Broadening the scope of the modified-Julia reaction : a mild and stereoselective method for the synthesis of (Z)-configurated α,β-unsaturated lactones Public Deposited

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  • An intramolecular variant of the modified-Julia olefination was demonstrated by the synthesis of α,β-unsaturated lactones in a mild and (Z)-selective fashion. The lynchpin reagent (benzothiazol-2-sulfonyl) acetic acid was synthesized in a straightforward fashion in 86% overall yield from commercially available 2-mercaptobenzothiazole via conversion to ethyl (benzothiazol-2-ylthio)acetate by base mediated alkylation with ethyl chloroactetate; saponification of the ester to (1,3-benzothiazol-2-ylthio)acetic acid; and, oxidation by ammonium molybdate and H₂O₂ to afford the key sulfonyl acid reagent. Through the use of an efficient dicyclohexylcarbodiimide coupling reaction, the acetic acid derivative was condensed with a series of ω-alkenyl carbinols to form the corresponding ω-alkenyl (benzothiazol-2-sulfonyl)acetates in moderate to excellent yields (60 – 94%). The esters were then subjected to ozonolysis conditions (O₃ in CH₂Cl₂) and, after subsequent reduction of the ozonide with dimethyl sulfide, the carboxaldehyde intermediates were immediately subjected to 1,8-diazabicycloundec-7-ene in CH₂Cl₂ (-78 °C to rt) to effect cyclic alkene formation. Successful production of the α,β-unsaturated lactones was observed for a variety of ring sizes (7, 12, 13, and 19) in moderate yields (30 – 45%), but comparable to other methods for lactone synthesis. Aldol condensation products resulting from the elimination of H₂O from the putative anti-β-alkoxy-benzothiazol-sulfones intermediates were also obtained from the smaller rings sizes, albeit in low yields (2 – 4%). The reaction conditions proved to be ideal for these simple substrates. Significantly, biasing factors such as Thorpe-Ingold effects were not required to aid macrocyclic lactone formation. The targeted α,β-unsaturated lactones were generated stereoselectively with predominantly (Z)-configuration (Z:E ≥ 85:15) in all cases examined.
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