Yohimbine alkaloids cyclization

Quinolizinium ions fused with indole are related to yohimbine alkaloids flavopereirine, sempervirine, reserpine, alstoniline, ajmaline, and so on. Parent indolo[2,3-a]quinolizinium salt (272) has been reported (87TL5259). l-Phenylsulfonyl-2-(2-pyridyl)indole 271 was treated with H-butyllithium to afford the 3-lithio species, which was quenched with bromoacetalde-hyde to give the cyclization product (48%). It was dehydrated with aq. NaOH to afford 272 (89%). Using this method, sempervirine (273) was obtained (88T3195). 

In the initial applications of Diels-Alder chemistry to yohimbine alkaloid synthesis, the Kametani (24-27) and Takano (28) groups have both examined reactions between furan derivatives and maleic anhydride. In the initial investigations of Kametani and his coworkers (24) (Scheme 3.10), the Diels-Alder adduct (57) of furan and maleic anhydride underwent bromolactonization to give the tricyclic carboxylic acid 58 (94). This compound has four [C(15), C(16), C(17), and C(18)] of the five contiguous stereocenters of the reserpine E-ring in place. Acid 58 was converted to diazoketone 59 which underwent Wolff rearrangement followed by tryptamine trapping to afford amide 60. Bischler-Napieralski cyclization of this substance afforded the tetracyclic... 

Stork and Livingston have also employed a Michael reaction methodology in a concise synthesis of alloyohimbone 247 (Scheme 3.37). In this sequence, the Schilf base 243, prepared from tryptamine and 4-methoxybenzaldehyde, underwent sequential Birch reduction and acylation to afford the cyclo-hexadiene 244. Hydrolysis provided the corresponding a, ) -unsaturated ketone. Under basic conditions, the key Michael addition took place to yield the cis-fused bicyclic lactam 245. Decarboxylation and ketalization afforded 246 which underwent Bischler-Napieralski cyclization and subsequent deke-talization to afford alloyohimbone 247. All in all. Stork has shown that Michael addition methodologies can be successfully employed to construct the pentacyclic yohimbine alkaloid skeleton in an eflBcient stereoselective manner. 

Wenkert has also employed a Dieckmann cyclization strategy to prepare a variety of yohimbine alkaloids (56-58). In formal syntheses of yohimbine (4) and ) -yohimbine (5) (Scheme 3.48) (56), nicotinaldehyde was initially... 

By using this same Dieckmann cyclization strategy. Wenkert and his coworkers have accomplished a synthesis of raunescine (288) (Scheme 3.54) (58). Accordingly, ketoester 319 was benzylated to provide enol ether 325. Sequential reduction of the double bond and ketone of 325 by the protocol employed in the deserpidine synthetic route provided the C(18) alcohol 326. Acylation of the hydroxyl group and hydrogenolysis gave raunescine. Similar to the efforts of Szantay, Wenkert s investigations clearly demonstrate how Dieckmann cyclization chemistry can be applied to the synthesis of a variety of yohimbine alkaloids. 

A final illustration of how Dieckmann cyclizations have been utilized in yohimbine alkaloid synthesis is found in the work of Winterfeldt and coworkers (59, 60). In these studies, this methodology was employed to construct the pentacyclic alkaloid skeleton found in thioketal 335 (Scheme 3.55). Reaction of j5-enaminoester 327, prepared by condensation of tryptamine and... 

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... 

The hydrogen abstraction, in this instance, presumably occurs at the P-carbon of the enone (139). The resultant biradical ring closes to afford the observed products. The ic-ic excited triplet state is involved in the conversion of the enone (141) into the spiroketone (142). The reaction again involves hydrogen abstraction by the ft-carbon followed by cyclization within the biradical. Photocyclization of enamides such as (143) has led to a new synthetic approach to the yohimbine anreserpine type alkaloids. " The photocyclization of the enone (144) provides a route for the synthesis of 3.10-dimethoxyprotoberberines. ... 

After deglucosylation, the pathway proceeds through a 4,21-Dehydrogeissoschizine derivative to ajmalicine (an a-Blocking spasmolytic agent, used for tinnitus and cranial trauma with an ergot derivative). If cyclization occurs between C-17 and C-18, the yohimbine nucleus is produced, whose derivatives include the Rauvolfia alkaloids reserpine and resdnnamine (antihypertensive activity). Ajmaline, formerly used as an antiarrythmic, also occurs in Rauvolfia species, and several of the enzymes in the pathway have been isolated. Recent considerations suggest that the C-16-C-5 bond may be formed before the N-4-C-21 bond (Fig. 38). 

The transformation of indole into corresponding oxindole alkaloids has been possible for some time now the reverse sequence has been achieved. The type of 2,3-seco-intermediate (47) arrived at by total synthesis above has been pro-duced " and then cyclized, in both heteroyohimbine (Scheme 12) and yohimbine... 

As with the PictetASpengler reaction, the Bischler-Napieralski cyclization has been used in alkaloid synthesis. For example, a synthesis of yohimbine and related alkaloids began with enantiomerically pure amide [364],... 

When the aldehyde partner of the Pictet-Spengler reaction with tryptamine is the terpene secologanin, strictosidine is formed as an entry toward the vast monoterpene indole alkaloids [32, 33]. Hydrolysis of the glucosidic part releases the strictosidine aglycone bearing an aldehyde, while imin-ium formation and further cyclization and reduction can lead to ajmalicine (from oxocyclization) or yohimbine (from car-bocyclization). These alkaloids are referred to as from the Corynanthe type, with the monoterpene carbon skeleton unmodified. Although it misses one carbon and has a very... 

In 2005, Ary a and co-workers reported on the stereocon-trolled solid-phase synthesis of a 90-membered library of indoline-alkaloid-like polycycles 41 and 42." These compounds are structurally related to a number of alkaloids such as vindoline, tabersonine, and yohimbine, and they could lead to compounds with similar or improved biological properties. Thus, chiral aminoindoline 36 was loaded via a silyl linker unit 37, deprotected, and reacted with an acid chloride to introduce the first point of diversity and to give 38. Treatment with piperidine removed the Fmoc group, and concomitant cyclization provided tricyclic... 

In subsequent studies, Szantay s group further improved their syntheses of yohimbine (4) and j5-yohimbine (5). In addition, the ketone 260 was resolved, thus effecting a chiral synthesis of these alkaloids (Scheme 3.43) (55). The levorotatory enantiomer of ketone 260 was converted to the a, -unsaturated ester (-h)-261 which was then cyclized by the Dieckman method to afford (—)-271. Treatment of this unsaturated ketone with sodium borohydride in the presence of nickel chloride afforded a 2 1 mixture of (—)-j -yohimbine (( —)-5) and ( + )-yohimbine ((-h)-4). Furthermore, the ( + )-ketone ((-h)-260) was carried through the aforementioned sequence to yield a mixture of (-l-)-j8-yohimbine ((-h)-5) and ( —)-yohimbine ((—)-4). 

N-Acyliminium ions are considerably more electrophilic than the iminium ions described earlier. As a result, their cyclizations have been used extensively in the service of complex molecule synthesis [104, 119]. A classic application was reported by van Tamelen m route to yohimbine (136), historically one of the most important members of the complex indole alkaloids (Scheme 11.21) [120], In the key cyclization event, oxidative cleavage of the vicinal diol in 133 afforded crude lactol 134. Treatment of 134 with phosphoric acid led to cyclization onto the indole, furnishing lactol 135 in 60% yield as a single diastereomer. 

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