Synlett 2017; 28(20): 2971-2975
DOI: 10.1055/s-0036-1590930
letter
© Georg Thieme Verlag Stuttgart · New York

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

Changjia Zhao
,
Mukund P. Sibi*
This research was partially supported by funds from NIH RO1-54656.
Further Information

Publication History

Received: 14 August 2017

Accepted after revision: 12 September 2017

Publication Date:
20 October 2017 (online)


Dedicated to Prof. Victor Snieckus on his 80th 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.

Supporting Information

 
  • 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.
    • 2a Asymmetric Synthesis II: The Essentials. 2nd ed.; Christmann M. Bräse S. Wiley-VCH; Weinheim: 2007
    • 2b Asymmetric Synthesis II. 2nd ed; Christmann M. Bräse S. Wiley-VCH; Weinheim: 2012
    • 2c Fundamentals of Asymmetric Catalysis. Walsh PJ. Kozlowski MC. University Science Books; Sausalito, CA: 2009
    • 3a Renaud P. Sibi MP. Radicals in Organic Synthesis . Vol. 1 and 2. Wiley-VCH; Weinheim: 2001
    • 3b Stereochemistry of Radical Reactions . Curran DP. Porter NA. Giese B. VCH; Weinheim: 1995
    • 3c Encyclopedia of Radicals in Chemistry, Biology and Materials . Chatgilialoglu C. Studer A.  Wiley-VCH; Weinheim: 2012
  • 7 Shaw MH. Twilton J. MacMillan DW. C. J. Org. Chem. 2016; 81: 6898
  • 11 All the starting enones and lactones used in this study are known in the literature, see Supporting Information.
  • 13 A variety of 3+ and 2+ chiral Lewis acids were screened with modest success; see Supporting Information for details.
  • 14 Sibi MP. Nad S. Angew. Chem. Int. Ed. 2007; 46: 9231
  • 15 Urabe H. Yamashita K. Suzuki K. Kobayashi K. Sato F. J. Org. Chem. 1995; 60: 3576
  • 16 For an example of conjugate addition of achiral copper reagent to α-alkylidene cyclopentanone see: Borner C. Dennis MR. Sinn E. Woodward S. Eur. J. Org. Chem. 2001; 2435
  • 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.
  • 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.