Wenkert cyclization

Model studies have demonstrated that the approach of Mariano and his coworkers does indeed permit rapid construction of the pentacyclic yohimbine skeleton (Scheme 129) (41, 42). For example, Diels-Alder reaction of dihydropyridine 193 with methyl vinyl ketone (194) afforded isoquinuclidene 195 which was sequentially ketalized, the nitrogen deprotected, and trypto-phylated to yield the model substrate 196. Treatment of 196 with t-butyl propiolate effected the crucial zwitterionic amino-Claisen rearrangement to efficiently provide the hexahydroisoquinoline 197 having the crucial cis-DE-ring fusion in place. Treatment of 197 under the Wenkert cyclization condi-... 

Clearly, this investigation demonstrated that the combined zwitterionic amino-Claisen rearrangement Wenkert cyclization methodologies constitute a rapid procedure for generating functionalized yohimbines. Moreover, the strategy is flexible and allows for the introduction of appropriate E-ring... 

As a result of the low yields for both the zwitterionic amino-Claisen and Wenkert cyclization processes, an alternative route to deserpidine was investigated (Scheme 3.33) (44). The authors reasoned that protection of the indole nitrogen would prevent the competing Michael addition of the indole moiety... 

Utilizing Wenkert s cyclization process, a number of new approaches have been elaborated for the synthesis of simple indolo[2,3-a]quinolizine derivatives. For example, treatment of JV-[2-(indol-3-yl)ethyl]piperidine (V-oxide (134) with trifluoroacetic anhydride gave piperideinium intermediate 135 in a Polonovski-type reaction, which could be cyclized in acidic medium to ( )-l (101). 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

Dihydrogambirtannine (337) has been achieved via two routes from N-[2-(indol-3-yl)ethyl]isoquinolinium salts. Wenkert and co-workers (183) first synthesized the stable intermediate 339, which could be hydrolyzed, decarboxy-lated, and cyclized in one step by the use of aqueous alkali to ( )-337. In a very similar approach, Beisler (184) caused the isoquinolinium salt 340 to react with sodium borohydride and sodium cyanide, and the resulting intermediate 341 was immediately treated with strong acid. This one-pot reaction gave ( )-di-hydrogambirtannine in an overall yield of 83%. 

The total synthesis of vallesiachotamine (9) and isovallesiachotamine (10) has been completed elegantly by Wenkert and Spitzner (393) by utilizing the addition of a silicon-stabilized anion to pyridinium salt 633 to achieve the properly substituted indoloquinolizidine 634 by cyclization, from which 9 and 10 could be prepared in racemic form by simple reaction steps. 

Stork and Guthikonda (15) have shown that the cyclization of iminium ion 46 (produced in situ) gave ( )-B-yohimbine (47) and Wenkert and co-workers (22) have further observed that the acid-catalyzed cyclization of enamines of type 48 yielded exclusively product 50 via the cyclization of iminium ion 49. In the last two examples, formation of the C —C bond is the result of a trans-addition on the iminium double-bond in agreement with the principle of stereoelectronic control. 

Cyclization of an indolylethyl-tetrahydropyridine derivative is also a key stage in an extremely brief and elegant synthesis of the yohimbine ring system and a number of ajmalicinoid bases by Wenkert and his collaborators.78 Thus, internal nucleophilic attack by enolate anion at the y-position to the nitrogen atom in (122) gave a tetrahydropyridine derivative which readily cyclized to the pentacyclic enamine (123), reduction of which gave (db)-pseudoyohimbone (124) (Scheme 11). 

The total synthesis of the tricyclic sesquiterpene (+)-P-copaene was accomplished by E. Wenkert and co-workers. The required bicyclic starting material was prepared in three steps from carvacrol. In the first step, carvacrol was subjected to typical Reimer-Tiemann conditions. The abnormal Reimer-Tiemann product, 6-dichloromethyl-3-isopropyl-6-methyl-cyclohexa-2,4-dienone, was obtained, and upon treatment with sodium carbonate in DMSO, cyclization occurred to afford a bicyclic halo ketone. The double bonds were then hydrogenated in the presence of Pd(C) catalyst. 

There are several isolated examples of conformationally constrained a-diazo ketones that, under catalysis by Cu salts, smoothly undergo intramolecular C—insertion. This cyclization was investigated in some detail by Wenkert, who found that it was not, in the acyclic series, a preparatively useful synthetic method (equation 22). ... 

Hubert in 1976 reported that rhodium acetate efficiently catalyzes diazo insertion into an alkene, to give the cyclopropane. In 1979, Southgate and Ponsford reported that rhodium acetate also catalyzes diazo insertion into a C—H bond. Prompted by these studies, Wenkert then demonstrated that cyclization of (58) to (59) proceeded much more efficiently with the rhodium carboxylates than it had with copper salt catalysis (equation 23). ... 

