Rifamycin Biosynthetic Congeners: Isolation and Total Synthesis of Rifsaliniketal and Total Synthesis of Salinisporamycin and Saliniketals A and B

Abstract

We describe the isolation, structure elucidation, and total synthesis of the novel marine natural product rifsaliniketal and the total synthesis of the structurally related variants salinisporamycin and saliniketals A and B. Rifsaliniketal was previously proposed, but not observed, as a diverted metabolite from a biosynthetic precursor to rifamycin S. Decarboxylation of rifamycin provides salinisporamycin, which upon truncation with loss of the naphthoquinone ring leads to saliniketals. Our synthetic strategy hinged upon a Pt(II)-catalyzed cycloisomerization of an alkynediol to set the dioxabicyclo[3.2.1]octane ring system and a fragmentation of an intermediate dihydropyranone to forge a stereochemically defined (E,Z)-dienamide unit. Multiple routes were explored to assemble fragments with high stereocontrol, an exercise that provided additional insights into acyclic stereocontrol during stereochemically complex fragment-assembly processes. The resulting 11-14 step synthesis of saliniketals then enabled us to explore strategies for the synthesis and coupling of highly substituted naphthoquinones or the corresponding naphthalene fragments. Whereas direct coupling with naphthoquinone fragments proved unsuccessful, both amidation and C-N bond formation tactics with the more electron-rich naphthalene congeners provided an efficient means to complete the first total synthesis of rifsaliniketal and salinisporamycin.

Marine natural products

“…For example, the isolation (from Salinispora arenicola), structure elucidation and subsequent total synthesis of rifsaliniketal 122 (ref. 63) along with the known and related rifamycin congeners salinisporamycin, 92 and salinketals A and B, 93 were reported. Other total syntheses of marine bacterial metabolites include (AE)-spiroindimicins B and C, 94 bacilosarcin C, 95 cyclomarins A 96 and D, 97 cyclomarazines A and B, 98 nitropyrrolins A, B and D, 99 actinophenanthroline A, 100,101 jiolide A, 102 heronamides A-C, 103 dermacozines A-C. 104 The proposed chemical structure of marineosin A was also successfully synthesised; the structure of the target compound was established following X-ray data analysis.…”

Living GenoChemetics by hyphenating synthetic biology and synthetic chemistry in vivo

“…Bacterial natural products represent an unparalleled starting point for drug discovery 1 , and there is much interest in the generation of analogs of such compounds in order to explore modes of action, determine structure-activity-relationships and improve bioavailability and bioactivity. Natural products and their analogs may of course be accessed through total synthesis; excellent recent examples include the total synthesis of the antibiotic marinomycin 2 and generation of rifamycin and the structurally related metabolite salinisporamycin 3 , 4 . Such studies are invaluable in developing methodology, revealing potential biogenic mechanisms and providing the only access to molecules generated by rare or hard to culture organisms.…”

Stereoselective Construction of (E,Z)‐1,3‐Dienes and Its Application in Natural Product Synthesis

“…This is illustrated in the syntheses of dehydronerol isovalerate, trichoverrol B (178!179), rifamycin, salinisporamycin, and saliniketals A and B (180!181, Scheme 70). [155][156][157][158][159] A related strategy was developed by Kunz featuring a one-pot sequence involving the esterification of vinyl acetic acid, an RCM, and a β-elimination. [153,160] This strategy was notably used in the total syntheses of Satractylodemayne C and F, stagonolide E, and curvulide A.…”