Alloyohimbane, synthesis

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]. 

This suite of BVMOs is available via whole-cell expression systems and represents a complementary platform of biocatalysts for diverse applications in chiral synthesis. Representatives of this collection were utilized in the enantiodivergent synthesis of the indole alkaloids alloyohimbane and antirhine from a fused bicyclic precursor (Scheme 9.19) [151]. 

An elegant one-pot bicycloannulation method for the synthesis of tetrahydroisoquinoline systems has been disclosed by Pawda et al. <1998TL4757, 2000JOC2684>. This method generates a transient thioisomilnchnone 423 that undergoes an intramolecular dipolar cycloaddition. The thus obtained cycloadduct 424 is next reduced with Raney-Ni, followed by LAH to furnish ( )-alloyohimbane 425 in 31% overall yield from 421 (Scheme 109). 

Padwa and co-workers (232,233) adapted their thioisomiinchnone generation-cycloaddition strategy to the synthesis of several tetrahydroisoquinoline alkaloids and the indolo[2,3-a]quinolizidine alkaloid alloyohimbane 333 (Scheme 10.44). 

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). 

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. 

The Yohimbe alkaloids such as alloyohimbane (1) and the antihypertensive drug reserpine constitute attractive goals for synthetic chemists. Syntheses of Yohimbe alkaloids from noncarbohydrates have been reported. " Synthesis of 1 from cellulose has also been achieved (Scheme 1). Pyrolysis of cellulose gave the levoglucosenone (l,6-anhydro-3,4-dideoxy- 3-D-glycero-hex-3-enopyrano-2-ulose, 2), which underwent Diels-Alder cycloaddition with... 

Isoquinolines are as important as quinolines in the ehemistry of natural produets and there are also many syntheses of these compounds. One of the most important Friedel-Crafts routes is the Bischler-Napieralski reaction.This process is the reaction of an N-acyl amine such as 272 with a reagent sueh as PPA or P2O5 to give an dehydroisoquinoline derivative (273). Wender and Smith used this reaction to convert 274 to 275 in 86% yield as part of a synthesis of yohimhan alkaloids. 167 Shea and co-worker used a similar reaction to synthesize alloyohimbane.l68... 

An application toward the synthesis of alloyohimbane required reacting the protected tryptamine derivative 42 with cyclohexadiene and formalin to obtain the requisite [2.2.2] bicyclic adduct 43 [17]. Under the standard aqueous aza Diels-Alder conditions, a modest 22% yield of 43 is obtained, which upon further elaboration involving Mariano s [18] aza Claisen rearrangement protocol yields alloyohimbane 44 (Scheme 2.5). 

This methodology was initially applied to a synthesis of (—)-alloyohimbane (82) (Scheme 3.13) (29). Readily available levoglucosenone (75), a product of cellulose pyrolysis, was the starting material. Diels-Alder reaction of 75 with 1,3-butadiene afforded adduct 76 which underwent Wolff-Kishner elimination and subsequent acylation to provide the bicyclic enol ether 77. Hydrolysis followed by oxidation and saponification afforded hydroxymethyl lactone 78 which was then condensed with tryptamine to yield the amide diol 79. Periodate cleavage of the diol was followed by conversion to chloride 80 which was cyclized to afford lactam 81. Subsequent Bischler-Napieralski cyclization followed by hydrogenation of the olefin moiety afforded the target ( )-alloyohimbane (82). 

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. 

The synthesis of yohimbane (120) and alloyohimbane (82) was improved by using a modified sequence which featured reductive photocyclization as the key step (Scheme 3.58) (63,69). Condensation of harmalane (336) with benzoyl chloride afforded enamide 348 which upon irradiation in the presence of sodium borohydride afforded a mixture of functionalized yohimbanes 349, 350, and 351. The overall yields and product distribution were found to be dependent on the solvent employed with the maximum yield of 350 (98%) being obtained in a mixture of MeCN and MeOH. Hydrogenation of 349... 

Recently, two enantioselective syntheses of (—)-alloyohimbane (82) have been reported. The synthetic route utilized by Riva s group featured an enzymatic hydrolysis as the key step (Scheme 3.8S) (135). Prochiral diester 489 was hydrolyzed with pig liver esterase to provide the hydroxyester (—)-490 in good yield and with a high enantiomeric excess. One carbon homologation of (—)-490 followed by subsequent lactonization generated the bi-cyclic lactone (—)-491. Condensation of (—)-491 with tryptamine afforded tetracyclic lactam (—)-81, an intermediate in Isobe s synthesis of (—)-alloyohimbane ((—)-82). 

Aube and his coworkers have also carried out an enantioselective synthesis of (—)-alloyohimbane ((—)-82) (Scheme 3.86) (136, 137). Their route highlighted a photochemical nitrogen insertion reaction of the intermediate oxaziridine 493. Bicyclic ketone 492 was condensed with (S)-(—)-a-... 

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