An Efficient Access to Aspermytin A and Oblongolide C through an Intramolecular Nitrile Oxide–Alkene [3+2] Cycloaddition

Abstract

The second generation synthesis of (+)-aspermytin A and the first total synthesis of (–)-oblongolide C have been accomplished employing an intramolecular nitrile oxide–alkene [3+2] cycloaddition as the key step.

Key words

total synthesis - enantioselectivity - cycloaddition - aspermytin A - nitrile oxide

• References and Notes

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Our reports on natural products synthesis using INOC, see:
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• 7 Analytical Data for 5 Colorless needles, mp 94.5–94.8 °C (Et₂O–hexane); [α]_D ²³ +22.6 (c 1.22, CHCl₃). IR (KBr): 2920, 1713, 1494, 1455, 1377, 946, 846 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 4.11 (d, J = 7.6 Hz, 1 H), 3.91 (d, J = 7.6 Hz, 1 H), 2.62 (ddd, J = 14.8, 4.8, 2.0 Hz, 1 H), 2.21 (dt, J = 14.0, 5.6 Hz, 1 H), 1.82–1.88 (dddd, J = 12.8, 5.6, 5.2, 1.6 Hz, 1 H), 1.72–1.76 (m, 2 H), 1.28 (dq, J = 12.4, 3.2 Hz, 1 H), 1.23–1.34 (m, 3 H), 1.13 (s, 3 H), 1.09–1.20 (m, 2 H), 0.87–0.96 (m, 1 H), 0.89 (d, J = 6.4 Hz, 3 H), 0.67 (q, J = 12.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.4 (C), 80.8 (CH₂), 54.2 (C), 51.3 (CH), 42.1 (CH₂), 36.0 (CH), 34.5 (CH₂), 33.5 (CH₂), 32.1 (CH), 27.7 (CH₂), 22.3 (CH₃), 21.9 (CH₂), 17.1 (CH₃). ESI-HRMS: m/z calcd for C₁₃H₂₁NONa [M + Na]⁺: 230.1521; found: 230.1519.
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• 13 The yields of the isoxazoline 5 from the literature known 8 via the oxime 12 and the nitroalkane 13 were 72% (6 steps) and 48% (4 steps), respectively.

