Total Synthesis and Structural Revision of Cephalosporolide J

Abstract

Herein, we report the first total synthesis of cephalosporolide J, which is a deep sea sediment derived polyketide harboring a unique bicyclo[3.3.0]furanolactone moiety. The adopted synthetic strategy consisted of the alkynylation of γ-lactone with lithium alkynyltrifluoroborate followed by a spiroketalization triggered by hydrogenation of the triple bond. Through this synthesis, the correct structure of cephalosporolide J is shown to be that of the 9-epi stereoisomer of the structure originally proposed.

Key words

cephalosporolide J - polyketide - bicyclo[3.3.0]furanolactone - total synthesis - structural revision

Publication History

Received: 06 October 2022

Accepted after revision: 24 October 2022

Accepted Manuscript online:
24 October 2022

Article published online:
23 November 2022

• References and Notes

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• 21 Procedure for the Synthesis of α,β-Unsaturated Ynone 8 BuLi (2.40 mL, 1.59 M in hexane, 3.76 mmol) was added slowly at –78 °C under argon to a solution of benzyl ether (+)-4 (1.71 g, 3.99 mmol) in THF (8.40 mL). The reaction mixture was stirred for 45 min at the same temperature, after which BF₃·OEt₂ (0.487 mL, 3.88 mmol) was added dropwise. Stirring was continued for 15 min, and then γ-lactone 7 (269 mg, 1.14 mmol) in THF (3.00 mL) was added. The resulting mixture was warmed to room temperature and stirred for 1 h, after which a solution of saturated aqueous NH₄Cl solution/aqueous NH₃ solution (1:8, v/v, 4.0 mL) was added. The mixture was allowed to warm to room temperature and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified with flash column chromatography on silica gel (hexane/EtOAc = 3:1 to 1:1) to give α,β-unsaturated ynone 8 (545 mg, 72% yield) as a colorless oil; R_f = 0.55 (hexane/EtOAc = 1:1); [α]_D ²⁵ +38.5 (c 2.16, CHCl₃). IR (neat): ν_max = 3434, 3069, 3031, 2929, 2857, 2209, 1756, 1676, 1112 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.60 (m, 4 H), 7.43–7.28 (m, 16 H), 4.78 (d, J = 11.6 Hz, 1 H), 4.61 (dd, J = 5.7, 7.9 Hz, 1 H), 4.53 (s, 2 H), 4.50 (d, J = 11.6 Hz, 1 H), 4.07 (m, 1 H), 3.86 (ddd, J = 4.7, 7.6, 10.5 Hz, 1 H), 3.79–3.66 (m, 4 H), 3.13 (d, J = 4.2 Hz, 1 H), 2.90 (d, J = 5.5 Hz, 1 H), 2.87 (dd, J = 8.3, 17.2 Hz, 1 H), 2.80 (dd, J = 4.2, 17.2 Hz, 1 H), 2.13–1.87 (m, 3 H), 1.78 (m, 1 H), 1.04–0.99 (m, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 186.2 (C), 137.6 (C), 137.2 (C), 135.5 (CH) × 4, 133.42 (C), 133.40 (C), 129.7 (CH), 129.6 (CH), 128.5 (CH) × 2, 128.4 (CH) × 2, 127.92 (CH) × 2, 127.87 (CH), 127.8 (CH), 127.70 (CH) × 2, 127.68 (CH) × 2, 127.66 (CH) × 2, 91.8 (C), 84.8 (C), 73.4 (CH₂), 72.6 (CH), 71.4 (CH₂), 69.8 (CH), 68.3 (CH₂), 65.3 (CH), 59.3 (CH₂), 49.0 (CH₂), 38.0 (CH₂), 32.9 (CH₂), 26.8 (CH₃) × 3, 19.1 (C). HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₄₁H₄₈O₆SiNa: 687.3118; found: 687.3119.
• 22 The relative configuration of the C6 spirocenter of the synthesized tricyclic lactones 9, 10, 12, and 13 is also supported by comparison of their NMR spectra with cephalosporolide E and F,¹² whose structures have been determined by X-ray crystallography (see the Supporting Information).
• 23 Raghavan S, Samanta PK. Synlett 2013; 24: 1983