Investigating the Enantiodetermining Step of a Chiral Lewis Base Catalyzed Bromocycloetherification of Privileged Alkenes

Published as part of the Cluster Alkene Halofunctionalization

Abstract

The development of catalytic, enantioselective halofunctionalizations of unactivated alkenes has made significant progress in recent years. However, the identification of generally applicable catalysts for wide range of substrates has yet to be realized. A detailed understanding of the reaction mechanism is essential to guide the formulation of a truly general catalyst. Herein, we present our investigations on the enantiodetermining step of a Lewis base catalyzed bromocycloetherification that provides important insights and design criteria.

Key words

Lewis base - halofunctionalization - alkenes - selenophosphoramides - bromocycloetherification - bromiranium ions

• References and Notes

• 1 New current address: Dietrich Böse, Boehringer Ingelheim RCV GmbH & Co KG, Dr.-Boehringer-Gasse 5-11, 1121 Vienna, Austria; e-mail: [e-mail].
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• 12 Experimental Procedures: Enantioselective Bromocycloetherification of 2-{[(tert-butyldimethylsilyl)oxy] methyl}-4-phenylpent-4-en-1-ol (12) A stock solution of 2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-phenylpent-4-en-1-ol (rac-12) (30 mg/1.0 mL) in CH₂Cl₂ was added (1.0 mL, 0.1 mmol) to cyclic sulfide 8 (0.01 mmol, 0.1 equiv) in a septum sealed sample vial at 20 °C. The solution was cooled to –78 °C, and a second stock solution of chloroacetic acid in CH₂Cl₂ (0.1 M, 1.0 mL, 0.1 mmol, 1.0 equiv) was added. After 10 min at this temperature a stock solution of NBS (0.1 M, 1.0 mL, 0.10 mmol, 1.0 equiv) was slowly added. After 13 h 1 mL of a stock solution of NaBH₄ in EtOH (50 mg/5 mL) was added. Then the reaction was slowly warmed to 0 °C (over approx. 2 h). Then 1 mL of H₂O and 1 mL of hexanes (HPLC grade) were added, and the mixture was stirred at 20 °C for 15 min. After phase separation, the organic phase was filtered through a plug of MgSO₄ and Celite and evaporated using a stream of nitrogen. The residue was dissolved in CDCl₃ and a ¹H NMR spectrum was collected to estimate conversion and product distribution. The diastereomeric ratio was found to be 13/14 = 41:59. Then the products were dissolved in THF (2 mL) at 20 °C and TBAF was added (95 mg, 0.3 mmol, 3.0 equiv). The reaction was stirred at 20 °C until full conversion was observed by TLC analysis (hexanes/EtOAc, 90:10). After 2.5 h 10 mL of diethyl ether were added, and the mixture was washed with sat. aq NH₄Cl solution (1 × 10 mL). The organic layer was dried over MgSO₄, filtered, and evaporated. Purification by column chromatography (hexanes/EtOAc, 90:10) yielded the pure products as a diastereomeric mixture. HPLC analysis revealed that both diastereoisomers were formed with an enantiomeric ratio of 60:40
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• 14 For all screening experiments CH₂Cl₂ with a water content of >500 μg/mL was applied. A stock solution (0.12 M) of 2,2-dimethyl-4-phenylpent-4-en-1-ol (17) in CH₂Cl₂ (0.25 mL, 0.03 mmol) was added to the indicated Lewis base (0.003 mmol, 0.1 equiv) in a septum-sealed sample vial at 20 °C. The solution was cooled to –78 °C, and a second stock solution of chloroacetic acid (CAA) in CH₂Cl₂ (0.12 M, 0.25 mL, 0.03 mmol, 1.0 equiv) was added. After 10 min at this temperature a stock solution of NBS (0.12 M, 0.25 mL, 0.03 mmol, 1.0 equiv) was slowly added. After 18 h 1 mL of a stock solution of NaBH₄ in EtOH (50 mg/5 mL) was added. Then the reaction was slowly warmed to 0 °C (over approx. 2 h). Then 1 ml of H₂O and 1 mL of hexanes (HPLC grade) were added, and the mixture was stirred at 20 °C for 15 min. After phase separation, the organic phase was filtered through a plug of MgSO₄ and Celite and evaporated using a stream of nitrogen. The residue was dissolved in CDCl₃ and a ¹H NMR spectrum was collected to estimate conversion and product distribution (d.r.). HPLC analysis was used to establish the enantioselectivities. HPLC: 18 t _R = 8.2 min; ent-18 t _R = 8.8 min (Chiralcel OJH, hexanes/2-propanol; 99:01, 0.4 mL/min, 220 nm, 20 °C). ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (s, 3 H), 1.21 (s, 3 H, 1′′-H), 2.25 (d, J = 12.8 Hz, 1 H, 3-Ha), 2.35 (d, J = 12.8 Hz, 1 H, 3-Hb), 3.63 (s, 2 H, 1′-H), 3.66 (d, J = 8.2 Hz, 1 H, 5-Ha), 3.82 (d, J = 8.3 Hz, 1 H, 5-Hb), 7.24–7.33 (m, 1 H), 7.37 (dd, J = 8.6, 6.9 Hz, 2 H), 7.43–7.48 (m, 2 H, PhH). ¹³C NMR (125 MHz, CDCl₃): δ = 27.0, 27.1, 40.8, 43.5, 51.9, 80.6, 86.0, 125.7, 127.3, 128.3, 144.7.
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