For theoretical studies on the intra- and intermolecular nitrile oxide–alkene [3+2] cycloadditions, see:
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• 18 The corresponding aldehyde was initially obtained by the reaction with IBX·MPO and the requisite enone 3 was generated by the subsequent addition of IBX in a one-pot process.
• 19 Analytical Data for 3 Colorless needles, mp 62.5–63.3 °C (hexane) (lit.² 62.3–62.6 °C). [α]_D ²⁹ –107 (c 1.74, CHCl₃) {lit.² [α]_D ²² –103 (c 0.91, CHCl₃)}. IR (KBr): 2934, 2839, 2734, 1733, 1660 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.52 (s, 1 H), 6.75 (dd, J = 10.0, 1.6 Hz, 1 H), 5.97 (dd, J = 10.0, 2.8 Hz, 1 H), 2.27 (tdd, J = 11.2, 2.8, 2.8 Hz, 1 H), 2.09 (ddd, J = 11.6, 10.8, 3.2 Hz, 1 H), 2.01 (ddd, J = 13.2, 3.2, 3.2 Hz, 1 H), 1.75–1.82 (m, 1 H), 1.47–1.64 (m, 1 H), 1.35 (dq, J = 13.2, 4.0 Hz, 1 H), 1.27 (dtd, J = 12.4, 12.0, 3.6 Hz, 1 H), 1.19 (s, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.94–1.07 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.5 (CH), 200.4 (C), 155.1 (CH), 127.1 (CH), 60.5 (C), 43.3 (CH), 40.2 (CH₂), 37.1 (CH), 34.0 (CH₂), 32.9 (CH), 26.0 (CH₂), 22.2 (CH₃), 11.0 (CH₃). ESI-HRMS: m/z calcd for C₁₃H₁₈O₂Na [M + Na]⁺: 229.1204; found: 229.1198.
• 20 Analytical Data for Aspermytin A (1) Colorless needles, mp 122–123 °C (hexane). [α]_D ²⁸ +7.64 (c 0.97, CHCl₃) {lit.¹ [α]_D ²⁵ +1.2 (c 0.102, CHCl₃)}. IR (KBr): 3501, 2946, 2910, 1686, 1659, 1374, 1342, 1073, 1042 cm^–1. ¹H NMR (400 MHz, C₅D₅N): δ = 6.44 (s, OH, D₂O exchangeable, 1 H), 5.93 (brs, OH, D₂O exchangeable, 1 H), 5.70 (dd, J = 10.0, 2.8 Hz, 1 H), 5.37 (dd, J = 10.0 Hz, 1.6 Hz, 1 H), 4.29 (br s, 2 H), 3.64 (dt, J = 17.6 Hz, 6.4 Hz, 1 H), 3.04 (dt, J = 17.6, 6.0 Hz, 1 H), 2.07 (dt, J = 10.4, 2.0 Hz, 1 H), 1.74–1.84 (m, 2 H), 1.63–1.68 (m, 2 H), 1.54 (s, 3 H), 1.49 (s, 3 H), 1.30–1.42 (m, 1 H), 1.04 (dq, J = 12.4, 2.8 Hz, 1 H), 0.98 (dq, J = 2.4, 12.4 Hz, 1 H), 0.84 (d, J = 6.4 Hz, 3 H), 0.78 (q, J = 12.4 Hz, 1 H). ¹³C NMR (100 MHz, C₅D₅N): δ = 214.1 (C), 135.5 (CH), 129.6 (CH), 73.3 (C), 57.8 (CH₂), 57.7 (C), 45.8 (CH₂), 43.8 (CH), 42.1 (CH₂), 38.9 (CH), 35.9 (CH₂), 33.6 (CH), 28.7 (CH₃), 28.0 (CH₂), 22.7 (CH₃), 12.8 (CH₃). ESI-HRMS: m/z calcd for C₁₆H₂₇O₃ [M + H] ⁺: 267.1960; found: 267.1966.
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• 21b Fernández-Megía E, Ley SV. Synlett 2000; 455
• 21c Yoshimura T, Yakushiji F, Kondo S, Wu X, Shindo M, Shishido K. Org. Lett. 2006; 8: 475
• 22 Analytical Data for 19 Colorless oil. [α]_D ²⁹ +61.2 (c 2.81, CHCl₃). IR (neat): 3541–2552 (v. broad), 3027, 2921, 2867, 1696, 1454, 1120, 1096, 735, 698 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.34–12.5 (br, 1 H), 7.23–7.38 (m, 5 H), 5.52 (d, J = 10.4 Hz, 1 H), 5.28 (dd, J = 10.4, 2.4 Hz, 1 H), 4.57 (d, J = 12.0 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 3.67 (d, J = 9.2 Hz, 1 H), 3.29 (d, J = 9.6 Hz, 1 H), 2.73–2.99 (br, OH, D₂O exchangeable, 1 H), 1.73–1.84 (m, 2 H), 1.59–1.69 (m, 3 H), 1.37–1.52 (m, 1 H), 1.19 (s, 3 H), 0.99 (q, J = 10.8 Hz, 1 H), 0.94–1.07 (m, 1 H), 0.88 (d, J = 6.4 Hz, 3 H), 0.75 (q, J = 12.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 181.2 (C), 137.6 (C), 134.0 (CH), 128.6 (CH), 128.3 (2 × CH), 127.5 (CH), 127.2 (2 × CH), 75.3 (C), 73.0 (CH₂), 73.0 (CH₂), 51.3 (C), 43.7 (CH), 41.3 (CH₂), 38.3 (CH), 35.3 (CH₂), 33.2 (CH), 27.5 (CH₂), 22.3 (CH₃), 12.4 (CH₃). ESI-HRMS: m/z calcd for C₂₁H₂₉O₄ [M + H]⁺: 345.2066; found: 345.2070.
• 23 Analytical Data for Oblongolide C (2) Colorless needles, mp 104–105 °C (Et₂O–hexane) (lit.⁴ amorphous powder). [α]_D ²⁷ –194 (c 1.11, CH₂Cl₂) {lit.⁴ [α]_D ²⁵ –184 (c 0.20, CH₂Cl₂). IR (KBr): 3398, 2950, 2921, 1740, 1237, 1122, 1021, 767, 733 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.65 (d, J = 10.0 Hz, 1 H), 5.55 (dd, J = 10.0, 2.4 Hz, 1 H), 4.26 (s, 2 H), 2.00 (t, J = 10.8 Hz, 1 H), 1.76 (s, OH, D₂O exchangeable, 1 H), 1.76–1.88 (m, 3 H), 1.42–1.50 (m, 2 H), 1.26–1.36 (m, 1 H), 1.14 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H), 0.85–0.95 (m, 1 H), 0.77 (q, J = 12.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 178.9 (C), 135.7 (CH), 125.6 (CH), 78.8 (C), 76.9 (CH₂), 49.4 (C), 43.8 (CH), 41.1 (CH₂), 36.3 (CH), 34.7 (CH₂), 32.8 (CH), 25.8 (CH₂), 22.2 (CH₃), 8.9 (CH₃). ESI-HRMS: m/z calcd for C₁₄H₂₀O₃Na [M + Na]⁺: 259.1310; found: 259.1304.