Enantioselective Synthesis of F-Ring Fragments of Kibdelone C via Desymmetrizing Bromolactonization of 1,4-Dihydrobenzoic Acid

Published as part of the Cluster Alkene Halofunctionalization

Abstract

We previously reported a bifunctional organic catalyst that promotes highly efficient enantioselective halolactonizations of a broad array of olefinic acids. As part of that work, we demonstrated the desymmetrization of a prochiral substrate through a catalytic enantioselective halolactonization, and we report herein the application of one such desymmetrization process to the syntheses of F-ring subunit synthons of (+)-kibdelone C.

Key words

organic catalysis - halolactonization - desymmetrization - natural product synthesis - kibdelone

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• 13 Experimental Procedure for ent-5
  N-Bromosuccinimide (3.871 g, 21.75 mmol) was added to a solution of dihydrobenzoic acid (4, 2.7 g, 21.8 mmol) and catalyst ent-1 (0.964 g, 2.18 mmol) in CH₂Cl₂/PhMe (1:1, 220 mL) at –50 °C, and the solution was stirred for 14 h. The reaction was quenched with sat. aq Na₂SO₃ (150 mL), and the mixture was allowed to warm to room temperature with vigorous stirring. The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 75 mL). The combined organic layers were washed with 5% aq Na₂CO₃ (2 × 150 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography, eluting with hexanes/EtOAc (9:1) to give 3.1 g (70%) of ent-5 as a white solid; mp 96–98 °C; spectra matched the previously reported data;^{14 1}H NMR (CDCl₃, 400 MHz): δ = 6.10–6.00 (m, 1 H), 5.90 (dddd, J = 9.9, 6.1, 1.8, 1.3 Hz, 1 H), 4.94 (dd, J = 5.7, 3.1 Hz, 1 H), 4.55 (q, J = 3.1 Hz, 1 H), 4.28 (t, J = 6.1 Hz, 1 H), 2.72 (m, 2 H) ppm. [α]_D ²⁵ –49.0 (c 1.0, CHCl₃). HPLC (210 nm): OD-H (1% i-PrOH/hexanes, 1.0 mL/min): t _R (major) = 16.6 min; t _R (minor) = 18.0 min. Recrystallization of ent-5 from hexanes (10 mg/100 mL) furnished 1.9 g (45%) of ent-5 as a single enantiomer. HPLC (210 nm): OD-H (1% i-PrOH/hexanes, 1.0 mL/min): t _R = 16.6 min.
• 14 Armstrong A. Braddock C. Jones AX. Clark S. Tetrahedron Lett. 2013; 54: 7004