Total synthesis of decarboxyaltenusin

Abstract

The total synthesis of decarboxyaltenusin (5'-methoxy-6-methyl-[1,1'-biphenyl]-3,3',4-triol), a toxin produced by various mold fungi, has been achieved in seven steps in a yield of 31% starting from 4-methylcatechol and 1-bromo-3,5-dimethoxybenzene, where the longest linear sequence consists of five steps. The key reaction was a palladium-catalyzed Suzuki coupling of an aromatic boronate with a brominated resorcin derivative.

Keywords: Suzuki coupling; biaryls; boronates; mycotoxins; polyketides.

Scheme 1

Biphenyl-derived mycotoxins.

Scheme 2

Synthesis of arylboronates 6. Conditions: a) TBSCl, DMAP, imidazole, DMF, 50 °C, 4 h (96%); b) NBS, MeCN, rt, 71 h (quant.); c) NBS, MeCN, rt, 72 h (R = TBS, 96%); d) BnBr, KI, K₂CO₃, DMF/acetone, 70 °C, 29 h, (R = Bn, 86%); e) R = TBS: BuLi, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, THF, −78 °C, 0.45–2 h, rt, 18 h (57%); R = Bn: bis(pinacolato)diboron, Pd(dppf)Cl₂·CH₂Cl₂ (cat.), KOAc, dioxane, 80 °C, 17 h (55%).

Scheme 3

Synthesis of aryl bromides 9. Conditions: f) BBr₃, −78 °C to rt, 18 h (71%); g) R = TBS: TBSCl, DMAP, imidazole, DMF, 55 °C, 4 h (73%); R = Bn: BnBr, K₂CO₃, DMF/acetone 1:2, 80 °C, 43 h (98%).

Scheme 4

Final steps in the synthesis of biaryl 1. Conditions: h) Pd(OAc)₂, SPhos, Cs₂CO₃, dioxane/H₂O 7:1, 70 °C, 18 h, (R = TBS: 98%, containing non-separable impurities; R = Bn: 89%) ; i) R = Bn: Pd/C (10%), H₂, THF, 8 bar, 24 h, 40 °C (88%).