The First Stereoselective Total Synthesis of Mangiferaelactone: An Antibacterial Fungal Nonanolide^[1]

Abstract

An antibacterial fungal nonanolide – mangiferaelactone – has been synthesized for the first time using d-ribose as the starting material. The synthesis includes the coupling of the alcohol and acid fragments of the molecule employing Yamaguchi esterification protocol followed by intramolecular ring-closure metathesis. The method has efficiently constructed the ten-membered lactone skeleton of the compound with four stereogenic centers containing appropriate functionalities.

Key words

mangiferaelactone - nonanolide - total synthesis - d-ribose - intramolecular ring-closing metathesis

• References and Notes

• 1 Part 81 in the series ‘Synthetic Studies on Natural Products’.
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• 18 Spectral data of some selected compounds are given below. Compound 8 [α]_D ²⁷ +1.6 (c 1.0, CHCl₃), IR (KBr): 3417, 2927, 2857, 1723, 1460, 1217, 1055, 927, 832, 770 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 6.06 (1 H, m), 5.43 (1 H, d, J = 16.0 Hz), 5.31 (1 H, d, J = 9.0 Hz), 4.64 (1 H, t, J = 7.0 Hz), 3.97 (1 H, dd, J = 8.0, 7.0 Hz), 3.66 (1 H, m), 1.73–1.68 (2 H, m), 1.60 (1 H, m), 1.49 (3 H, s), 1.38 (3 H, s), 1.32–1.21 (10 H, m), 0.89 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 134.7, 118.5, 108.6, 81.0, 79.0, 70.1, 33.6, 31.8, 29.5, 29.2, 27.8, 25.4, 25.2, 22.6, 14.1. ESI-MS: m/z = 279 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₅H₂₉O₃ [M + H]⁺: 257.1992; found: 257.1987. Compound 8a [α]_D ²⁷ –7.66 (c 1.0, CHCl₃). IR (KBr): 3458, 2957, 2896, 1470, 1256, 1086, 924 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 5.59 (1 H, m), 5.35 (1 H, d, J = 16.0 Hz), 5.29 (1 H, d, J = 9.0 Hz), 4.58 (1 H, t, J = 7.0 Hz), 4.01 (1 H, t, J = 7.0 Hz), 3.57 (1 H, m), 2.11 (1 H, br s), 1.51 (3 H, s), 1.47–1.41 (2 H, m), 1.40 (3 H, s), 1.37–1.21 (10 H, m), 0.89 (3 H, t, J = 7.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 134.1, 119.2, 108.5, 80.7, 79.1, 69.6, 33.8, 31.7, 29.5, 29.2, 27.5, 25.5, 22.6, 14.0. ESI-MS: m/z = 279 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₅H₂₉O₃ [M + H]⁺: 257.1798; found: 257.1782. Compound 12 [α]_D ²⁷ +18.33 (c 1.0, CHCl₃). IR (KBr): 2985, 2934, 1732, 1372, 1163, 1041 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 4.20–4.11 (4 H, m), 3.72–3.61 (2 H, m), 2.57–2.38 (2 H, m), 2.01–1.82 (2 H, m), 1.41 (3 H, s), 1.32 (3 H, s), 1.26 (3 H, t, J = 7.0 Hz), 0.90 (9 H, s), 0.08 (6 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 173.3, 107.8, 77.6, 76.5, 61.7, 60.2, 31.3, 28.1, 25.9, 25.5, 24.7, 14.2, –5.5. ESI-MS: m/z = 347 [M + H]⁺, 369 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₇H₃₄O₅NaSi [M + Na]⁺: 369.2459; found: 369.2533. Compound 9 [α]_D ²⁷ +2.02 (c 1.0, CHCl₃). IR (KBr): 3446, 2930, 2858, 1712, 1377, 1100, 840, 773 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 4.20–4.08 (2 H, m), 3.71–3.60 (2 H, m), 2.65–2.43 (2 H, m), 2.01–1.1.79 (2 H, m), 1.41 (3 H, s), 1.32 (3 H, s), 0.89 (9 H, s), 0.07 (6 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 178.6, 108.0, 77.6, 76.4, 61.7, 31.1, 28.1, 25.8, 25.5, 24.6, 18.3, –5.4, –5.5. ESI-MS: