Synlett 2008(2): 289-293  
DOI: 10.1055/s-2007-1000845
LETTER
© Georg Thieme Verlag Stuttgart · New York

Enzymatic Resolution of Chlorohydrins for the Synthesis of Enantiomerically Enriched 2-Vinyloxiranes

J. Adam McCubbin, Matthew L. Maddess, Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
Fax: +1(416)9468185; e-Mail: mlautens@chem.utoronto.ca;
Further Information

Publication History

Received 24 August 2007
Publication Date:
21 December 2007 (online)

Abstract

A series of vinylchlorohydrins are resolved by enzymatic kinetic resolution. The resulting R-alcohols, obtained in up to 99% ee, are stereoselectively converted into vinyloxiranes in high yield. The S-acetates, obtained in up to 99% ee were either deprotected to S-alcohols, or cyclized directly to vinyl oxiranes under basic conditions, with moderate to no loss in ee. The results are consistent with a racemization mechanism involving reversible migration of the ace­tate during deprotection.

    References and Notes

  • 1a Yudin AK. Aziridines and Epoxides in Organic Synthesis   Wiley-VCH; Weinheim Germany: 2006. 
  • 1b Pineschi M. Eur. J. Org. Chem.  2006,  3747 
  • 1c Gansäuer A. Fan CA. Keller F. Karbaum P. Chem. Eur. J.  2007,  13:  8084 
  • 1d Eissler S. Stronicius A. Nahrwold A. Sewald N. Synthesis  2006,  3747 
  • 1e Miyashita K. Imanishi T. Chem. Rev.  2005,  105:  4515 
  • 1f Watkins EB. Chittiboyina AG. Avery MA. Eur. J. Org. Chem.  2006,  4071 
  • For recent examples, see:
  • 2a Burke CP. Shu L. Shi Y. J. Org. Chem.  2007,  72:  6320 
  • 2b Colladon M. Scarso A. Sgarbossa P. Michelin RA. Strukul G. J. Am. Chem. Soc.  2007,  129:  7680 
  • 2c Zhang W. Yamamoto H. J. Am. Chem. Soc.  2007,  129:  286 
  • 2d Barlan AV. Basak A. Yamamoto H. Angew. Chem. Int. Ed.  2006,  45:  5849 
  • 2e Gelacha FG. Bitterlich B. Anilkumar G. Tse MK. Beller M. Angew. Chem. Int. Ed.  2007,  46:  7293 
  • 2f Sawada Y. Matsumoto K. Katsuki T. Angew. Chem. Int. Ed.  2007,  46:  4559 
  • 2g Peris G. Jakobische CE. Miller SJ. J. Am. Chem. Soc.  2007,  129:  8710 
  • 2h Taber DF. Liang J. J. Org. Chem.  2007,  72:  431 
  • Reviews:
  • 2i Shi Y. In Handbook of Chiral Chemicals   Vol. 2:  Ager D. CRC Press; Boca Raton Florida: 2006. 
  • 2j McGarrigle EM. Gilheany DG. Chem. Rev.  2005,  105:  1563 
  • 2k Xia Q.-H. Ge H.-Q. Ye C.-P. Liu Z.-M. Su K.-X. Chem. Rev.  2005,  105:  1603 
  • 2l Marco-Contelles J. Molina MT. Anjum S. Chem. Rev.  2004,  104:  2857 
  • For enantioselective syntheses of vinyloxiranes, see:
  • 3a Evans DA. Aye Y. J. Am. Chem. Soc.  2007,  129:  9606 
  • 3b Burke CP. Shi Y. Angew. Chem. Int. Ed.  2006,  45:  4475 
  • 3c Zenardi J. Lamazure D. Minière S. Reboul V. Metzner P. J. Org. Chem.  2002,  67:  9083 
  • 3d Solladié-Cavallo A. Bouérat L. Roje M. Tetrahedron Lett.  2000,  41:  7309 
  • 3e Trost BM. McEachern EJ. J. Am. Chem. Soc.  1999,  121:  8649 
  • 3f Schaus SE. Brandes BD. Larrow JF. Tokunaga M. Hansen KB. Gould AE. Furrow ME. Jacobsen EN. J. Am. Chem. Soc.  2002,  124:  1307 
  • 3g Ready JM. Jacobsen EN. J. Am. Chem. Soc.  2001,  123:  2687 
  • For examples of stereoselective reactions of vinyloxiranes, see:
