also been described to afford cyclopentenones [27]. 

Analogous to the method of van Tamelen (Volume VII, p. 51) and following that due to Corsano and Panizzi (25), a stereospecific synthesis of dl-yohimbane has been achieved (17) as shown in the sequence XLI to XLVI. Though none of the reactions are essentially new, the experimental skill necessary to manipulate often intractable substances was first-rate. Inversion of configuration at the stage XLII to XLIII was a welcome bonus. 

The stereochemistry at positions 3,15, and 20 is preserved in alloyo-himbone (LXIV) and its reduction product, alloyohimbane (3a, 15a,20a-yohimbane, LXV), of which several syntheses have been reported (Volume VII, p. 58) (30). In a recent synthesis, tryptamine (XXVI) was condensed with 4-methoxyhomophthalic anhydride (LXVI) to the amide LXVII. This in the five stages shown was converted to LXVIII and the latter, through another series of reactions, converted to LXX consisting of two epimers which were separable. Tosylation of the hydroxyl and ultimate reduction with lithium aluminum hydride generated alloyohimbane (LXV) (31). 

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. 

The closure of the new 6-membered lactam ring to give 16 from 15 is based on extensive literature precedent from synthetic work in the yohimbane-type indole alkaloids.The mechanism of this Bischler-Napieralski reaction involves conversion of the amide function to an imidoyl chloride, which makes Cn electrophilic enough to add to the two position of the indole. ... 

Complex examples of the diene-alkyne [4+2] cycloaddition reaction have been illustrated in syntheses of a yohimban alkaloid and vitamin D analogs (Scheme 3-21). A representative procedure for the synthesis of a vitamin D analog is provided below. 

One application of this reaction was in the synthesis of yohimban 11.17 (Scheme 11.6). The cycloaddition precursor 11.14 could be easily built up from tryptamine 11.13 and the cyclization employed a nickel/phosphite catalyst system. Selective reduction of the less-hindered alkene, protio-desilylation and a Bischler-Napieralski reaction gave the desired pentacyclic system 11.16. Reduction of the remaining alkene gave yohimban 11.17... 

Scheme 14.8 (a) Synthesis of (+)-conicol from three components, (b) Double Michael reaction/Pictet Spengler cychzation for the synthesis of inside yohimbanes. (c) Michael/Michael/Aldol-Henry polycycbzation that furnishes steroids. 

Diels-Alder reaction has been used to construct the D and E-rings of the yohimbane backbone simultaneously (31-35). 

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. 

The synthesis began with the silver ion catalyzed reaction between diazoketone 453 and tryptamine which afforded amide 454. When 454 was subjected to Bischler-Napieralski cyclization conditions, tetracyclic ester 455 formed along with the pentacyclic lactam 456 containing a trans DE-ring fusion. Treatment of 455 with mild base effected cyclization to produce the cis-fused pentacyclic lactam 457 which was reduced to provide alloyohim-bane (82). Alternatively, lactam 456 was reduced to provide 458, a substance which Ninomiya had previously converted to yohimbane (120) (61). 

In a concise synthesis of 15,16,17,18,19,20-hexahydroyohimbane (461), Pandey and Tiwari also utilized D-ring closure as the final step in a sequence for generation of the yohimbane skeleton (Scheme 3.80). Cyclization of the amino-aryl bromide 459 was achieved by a palladium-mediated carbon monoxide insertion reaction. The resulting amide 460 was reduced to provide the desired target 461. 

One strategy which has been successfully utilized in yohimbine alkaloid synthesis involves the use of cyclization reactions of either pyridinium or isoquinolinium cations to install the respective D or DE-ring units. Wenkert and his coworkers have popularized this methodology, as exemplified by their synthesis of hexahydroyohimbine (473) (Scheme 3.82) (131). In this sequence, AT-tryptophylpyridinium salt 468, prepared by reaction of 3-formylpyridine and tryptophyl bromide, was treated with the enolate anion of methyl aceto-acetate to afford isoquinolone 469. Methylation of this material provided isoquinolinium salt 472 which upon reduction followed by acid mediated cyclization provided yohimbane 473. This methodology represents a rather... 

In a manner quite similar to that of Wenkert, Lounasmaa and his coworkers have utilized isoquinolinium salt cyclization reactions to prepare yohimbanes. For example, isoquinoline 474 was alkylated with tryptophyl bromide to yield iV-tryptophyl isoquinolinium salt 476 (Scheme 3.83) (133). Reduction of 476 with dithionate directly afforded dihydrogambirtannine (478) which could be converted by oxidation to ourouparine (480). Further reduction with dithionite provided gambirtannine (482). These reactions were also carried out on compounds in the descarbomethoxy series resulting in syntheses of the gambirtannine analogs 479,481, and 483. 

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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