title: 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.
authors.affiliation: Department of Biochemistry and ‡Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and ‡Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and ‡Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Yazmin P
authors.initials: YP
authors.lastname: Carrasco
authors.affiliation: Department of Biochemistry and ‡Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: John B
authors.initials: JB
authors.lastname: MacMillan
authors.affiliation: Department of Biochemistry and ‡Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas , 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
authors.forename: Jef K
authors.initials: JK
authors.lastname: De Brabander
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D003653:Decarboxylation; D006860:Hydrogen Bonding; D008848:Micromonosporaceae / Q000378:metabolism; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry; D009285:Naphthoquinones / Q000737:chemistry; D012294:Rifamycins / Q000096:biosynthesis / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D009281:Naphthalenes; D009285:Naphthoquinones; D012294:Rifamycins; C517709:saliniketal A; C517708:saliniketal B; C544882:salinisporamycin