Synlett 2018; 29(04): 433-439
DOI: 10.1055/s-0036-1590951
cluster
© Georg Thieme Verlag Stuttgart · New York

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

Dietrich Böse
,
University of Illinois at Urbana-Champaign, Department of Chemistry, 600 S Mathews Ave., Urbana, IL 61801, USA   Email: sdenmark@illinois.edu
› Author Affiliations
We are grateful to the National Institutes of Health (R01 GM085235) for financial support.
Further Information

Publication History

Received: 19 September 2017

Accepted after revision: 13 October 2017

Publication Date:
13 November 2017 (online)


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.

Supporting Information

 
  • 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: dietrich.boese@boehringer-ingelheim.com.
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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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