First Total Synthesis of Oxirapentyn D, a Highly Oxidized Chromene Natural Product

Dedicated to Prof. Victor Snieckus on occasion of his 80^th birthday

Abstract

The first total synthesis of oxirapentyn D from myo-inositol has been achieved by utilizing chelation-directed bridgehead lithiation of a hydrazone derivative.

Key words

natural product synthesis - meroterpenoids - hydrazones - bridgehead functionalization - epoxidation - total synthesis

• References and Notes

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• 11 A 5:1 mixture of isomers 9a and 9b was used for the experiments listed in Table 2.
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• 17 The geometries of hydrazones 11 and 12 were determined by extensive NMR analysis (NOESY); see the Supporting Information.
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• 19 ¹H NMR analysis suggested the methylation occurred selectively at the amino nitrogen of the hydrazone, not at the imino nitrogen, judging from a 6 H singlet for the methyl groups; see Supporting Information.
• 20 The structure of ketone 14 was determined by ¹H and ¹³C NMR analyses.
• 21 The equatorial orientation of the C2 iodine atom was assigned by ¹H NMR. The J-values between the C2 methine and the C3 methylene protons were 4.4 and 13.1 Hz, respectively, the latter indicating an antiperiplanar relationship of the H2 and H3α protons.
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• 26 mCPBA and basic Oxone gave epoxide 18 and its diastereomer. DMDO afforded no reaction.
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• 30 HFIP afforded the best result among several fluorinated alcohols [F₃CCH₂OH, (F₃C)₃COH, and PhC(CF₃)₂OH].
• 31 The stereochemistry of the C2 hydroxy group was assigned by comparing the H2–H3 coupling constant of 19 with that of its C2 epimer (obtained by oxidation of triol 5 with Oxone; see Supporting Information). The C2 epimer of 19 showed a large coupling constant (J = 11.7 Hz), indicating an equatorial disposition of the C2 hydroxy group. Further support was obtained from the downfield shift of the 2-OH proton of 19 (δ = 3.3), which suggested the presence of hydrogen bonding between the axial hydroxy group and the orthoester oxygen.
• 32 The structures of 4 and 4′ were determined by ¹H and ¹³C NMR, and by extensive NMR analysis (HMBC): see the Supporting Information.
• 33 TLC analysis showed that the reaction stopped without obvious reason. There are two conceivable explanations for this. The first is that the oxidant interacted with product 4 or 4′. To examine this possibility, we studied the reverse addition of the alcohol 19 and found that the yield of 4 + 4′ decreased (14%; recovery: 60%). The second is that deprotonation of an adduct of the alcohol and the oxidant was slow. However, addition of base (pyridine) was not effective (4+ 4′: 38%, recovery: 9%).
• 34 Oxirapentyn D (1) by Nucleophilic Addition of Acetylide 21 to Ketone 4 An equilibrium mixture of ketone 4 and its hydrate 4′ (4.9 mg, 0.017 mmol) was azeotropically dried with toluene and dissolved in THF (0.34 mL). A 0.20 M solution of acetylide 21 in THF (0.43 mL, 0.086 mmol) was added at –78 °C, and the mixture was stirred for 2 h at –78 °C. The reaction was stopped by the addition of sat. aq NH₄Cl, and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, hexane–EtOAc (1:1)] to give a white solid; yield: 3.2 mg (53%); mp 213–217 °C (EtOAc–hexane); R_f = 0.57 (hexane–EtOAc, 1:5). IR (neat): 3472, 2955, 2925, 2853, 2226, 1615, 1434, 1402, 1296, 1230, 1176, 1138, 1080, 999, 948, 905, 853, 827 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 1.30 (s, 3 H), 1.39 (s, 3 H), 1.51 (s, 3 H), 1.78 (dd, J = 15.1, 2.4 Hz, 1 H), 1.91 (t, J = 1.1 Hz, 3 H), 2.52 (dd, J = 15.1, 3.6 Hz, 1 H), 3.16 (s, 1 H, OH), 3.32 (d, J = 11.6 Hz, 1 H, OH), 3.46 (ddd, J = 11.6, 3.6, 2.4 Hz, 1 H), 3.60 (d, J = 9.7 Hz, 1 H, OH), 4.02 (dd, J = 9.7, 3.4 Hz, 1 H), 4.12 (d, J = 1.7 Hz, 1 H), 4.18 (dd, J = 3.4, 1.9 Hz, 1 H), 4.19–4.20 (m, 1 H), 5.33 (quint, J = 1.6 Hz, 1 H), 5.38–5.39 (m, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 21.9, 23.1, 24.4, 26.3, 31.4, 60.1, 68.6, 70.8, 71.0, 72.7, 73.9, 75.8, 76.5, 86.8, 87.7, 108.8, 123.9, 125.5. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₈H₂₄NaO₇: 375.1414; found: 375.1398. UV (MeCN, 6.81 × 10^–5 M): λ_max (log ε) = 221 (3.47), 228 (3.41) nm.
• 35 The stereoselectivity is rationalized by the precoordination of alkynyl lithium species with the oxygen-rich functionality on the trioxaadamantane skeleton.
• 36 CCDC 1581357 contains the supplementary crystallographic data for compound 1. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.