A Chemoenzymatic and Fully Stereocontrolled Total Synthesis of the Antibacterial Natural Product (−)‐Platencin

Abstract

The natural product (-)-platencin is a potent antibacterial agent that exerts its effects through a novel mode of action. As such, it is an important lead in the development of next-generation antibacterials that are urgently needed because of the rapidly developing resistance to current therapies. The work reported here concerns the development of a convergent and chemoenzymatic total synthesis of (-)-platencin by methods that should provide access to a range of biologically relevant analogues. The key step involves a thermally promoted and facially selective intramolecular Diels-Alder (IMDA) cycloaddition reaction to give an adduct that embodies the tricarbocyclic core of (-)-platencin. This adduct was elaborated over thirteen steps to the natural product. The substrate for the IMDA reaction was prepared by Stille cross-coupling of a Z-configured alkenylstannane with an iodinated diene obtained in an enantiomerically pure form through the whole-cell biotransformation of iodobenzene.

A Second-Generation Chemoenzymatic Total Synthesis of Platencin

“…85% yield. The spectroscopic data derived from this material were in complete accord with those reported by both our group 9 and by others.…”

“…In contrast to observations of Nicolaou and co-workers, 6b it was found that the t-butyl ester moiety within this last compound could be cleaved using trifluoroacetic acid (TFA, at 18 °C for 0.5 h) without any accompanying conversion of the exocyclic olefin to its endocyclic isomer. Platencinic acid (23) 6,8,9,24 was thus formed in ca. 85% yield.…”

“…Furthermore, introducing the required C4 methyl and propionic acid groups in an efficient and stereocontrolled manner proved problematic. In an attempt to address these issues, we recently reported 9 an alternate IMDA-based approach that delivered a more highly functionalised form of compound 3 and one that could be converted, over a further thirteen steps, into platencin. However, significant functional group incompatibilities were encountered in this first chemoenzymatic total synthesis of the title natural product.…”

“…[21][22][23] The reaction proceeded rapidly under ultrasonication conditions and afforded dione 21 5a in 81% yield. Selective methylenation of the nonconjugated ketone carbonyl moiety within compound 21 was achieved using the Wittig reagent under carefully controlled conditions, 9 to afford the previously reported ester 22 6b in 85% yieled. In contrast to observations of Nicolaou and co-workers, 6b it was found that the t-butyl ester moiety within this last compound could be cleaved using trifluoroacetic acid (TFA, at 18 °C for 0.5 h) without any accompanying conversion of the exocyclic olefin to its endocyclic isomer.…”

“…9 Thus, the acetonide residue associated with compound 5 was cleaved using acid-activated Dowex-50 resin in a metha- …”