Total Synthesis of (±)-Moluccanic Acid Methyl Ester

Abstract

An effective total synthesis of the trinorditerpenoid moluccanic acid methyl ester has been achieved. The synthesis features a Robinson annulation, followed by aromatization to construct the aromatic ring and Baeyer–Villiger oxidation of the A ring to finish the target molecule.

Key words

aromatization - moluccanic acid - diterpenoids - Baeyer–Villiger oxidation - Robinson annulation

• References and Notes

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• 14 Methyl 3-[(1S,2R)-7-Hydroxy-2-(2-hydroxypropan-2-yl)-1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl]-propanoate (15) and Methyl 3-[(1S,2S)-7-Hydroxy-1-methyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-naphthalen-1-yl]propanoate (2) PTSA monohydrate (2.03 g, 10.7 mmol) was added in one portion to a stirred solution of lactone 14 (520 mg, 1.34 mmol) in MeOH (10 mL) at r.t. The resulting solution was stirred overnight, treated with sat. NaHCO₃ solution (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with sat. NaCl solution (30 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (PE–EtOAc = 9:1 to 4:1) to give the two esters 15 (320 mg, 60%) and 2 (160 mg, 30%) as colorless oils. Ester 2: R_f = 0.33 (PE–EtOAc = 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.19 (s, 3 H, 1-CH₃), 1.77 (s, 3 H, CH ₃C=CH₂), 1.56 (s, 3 H, 5-CH₃), 1.80–2.15 (m, 5 H, 2′-H, 2 × 3′-H, 2 × 3-H), 2.21–2.29 (m, 1 H, 2′-H), 2.38 (dd, J = 11.4, 3.0 Hz, 1 H, 2-H), 2.68–2.75 (m, 2 H, 2 × 4-H), 3.61 (s, 3 H, OCH₃), 4.69 (br s, 1 H, =CH₂), 4.94 (br s, 1 H, =CH₂), 6.61 (dd, J = 8.1, 2.5 Hz, 1 H, 6-H), 6.75 (d, J = 2.5 Hz, 1 H, 5-H), 6.89 (d, J = 8.1 Hz, 1 H, 8-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.8 (CH₃C=CH₂), 24.7 (C-3), 27.8 (1-CH₃), 29.5 (C-2′, C-4), 34.6 (C-3′), 41.1 (C-1), 47.0 (C-2), 51.7 (OCH₃), 112.9 (C-8), 113.3 (C-6), 114.3 (C=CH₂), 129.1 (C-4a), 130.1 (C-5), 144.5 (C-8a), 146.6 (C=CH₂), 154.0 (C-7), 175.0 (ester). ESI-HRMS: m/z calcd for C₁₈H₂₄O₃Na [M + Na]⁺: 311.161766; found: 311.161980. Ester 15: R_f = 0.10 (PE–EtOAc = 4:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.29 [s, 3H, C(CH₃)₂], 1.35 (s, 3 H, 1-CH₃), 1.47 [s, 3 H, C(CH₃)₂], 1.50–1.76 (m, 3 H, 2 × 3-H, 2-H), 1.92–2.10 (m, 3 H, 2 × 3′-H, 2′-H), 2.17 (s, 1 H, OH), 2.56–2.69 (m, 2 H, 2′-H, 4-H), 2.82–2.88 (m, 1 H, 4-H), 3.60 (s, 3 H, OCH₃), 6.58 (dd, J = 8.3, 2.5 Hz, 1 H, 6-H), 6.79 (d, J = 2.3 Hz, 1 H, 8-H), 6.85 (d, J = 8.3 Hz, 1 H, 5-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 24.5 (C-3), 26.8 [C(CH₃)₂], 27.2 (1-CH₃), 29.6 (C-4), 30.7 [C(CH₃)₂], 33.2 (C-2′), 36.6 (C-3′), 43.4 (C-1), 48.7 (C-2), 51.8 (OCH₃), 75.5 [C(CH₃)₂], 112.9 (C-6), 113.2 (C-8), 129.6 (C-4a), 129.8 (C-5), 146.4 (C-8a), 154.4 (C-7), 176.3 (C-1′) ppm. ESI-HRMS: m/z calcd for C₁₈H₂₆O₄Na [M + Na]⁺: 329.172330; found: 329.172482
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