Yohimbane alkaloids, synthesis

The route employed to prepare indanone 51 involved the cycloaddition-hydrolysis-aldol sequence shown in Scheme 3.9. Accordingly, condensation of cyclopentenone 52 with ynamine 53 (84) afforded the bicyclic enamine 54 which was converted to indanones 51 and 55 by hydrolytic cyclobutane ring opening followed by intramolecular aldol condensation. Interestingly, treatment of 54 with aqueous formic acid yielded indanone 51 which has stereochemistry complementary to that at C(15) and C(20) in reserpine. In contrast, hydrolysis of this substance with aqueous hydrochloric acid afforded the trans-fused indanone 55. Subsequent to this work, the Ficini group found that esterification of 51 followed by photochemically induced addition of methanol afforded adduct 56 which has four of the reserpine stereocenters in place (23). While no further work on this problem has been reported, these preliminary investigations demonstrate a novel use of [2 -h 2] photocycloaddition chemistry in potential approaches to yohimbane alkaloid 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... 

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. 

An early application of enamide photocyclizations to yohimbine alkaloid synthesis is illustrated by Ninomiya and coworkers synthesis of yohimbane (120), epiyohimbane (347) and alloyohimbane (82) (Scheme 3.57) (61, 63, 69). These compounds were prepared by a short sequence starting with har-malane (336) which was condensed with acid chloride 341 to provide enamide 342. Irradiation of 342 in benzene followed by reduction afforded a mixture of the stereoisomeric pentacyclic lactams 344, 345, and 346 which were reduced to provide yohimbane (120), epiyohimbane (347), and alloyohimbane (82), respectively. While the yield of the photocyclization process was modest, this route demonstrated how enamide photocyclizations can be used to rapidly construct pentacyclic yohimbane targets. 

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... 

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. 

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

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). 

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