Chiral Aziridination of Olefins Using a Chiral Sulfinamide as the Nitrogen Source

Abstract

Chiral aziridination of cyclic α-bromoenones is achieved by the use of the lithium salt of (S _S)-(+)-p-toluenesulfinamide, which leads to products with diastereomeric excesses in the range of 30-65% using a simple protocol. A key factor associated with chiral induction is the incorporation of the reacting olefin in a cycle, indicating the importance of conformational restriction in the reacting double bond.

aminations - chirality - cyclizations - enones - Michael additions

References and Notes

1a Aziridines and Epoxides in Organic Synthesis   Yudin AK. Wiley-VCH; Weinheim: 2006. 

1b Jacobsen EN. Comprehensive Asymmetric Catalysis   Vol. 2:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 1999.  p.607 

1c Pearson WH. Lian BW. Bergmeier SC. In Comprehensive Heterocyclic Chemistry II   Vol. 1A:  Padwa A. Pergamon; Oxford: 1996.  p.1 

1d Rai KML. Hassner A. In Comprehensive Heterocyclic Chemistry II   Vol. 1A:  Padwa A. Pergamon; Oxford: 1996.  p.6196 

2 For useful biological activities of aziridines, see: Yadav LD. Rai A. Rai VK. Awasthi C. Tetrahedron Lett.  2008,  49:  687 ; and references therein

For the synthesis of oseltamivir, the anti-influenza neuraminidase inhibitor, using an aziridine intermediate, see:

3a Nie L.-D. Shi X.-X. Ko KH. Lu W.-D. J. Org. Chem.  2009,  74:  3970 

3b Yamatsugu K. Yin L. Kamijo S. Kimura Y. Kanai M. Shibasaki M. Angew. Chem. Int. Ed.  2009,  48:  1070 

3c Satoh N. Akiba T. Yokoshima S. Fukuyama T. Tetrahedron  2009,  65:  3239 

3d Trost BM. Zhang T. Angew. Chem. Int. Ed.  2008,  47:  3759 

3e Shibasaki M. Kanai M. Eur. J. Org. Chem.  2008,  1839 

3f Yeung Y.-Y. Hong S. Corey EJ. J. Am. Chem. Soc.  2006,  128:  6310 

3g Fukuta Y. Mita T. Fukuda N. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2006,  128:  6312 

For azinomycins, see:

4a Hodgkinson TJ. Shipman M. Tetrahedron  2001,  57:  4467 

4b Coleman RS. Kong JS. Richardson TE. J. Am. Chem. Soc.  1999,  121:  9088 

4c Coleman RS. Li J. Navarro A. Angew. Chem. Int. Ed.  2001,  40:  1736 

5 Remers WA. In The Chemistry of Antitumor Antibiotics   Vol. 1:  Wiley-Interscience; New York: 1979.  p.242 

5b Kasai M. Kono M. Synlett  1992,  778 

6a Taylor AM. Schreiber SL. Tetrahedron Lett.  2009,  50:  3230 

6b Chan JWW. Ton TMU. Zhang Z. Xu Y. Chan PWH. Tetrahedron Lett.  2009,  50:  161 

6c Singh GS. D’hooghe M. De Kimpe N. Chem. Rev.  2007,  107:  2080 

6d Muller P. Fruit C. Chem. Rev.  2003,  2905 

6e Sweeney JB. Chem. Soc. Rev.  2002,  31:  247 

6f Ibuka I. Chem. Soc. Rev.  1998,  27:  145 

6g Osborn HMI. Sweeney JB. Tetrahedron: Asymmetry  1997,  8:  1693 

6h Li A.-H. Dai L.-X. Aggarwal VK. Chem. Rev.  1997,  97:  2341 

6i Tanner D. Angew. Chem., Int. Ed. Engl.  1994,  33:  599 

7a Minakata S. Morino Y. Oderaotoshi Y. Komatsu M. Chem. Commun.  2007,  3337 

7b D’hooghe M. Boelens M. Piqueur J. Kimpe N. Chem. Commun.  2007,  1927 

8a Fioravanti S. Morea S. Morreale A. Pellacani L. Tardella PA. Tetrahedron  2009,  65:  484 

8b Chigboh K. Morton D. Nadin A. Stockman RA. Tetrahedron Lett.  2008,  49:  4768 