Wenkert demonstrated that cyclization of the diazomethyl ketone corresponding to (72) proceeds to give predominantly the rra j-hydrindan (equation 2S)P Taber showed that the degree of diastereoselectivity in the cyclization of (72) to (73) and (74) is affected by the ligands on rhodium (equation 28). ... 

In support of an ingenious scheme for the biosynthesis of vinca and iboga alkaloids proposed by Wenkert is an interesting synthesis accomplished by Kutney, Brown, and Piers by transannular cyclization of carbomethoxydihydrocleavamine (I), accomplished by oxidation with mercuric acetate in acetic acid at room temperature. Chromatography afforded as the main product the vinca alkaloid vincadifformine. 

As mentioned previously, there are many Mannich-type cyclizations of acetals that undoubtedly occur via enol ether intermediates and afford -amino acetal products. A prototypical example is presented in Scheme 12. In this sequence, due to Wenkert, the iminium ion precursor is formed by semihydrogenation of a nicotinic ester salt. ... 

Reaction with enoi ethers. Wenkert and co-workers have examined the copper-catalyzed decomposition of this -diazo compound in the presence of an enol ether of an aldehyde (1) and a ketone (5). In the first case, the expected cyclopropane ester (2) was obtained. This was reduced by lithium aluminum hydride to the diol, which cyclized to the hemiaceta (3) on exposure to acid. Collins oxidation of 3 gave the spiro- 3-methylene-y-lactone 4. 

Wenkert s new route °° to eburnamonine (221) (Scheme 30) involves a neat extension of the preparation of 1,4-diketones, via cyclopropanoid intermediates, which allows the formation of y-imino- or y-keto-acids. Two variations of this approach were reported, all the stages in which were high-yielding, given the essential starting materials (222) and (223). In both variations the intermediate y-substituted acid was stabilized by cyclization, Le. as (224) or (225). Condensation with the appropriate indolylethyl derivative then led to the common intermediate (226), which on thermolysis gave ( )-ebumamonine (221). 

Wenkert has developed an interesting synthesis of the a- and 8-himalchenes (13 and 14) which uses an intramolecular Diels-Alder reaction as the key step in establishing the proper carbon skeleton. The bicyclic unsaturated ketone served as an appropriate precursor which could be converted readily to either of the two himalchenes 13 and W and was itself produced by the cyclization of the triene 1 in unspecified yield. 

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... 

Wenkert also applied the Dieckmann methodology to the preparation of pseudoyohimbine (6) and pseudoyohimbone (309) (Scheme 3.50) (56). Treatment of 302 with base effected the desired cyclization to provide regioisomers 307 and 308. Ketoester 307 was hydrogenated to yield pseudoyohimbine (6). Additionally, 308 was saponified and decarboxylated to afford pseudoyohimbone (309). 

Wenkert has also reported an alternative preparation of the pseudoyohimbine precursor 307 (Scheme 3.52) (58). Enol ether 312 was converted to ketal 316 which underwent the crucial Dieckmann cyclization to afford ketal 317. Removal of the oxygen functionality at C(18) was achieved by conversion to the corresponding thioketal which was desulfurized to provide 307. 

Wenkert has applied the Dieckmann methodology to the preparation of the more highly oxygenated yohimbines, deserpidine (3) and raunescine (288) (57, 58). To prepare deserpidine (Scheme 3.53), enol ether 313 was first converted to its ketal. Dieckmann cyclization then afforded the ketoester ketal... 

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. 

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... 

In a manner quite similar to that of Wenkert, Lounasmaa and his coworkers have utilized isoquinolinium salt cyclization reactions to prepare yohimbanes. For example, isoquinoline 474 was alkylated with tryptophyl bromide to yield iV-tryptophyl isoquinolinium salt 476 (Scheme 3.83) (133). Reduction of 476 with dithionate directly afforded dihydrogambirtannine (478) which could be converted by oxidation to ourouparine (480). Further reduction with dithionite provided gambirtannine (482). These reactions were also carried out on compounds in the descarbomethoxy series resulting in syntheses of the gambirtannine analogs 479,481, and 483. 

A key observation by Wenkert proved vital in the subsequent popularity of rhodium as a highly effective catalyst for the generation of carbenes from diazoketones and their engagement in C-H insertion reactions (Equation 27) [15, 16, 88], In this experiment, treatment of diazoketone 153 with Rh2(OAc)4 led to a stereoselective C-H insertion reaction to generate ketone 154 in 59% yield [88], Importantly, no cyclization was observed in the presence of CuSO,. 

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