Gram-Scale Total Synthesis of Cordiachrome B

Abstract

Cordiachromes A–C are terpenoid benzoquinones that exhibit significant antimalarial, antimycobacterial, antifungal, antileishmanial, and cytotoxic activities. Herein, we report a gram-scale total synthesis of cordiachrome B from inexpensive, commercially available 3-methoxybenzaldehyde in six linear steps. Highlights of the synthesis include a Ti(O-i-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction to construct the desired cis configuration at the B–C ring junction, matching that of the natural product; an N,N,N′-trimethylethylenediamine-directed regioselective methylation; a Pd-catalyzed ortho-C–H methoxylation enabled by a monodentate transient directing group to give 3,6-dimethoxy-2-methylbenzaldehyde on a large scale for the PEDA reaction; and a Tebbe olefination to convert the carbonyl group into the methylene group required for the natural product. The concise and scalable synthesis provides a novel strategy for producing these natural products and related congeners for further medicinal-chemistry studies. Cordiachrome B was shown, for the first time, to exhibit a moderate antibacterial activity against Staphylococcus aureus and its methicillin-resistant strain.

Key words

cordiachrome B - total synthesis - gram-scale synthesis - photoenolization - Diels–alder reaction

Publication History

Received: 14 November 2024

Accepted after revision: 12 December 2024

Article published online:
10 February 2025

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• 22 Chordiachrome B A solution of ceric ammonium nitrate (7.5 g, 13.8 mmol, 2.5 equiv) in H₂O (45 mL) was added over 3-min to a solution of 15 (1.5 g, 5.4 mmol, 1.0 equiv) in MeCN (180 mL) and Et₂O (180 mL) cooled to 0 °C in an ice–brine bath under N₂. The resulting yellow solution was stirred in the ice–brine bath for 30 min then diluted with H₂O (150 mL) and extracted with CH₂Cl₂ (3 × 400 mL). The combined extracts were washed with brine, dried (MgSO₄), and concentrated in vacuo. The solid residue was purified by flash column chromatography [silica gel, EtOAc–hexane (10:1)] to give a pale-yellow solid; yield: 1.2 g (95%). ¹H NMR (400 MHz, CDCl₃): δ = 6.70 (q, J = 10.0 Hz, 2 H), 4.71 (s, 1 H), 4.36 (s, 1 H), 2.82–2.77 (m, 1 H), 2.55–2.47 (m, 1 H), 2.39–2.20 (m, 2 H), 2.17–2.16 (m, 1 H), 2.11–2.06 (m, 1 H), 2.03–1.98 (m, 1 H), 1.72–1.62 (m, 3 H), 1.46–1.38 (m, 1 H), 0.96 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.4, 187.2, 148.4, 140.7, 139.9, 136.5, 136.3, 107.3, 44.6, 37.1, 34.8, 34.0, 30.4, 27.5, 23.8, 23.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₉O₂: 243.1385; found: 243.1385.