Concise Total Synthesis of Curvulone B

Abstract

A concise and convergent stereoselective synthesis of curvulone B is described. The synthesis utilized a tandem isomerization followed by C–O and C–C bond-forming reactions following Mukaiyama-type aldol conditions for the construction of the trans-2,6-disubstituted dihydropyran ring system as the key steps. Other important features of this synthesis are a cross-metathesis, epimerization, and Friedel–Crafts acylation.

Key words

curvulone B - natural products - Mukaiyama–aldol reaction - Friedel–Crafts acylation reaction

Publication History

Received: 08 October 2020

Accepted after revision: 26 October 2020

Accepted Manuscript online:
26 October 2020

Article published online:
24 November 2020

• References and Notes

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• 10 [(2R,6R)-6-Methyl-5,6-dihydro-2H-pyran-2-yl]acetaldehyde (5) I₂ (0.89 g, 3.51 mmol) was added to a stirred solution of aldehyde 7 (2.0 g, 17.54 mmol) and trimethyl(vinyloxy)silane (3.85 mL, 26.31 mmol) in anhyd CH₂Cl₂ (50 mL) at 0 °C, and the mixture was allowed to warm to rt. When the reaction was complete (TLC), it was quenched with sat. aq Na₂S₂O₃ (30 mL), and the mixture was extracted with CH₂Cl₂ (2 × 50 mL). The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:5)] to give a pale-yellow liquid; yield: 1.99 g (81%); [α]_D ²⁰ –68.0 (c = 0.85, CHCl₃). IR (neat): 3033, 2971, 2928, 1721, 1636, 1373, 1187, 1137, 1090 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 9.81 (s, 1 H), 5.87 (m, 1 H), 5.70 (d, J = 11.7 Hz, 1 H), 4.78 (m, 1 H), 3.83 (m, 1 H), 2.76 (ddd, J = 16.2, 8.8, 3.0 Hz, 1 H), 2.55 (dd, J = 16.2, 4.7 Hz, 1 H), 2.06–1.91 (m, 2 H), 1.21 (d, J = 6.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 201.0, 127.5, 125.2, 67.6, 64.1, 47.9, 31.5, 20.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₂NaO₂: 163.0728; found: 163.0724.
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• 16 Curvulone B (2) A suspension of Al powder (192 mg, 7.37 mmol) in anhyd benzene (5 mL) was treated with I₂ (0.7 g, 2.74 mmol) under argon, and the violet mixture was stirred under reflux for 30 min until the mixture became colorless. The mixture was then cooled to 0 °C, and TBAI (12.7 mg, 0.034 mmol) and phloroglucinol (108 mg, 0.85 mmol) were added, followed by a solution of 11 (60 mg, 0.17 mmol) in anhyd benzene (2 mL) added in one portion. The resulting green–brown suspension was stirred for 30 min at 0 °C. When the reaction was complete (TLC), it was quenched with sat. aq aqueous Na₂S₂O₃ (10 mL), and the mixture was diluted with EtOAc (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic extracts were washed with brine (25 mL), filtered, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, EtOAc–hexane (1:1)] to give a colorless liquid; yield: 50 mg (91%); [α]_D ²⁰ –18.2 (c = 0.2, EtOH). IR (neat): 3410, 2928, 1713, 1613, 1451, 1334, 1166 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.79 (s, 1 H), 6.28 (d, J = 2.3 Hz, 1 H), 6.22 (d, J = 2.3 Hz, 1 H), 6.08 (br s, 1 H), 4.13 (brtt, J = 10.5, 2.3 Hz, 1 H), 3.92 (d, J = 16.5 Hz, 1 H), 3.70 (s, 3 H), 3.57 (m, 1 H), 3.51 (d, J = 16.6 Hz, 1 H), 3.30 (dd, J = 14.3, 10.1 Hz, 1 H), 2.56 (dd, J = 14.3, 3.1 Hz, 1 H), 1.85 (m, 1 H), 1.65–1.50 (m, 3 H), 1.42 (m, 1 H), 1.25 (m, 1 H), 1.17 (d, J = 6.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 204.2, 172.4, 159.4, 135.7, 120.7, 111.7, 104.0, 77.8, 74.8, 52.0, 49.0, 39.7, 32.6, 30.7, 23.1, 21.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₂₃O₆: 323.1489; found: 323.1494.