Enantioselective Cascade Radical Addition-Cyclization of Oxime Ethers

Abstract

The chiral Lewis acid promoted reaction of oxime ethers proceeded smoothly with good enantio- and diastereoselectivities via a cascade radical addition-cyclization process.

radical - enantioselective - Lewis acid - oxime ether - cascade

References and Notes

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8 Transfer of chirality in radical cyclization has been reported. See: Curran DP. Liu W. Chen CH.-T. J. Am. Chem. Soc.  1999,  121:  11012 

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16

Oxime ethers and hydrazones have emerged as excellent radical acceptors.

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18

The absolute configuration at the stereocenter of cis-3a was assumed from the similarity between the present reaction and the previously reported reaction.⁹ The relative configuration of the trans and cis diastereomers was determined by NOESY experiments.

19

Since the activity of triethylborane also influenced the enantioselectivity, we used a newly opened bottle of 1 M Et₃B in hexane for this experiment.

20

We also tested the effect of additives and other radical initiators. When a stoichiometric amount of Bu₃SnH was employed as a chain carrier, the enantioselectivity was remarkably diminished, leading to a 40% ee of cis-3a in 8% yield after being stirred at -78 °C for 3 h. In the case of the reaction using Et₂Zn or 9-BBN as a radical initiator, no reaction occurred.

21

Typical Experimental Procedure:
A solution of oxime ether 1a (41 mg, 0.12 mmol), Zn(OTf)₂ (43 mg, 0.12 mmol) and ligand 2 (43 mg, 0.12 mmol) in CH₂Cl₂ (1.0 mL) was stirred for 30 min under a nitrogen atmosphere at 20 °C. To the reaction mixture were added i-PrI (0.36 mL, 3.6 mmol) and Et₃B (1.0 M in hexane, 2.4 mL, 2.4 mmol) at -78 °C. After being stirred at the same temperature for 10 h, the reaction mixture was diluted with sat. NaHCO₃ and then extracted with EtOAc. The organic phase was dried over MgSO₄ and concentrated at reduced pressure. Purification of the residue by column chromatography (hexane-EtOAc, 2:1) afforded product 3a (32 mg, 70%) as a mixture of cis and trans isomers which were separated by column chromatography (hexane-EtOAc, 4:1). The enantioselectivity of products was determined by HPLC using AD-H column.
Representative Characterization Data: cis-3a: colorless oil; [α]²⁷ _D -11.4 (c = 0.28, CHCl₃; 85% ee). IR (CHCl₃): 1704 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.27-7.46 (m, 10 H), 5.35 (s, 1 H), 4.98 (d, J = 11.0 Hz, 1 H), 4.93 (d, J = 11.0 Hz, 1 H), 4.60 (s, 2 H), 3.28-3.37 (m, 2 H), 3.23 (m, 1 H), 1.75 (m, 1 H), 1.50 (dd, J = 4.8, 14.6 Hz, 1 H), 1.21 (dd, J = 7.4, 14.6 Hz, 1 H), 1.15 (s, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H). ¹³C NMR (126 Hz, CDCl₃): δ = 173.4, 137.3, 135.3, 129.5, 128.9, 128.6 (2 × C), 128.4, 128.1, 76.6, 76.3, 61.8, 49.1, 44.5, 39.2, 25.0, 24.1, 23.7, 22.0. MS (FAB⁺): m/z = 383 (88) [M + H⁺], 91 (100). HRMS (FAB⁺): m/z [M + H⁺] calcd for C₂₃H₃₁N₂O₃: 383.2335; found: 383.2331.
trans-3a: colorless oil. IR (CHCl₃): 1705 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.27-7.47 (m, 10 H), 5.37 (s, 1 H), 4.97 (d, J = 11.0 Hz, 1 H), 4.93 (d, J = 11.0 Hz, 1 H), 4.61 (s, 2 H), 3.56 (m, 1 H), 3.44 (dd, J = 7.0, 8.9 Hz, 1 H), 3.04 (dd, J = 6.4, 8.9 Hz, 1 H), 1.64 (m, 1 H), 1.39-1.52 (m, 2 H), 1.00 (s, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 0.83 (d, J = 6.7 Hz, 3 H). ¹³C NMR (126 Hz, CDCl₃): δ = 174.0, 137.3, 135.3, 129.5, 128.9, 128.6, 128.5 (2 × C), 128.1, 76.5, 76.4, 56.9, 49.3, 44.7, 44.6, 24.7, 24.5, 22.9, 17.5. MS (FAB⁺): m/z = 383 (63) [M + H⁺], 91 (100). HRMS (FAB⁺): m/z [M + H⁺] calcd for C₂₃H₃₁N₂O₃: 383.2335; found: 383.2342.