Development of a Stereospecific Strategy for the Total Synthesis of Diplodialide C and Formal Synthesis of (–)-Curvularin

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

• References and Notes

• 1 Rawlings BJ. Nat. Prod. Rep. 1997; 14: 523
• 2a Wada K, Ishida T. J. Chem. Soc., Chem. Commun. 1975; 209
• 2b Wada K, Ishida T. J. Chem. Soc., Chem. Commun. 1976; 340
• 2c Wada K, Ishida T. J. Chem. Soc., Perkin Trans. 1 1979; 1154
• 3a Wakamatsu T, Akasaka K, Ban Y. Tetrahedron Lett. 1977; 18: 2755
• 3b Wada K, Ishida T. J. Chem. Soc., Chem. Commun. 1977; 337
• 3c Wakamatsu T, Akasaka K, Ban Y. J. Org. Chem. 1979; 44: 2008
• 3d Anand RV, Baktharaman S, Singh VK. J. Org. Chem. 2003; 68: 3356
• 3e Sharma GV. M, Reddy KL. Tetrahedron: Asymmetry 2006; 17: 3197
• 3f Tadross PM, Virgil SC, Stoltz BM. Org. Lett. 2010; 12: 1612
• 3g Pratapareddy B, Sreenivasulu R, Hatti I, Rao NV. B, Raju RR. Monatsh. Chem. 2015; 146: 1921
• 3h Ramanujan V, Kumar CN. S. S. P. ARKIVOC 2018; (vii): 332
• 3i Gao DW, Jamieson CS. Wang G, Yan Y, Zhou J, Houk KN, Tang Y. J. Am. Chem. Soc. 2021; 143: 80
• 4a Subba S, Saha S, Mandal S. SynOpen 2020; 4: 66
• 4b Subba S, Saha S. Synth. Commun. 2022; 52: 704
• 4c Subba S, Saha S, Mandal S, Ghosh A J, Saha T. Tetrahedron Lett. 2022; 106: 154081
• 5 Lua BL. Williams G. M. Verdon D. J, Dunbar PR, Brimble MA. J. Med. Chem. 2020; 63: 2282
• 6 Liang Q, Sun Y, Yu B, She X, Pan X. J. Org. Chem. 2007; 72: 9846
• 7a Sharma BM, Gontala A, Kumar P. Eur. J. Org. Chem. 2016; 1215
• 7b Lacuna JG, Domínguez G, Urgoiti JB, Castells JP. Org. Biomol. Chem. 2019; 17: 9489
• 8 Reddy GV, Kumar RS. C, Sreedhar E, Babu KS, Rao JM. Tetrahedron Lett. 2010; 51: 1723
• 9 Vintonyak VV, Kunze B, Sasse F, Maier ME. Chem. Eur. J. 2008; 14: 11132
• 10a Dinh M, Bouzbouz S, Péglion JL, Cossy J. Tetrahedron 2008; 64: 5703
• 10b Narita K, Matsuhara K, Itoh J, Akiyama Y, Dan S, Yamori T, Ito A, Yoshida M, Katoh T. Eur. J. Med. Chem. 2016; 121: 592
• 11a Elzner S, Schmidt D, Schollmeyer D, Erkel G, Anke T, Kleinert H, Förstermann U, Kunz H. ChemMedChem 2008; 3: 924
• 11b Liang Q, Sun Y, Yu B, She X, Pan X. J. Org. Chem. 2007; 72: 9846
• 11c Bracher F, Schulte B. Liebigs Ann./Recl. 1997; 1979
• 11d Gerlach H. Helv. Chim. Acta 1977; 60: 3039
• 11e Krishna MR, Sridhar G, Syed T, Jayaprakash HV. Synth. Commun. 2022; 52: 37
• 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: R_f = 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: R_f = 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.