  • 4a Fedorov A. Fu C. Heimgartner H. Helv. Chim. Acta  2006,  89:  456 
  • 4b Marié J.-C. Courillon C. Malacria M. Eur. J. Org. Chem.  2006,  463 
  • 4c Nagumo S. Miyoshi I. Akita H. Kanahara N. Tetrahedron Lett.  2002,  43:  2223 
  • 4d Antonioletti R. Bovicelli P. Fazzolari E. Righi G. Tetrahedron Lett.  2000,  41:  9315 
  • 4e Baylon C. Prestat G. Heck M.-P. Mioskowski C. Tetrahedon Lett.  2000,  41:  3833 
  • 4f Olofsson B. Somfai P. J. Org. Chem.  2002,  67:  8574 
  • 4g Besse P. Veschambre H. Tetrahedron  1994,  50:  8885 
  • 4h Hudlicky T. Tian X. Königsberger K. Rouden J. J. Org. Chem.  1994,  59:  1358 
  • 4i Satake A. Shimizu I. Yamamoto A. Synlett  1995,  64 
  • 4j Shao H. Zhu Q. Goodman M. J. Org. Chem.  1995,  60:  790 
  • 4k Kim N.-S. Choi J.-R. Cha JK. J. Org. Chem.  1993,  58:  7096 
  • 4l Ha JD. Kim SY. Lee SJ. Kang SK. Ahn JH. Kim SS. Choi J.-K. Tetrahedron Lett.  2004,  45:  5969 
  • For examples of lipase-mediated resolution of simple chlorohydrins, see:
  • 5a Pamies O. Bäckvall J.-E. J. Org. Chem.  2002,  67:  9006 
  • 5b Ader U. Schneider MP. Tetrahedron: Asymmetry  1992,  3:  521 
  • 5c Chen CS. Liu YC. Tetrahedron Lett.  1989,  30:  7165 
  • 5d Hiratake J. Inagaki M. Nishioka T. Oda J. J. Org. Chem.  1988,  53:  6130 
  • 5e Thakkar NV. Banerji AA. Bevinakatti HS. Biotech. Lett.  1994,  16:  1299 
  • 5f Scilimati A. Di Bono G. Synthesis  1995,  699 
  • 5g Kamal A. Chouhan G. Tetrahedron: Asymmetry  2005,  16:  2784 
  • 5h Pederson RL. Liu KKC. Rutan JF. Chen L. Wong CH. J. Org. Chem.  1990,  55:  4897 
  • For alternative enantioselective syntheses of vinyloxiranes using enzymes, see:
  • 5i Vankar PS. Bhattacharya I. Vankar YD. Tetrahedron: Asymmetry  1996,  7:  1683 
  • 5j Haak RM. Tarabiono C. Janssen DB. Minnaard AJ. de Vries JG. Feringa BL. Org. Biomol. Chem.  2007,  5:  318 
  • For reviews, see:
  • 6a Schoffers E. Golebiowski A. Johnson CR. Tetrahedron  1996,  52:  3769 
  • 6b Johnson CR. Acc. Chem. Res.  1998,  31:  333 
  • 6c Johnson CR. Wells GW. Curr. Opin. Chem. Biol.  1998,  2:  70 
  • 6d Garcia-Urdiales E. Alfonso I. Gotor V. Chem. Rev.  2005,  105:  313 
  • 6e Ghanem A. Aboul-Enein HY. Chirality  2005,  17:  1 
  • 6f Wong C.-H. Whitesides GM. In Enzymes in Synthetic Organic Chemistry   Elsevier Science; New York: 1994. 
  • 7a Taber DF. Jiang Q. J. Org. Chem.  2001,  66:  1876 
  • 7b Zhu B. Panek JS. Tetrahedron Lett.  2000,  12:  1863 
  • 8 Lautens M. Maddess ML. Sauer ELO. Ouellet SG. Org. Lett.  2002,  4:  83 
  • 13 See for example: Lopez R. Montero E. Sanchez F. Canada J. Fernandez-Mayoralas A. J. Org. Chem.  1994,  59:  7027 
  • 16 Zhu L. Kedenburg JP. Xian M. Wang PG. Tetrahedron Lett.  2005,  46:  811 
  • 18a Goering HL. Doi JT. McMichael KD. J. Am. Chem. Soc.  1964,  86:  1951 
  • 18b Lewis ES. Hill JT. J. Am. Chem. Soc.  1969,  91:  7458 
  • 19 Babler JH. Olsen DO. Arnold WH. J. Org. Chem.  1974,  32:  1656 
  • 20 Chevrin C. Le Bras J. Hénin F. Muzart J. Tetrahedron Lett.  2003,  44:  8099 
  • 21 March J. Advanced Organic Chemistry   4th ed.:  Wiley; New York: 1992. 
9

When 1a was subjected to the resolution conditions at 60 °C, no selectivity was observed.

