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Synlett 2008(3): 433-437  
DOI: 10.1055/s-2008-1032057
LETTER
© Georg Thieme Verlag Stuttgart · New York

Nonenzymatic Kinetic Resolution of 3-Hydroxyalkanamides with Chiral Copper Catalyst

Yosuke Demizu, Yuki Kubo, Yoshihiro Matsumura, Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Fax: +81(95)8192476; e-Mail: onomura@nagasaki-u.ac.jp;
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Publication History

Received 29 October 2007
Publication Date:
16 January 2008 (online)

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Abstract

Kinetic resolution of 3-hydroxyalkanamides with good to high selectivities was achieved by benzoylation using copper(II) triflate and (R,R)-PhBox [2,2′-isopropylidenebis(4-phenyl-2-oxazoline)] as catalyst, which also mediated enantioselective tosylation of 2,2-bis(hydroxymethyl)alkanamides with high efficiency.

Key words - kinetic resolution - 3-hydroxyalkanamides - acylations - chiral copper complex - molecular recognition

    References and Notes

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12

Typical Procedure for Kinetic Resolution: To a solution of Cu(OTf)2 (0.05 mmol, 18.1 mg) and (R,R)-PhBox (0.05 mmol, 16.7 mg) in EtOAc (2 mL) were added dl-6a (0.5 mmol, 89.6 mg), K2CO3 (0.5 mmol, 69.1 mg) and benzoyl chloride (0.25 mmol, 0.029 mL). After stirring for 2 h at r.t., to the reaction mixture H2O (10 mL) was added. The organic portion was extracted with EtOAc (3 × 20 mL). The combined organic layer was dried over MgSO4 and the solvent was removed in vacuo. The residue was chromatographed on SiO2 (n-hexane-EtOAc, 3:1) to afford (S)-7a (58.1 mg, 41% yield, 85% ee) as a white solid; mp 98-99 °C; [α]D 23 +55.4 (c = 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 8.03 (d, J = 7.2 Hz, 1 H), 7.78 (br s, 1 H), 7.56 (t, J = 9.0 Hz, 1 H), 7.38-7.51 (m, 4 H), 7.29 (t, J = 9.0 Hz, 3 H), 7.09 (t, J = 9.0 Hz, 1 H), 5.50-5.63 (m, 1 H), 2.85 (dd, J = 6.3, 14.4 Hz, 1 H), 2.68 (dd, J = 6.3, 14.4 Hz, 1 H), 1.51 (d, J = 6.3 Hz, 3 H). Optical purity of product (S)-7a was determined by chiral HPLC: Dicel Chiralcel OD-H column (φ: 4.6 mm, l: 250 mm), n-hexane-isopropanol (10:1), wavelength: λ = 220 nm, flow rate: 1.0 mL/min, t R = 20.0 min [(R)-7a], t R = 22.5 min [(S)-7a].

13

The absolute stereoconfiguration of recovered (R)-6a was determined by comparing with the specific rotation of an authentic sample. Compound (R)-6a (74% ee): [α]D 22 -28.6 (c = 1.1, CHCl3) [lit. [14] (R)-6a [α]D 20 -37 (c = 1.0, CHCl3)].

15

The selectivity factor s was determined using the equation s = k rel ( fast/slow) = ln[(1 - C)(1 - eeA)]/ln[(1 - C)(1 + eeA)], where C = eeA/(eeA + eeB), eeA = ee of recovered starting material, eeB = ee of product: Kagan H. B., Fiaud J. C.; Topics in Stereochemistry; Vol. 18. Eliel E. L.; Wiley & Sons: New York, 1988; 249-330.

16

Absolute stereoconfigurations of 7ap-at,av,aw shown in Table [3] were deduced on the basis of those of (S)-7a and (R)-7au.

17

The absolute stereoconfiguration of (R)-7au was determined by comparing with that of authentic (S)-7au, which was prepared from commercially available (S)-(-)-3-hydroxy-3-phenylpropionitrile: Dicel Chiralcel OD-H column (φ: 4.6 mm, l: 250 mm), n-hexane-isopropanol (10:1), wavelength: λ = 220 nm, flow rate: 1.0 mL/min, t R = 36 min [(R)-7au], t R = 42 min [(S)-7au]. (R)-7au (74% ee): [α]D 25 -13.8 (c = 1.0, CHCl3).

18

Kinetic resolution of dl-6a with p-TsCl gave S-configured tosylated product with somewhat lower yield (36%) and enantioselectivity (67% ee) than those of benzoylation.

19

Specific rotations. 11a: [α]D 28 -16.4 (c = 1.0, CHCl3). 11b: [α]D 28 +6.9 (c = 1.0, CHCl3). 11c: [α]D 28 +0.6 (c = 1.0, CHCl3). 12a: [α]D 24 +15.2 (c = 0.95, CHCl3). 12b: [α]D 24 -21.8 (c = 1.0, CHCl3). 12c: [α]D 26 -43.2 (c = 1.0, CHCl3).

21

Mesylation of (R)-6a followed by cyclization under basic conditions gave the corresponding optically active β-lactam with complete stereoinversion. [16]