Mechanism of the Fischer Indole Synthesis

Using the Fisher indoles as a context for these studies introduces the need to convert sp2-hybridized C(16) of 42a into a quaternary carbon bearing two methyl groups, . Toward this end, we discovered that hydride addition to an intermediate fulvene 46, a species inadvertently derived from the alcohol 42a upon N-BOC protection conditions, provided a cyclopentadienylide anion intermediate that methylates exclusively at C(16). This intermediate anion could, in principle, methylate at C(10) as well, but an incipient 1,3 diaxial interaction between the incoming methyl electrophile and the axial CH3 of C(12) apparently thwarts this reaction trajectory. Of course, use of hydride as a nucleophile leaves C(11) in 47 devoid of functionality. Application of this methylation procedure in Fisher indole synthesis therefore will have to employ a nucleophilic species with fulvene 46 that preserves the opportunity to further functionalize C(11) as is required for 5.

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A series of cyclohexenyl alcohol-based substrates were prepared in order to test the feasibility of accessing the tetracyclic skeleton of the Fisher indoles via this methodology (cf. 5, , , and ). The majority of these species were prepared by application of the chemistry developed for ; Sonogashira coupling of 12i with the requisite cyclohexenyl iodide 26 followed by alkyl cuprate-mediated propargylic displacement of the acetate function in 27 to deliver the allene product 28. Since the cuprate required to prepare 37 (see ) was not available, we resorted to the Krause chemistry with the highly functionalized cyclohexenyl zincate derived from 35a and the propargyl acetate 36, itself prepared from 11 and the TBS ether of propargyl alcohol. The various cyclohexenyl iodides 34 and 35a–c were synthesized from the commercially available dione 31 using routine and well-documented chemistry, . The free hydroxyl substrate 29 was conveniently available by desilylation of 28a. The ketone 30, prepared via oxidation of 29, was synthesized as well. The rationale behind the choice of these cyclohexenyl substrates was 2-fold; (1) the relationship between substrate structure and product regiochemistry was still underdeveloped at this early juncture of the research, and so probing the influence of allylic oxygen substitution (sterics, electronics?) on C–C vs C–N bond formation seemed appropriate, and (2) for the first time, the issue of relative stereochemistry, as is relevant to the C(10)/C(11) stereogenic centers in the Fisher indoles (cf. 5, ) can be addressed–how will the preexisting C(11) stereogenic center (–OR) influence the stereochemical outcome at C(10) upon C(3)/C(10) bond formation during electrocyclization of an indolidene species related to 3a?


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The Fischer Indole synthesis: reaction mechanism …

Potential natural product targets for this developing methodology are plentiful, provided that both stereochemical and regiochemical requirements can be met by the allenyl azide cascade cyclization. For example, the Fisher indoles (cf. 5), the indole diterpenes (cf. 6), and the unique triindole yeast isolate malasseziacitrin (7) all fall under this general structural class, . Reaction chemistry that evolves from reactive indolidene intermediates of the type 3 has not been well described. One notable exception involves the proposed intermediacy of indolidene (or protonated indolidene) species in the syntheses of ibogaine derivatives and dimeric alkaloids of the vinblastine series, . The fact that this putative intermediate is reactive (electrophilic) enough to efficiently trap the sterically hindered and modestly nucleophilic aryl ring of vindoline suggests that further development of the reaction chemistry of indolidenes has the potential for advances in several areas of indole synthesis/functionalization.