Yohimban, synthesis

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]. 

In a previously described approach, a largely similar strategy was employed in order to generate enantio-selectively (—)-allo-yohimbane [84]. Yohimbane alkaloids such as reserpine and yohimbine were of long-standing interest from pharmacological and synthetic points of view, and the first enantio-selective (—)-alloyohimban synthesis was reported some time ago by Isobe et al. [88]. 

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

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). 

Sensitized photocyclization was used as a key step in the synthesis of the -ring functionalized alkaloid, yohimbane 267 (Scheme 63) [310]. 

The asymmetric total synthesis of rauwolfia alkaloids (-)-yohimbane and (-)-alloyohimbane was carried out by S.C. Bergmeier et al. by utilizing a novei aziridine-allylsilane cyclization and the Bischler-Napieralski isoquinoline synthesis as key steps.These alkaloids have a characteristic pentacyclic ring framework and exhibit a wide range of interesting biological activities such as antihypertensive and antipsychotic properties. 

Bergmeier, S. C., Seth, P. P. Aziridine-Allylsilane-Mediated Total Synthesis of (-)-Yohimbane. J, Org, Chem, 1999, 64, 3237-3243. 

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). 

Autrey and Scullard used this fragmentation in a synthesis of corynantheine (11) from yohimban-l7-one (7). The synthesis also involved a novel desulfurization of the enol thioether (9) without reduction of the vinyl group. This step... 

Full papers dealing with the chemistry of gambirtannine, oxy-gambirtannine, dihydrogambirtannine 56), deserpidine, and raujemi-dine (57) have appeared. A new base, excelsinine (10-methoxycorynan-thine, C26H26N2O4, mp 201°) has been isolated from Aspidosperma excelsum (58). A new synthesis of ( )-yohimbane has been published (59), and 7-benzyl-7i/-yohimbanes have been prepared and their ORD curves examined (60). 

Novel routes to p5UToles, indoles, and carbazoles - Applications in total synthesis of alkaloids including fused indolizidines, yohimbanes, Amarylhdaceae alkaloids, and carbazoles 05COC1601. 

Scheme 5. Synthesis of yohimbane via metal-catalyzed [4+2] cycloaddition.

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). 

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. 

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