Yohimbine synthesis steps

The first total synthesis of D/E-trans annellated yohimbines, e.g., ( )-yohim-bine (74) and ( )-pseudoyohimbine (88), was published in preliminary form by van Tamelen and co-workers (218) in 1958, while full details (219) appeared only in 1969. Key building block 393, prepared from butadiene and p-quinone, was condensed with tryptamine, yielding unsaturated amide 394, which was subsequently transformed to dialdehyde derivative 396. Cyclization of the latter resulted in pseudoyohimbane 397. Final substitution of ring E was achieved via pyrolysis, oxidation, and esterification steps. As a result of the reaction sequence, ( )-pseudoyohimbine was obtained, from which ( )-yohimbine could be prepared via C-3 epimerization. 

An efficient synthesis of ( )-yohimbine has been published by Stork and Guthikonda (222). Reaction of the pyrrolidine enamine of A-methylpiperidone with methyl 3-oxo-4-pentenoate gave 411 in good yield. Reduction of 411 with lithium in liquid ammonia furnished trans-TV-methyldecahydroisoquinolone 412. This building block was transformed in simple reaction steps to secoyohimbane 413 from which ( )-yohimbine could be obtained by oxidative cyclization with... 

Witkop and Goodwyn reported (288) that ozonolysis of yohimbine (74) and its derivatives led to the corresponding quinolone derivatives. This reaction has been thoroughly investigated by Winterfeldt (289). For example, autooxidation of lactam 347 resulted in quinolone 599, which upon treatment with phosphoryl chloride, followed by catalytic reduction, gave pyrrolo[3,4-h]quioline derivative 600 (290). This transformation was also used as a key step in the biomimetic synthesis of camptothecin (601), performed by Winterfeldt et al. (291, 292). 

That the major condensation step of aldehyde CCLXVIII and tryp-tamine can in fact occur under physiological conditions has been amply demonstrated by Hahn (351) in a striking physiological synthesis of a base with the yohimbine skeleton (CCLXX). Hahn s demonstration of spontaneous condensation at the indole a-position, however, casts doubt on the facility of the jS-condensation required for the Strychnos alkaloids and leads us to consider a variation of the scheme in which the a-position is oxidized first to an oxindole, thus forcing condensation only at the (8-position. That the j8-position of oxindoles is an adequate anionoid source is shown by the recent demonstration... 

Intramolecular acylations of the Bischler-Napieralski type have been used as crucial steps in the synthesis of indole alkaloids of the yohimbine class <94JCS(Pl)299, 94TL1071>. Also, the aluminum chloride-catalysed reaction of the indolosuccinic anhydride (46) gave the bridged cyclic product (47) rather than the cyclopentanone (49), presiunably because the reaction involves initial acylation at C-3 and reaction via the less strained intermediate is favored. Formation of the cyclopentanone (49) can be achieved using the polyphosphate ester cyclodehydration of the modified intermediate (48) (Scheme 13) <90JCS(Pi)2487>. 

Thus, the remaining steps to the alkaloids yohimbine and alloyo-himbine gave us no problem, thus furnished a novel and practical synthesis of both alkaloids as summarized in the scheme. 

In 2008, a similar asymmetric Pictet-Spengler reaction was applied to the total synthesis of (+)-yohimbine (209) (11 steps, 14% overall yield), an important member of the monoterpenoid indole alkaloids as shown in Scheme 17.35 [82]. The synthesis involved two key steps, which are the acyl-Pictet-Spengler reaction of tryptamine derivative 199 with aldehyde 203 (97% ee) and a stereoselective intramolecular Diels-Alder reaction of 206 with the simultaneous generation of four new stereogenic centers [83]. 

The same protocol was also applied successfully to the total synthesis of (-i-)-yohimbine (447) (388) (A chiral phosphoric acid-catalyzed approach towards this target was discussed earlier (see Scheme 99)). hi contrast to Hiemstra s approach employing a later stage organocatalytic Pictet-Spengler reaction (385), Jacobsen s synthesis of 447 commenced with the thiourea 473-catalyzed acyl-Pictet-Spengler reaction between tryptamine 468 and the protected hydroxyaldehyde 474. Intermediate 475 was then employed successfully to access (-i-)-yohimbine (447) in a total of 11 steps and in 14% overall yield (Scheme 104) (388). 

Pseudo-yohimbine (55) has been prepared by a six-step procedure which depends on a novel indolbquinolizidine synthesis. The crucial reaction is the ability of an N-alkyl-j8-acylpyridinium salt to accept carbon nucleophiles at its y-carbon site, with subsequent acid-catalysed cyclization at its unsubstituted a-carbon centre (Scheme 95). ... 

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. 

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