8c Duan P.-W. Chiu C.-C. Lee W.-D. Pan LS. Venkatesham U. Tzeng Z.-H. Chen K. Tetrahedron: Asymmetry  2008,  19:  682 

8d Fernandez I. Valdivia V. Gori B. Alcudia F. Alvarez E. Khiar N. Org. Lett.  2005,  7:  1307 

8e Ulukanli S. Karabuga S. Celik A. Kazaz C. Tetrahedron Lett.  2005,  46:  197 

8f Chenna PHD. Peillard FR. Dauban P. Dodd RH. Org. Lett.  2004,  6:  4503 

8g Cavallo AS. Roje M. Welter R. Sinjic V. J. Org. Chem.  2004,  69:  1409 

8h Redlich M. Hossain MM. Tetrahedron Lett.  2004,  45:  8987 

8i Calhorda MJ. Vaz PD. Chemtracts: Inorg. Chem.  2004,  17:  396 

8j Barros MT. Maycock CD. Ventura MR. Tetrahedron Lett.  2002,  43:  4329 

8k Gillespie KM. Sanders CJ. Shaughnessy PO. Westmoreland I. Thickitt CP. Scott P. J. Org. Chem.  2002,  67:  3450 

8l Nishimura M. Minakata S. Takahashi T. Oderaotoshi Y. Komatsu M. J. Org. Chem.  2002,  67:  2101 

8m Aggarwal VK. Alonso E. Ferrara M. Spey SE. J. Org. Chem.  2002,  67:  2335 

8n Wei H.-X. Kim SH. Li G. Tetrahedron  2001,  57:  8401 

9 Pereira MM. Santos PPO. Reis LV. Lobo AM. Prabhakar S. J. Chem. Soc., Chem. Commun.  1993,  38 

10a Antunes MM. Bonifácio VDB. Nascimento CC. Lobo AM. Branco PS. Prabhakar S. Tetrahedron  2007,  63:  7009 

10b Antunes AMM. Marto SJ. Branco PS. Prabhakar S. Lobo AM. Chem. Commun.  2001,  405 

11a Aires-de-Sousa J. Prabhakar S. Lobo AM. Rosa AM. Gomes MJS. Corvo MC. Williams DJ. White AJP. Tetrahedron: Asymmetry  2002,  12:  3349 

11b Aires-de-Sousa J. Lobo AM. Prabhakar S. Tetrahedron Lett.  1996,  37:  3183 

12 Murugan E. Siva A. Synthesis  2005,  2022 

13a Davis FA. Wu Y. Yan H. McCoull W. Prasad KR. J. Org. Chem.  2003,  68:  2410 

13b Davis FA. Zhou P. Reddy GV. J. Org. Chem.  1994,  59:  3243 

14 The lithium salt of (S _S)-(+)-1 was prepared as in: Wenschuh V. Fritzsche B. J. Prakt. Chem.  1970,  312:  129 ; its configuration stability in the chiral sulfur was ascertained by recovering (S _S)-(+)-1 with the same specific rotation of +85.6 (c 0.95, CH₃Cl) from the salt

15

This compound is commercially available from Sigma-Aldrich Co (http://www.sigmaaldrich.com).

All α-bromo(iodo)olefins 2 were obtained by dihalogenation of the double bond followed by base-catalyzed elimination of the β-halogen while reforming the olefin:

16a Compound 2a: Kowalski CJ. Weber AE. Fields KW. J. Org. Chem.  1982,  47:  5088 

16b Compounds 2b,c: Bordwell FG. Wellman KM. J. Org. Chem.  1963,  28:  2544 

16c Compound 2d: Smith AB. Branca SJ. Guaciaro MA. Wovkulich PM. Korn A. Org. Synth., Coll. Vol. VII  1990,  271 

16d Compound 2e: Johnson CR. Adams JP. Braun MP. Senanayake CBW. Wovkulich PM. Uskokovic MR. Tetrahedron Lett.  1992,  7:  917 

16e Compound 2f: Wakui T. Otsuji Y. Imoto E. Bull. Chem. Soc. Jpn.  1974,  2267 

16f Compound 2g: Amice P. Blanco L. Conia JM. Synthesis  1976,  196 

16g Compound 2h: Crossland I. Bock K. Norrestam R. Acta Chem. Scand., Ser. B  1985,  39:  7 

16h Nield CH. J. Am. Chem. Soc.  1945,  67:  1145 

16i Compound 2i: Carlier P. Gelas-Mialhe Y. Vessiere R. Can. J. Chem.  1977,  55:  3190 

17

CCDC 741870 contains the crystallographic data which can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing [e-mail]. ac.uk, or by contacting CCDC, UK; fax: [phone].

