Enantioselective and Diastereoselective Conjugate Radical Additions to α-Arylidene Ketones and Lactones

Dedicated to Prof. Victor Snieckus on his 80^th birthday

Abstract

A highly stereoselective conjugate radical addition to arylidene ketones and lactones has been developed. The conjugate radical additions using chiral salen Lewis acids proceeds with up to 99:1 dr and 87% ee in good to excellent chemical yields.

Key words

enantioselective radical reaction - arylidene ketones and lactones - diastereoselectivity - conjugate addition - chiral salen Lewis acid

• References and Notes

• 1 Beijing Pharmin Technology Company Limited, Room 202, Unit 2, Huilongsen Park, No 99, Kechuang 14th Street, Beijing Economic-Technological Development Area, Beijing, 101111, P. R. of China.
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• 17 We have not established the relative stereochemistry of the major isomer. As noted in ref. 14, we speculate that the newly formed chiral center controls the stereochemistry of the H-atom-transfer step.

For stereochemical models of single-point binding substrates to chiral salens, see:
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• 19 Representative Procedure for Radical Addition To a 6 dram vial were added substrate (0.3 mmol) and Lewis acid 4 (0.09 mmol, 30 mol%). The vial was sealed with a septum, the air was removed from the vial via a vacuum pump, nitrogen was charged. To the mixture was then charged solvent (CH₂Cl₂, 8 mL), the mixture was stirred at r.t. for 20 min. Then the mixture was cooled to –78 °C, radical precursor (1.5 mmol, 5 equiv), triethylborane solution (1.0 M in hexane, 1.2 mL, 4 equiv), tributyltin hydride (0.24 mL, 0.9 mmol, 3 equiv), and oxygen gas (10 mL) were added successively via syringe. The reaction was stirred at –78 °C for 2–3 h until TLC analysis indicated disappearance of starting material. To the mixture was added silica gel (3.6 g), the solvent was removed under reduced pressure, the residue was first washed with hexanes (100 mL), then Et₂O (100 mL). To the ether solution was added silica gel (1.8 g), the solvent was removed under reduced pressure. The residue was subjected to flash chromatography using hexane/EtOAc (9:1) as eluent to afford the conjugate addition product. 2-(2-Methyl-1-phenylpropyl)-cyclopentanone (2) 88 mg (0.5 mmol), yield 81%, dr 99:1, ee 75% by HPLC (210 nm, 25 °C, OJ-H column Chiralcel, 0.46cm × 25 cm, from Daicel Chemical Ind., Ltd., 1% i-PrOH/hexanes, 0.5 mpm, t _R (major) = 18.5 min; t _R (minor) = 14.4 min). [α]_D +71.3 (c 0.3, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.65 (d, J = 6.4 Hz, 3 H), 0.95 (t, J = 6.8 Hz, 3 H), 1.56–2.46 (m, 8 H), 2.61 (dd, J = 10.4, 3.6 Hz, 1 H), 7.11–7.25 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.9, 22.0, 22.1, 26.9, 29.7, 39.4, 52.7, 53.8, 126.4, 128.5, 128.8, 144.2, 220.3. IR: 3062, 3029, 2960, 2894, 2871, 1733, 1493, 1470, 1407, 1385, 1273, 1152 cm^–1. HRMS: m/z calcd for C₁₅H₂₀ONa⁺: 239.1406; found: 239.1400.