m/z = 341 [M + Na]. ESI-HRMS: m/z calcd for C₁₅H₃₀O₅NaSi [M + Na]⁺: 341.1753; found: 341.1743. Compound 13 [α]_D ²⁷ +6.66 (c 1.0, CHCl₃). IR (KBr): 2930, 2859, 1738, 1647, 1464, 1079, 840, 774 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 5.80 (1 H, m), 5.32 (1 H, d, J = 16.0 Hz), 5.21 (1 H, d, J = 9.0 Hz), 4.92 (1 H, m), 4.60 (1 H, t, J = 7.0 Hz), 4.21–4.07 (3 H, m), 3.71–3.60 (2H, m), 2.50 (1 H, m), 2.34 (1 H, m), 1.99–1.80 (2 H, m), 1.75–1.57 (2 H, m), 1.48 (3 H, s), 1.39 (3 H, s), 1.37 (3 H, s), 1.32 (3 H, s), 1.30–1.21 (10 H, m), 0.92–0.82 (12 H, m), 0.07 (6 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 172.2, 133.2, 118.4, 108.4, 107.9, 78.9, 78.3, 77.6, 76.5, 71.8, 61.7, 31.8, 31.4, 31.2, 29.5, 29.2, 28.2, 27.6, 25.8, 25.5, 25.2, 24.6, 24.5, 22.6, 18.2, 14.1, –5.4. ESI-MS: m/z = 579 [M + Na]⁺. ESI-HRMS: m/z calcd for C₃₀H₅₇O₇Si [M + H]⁺: 556.3839; found: 556.3853. Compound 16 [α]_D ²⁷ +3.04 (c 1.0, CHCl₃). IR (KBr): 3456, 2927, 2859, 1735, 1217, 1165, 1042, 865, 771 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.83 (2 H, m), 5.34 (1 H, d, J = 16.0 Hz), 5.26 (1 H, d, J = 16.0 Hz), 5.22 (1 H, d, J = 9.0 Hz), 5.14 (1 H, d, J = 9.0 Hz), 4.92 (1 H, m), 4.61 (1 H, t, J = 7.0 Hz), 4.20–4.14 (2 H, m), 2.44–2.32 (2 H, m), 1.90–1.78 (2 H, m), 1.70 (1 H, m), 1.61 (1 H, m), 1.48 (3 H, s), 1.37 (3 H, s), 1.32–1.21 (10 H, m), 0.87 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 172.9, 140.3, 133.2, 118.5, 115.1, 108.8, 78.8, 78.3, 72.0, 31.8, 31.4, 31.1, 29.5, 29.1, 27.5, 25.2, 24.5, 22.6, 14.0. ESI-MS: m/z = 391 [M + Na]⁺. ESI-HRMS: m/z calcd for C₂₁H₃₇O₅ [M + H]⁺: 369.2635; found: 369.2632. Compound 7 [α]_D ²⁷ –4.40 (c 1.0, CHCl₃). IR (KBr): 3447, 2927, 2859, 1729, 1643, 1458, 1071, 769 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.82 (1 H, dd, J = 16.0, 3.0 Hz), 5.66 (1 H, ddd, J = 16.0, 10.0, 2.0 Hz), 4.92 (1 H, td, J = 7.0, 3.0 Hz), 4.69 (1 H, m), 4.18 (1 H, m), 3.97 (1 H, dd, J = 10.0, 5.0 Hz), 2.34 (1 H, m), 2.11–2.00 (2H, m), 1.79 (1 H, m), 1.55 (3 H, m), 1.50 (1 H, m), 1.48 (1 H, m), 1.38 (3 H, s), 1.32–1.21 (10 H, m), 0.87 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 175.1, 131.0, 126.8, 109.4, 78.8, 75.8, 75.7, 71.1, 33.9, 32.1, 32.0 (2 C), 31.2, 30.5, 28.4, 26.1, 24.5, 22.9, 14.1. ESI-MS: m/z = 341 [M + H]⁺, 363 [M + Na]⁺. ESI-HRMS: m/z calcd for C₁₉H₃₆O₅N [M + NH₄]⁺: 358.1105; found: 358.1150. Magniferaelactone (1) [α]_D ²⁷ –2.34 (c 1.0, MeOH); lit.⁶ [α]_D ²⁰ –1.7 (c 0.17, MeOH). IR (KBr): 3423, 2928, 2854, 1733, 1461, 1369, 1161, 1066, 771 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 5.92 (1 H, dd, J = 15.5, 2.0 Hz), 5.49 (1 H, ddd, J = 15.5, 10.0, 2.0 Hz), 5.17 (1 H, td, J = 10.0, 5.0 Hz), 5.12 (1 H, td, J =10.0, 2.5 Hz), 4.39 (1 H, br d, J = 2.0 Hz), 3.52 (1 H, dd, J = 10.0, 2.5 Hz), 2.61–2.52 (4 H, br s), 2.32 (1 H, m), 2.08 (1 H, m), 1.98 (1 H, m), 1.91 (1 H, m), 1.84 (1 H, m), 1.48 (1 H, m), 1.36–1.24 (10 H, m), 0.89 (3 H, t, J = 7.0 Hz). ¹³C NMR (125 MHz, CD₃OD): δ = 175.9, 175.8, 173. 136.1, 123.9, 78.3, 74.7, 73.6, 72.3, 33.2, 32.9, 32.3, 30.9, 30.8 (2 C), 30.5 (2 C), 25.8, 23.9, 14.6. ESI-MS: m/z = 423 [M + Na]⁺. ESI-HRMS: m/z calcd for C₂₀H₃₆O₈N [M + NH₄]⁺: 418.2435; found: 418.2431.