18 For stabilization involving lithium chelation in an eight-membered ring, see: Davis FA. Reddy RT. Reddy RE. J. Org. Chem.  1992,  57:  6387 

19 Molander GA. Stengel PJ. Tetrahedron  1997,  53:  8887 

20 Parker D. Chem. Rev.  1991,  91:  1441 

21

Full coordinates and other information about the calculations can be found via the following digital repository entries: 10042/to-2308, 10042/to-23010, 10042/to-2311, 10042/to-2312, 10042/to-2314 and 10042/to-2315, resolved as e.g. http://dx.doi.org/10042/to-2308. An interactive version of this figure can be viewed via the HTML version of this article.

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Typical Experimental Procedure for Aziridination
To a dry THF solution of 2-bromocyclohex-2-en-1-one (2a, 0.286 mmol), under nitrogen atmosphere and protected from light at -78 ˚C, was added the lithium salt of chiral sulfinamide 1 (0.858 mmol) and the reaction allowed to reach r.t. After 30 min the solvent was removed under reduced pressure and the residue dissolved in EtOAc, washed with aq NH₄Cl (10%), and after drying and solvent removal, the remaining residue was purified via silica gel PTLC (EtOAc-n-hexane, 1:1) to afford a mixture of the title aziridines 3Aa (major)/3Ba (minor); yield 62%. Separation of both diastereomers was achieved by 2 × PTLC of the mixture.
Compound 3Aa(major): mp 70-71 ˚C (EtOAc-n-hexane); [α]_D ^²³ +64.6 (c 0.99, CHCl₃).
Compound 3Ba(minor): mp 90-91 ˚C (EtOAc-n-hexane); [α]_D ^²³ +89.4 (c 1.44, CHCl₃). ^¹H NMR (400 MHz, CDCl₃; 3Aa/3Ba = 77:23): δ = 7.60 (2 H, d, J = 8.2 Hz, minor), 7.55 (2 H, d, J = 8.2 Hz, major), 3.23 (1 H, d, J = 6.3 Hz, minor), 3.13 (1 H, d, J = 6.3 Hz, major), 3.06 (1 H, d, J = 6.3 Hz, major), 2.94 (1 H, d, J = 6.3 Hz, minor). MS (CI): m/z (%) = 249 (100) [M⁺]. Anal. Calcd for C₁₃H₁₅NO₂S: C, 62.62; H, 6.06; N, 5.62. Found: C, 62.31; H, 6.34; N, 5.74.
Compound 3b: oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.59 (2 H, d, J = 8.1 Hz, minor), 7.55 (2 H, d, J = 8.1 Hz, major), 3.08 (1 H, d, J = 6.3 Hz, major), 2.94 (1 H, d, J = 6.4 Hz, minor), 2.85 (1 H, d, J = 6.4 Hz, minor), 2.77 (1 H, d, J = 6.3 Hz, major). HRMS: m/z calcd for C₁₅H₁₉NO₂S: 277.11365; found: 277.11344. Anal. Calcd for C₁₅H₁₉NO₂S: C, 64.95; H, 6.90; N, 5.05. Found: C, 65.27; H, 7.16; N, 4.95.
Compound 3c: mp 64-65 ˚C (EtOAc-n-hexane). ^¹H NMR (400 MHz, CDCl₃): δ = 3.79 (2 H, d, J = 5.4 Hz, minor), 3.64 (1 H, d, J = 5.6 Hz, major), 3.41 (1 H, d, J = 6.2 Hz, major), 3.30 (1 H, d, J = 6.2 Hz, minor). MS (EI): m/z (%) = (1.1) 402 [M + 1]⁺. Anal. Calcd for C₂₅H₂₃NO₂S: C, 74.78; H, 5.77; N, 3.49. Found: C, 75.16; H, 5.74; N, 3.37.
