Enantioselective Formal Total Synthesis of Damsin

Abstract

Enantioselective formal total synthesis of damsin, which was isolated from Compositae Ambrosia maritima L., is described. The highly enantio- and diastereoselective catalytic Mukaiyama–Michael reaction and subsequent highly stereoselective epimerization shorten the synthetic steps. It is also reported that the enolate, which was formed by the reaction of β-keto sulfone with lithium naphthalenide, reacted with methyl cyanoformate to form a quaternary stereogenic center in high yield with high stereoselectivity. This finding extends the synthetic chemistry starting from β-keto sulfones.

Key words

asymmetric catalysis - enantioselective - Mukaiyama–­Michael reaction - stereoselective - total synthesis - damsin - pseudoguaianolides

Publication History

Received: 20 December 2022

Accepted after revision: 20 January 2023

Accepted Manuscript online:
20 January 2023

Article published online:
15 February 2023

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• 10 Compound 13 – Procedure To a stirred solution of naphthalene (837 mg, 6.53 mmol) in THF (21.8 mL) was added Li (45.9 mg, 6.61 mmol) at room temperature. After 6 h, the resulting mixture was added to 12 (318 mg, 1.09 mmol) in THF (5.44 mL) at –78 ℃. After stirring the mixture at the same temperature for 10 min, NCCO₂Me (0.432 mL, 5.44 mmol) was added to the mixture at the same temperature. The mixture was stirred at –78 ℃ for 70 min and then quenched with saturated aqueous NaHCO₃ solution (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (hexane/ethyl acetate = 20/1) to afford 13 (206 mg, 90%) as a colorless oil: R_f = 0.64 (hexane/ethyl acetate = 2/1). ¹H NMR (500 MHz, CDCl₃): δ = 5.66 (ddd, J = 16.0, 10.0, 7.5 Hz, 1 H), 5.03 (d, J = 16.0 Hz, 1 H),4.99 (d, J = 10.0 Hz, 1 H), 3.72 (s, 3 H), 2.58 (ddd, J = 11.0, 11.0, 6.5 Hz, 1 H), 2.46–2.30 (m, 2 H), 2.19–2.08 (m, 2 H), 1.47 (dddd, J = 12.5, 12.5, 12.5, 8.5 Hz, 1 H), 1.23 (s, 3 H), 0.92 (d, J = 6.5 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 216.0, 173.7, 142.0, 114.3, 59.4, 52.6, 50.1, 40.0, 37.6, 25.5, 18.9, 12.9. HRMS (ESI): m/z [M+Na⁺] calcd for C₁₂H₁₈NaO₃: 233.1154; found: 233.1149; [α]_D ²¹ +77 (c 0.12, CH₂Cl₂).
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