A Convergent Approach to the Forskolin Skeleton

Abstract

A convergent approach to the forskolin skeleton is described. Assembly of a simplified tricyclic framework is achieved in a single step via the dihydropyrone Diels–Alder reaction. Selective manipulation of the resulting cycloadduct, in conjunction with an unusual equilibration of the C8 stereocenter, provides access to scaffolds that differ in relative stereochemistry at both the A/B and B/C ring junctions.

Key words

Diels–Alder reaction - fused ring systems - regioselectivity - diastereoselective synthesis - equilibration - forskolin - natural product analogues

Publikationsverlauf

Eingereicht: 06. März 2024

Angenommen nach Revision: 23. April 2024

Artikel online veröffentlicht:
06. Mai 2024

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• 23 Diels–Alder Adduct 12 A solution of KHMDS (35 mL of an 0.5 M solution in toluene, 17.5 mmol) in 20 mL THF was cooled to –78 °C. Acetyl cyclohexene (2.00 g, 16.0 mmol) in 20 mL THF was added dropwise via cannula, and the resulting mixture was allowed to warm slowly to –30 °C, then cooled back to –78 °C. TBSCl (4.82 g, 32.0 mmol) in 20 mL THF was then added dropwise. After 1 h, the mixture was warmed slowly to room temperature and stirred for an additional hour. Anhydrous diethyl ether (150 mL) was added, and the resulting mixture was filtered through a bed of Celite. The filtrate was concentrated in vacuo to give the diene 10 as a colorless oil that was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ = 6.26 (1 H, m), 4.34 (1 H, s), 4.18 (1 H, s), 2.14 (4 H, m), 1.67 (2 H, m), 1.58 (2 H, m), 0.98 (9 H, s), 0.18 (6 H, s). A solution of the crude diene 10 (16.0 mmol) and dihydropyrone 11 (4.75 g, 24.0 mmol) in 60 mL CH₂Cl₂ was cooled to 0 °C. A freshly prepared solution of zinc chloride (2.20 g, 16.0 mmol in 20 mL THF) was then added dropwise. The resulting mixture was warmed slowly to room temperature and stirred for 10 h, then quenched with saturated aqueous NaHCO₃ and extracted with CH₂Cl₂ (3×). The combined organics were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO₂, hexanes:EtOAc, 20:1) to afford the Diels–Alder adduct 12 as a pale yellow oil (5.91 g, 85%). ¹H NMR (CDCl₃, 300 MHz): δ = 4.72 (1 H, d, J = 5.3 Hz), 4.17 (2 H, m), 3.00 (1 H, m), 2.92 (1 H, m), 2.57 (1 H, d, J = 17.5 Hz), 2.39 (1 H, d, J = 17.5 Hz), 2.36 (1 H, m), 2.22 (1 H, d, J = 18.1 Hz), 1.82 (1 H, m), 1.72 (1 H, m), 1.58 (3 H, m), 1.37 (3 H, s), 1.34 (2 H, m), 1.32 (3 H, s), 1.25 (3 H, t, J = 7.1 Hz), 0.92 (9 H, s), 0.10 (3 H, s), 0.07 (3 H, s). ¹³C NMR (CDCl₃, 75 MHz): δ = 207.2, 170.0, 136.2, 116.8, 73.1, 69.1, 62.8, 61.6, 51.1, 40.7, 33.3, 33.1, 31.0, 27.8, 27.6, 27.1, 26.9, 25.8, 18.2, 14.0, -4.1. IR (neat): 2931, 2857, 1746, 1707, 1668, 1253, 1191, 1071, 1030 cm^–1. HRMS (ESI): m/z calcd for C₂₄H₄₀O₅Si [M + Na]⁺: 459.2537; found: 459.2517.