10

General Procedure
A dry flask was charged with racemic alcohol 1 and vinyl acetate (1.0 mL/mmol). The resulting solution was stirred at 5, 25, or 60 °C and Amano lipase AK (3.0 mass equiv) was added as a single portion. Reaction progress was monitored by CSP-HPLC. At approximately 50% conversion, the suspension was filtered through a pad of Celite, washing with EtOAc (100 mL). The solution was concentrated in vacuo and the crude residue was purified by flash chromatography (5-10% EtOAc-hexane) to afford two fractions: (S)-2 (acetate, 1st eluted) and (R)-1 (alcohol, 2nd eluted). The alcohols (R)-1a-h displayed spectral properties in accordance with the racemates (see ref. 8). The acetates (S)-2a-h were characterized by 1H and 13C NMR, HRMS and CSP-HPLC.
Compound (S)-2a: 1H NMR (400 MHz, CDCl3): δ = 7.34-7.29 (m, 2 H), 7.28-7.18 (m, 3 H), 6.67-6.61 (d, J = 15.9 Hz, 1 H), 6.12-6.05 (dd, J = 15.9, 6.1 Hz, 1 H), 5.57-5.52 (dt, J = 6.1, 6.1 Hz, 2 H), 2.06 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 170.0, 135.7, 134.9, 128.7, 128.5, 126.8, 123.7, 73.7, 45.6, 21.1. HRMS (EI): m/z calcd for C12H13ClO2 [M+]: 224.0604; found: 224.0608. HPLC [CHIRALCEL OD, 1.0 mL/min, hexane-i-PrOH (98:2), 30 °C, 1 µL injection] t R1 (minor) = 12.4 min, t R2 (major) = 15.1 min; 99% ee.

11

The procedure reported in ref. 8 was used, and afforded the vinyloxiranes (R)-3a-f with spectral data consistent with that reported therein.

12

If the reaction was quenched before completion, the ee of the unreacted acetate was identical to that of the starting acetate before addition of the reducing agent. Deprotection was complete after 15 min, but the ee of the alcohol remained unchanged if left unquenched for a full hour.

14

General Procedure
A dry flask was charged with resolved acetate (S)-2 and heptane (10 mL/mmol). The resulting solution was cooled to -78 °C under Ar and DIBAL-H as a 1.0 M solution in heptane (1.1 equiv) was added dropwise via syringe. The solution was stirred at -78 °C for 15 min, followed by the addition of an equal volume of a sat. aq solution of Rochelle’s salt. The mixture was transferred to a separatory funnel and extracted twice with Et2O (25 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (10% EtOAc-hexane) to afford the desired alcohol (S)-1. The products displayed spectral characteristics in accord with the racemate (see ref. 8).

15

General Procedure
To a round-bottom flask was added resolved acetate (S)-2 and MeOH (10 mL/mmol) and the reaction vessel cooled in an ice bath. Then, K2CO3 (1.1 equiv) was added portionwise as a solid. The heterogeneous reaction was stirred at 0 °C and the progress monitored by TLC for the consumption of starting material. After 1 h, the reaction was quenched carefully by the addition of sat. aq NH4Cl, and after an equal volume had been introduced the reaction mixture was concentrated, diluted with Et2O and transferred to a separatory funnel. The organic layer was isolated, the aqueous layer extracted with Et2O and the combined organics dried with MgSO4, filtered, and concentrated in vacuo to afford the desired vinyloxirane (S)-3 in sufficient purity for subsequent reactions. The product displayed spectral characteristics in accord with the racemates (see ref. 8).

17

The experimental details for this reaction were not included in ref. 16; however, they were obtained through personal communication with the authors.

22

Alternatively, racemization could occur under certain conditions via ionization of 4a, followed by internal return.