Compound 3d (major): mp 97-98 ˚C (Et₂O-n-hexane); [α]_D ^²³ +22.0 (c 0.90, CHCl₃).
Compound 3d (minor): mp 105-106 ˚C (Et₂O-n-hexane); [α]_D ^²³ +12.4 (c 2.03, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.62 (2 H, d, J = 8.2 Hz, minor), 7.54 (2 H, d, J = 8.2 Hz, major), 3.56 (1 H, m, minor), 3.53 (1 H, m, major), 3.11 (1 H, d, J = 4.3 Hz, major), 3.08 (1 H, d, J = 4.3 Hz, minor). HRMS-FAB: m/z calcd for C₁₂H₁₄NO₂S: 236.074526; found: 236.075172.
Compound 3f: oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.60 (2 H, d, J = 7.8 Hz, minor), 7.54 (2 H, d, J = 7.8 Hz, major), 3.23 (1 H, d, J = 4.4 Hz, minor), 3.21 (1 H, d, J = 4.4 Hz, major), 3.13 (1 H, d, J = 4.4 Hz, major), 3.10 (1 H, d, J = 4.4 Hz, minor). MS (FI): m/z (%) =(100) 263 [M⁺]. Anal. Calcd for C₁₄H₁₇NO₂S: C, 63.85; H, 6.51; N, 5.32. Found: C, 62.95; H, 6.81; N, 5.17.
Compound 3g: mp 92-93 ˚C (Et₂O-n-pentane). ^¹H NMR (400 MHz, CDCl₃): δ = 7.61 (2 H, d, J = 8.1 Hz, minor), 7.56 (2 H, d, J = 8.1 Hz, major), 3.13 (1 H, J = 7.7, 1.5 Hz, major), 3.06 (1 H, m, minor), 2.97 (1 H, dd, J = 7.7, 4.6 Hz, major), 2.80 (1 H, m, minor). MS (EI): m/z (%) =(18) 263 [M⁺]. Anal. Calcd for C₁₄H₁₇NO₂S: C, 63.85; H, 6.51; N, 5.32. Found: C, 62.62; H, 6.72; N, 5.29.
Compound 3h: diasteriomeric mixture (1:1), mp 69-71 ˚C, 77-80 ˚C (EtOAc). ^¹H NMR (400 MHz, CDCl₃): δ = 2.81
(1 H, d, J = 4.1 Hz), 2.79 (1 H, d, J = 7.3 Hz), 2.71 (1 H, d, J = 6.9 Hz), 2.24 (1 H, d, J = 3.7 Hz). HRMS (EI): m/z calcd for C₁₆H₁₅NO₂S: 285.08235; found: 285.083598. Anal. Calcd for C₁₆H₁₅NO₂S: C, 67.34; H, 5.30; N, 4.91. Found: C, 67.34; H, 5.30; N, 4.91.
Compounds 3i: 3Ai: mp 103-105 ˚C (EtOAc); [α]_D ^²³ -15.1 (c 3.30, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 3.91 (1 H, dd, J = 6.5, 3.3 Hz), 2.89 (1 H, d, J = 3.3 Hz), 2.66 (1 H, d, J = 6.5 Hz). Anal. Calcd for C₁₅H₁₅NO₃S₂: C, 56.05; H, 4.70; N, 4.36. Found: C, 55.87; H, 4.76; N, 4.38. 3Bi: mp 120-121 ˚C (EtOAc); [α]_D ^²³ +7.4 (c 2.04, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 3.70 (1 H, dd, J = 6.3, 3.2 Hz), 2.75 (1 H, d, J = 6.3 Hz), 2.43 (1 H, br d); the attribution to 3Ai and 3Bi may be reversed. HRMS (EI): m/z calcd for C₁₅H₁₅NO₃S₂: 321.04933; found: 321.04958.
Oxidation of 3Aa/3Ba
To a solution of 3Aa/3Ba (0.2 mmol) was added MCPBA (0.4 mmol), and after 18 h at r.t. the solvent was removed and the enantiomeric mixture of 4Aa/4Ba isolated (yield 99%); ee 53% from ^¹H NMR (400 MHz, CDCl₃): δ = 3.45 (1 H, H₂) split by addition of Eu(hfc)₃.