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Synlett 2025; 36(06): 679-682
DOI: 10.1055/s-0043-1775057
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Development of a Stereospecific Strategy for the Total Synthesis of Diplodialide C and Formal Synthesis of (–)-Curvularin

Ravan Kumar
,
Amit Banerjee
,
Sumit Saha  ∗
The authors acknowledge the National Institute of Technology (NIT) Sikkim for infrastructure support. Mr. Ravan Kumar acknowledges fellowship support from the NIT Sikkim.
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Abstract

A concise and efficient stereospecific approach for the total synthesis of diplodialide C (R,R and S,S isomers) has been demonstrated using chiral homoglycidol and propylene oxide as a source of starting material. Further oxidized ketolide product derived from diplodialide C (S,S isomer) was applied to the formal synthesis of (–)-curvularin following reported known literature.

Key words

total synthesis - natural products - pentaketides - macrolide - epoxides - Shiina macrolactonization

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1775057.
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Publication History

Received: 27 July 2024

Accepted after revision: 15 August 2024

Article published online:
19 September 2024

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  • 12 Synthesis of (R)-1-(Benzyloxy)hept-6-yn-3-ol (4a) To a two-neck flask previously dried and equipped with a condenser, magnesium turnings (1.02 g, 42.08 mmol, 15 equiv) were activated with a crystal of I2 by heating using a hot air gun under vacuum and was allowed for cooling down to room temperature under argon atmosphere. HgCl2 (46 mg, 0.17 mmol, 0.06 equiv) and Et2O (10 mL) were added under argon atmosphere. Then, 80% (w/w) propargyl bromide in toluene (1.6 mL, 16.83 mmol, 6 equiv) was slowly added at 0 °C, and the flask was warmed to 40 °C to begin reflux. It was placed in the ice bath again for 15 min. After 15 min, the resulting reaction mixture was allowed to stir for 1 h at room temperature. The resulting dark grey solution was then diluted with Et2O (20 mL), then a solution of epoxide 3a (500 mg, 2.81 mmol, 1 equiv) in Et2O (20 mL) was added dropwise at –10 °C, and the reaction was allowed to stir for 2 h at room temperature. After 2 h, the reaction was poured into a saturated aqueous solution of NH4Cl (30 mL), and the aqueous layer was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with cold water (3 × 50 mL) and brine (20 mL, dried over anhydrous Na2SO4, and concentrated in vacuum. The crude material was purified by column chromatography on silica gel (10% EtOAc in petroleum ether) to get the pure product 4a as pale yellow oil (533 mg, 2.44 mmol, 87%). TLC: Rf = 0.43 (10% EtOAc in petroleum ether). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.28 (m, 5 H), 4.53 (s, 2 H), 3.98–3.92 (m 1 H), 3.76–3.64 (m, 2 H), 2.36–2.31 (m, 2 H), 1.95 (t, J = 2.6 Hz, 1 H), 1.80–1.75 (m, 2 H), 1.71–1.65 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 137.95, 128.61, 127.93, 127.82, 84.45, 73.51, 70.30, 69.24, 68.59, 36.40, 35.98, 14.94. HRMS: m/z calcd for C14H19O2 [M + H]+: 219.1385; found: 219.1383.
  • 13 Synthesis of (4R,10R)-4-(Methoxymethoxy)-10-methyloxecan-2-one (11a) MNBA (146 mg, 0.423 mmol, 3 equiv) was added to the solution of 10a (35 mg, 0.141mmol, 1 equiv), triethylamine (0.1 mL, 0.705 mmol, 5 equiv) in DCM (2 mL). The resulting solution was stirred at room temperature for 3 h, diluted with toluene (10 mL), and added to a refluxing solution of 4-dimethylaminopyridine (103 mg, 0.846 mmol, 6 equiv) and toluene (35 mL) over 4 h. The reaction mixture was allowed to reflux for 8 h, cooled to room temperature, toluene was evaporated, then sat. aq. NaHCO3 was added to it and also ethyl acetate (30 mL). The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (20 mL) thrice. The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography in silica gel to give 11a (16.9 mg, 52%) as colorless oil. TLC: Rf = 0.28 (10% EtOAc in petroleum ether). 1H NMR (500 MHz, CDCl3): δ = 5.02– 4.99 (m, 1 H), 4.66 (s, 2 H), 4.24–4.20 (m, 1 H), 3.37 (s, 3 H), 2.92–2.88 (m, 1 H), 2.35 (dd, J = 15.8, 10.8 Hz, 1 H), 1.97–1.91 (m, 1 H), 1.80–1.74 (m, 2 H), 1.58–1.39 (m, 6 H), 1.26 (d, J = 6.5 Hz, 3 H), 1.07–1.02 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 170.71, 95.50, 73.36, 71.93, 55.54, 41.71, 34.71, 29.85, 25.48, 23.66, 23.31, 19.58. HRMS: m/z calcd for C12H23O4 [M + H]+: 230.1596; found: 230.1590.