Toward the Total Synthesis of Hygrocin B and Divergolide C: Construction of the Naphthoquinone–Azepinone Core

Abstract

A highly regioselective Diels-Alder approach toward the bioactive natural products hygrocin B and divergolide C is presented. The route uses an unusual benzoquinone-azepinone dienophile prepared in 8 steps from ethyl 8-methoxy-1-naphthoate, by a route which includes, as key steps, a Birch alkylation and a Beckmann rearrangement of a tetralone oxime, both of which are demonstrated on multigram scale. The naphthoquinone-azepinone core is suitably functionalized for addition of the ansa-chain, found in the natural products.

Structural Diversity and Biological Activities of Novel Secondary Metabolites from Endophytes

“…Compound 1 showed the strongest antibacterial activity against Mycobacterium vaccae with an inhibitory zone of 19 mm at 50 μg per paper disk in the disk diffusion assay, while compound 4 demonstrated marked cytotoxicity against several cancer cell lines, with IC 50 values ranging from 1.0 to 2.0 μM [ 28 ]. Their intriguing structures and associated antibacterial or antitumor activities have stimulated various synthetic methods towards divergolides [ 32 , 33 ], and scientific interest in biosynthetic gene clusters [ 29 ].…”

1,3-Dipolar cycloaddition reactions of azomethine ylides with aromatic dipolarophiles

“…6,7 Well-studied examples of dearomatization processes include Birch reduction, [8][9][10][11] enzymatic cis-dihydroxylation, [12][13][14] oxidative dearomatization of phenols, [15][16][17][18][19][20][21] enzymatic benzene reductions, 22 transition-metal complexing dearomatizations, [23][24][25] nucleophilic dearomatization processes [26][27][28][29][30][31] and catalytic hydrogenation. [32][33][34][35] An alternative dearomatization process would involve a [4+2] or [3+2] cycloaddition reaction of a diene or 1,3-dipole with an aromatic carbon-carbon double bond.…”

Total Synthesis of Divergolides E and H

“…[1a] Subsequent studies based on genomic analyses provided greater insights into the biosyntheses of these structures. These compounds have been reported to show moderate antibiotic activity against an umber of strains,i ncluding some that show drug resistance,though these studies are limited to zone inhibition assays.T hese structures have been the subject of several synthetic studies [4] and the total synthesis of 2,t he only member of the family to be synthesized, was recently reported by Tr auner and co-workers. These compounds have been reported to show moderate antibiotic activity against an umber of strains,i ncluding some that show drug resistance,though these studies are limited to zone inhibition assays.T hese structures have been the subject of several synthetic studies [4] and the total synthesis of 2,t he only member of the family to be synthesized, was recently reported by Tr auner and co-workers.…”

“…[1c, 2, 3] Structurally disparate members of this family (Figure 1) include the bridged bicyclic acetal divergolide E( 1), the naphthoquinone divergolide I ( 2), and the alkylidene chromene divergolide B( 3). These compounds have been reported to show moderate antibiotic activity against an umber of strains,i ncluding some that show drug resistance,though these studies are limited to zone inhibition assays.T hese structures have been the subject of several synthetic studies [4] and the total synthesis of 2,t he only member of the family to be synthesized, was recently reported by Tr auner and co-workers. [5] This manuscript describes the first total synthesis of 1 and its acyl-migrated isomer divergolide H (4).…”