Total Synthesis of Salimabromide: A Tetracyclic Polyketide from a Marine Myxobacterium

Abstract

Salimabromide is an antibiotic polyketide that was previously isolated from the obligate marine myxobacterium Enhygromyxa salina, and its densely functionalized and conformationally rigid tetracyclic framework is unprecedented in nature. Herein we report the first chemical synthesis of the target structure by employing a series of well-orchestrated, robust transformations, highlighted by an acid-promoted, powerful Wagner-Meerwein rearrangement/Friedel-Crafts cyclization sequence to forge the two adjacent quaternary carbon centers embedded in the tetrahydronaphthalene. A high-yielding ketiminium mediated [2+2]-cycloaddition was also utilized for the simultaneous construction of the remaining three stereocenters.

Scheme 1. (a) Structural Diversity Produced by Marine Myxobacteria and (b) Key Retrosynthetic Bond Disconnections for Salimabromide (1)

Scheme 2. Synthesis of the Tetrahydronaphthalene Framework via Consecutive Wagner–Meerwein Rearrangement and Friedel–Crafts Cyclization

Reagents and conditions: (a) [Ba(OH)₂·H₂O, C-200], pinacolone 9, EtOH, 78 °C; (b) Pd/C, H₂, EtOAc, 23 °C, 76–82% over two steps; (c) NaH, DMSO, 70 °C, then Me₃SI, 0 to 23 °C; (d) H₂SO₄, HFIP, 23 °C, 41% for 12, 5% for 13 over two steps.

Scheme 3. Total Synthesis of Salimabromide

Reagents and conditions: (a) TBDPSCl, imidazole, DMAP, DMF, 23 °C; (b) DDQ, dioxane, 93 °C, 91% over two steps; (c) LiPPh₂, THF, 60 °C; (d) PhNTf₂, NEt₃, THF, 23 °C, 99% over two steps; (e) ZnEt₂, Pd(dppf)Cl₂, dioxane, 70 °C, 92%; (f) TBAF, THF, 23 °C, 99%; (g) DMP, K₂CO₃, CH₂Cl₂, 0 to 23 °C, 96%; (h) NaHMDS, 17, THF, −78 to +23 °C, 85%; (i) pyrrolidine, 100 °C, 99%; (j) Tf₂O, 2,4,6-collidine, ClCH₂CH₂Cl, 80 °C, 89%; (k) SeO₂, SiO₂, dioxane, 120 °C, 47% over five cycles; (l) t-BuCHO, Cu(OAc)₂, O₂ (1 atm), ClCH₂CH₂Cl, 23 °C, then DMP, NaHCO₃, CH₂Cl₂, 79%, 23:24 = 1:3.2; (m) AgTFA, Br₂, CF₃COOH, 50%.