Concise Synthesis of Key 3-Polyenoyl-5-methylenefuran-2,4-dione Putative Intermediates in Quartromicin Biosynthesis

Abstract

Concise syntheses of two 3-polyenoyl-5-methylenefuran-2,4-diones, which are proposed to be key intermediates in the biosynthesis of the unusual 32-membered carbocycle-containing quartromicin antibiotics, are reported involving acylation of 3-lithio-4-methoxy-5-methylene-5H-furan-2-one as a key step.

Key words

antibiotics - biosynthesis - acylations - spirotetronates - quartromicins

References and Notes

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1

Current address: L. J. Montgomery, Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak SK23 OPG, U.K.

17

General Procedure for the Acylation of Compounds 18 and 28: To a stirred solution of 2,2,6,6-tetramethyl-piperidine (TMP, 0.84 mL, 5.00 mmol) in THF (5.50 mL) at -78 ˚C under argon was added n-BuLi (1.60 M in hexanes, 3.70 mL, 5.92 mmol) dropwise. After 15 min the solution was warmed to r.t. and stirred for a further 30 min to give a 0.5 M solution of LTMP. To a stirred solution of 18 or 28 (1.4 mmol) in THF (20 mL) at -78 ˚C under argon was added a solution of LTMP (0.5 M in THF, 4.40 mL, 2.20 mmol) dropwise. After stirring for 1 h, a solution of ester (0.70 mmol) in THF (2 mL) was added dropwise. The reaction mixture was stirred at -78 ˚C for 24 h and quenched with sat. citric acid (20 mL). The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (5 × 50 mL). The combined organic layers were dried with MgSO₄ and the solvent was removed in vacuo.
Purification and Characterization of Compound 29: Purification by flash column chromatography (hexane-EtOAc, 5:1) yielded the product as a yellow oil. ^¹H NMR (400 MHz, CDCl₃): δ = 1.34 (t, J = 7.0 Hz, 3 H), 1.74 (d, J = 7.0 Hz, 3 H), 1.83 (s, 3 H), 1.99 (s, 3 H), 2.02 (s, 3 H), 4.14 (q, J = 7.0 Hz, 2 H), 5.13 (d, J = 1.0 Hz, 1 H), 5.17 (d, J = 1.0 Hz, 1 H), 5.61 (q, J = 7.0 Hz, 1 H), 6.16 (s, 1 H), 6.55 (dd, J = 11.0, 15.0 Hz, 1 H), 6.67 (d, J = 15.0 Hz, 1 H), 7.04 (d, J = 11.0 Hz, 1 H). ^¹³C NMR (175 MHz, CDCl₃): δ = 11.6, 14.0, 14.2, 14.9, 16.6, 70.1, 93.9, 104.8, 122.4, 129.6, 132.6, 134.0, 135.4, 142.4, 146.9, 149.4 149.5, 164.4, 166.6, 190.6. IR(film): 2921, 1768, 1667 cm^-¹. HRMS (ESI): m/z calcd for C₂₀H₂₄O₄Na⁺: 351.1561; found: 351.1573.