Concise Chemoenzymatic Synthesis of Fasamycin A

Abstract

We report the development of a chemoenzymatic approach towards fasamycin A, a halogenated naphthacenoid that exhibits activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. The synthesis was accomplished in a convergent manner: two fragments were combined together via Michael−Dieckmann condensation to afford a dimethylnaphthacenone system. Finally, an enzymatic halogenation was employed to introduce the requisite chlorine substituent of the natural product at a late stage. 24 D = +5.7 (c = 0.20 in MeOH). ASSOCIATED CONTENT Supporting InformationProtein and DNA sequences, 1 H and 13 C NMR data and HPLC traces.

Expanding the Chemical Diversity of Fasamycin Via Genome Mining and Biocatalysis

“…Although FasV ed , AccV, and ForV are homologues to each other (FasV ed and AccV 58.5% identity, FasV ed and ForV 59.8% identity, AccV and ForV 67.7% identity), the order of the halogenation of FasV ed , AccV, and ForV in fasamycin (from eDNA), accramycin, and formicamycin biosynthesis is different. On the basis of in vitro results or the corresponding halogenated product profiles, FasV ed should sequentially catalyze halogenation at C-16 and C-14 of fasamycin (from eDNA), , and AccV follows the halogenation order from C-14 to C-22, C-4, and C-2 in the biosynthesis of accramycins, , while ForV halogenation starts at C-2 and C-22 in formicamycins (Figure , Figure S2, Supporting Information). , FasV sk shows higher similarity to ForV than to AccV and FasV ed (FasV sk and ForV 92.8% identity, FasV sk and AccV 67.5% identity, FasV sk and FasV ed 59.8% identity).…”

“…By utilizing a different protein target from those of methicillin and vancomycin, fasamycin-type products are highly active against MRSA and VRE. , This fascinating biological activity is attractive for developing better antibiotics via structural engineering. However, the complexity of the fasamycin structure, especially the axial chirality, renders chemical access to its bioactive structural diversity very challenging. − Therefore, other approaches, especially from the aspect of biosynthetic engineering and genome mining, are highly appreciated. , …”

Current Progress in the Chemoenzymatic Synthesis of Natural Products

“…One of the principal scientists featured throughout this review, Hans Renata, pushes the boundaries of the utility and elegance of chemoenzymatic synthesis across multiple complex classes of molecules. The work of the Renata group is often impressive in its nuanced design which is integrated within traditional synthetic sequences [ 20 , 22 , 23 , 31 , 32 , 33 ]. In a recent paper they disclosed the synthesis of chrodrimanin C ( 3 ), verruculide A, and polysin using multiple chemoenzymatic steps ( Scheme 1 ) [ 33 ].…”

“…The work of the Renata group is often impressive in its nuanced design which is integrated within traditional synthetic sequences [ 20 , 22 , 23 , 31 , 32 , 33 ]. In a recent paper they disclosed the synthesis of chrodrimanin C ( 3 ), verruculide A, and polysin using multiple chemoenzymatic steps ( Scheme 1 ) [ 33 ]. A key step featured in these syntheses is an enzymatic hydroxylation of a 6,6,5 or 6,6,6, steroid core, intermediate 1 in the case of chrodrimanin C ( 3 ).…”

“…A recent synthesis of fasamycin A ( 6 ) from the precursor naphthacemycin B1, utilizing a highly unusual enzymatic halogenation, was recently reported by the Renata group ( Scheme 6 ) [ 33 ]. The report involved a convergent synthesis that culminated with a halogenation via a chemoenzymatic system that contained a flavin-dependent halogenase, CtcQ as a reductase, Opt13 to regenerate NADH, and NADH/NADPH.…”