Yohimbine, synthesis

In an intramolecular variation of this reaction, the use of sterically defined alkenes permits a stereoselective construction of stereogenic centers of six-membered heterocycles, as demonstrated in the following example for the key building block 52 of a yohimbine synthesis [16] ... 

This chapter will address developments in yohimbine synthesis of the past 10-12 years. A number of reviews have already been published in this area (3-15). Additionally, the spectroscopic properties of these alkaloids have also been investigated (16-18) although a discussion is beyond the scope of this chapter. Unlike other reviews in this field, this report will focus exclusively on the approaches designed to tackle the synthetic challenges presented by the yohimbine alkaloids and will be organized by the methodologies actually used rather than by the specific natural product targets. 

A further application of the enamide photocyclization in yohimbine synthesis is demonstrated by Ninomiya s preparation of naucleficine (378) (Scheme 3.64) (68) Enamide 376, prepared from 336 and aroyl chloride 375, was irradiated under non-reducing conditions to form oxygambirtannine (127). Finally, a reduction-oxidation sequence afforded the target. 

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 same author has shown by repetition of the early experiments already referred to (p. 507) that when yohimbine hydrochloride is distilled with zinc dust there is formed in addition to harman (XVII), p-cresol, which must originate from ring E of the yohimbine formula (XIV) by inclusion of C as the methyl group. Witkop s formula for yobyrine (IV6) received prompt confirmation by Clemo and Swan s synthesis of this base by... 

The chemistry of yohimbine is also under active discussion and new papers have appeared, or are promised, dealing with the structure and synthesis of ketoyobyrine. ... 

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... 

During the past two decades a great number of papers have been published on the isolation, structure elucidation, synthesis and transformation, biogenesis, chemotaxonomy, and pharmacology of indole alkaloids. In this chapter we summarize the new results that appeared from 1968 to mid 1984 for the cory-nantheine-yohimbine group of monoterpene indole alkaloids with greater emphasis on their chemistry, excluding the related oxindoles and heteroyohimbines. 

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. 

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. 

In 1969, Szantay and co-workers published a linear synthesis of (+)-yohimbine and (—)-P-yohimbine (75) in full detail (220). Tetracyclic key intermediate 400, obtained from 3,4-dihydro-p-carboline and a properly substituted a,p-unsatu-rated ketone (173), was treated with a proper phosphonoacetic acid derivative to give unsaturated nitrile 401 or unsaturated ester 402. Catalytic reduction of the latter resulted almost exclusively in 404 with normal stereo arrangement, while reduction of 401 supplied a mixture of normal and epialloindolo[2,3-a] quinolizines 403 and 405, respectively. Dieckmann ring closure of diester 404 gave 18a-methoxycarbonylyohimbone (407) as the thermodynamically favored... 

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... 

Kametani and his collaborators presented two different approaches for the synthesis of ( )-yohimbine and ( )-p-yohimbine 223-226). The first one (223, 224) utilizes Stork s method for the Robinson reaction of the enamine derived from octahydroindolo[2,3-a]quinolizin-2-one (414) to produce 15,16-didehydroyohimbinone (410), prepared first by Szantay et al. (74, 221). 

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. 

The general method for the synthesis of different indoloquinolizine alkaloids via IV-tryptophyl 3-substituted pyridinium salts, developed by Wenkert and his collaborators, has been extended for the synthesis of yohimbine alkaloids (227-229). 

Another formal total synthesis of ( )-yohimbine has been worked out by Wenkert et al. (229) by preparing O-methylhexadehydroyohimbine (420), which was first prepared by Kametani and co-workers (224-226) as a key intermediate toward ( )-yohimbine. In Wenkert s approach, pyridinium salt 427 was y-alkylated with acetoacetic ester anion. The product 428 then underwent intramolecular condensation, affording tetracyclic quinone 429. Methylation of 429... 

Ninomiya and co-workers have also published a formal total synthesis of ( )-yohimbine (230). Photocyclization of unstable enamide 431, obtained from har-... 

The total synthesis of ( )-yohimbine via regioselective functionalization of 18,19-dehydroyohimbinone (434) has been reported by Ninomiya et al. (231). Key intermediate 434 was prepared by enamide photocyclization of 432, fol-... 

More recently, Szdntay and co-workers (232) succeeded in performing the enantioselective total synthesis of both natural and unnatural antipodes of yohimbine and -yohimbine. Utilizing second-order asymmetric induction, either the levorotatory or dextrorotatory antipode of key tetracyclic intermediate 400 could be obtained by the use of (—)- or (+)-tartaric acid, respectively. 

After an interval of more than 20 years, a second synthesis of ( )-deserpidine and the achievement of some stereoisomers of ( )-raunescine (114) have been reported by Szdntay and co-workers (250,255). The basic idea of this linear total synthesis was similar to that utilized by them for the synthesis of yohimbine alkaloids. First, tetracyclic key intermediate 467 was prepared (253), in which the methoxy substituent of the side chain, on the one hand, represents the future C-18—O bond of the end product and will, on the other hand, control the regioselectivity of the Dieckmann ring closure. 

It should be noted that dialcohols 486, 487, and 488, obtained during the synthesis are stereoisomers of 18-hydroxy-a-yohimbine, which has an al-... 

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). 

Ninomiya et al. (398) reported the total synthesis of 19,20-dehydroyohimbine (78), 19,2O-dehydro-0-yohimbine (82), as well as 19,20-dehydro-a-yohimbine... 

This compound, the active constituent of Tabernanthe iboga, a plant used for its psychic effects by African natives, has recently been synthesized. However, there seems to be nothing in the trip it produces to justify the arduous synthesis (likewise for the structurally similar yohimbine). 

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