Synthesis of Onychine and Formal Synthesis of Eupolauridine via the Vinylogous Aza-Morita-Baylis-Hillman Reaction

Abstract

A concise and efficient synthesis of the antimycotic alkaloid onychine was developed, based on the vinylogous aza-MoritaBaylis-Hillman reaction of N-(benzylidene)benzenesulfonamide with methyl 2,4-pentadienoate, followed by intramolecular conjugate addition, Friedel-Crafts acylation, methyl cuprate addition, and aromatization.The 4-azafluorenones are a group of biologically interesting alkaloids found in trees of the family Annonaceae. 1 Onychine (1, Figure 1) was the first 4-azafluorenone to be discovered and was initially isolated from the trunkwood of the Brazilian tree Onychopetalum amazonicum in 1976. 2 The structure originally assigned to onychine 1 was erroneous; however, it was later corrected on the basis of NMR studies and total synthesis. 3 Interestingly, Taylor and co-workers 4 completed the first synthesis of this compound as an intermediate en route to the related alkaloid eupolauridine (2), before onychine was discovered as a natural product. It was not until 1979 that Koyama et al. 3a realized that the structures of the Taylor intermediate and the natural product were identical. Alkaloids 1 and 2 display antimycotic activity against C. albicans, 5,6 as well as antibacterial activity, 6 prompting the development of several approaches toward their synthesis. Onychine has been prepared by an enamine triazine cycloaddition, 3b a Yb(OTf) 3 -catalyzed [4+2] cycloaddition, 7 a Pummererdipolar cycloaddition cascade, 8 an oxidative thermal rearrangement of 2-indanone oxime O-crotyl ether, 9 zeolite 10 or polyphosphoric acid catalyzed 11 cyclizations of 2-aryl-3-nicotinic acid derivatives, Pd(0)-catalyzed cross coupling of aryl-12 or methylboronic acids 13 with 2-halopyridines, and via an aza-Wittig reaction. 14 Figure 1We recently reported a novel vinylogous variation of the aza-Morita-Baylis-Hillman (aza-MBH) reaction, 15 in which suitably activated dienes 4 reacted with imines 3 in the presence of the nucleophilic catalyst 3-hydroxyquinuclidine (HQD) to afford products 5. 15a,b During these investigations, we observed that when the electronwithdrawing group (EWG) was a sulfonyl or ester moiety, the aza-MBH adduct cyclized via a base-catalyzed intramolecular conjugate addition to afford tetrahydropyridine derivatives 6. Unfortunately, this cyclization occurred exclusively from the E-isomers of 5, as the Zisomers did not have the appropriate geometry to assume the required six-membered transition state for intramolecular conjugate addition. Furthermore, the aza-MBH reactions with these EWG typically gave only moderate to low selectivities, with E/Z ratios ranging from 50:50 to 80:20. In order to overcome this limitation, we employed a convenient in situ photoisomerization of the E/Z mixtures during the cyclization procedure, resulting in the equilibration and ultimate consumption of both geometrical isomers (Scheme 1). We now demonstrate the application of this methodology to the total synthesis of the alkaloid onychine (1). Scheme 1The tetrahydropyridine 7, which we had prepared previously in two separa...

Collective Total Synthesis of 4‐Azafluorenone Alkaloids

“…[27] Although no example for onychine (4) synthesis was provided, tert-butyl hydroperoxide (TBHP) has been successfully employed in the radical cyclization of 3hydroxymethyl-2-phenylpyridine, 2-(pyridinyl)benzylalcohols [28] and nicotinaldehydes [29] for the synthesis of various 1-, 2-, 3and 4-azafluorenones, respectively. Further noteworthy synthetic strategies for onychine (4) synthesis include biaryl linkage of azabenzophenones via Pd-catalyzed intramolecular Heck reaction [30] (Scheme 2, III), application of the aza-Morita-Baylis-Hillman reaction, [31] as well as directed ortho-metalation of 2-(4chloro-2-pyridyl)benzamide and subsequent methylation via Suzuki-Miyaura cross-coupling. [32] Finally, thermal cyclization of both indanoneoxime O-crotyl ethers [33] (Scheme 2, IV) and indanone N-propargyl enamines have been reported, [34] although plausibly affording isomeric mixtures of 4-azafluorenones with respect to the position of the methyl group.…”