A Short and Scalable Total Synthesis of (±)-β-Eudesmol

Dedication

This paper is dedicated to Prof. S. Chandrasekaran on his 80th birthday.

Abstract

A concise, protecting group-free approach has been developed for the total synthesis of (±)-β-eudesmol (1), completed in four steps with an overall yield of 24%. This synthesis features a copper-catalyzed Michael addition followed by an in situ aldol reaction, and a one-step Fe(III)/Et₃SiH-mediated radical cyclization–oxidation sequence that efficiently constructs the eudesmane skeleton. With its operational simplicity and scalability, this strategy provides a valuable platform for the synthesis of structurally related sesquiterpenoid architectures, paving the way for further biological and structural investigations.

Keywords

Terpenoids - Michael addition - Aldol reaction - Oxidative cyclization - Natural product total synthesis

Publication History

Received: 18 April 2025

Accepted after revision: 21 May 2025

Article published online:
31 July 2025

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• 14 (±)-β-Eudesmol 1: An oven-dried 2-neck round bottom flask (10 mL) was equipped with a stir bar (magnetic bead) to which Ph₃PMeBr (191.21 mg, 0.53 mmol, 3 equiv) was added under argon atmosphere. The set-up was kept at 0 °C using an ice bath to which 2.5 mL dry THF was added. After stirring the reaction mixture for 10 min, t-BuOK (70 mg, 0.62 mmol, 3.5 equiv) was added in portions. The homogeneous yellow solution was stirred further at 0 °C for 15 min. Ketone 9 (40 mg, 0.178 mmol, 1 equiv) in 1 mL THF was then added drop-wise and stirred at 0 °C for 30 min until complete consumption of the starting material was monitored by TLC analysis. After the reaction completion, the mixture was quenched using a saturated aqueous solution of NaHCO₃ (5 mL) and stirred for a further 10 min. The reaction mixture was partitioned between the saturated aqueous solution of NaHCO₃ and EtOAc. The organic layer was separated and washed with H₂O (5 mL) and saturated aqueous NaCl solution (5 mL), and the combined aqueous layers were further extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (SiO₂, hexanes:EtOAc, 9:1) gave pure 1 (33.2 mg, 0.149 mmol, 84% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 4.71 (d, J = 1.9 Hz, 1H), 4.44 (d, J = 1.8 Hz, 1H), 2.34–2.27 (m, 1H), 2.04–1.94 (m, 1H), 1.80–1.73 (m, 1H), 1.67–1.60 (m, 4H), 1.60 (s, 1H), 1.55–1.52 (m, 1H), 1.45–1.41 (m, 1H), 1.39–1.35 (m, 1H), 1.34–1.30 (m, 1H), 1.29–1.26 (m, 1H), 1.21 (s, 6H), 1.20–1.17 (m, 1H), 1.15–1.11 (m, 1H), 0.70 (s, 3H). ¹³C NMR (101 MHz, CDCl₃): δ 151.21, 105.37, 72.98, 49.87, 49.52, 41.92, 41.20, 36.96, 35.96, 27.24, 27.20, 25.09, 23.56, 22.45, 16.36. HRMS (ESI): m/z calcd for C₁₅H₂₇O [M+H]⁺ 223.2057, found 223.2061.