Vinylogous Addition of Siloxyfurans to Benzopyryliums: A Concise Approach to the Tetrahydroxanthone Natural Products

Abstract

A concise approach to the tetrahydroxanthone natural products has been developed employing vinylogous addition of siloxyfurans to benzopyryliums and a late stage Dieckmann cyclization. Using this methodology, chiral, racemic forms of the natural products blennolides B and C have been synthesized in a maximum of four steps from a 5-hydroxychromone substrate. The regio-and diastereoselectivity of vinylogous additions was probed using computational studies which suggest involvement of Diels-Alder-like transition states.Tetrahydroxanthones are a class of mycotoxins 1 bearing both monomeric and dimeric frameworks. The recently isolated tetrahydroxanthones blennolides A (1) and B (2) ( Figure 1) 2 are monomer units of the antitumor agents secalonic acids B (3) and D (4), 3 the latter which exhibits antibacterial, cytostatic, and anti-HIV properties. 4 Blennolide C (5), the methyl isomer of 1, and the antifungal agent parnafungin A (6) 5 also possess the characteristic dihydro-2H-xanthenone framework found in many tetrahydroxanthones. Related, isomeric natural products including paecilin B (7) (stereochemistry unassigned) containing the isomeric chromone lactone moiety have also been reported. 6 Recently, Bräse and Nicolaou have reported elegant approaches to blennolide C (5) and the related natural product diversonol employing biomimetic construction of the tetrahydroxanthone core. 7 Herein, we describe a concise approach to racemic blennolides and related tetrahydroxanthones employing a "retrobiomimetic" process 8 involving vinylogous addition of siloxyfurans to benzopyryliums.Biosynthetically, the blennolides appear to be derived from a sequence involving oxidation of benzophenone ester 8, oxa-Michael addition, and reduction to dihydro-2H-xanthenone 9 (Figure 2, (a)). 9 The chromone lactone structure 10 found in paecilin B (7) 6 appears to be derived from hydrolysis/lactonization of the tetrahydroxanthone framework. 6b,c We envisioned that precursor 11 may be obtained by vinylogous addition of siloxyfurans 10 to activated benzopyrylium salts 12. 11 Conjugate reduction of butenolide 11 should afford chromone lactone 10. The last step in the sequence entails a "retrobiomimetic" transformation 8 in which tetrahydroxanthones 9 may be produced by Dieckmann cyclization 7k of chromone lactones 10. We initiated our study by treating the readily available 5-hydroxychromone 13 12,13 with a number of Lewis acids in an effort to promote vinylogous addition of 2-trimethylsilyloxy furan (Scheme 1). Unfortunately, in our initial experiments we did not observe substantial adduct formation. In light of the high reactivity of 4-siloxy-1-benzopyrylium salts towards carbon nucleophiles, 11a,b we focused our efforts on silyl triflate activation of chromone 13.In particular, we reasoned that dialkylsilyl ditriflate reagents, generally used to protect diols as silylenes, 14 may directly afford activated siloxybenzopyrylium species. In the event, treatment of 13 with diisopropyl silyl ditriflate in the presence of 2,6-lutidin...

Antifungal Polyketides and Other Compounds from Amazonian Endophytic Talaromyces Fungi

“…So far, only paecilin C was evaluated for its antibacterial potential, however, showed no activity. 27 Therefore, this is the first report of the antifungal activity of a paecilin derivative.…”

“…(marine organism). 27 This is the first report of all identified polyketides in endophytic Talaromyces strains. Cordyanhydrides (7 and 8) were originally described from the insect pathogen fungus Cordyceps pseudomilitaris, 24 and more recently from Paecilomyces tenuipes, 29 and Dwayaangam colodena.…”

A Convergent Synthesis of Gonytolide C Using an Intramolecular Oxa‐Michael Addition

“…Recently, a number of reports of synthetic work towards gonytolide C (2a) have been published (Scheme 1). [5][6][7][8] A racemic synthesis of (±)-gonytolide C (2a) and (±)-epi-gonytolide C (2b) was incidentally reported by the Porco group in 2011 en route to a different natural product, before the gonytolides had been isolated. [5] A vinylogous addition of ners were established.…”

“…[5][6][7][8] A racemic synthesis of (±)-gonytolide C (2a) and (±)-epi-gonytolide C (2b) was incidentally reported by the Porco group in 2011 en route to a different natural product, before the gonytolides had been isolated. [5] A vinylogous addition of ners were established. The synthesis enabled further investigation of an asymmetric oxa-Michael cyclisation to prepare gonytolide C, demonstrating the utility of this strategy for synthesis of 2,2-disubstituted chromanones.…”

Fungal Anticancer Metabolites: Synthesis Towards Drug Discovery

“…The synthetic strategy entailed the preparation of a hemisecalonic derivative (monomeric natural tetrahydroxanthenones 15 such as blennolide A) [114] and then its conversion to the corresponding iodide and stannane. …”