Total Synthesis of Homodimericin A

Abstract

We report the concise total synthesis of homodimericin A (1), a recently identified fungal metabolite bearing an unprecedented molecular architecture. The success of the approach hinges on a series of rationally designed and bioinspired transformations, including a Moore rearrangement to assemble the monomeric hydroquinone precursor, homodimerization through double Michael addition to construct the planar A/B/C tricyclic framework, and a tandem Diels–Alder reaction/carbonyl–ene cyclization to forge the congested D/E/F tricyclic cage motif. Unequivocal evidence for the elucidated structure of homodimericin A was also provided by this study.

Chimeric natural products derived from medermycin and the nature-inspired construction of their polycyclic skeletons

“…Chimedermycin A (1) was determined to have a molecular formula of C 40 H 43 NO 13 based on the high-resolution electrospray ionization mass spectrometry (HRESIMS) peak at m/z 746.2798 [M + H] + . Analysis of its 1 H and 13 C NMR data and comparison with those of medermycin (9) suggested that compound 1 contains a pyranonaphthoquinone moiety similar to medermycin [21][22][23] . The other part of compound 1 was determined to be 6-deoxy-dihydrokalafungin (DDHK) 24,25 by analysis of the remaining signals in the 1 H and 13 C NMR spectra.…”

“…Analysis of its 1 H and 13 C NMR data and comparison with those of medermycin (9) suggested that compound 1 contains a pyranonaphthoquinone moiety similar to medermycin [21][22][23] . The other part of compound 1 was determined to be 6-deoxy-dihydrokalafungin (DDHK) 24,25 by analysis of the remaining signals in the 1 H and 13 C NMR spectra. The connection between the medermycin moiety and DDHK moiety was confirmed by the heteronuclear multiple bond correlations (HMBCs) of H-4 to C-11′′, H-5 to C-10′′, and H-9′′ to C-14 (Supplementary Fig.…”

“…The relative configurations of chimedermycin A (1) were determined by nuclear Overhauser effect spectroscopy (NOESY) correlations (Supplementary Fig. 2), coupling constant analysis (Supplementary Table 1), and 13 C NMR calculations [26][27][28] (Supplementary Fig. 3, Supplementary Data 1-4).…”

“…3a). 4-Hydroxyphenylpyruvic acid (13) and medermycin (9) are considered two biosynthetic precursors of chimedermycin H (8). 4-Hydroxyphenylpyruvic acid (13) can be easily oxidized into quinone methide by molecular oxygen.…”

“…The enzymatic catalysis of these reactions has attracted great attention [8][9][10] . Moreover, chemists have constructed these complex skeletons using efficient synthesis strategies [11][12][13][14] . A growing number of natural products possessing unprecedented chimeric frameworks formed through spontaneous chemical reactions have been discovered, such as discoipyrroles 15 , pyonitrins 16 , and dibohemamines 17 .…”