Total Synthesis and Cytotoxic Activity of 7-O-Methylnigrosporolide and Pestalotioprolide D

Abstract

A convergent total synthesis of 7-O-methylnigrosporolide and pestalotioprolide D has been accomplished in 17 linear steps and overall yields of 1.7% and 2.6%, respectively, starting from (S)-propylene oxide and (S)-benzyl glycidyl ether. Our synthesis exploited an acetylide addition and a Shiina macrolactonization to assemble the macrocycle, a Lindlar reduction, and Wittig and Still–Gennari olefinations to construct the three alkene groups, as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic center. The selection of the silyl protecting group of the C-4 alcohol was crucial for the final deprotection step. Our synthesis also led to a hypothesis that pestalotioprolide D might be an artifact of 7-O-methylnigrosporolide. The cytotoxic activities of the two synthetic compounds against six human cancer cell lines were evaluated. Synthetic pestalotioprolide D showed more potent cytotoxic activity than 7-O-methylnigrosporolide against all the cancer cell lines tested, and the SiHa cervical cancer cell line was the most sensitive to both synthetic compounds.

Key words

total synthesis - cytotoxicity - macrolactones - 7-O-methyl­nigrosporolide - pestalotioprolide D

Publication History

Received: 30 January 2022

Accepted after revision: 09 March 2022

Accepted Manuscript online:
09 March 2022

Article published online:
06 April 2022

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• 25 7-O-Methylnigrosporolide (1): AcOH (340 μL, 0.006 mmol, 0.05 equiv) and a 1.0 M solution of TBAF in THF (250 μL, 0.96 mmol, 8.0 equiv) were sequentially added dropwise to a solution of macrolactone 20 (60 mg, 0.12 mmol) in anhyd THF (3 mL, 0.04 M) at 0 °C. The mixture was stirred at 0 °C to rt for 1 h and then heated at 63 °C for 9 h. The mixture then cooled to rt and the reaction was quenched with sat. aq NaHCO₃ (5 mL) and H₂O (3 mL). The organic phase was extracted with EtOAc (4 × 5 mL), washed with brine, and dried (Na₂SO₄). Purification of the crude residue by column chromatography (silica gel, 10–30% EtOAc–hexanes) gave a colorless oil; yield: 17.3 mg (50%, 72% based on recovered starting material); R_f = 0.12 (40% EtOAc–hexanes); [α]_D ²⁵ +66.8 (c 0.2, MeOH). IR (thin film): 3422, 2929, 1717, 1255, 1062, 948 cm^–1. ¹H NMR (300 MHz, CD₃OD): δ = 6.93 (dd, J = 15.3, 6.9 Hz, 1 H), 6.08 (d, J = 15.6 Hz, 1 H), 5.65 (dd, J = 11.4, 4.5 Hz, 1 H), 5.49 (td, J = 11.1, 3.3 Hz, 1 H), 5.27 (td, J = 11.7, 2.4 Hz, 1 H), 5.17–5.10 (m, 2 H), 5.01–4.91 (m, 1 H), 4.70 (t, J = 9.6 Hz, 1 H), 3.27 (s, 3 H), 2.62–2.48 (m, 1 H), 2.04–1.85 (m, 2 H), 1.81–1.67 (m, 1 H), 1.51–1.40 (m, 1 H), 1.28 (d, J = 6.3 Hz, 3 H), 1.11–1.06 (m, 1 H). ¹³C NMR (75 MHz, CD₃OD): δ = 168.3, 149.9, 136.3, 135.1, 130.4, 128.6, 121.5, 74.3, 73.4, 69.6, 55.4, 35.6, 30.7, 26.8, 20.7. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₂NaO₄: 289.1416; found: 289.1410. Pestalotioprolide D (2) A 1.0 M solution of TBAF in THF (150 μL, 0.15 mmol, 5.0 equiv) was added dropwise to a solution of macrolactone 20 (15 mg, 0.03 mmol) in anhyd THF (1.2 mL, 0.025 M) at 0 °C, and the mixture was stirred from 0 °C to rt for 1.5 h. The reaction was quenched with sat. aq NaHCO₃ (3 mL) and H₂O (2 mL). The aqueous phase was extracted with EtOAc (4 × 5 mL) and the organic phase was washed with brine and dried (Na₂SO₄). Purification of the crude residue by column chromatography (silica gel, (5–20% EtOAc–hexanes) gave a colorless oil; yield: 5.8 mg (75%): R_f = 0.21 (20% EtOAc–hexanes); [α]_D ²⁶ –35.6 (c 0.1, MeOH). IR (thin film): 2931, 1724, 1406, 1237, 1085, 953 cm^–1. ¹H NMR (300 MHz, CD₃OD): δ = 6.31 (d, J = 11.1 Hz, 1 H), 5.89 (dd, J = 11.1, 9.6 Hz, 1 H), 5.79 (app t, J = 9.6 Hz, 1 H), 5.71–5.63 (m, 1 H), 5.22 (app t, J = 9.6, 1 H), 4.94–4.90 (m, 1 H), 3.29 (s, 3 H), 2.96 (ddd, J = 17.4, 10.8, 2.7, 1 H), 2.79 (ddd, J = 15.0, 10.5, 2.7, 1 H), 2.73 (ddd, J = 17.4, 6.6, 2.4 Hz, 1 H), 2.40 (ddd, J = 15.3, 6.9, 3.0 Hz, 1 H), 2.19–2.05 (m, 1 H), 1.91–1.79 (m, 1 H), 1.70–1.61 (m, 1 H), 1.59–1.47 (m, 1 H), 1.38–1.26 (m, 1 H), 1.24 (d, J = 6.3 Hz, 3 H), 0.98–0.83 (m, 1 H). ¹³C NMR (75 MHz, CD₃OD): δ = 201.5, 174.6, 145.5, 134.9, 129.8, 127.4, 73.2, 73.0, 56.0, 40.9, 37.3, 30.0, 29.9, 28.2, 20.3. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₂NaO₄: 289.1416; found: 289.1410.