Parallel Kinetic Resolution of 1-Phenylethanol Using Quasi-Enantiomeric Active Esters

Abstract

The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-enantiomeric pentafluorophenyl esters is discussed. The levels of diastereoselectivity were excellent (>88% de) leading to separable quasi-enantiomeric esters in good yields.

chiral auxiliaries - chiral resolution - kinetic resolution - molecular recognition - stereoselectivity

References and Notes

For reviews see:

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4 For a comprehensive review into quasi-enantiomers, see: Zhang Q. Curran DP. Chem. Eur. J.  2005,  11:  4866 

5a Davies SG. Diez D. El Hammouni MM. Garner AC. Garrido NM. Long MJ. Morrison RM. Smith AD. Sweet MJ. Withey JM. Chem. Commun.  2003,  2410 

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6a Coumbarides GS. Dingjan M. Eames J. Flinn A. Motevalli M. Northen J. Yohannes Y. Synlett  2006,  101 

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6b Coumbarides GS. Eames J. Flinn A. Northen J. Yohannes Y. Tetrahedron Lett.  2005,  46:  849 

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6e Boyd E. Chavda S. Eames J. Yohannes Y. Tetrahedron: Asymmetry  2007,  18:  476 

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The use of ten equivalents of racemic alcohol has been reported by:

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7b Miller SJ. Copeland GT. Papaioannou N. Horstmann TE. Ruel EM. J. Am. Chem. Soc.  1998,  120:  1629 

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7e

See also ref. 18.

7f

For our study, an excess of alcohol rac-16 was used to minimize epimerisation of the product, potential racemisation of the active ester(s) and as a competitive Lewis base.

8

Alternatively, n-BuLi (in hexanes) and PhLi (in dibutyl ether) could be used but they contained traces of lithium butoxide which can lead to the formation of an inseparable by-product, butyl 2-phenylpropionate (in 16% and 5% yields for n-BuLi and PhLi, respectively). Characterisation data for butyl 2-phenylpropionate; R _f [light PE (40-60 °C)-Et₂O, 1:1] 0.80. IR (film): 1674 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.15-7.28 (m, 5 H, 5 × CH, Ph), 3.99 (td, J = 1.5, 6.8 Hz, 2 H, OCH₂), 3.63 (q, J = 7.2 Hz, 1 H, CHMe), 1.43-1.52 (m, 2 H, CH₂), 1.42 (d, J = 7.2 Hz, 3 H, CHMe), 1.18-1.28 (m, 2 H, CH₂), 0.79 (t, J = 7.5 Hz, 3 H, Me). ¹³C NMR (100 MHz, CDCl₃): δ = 174 (C=O), 140.6 (i-C, Ph), 128.4, 127.4, 126.9 (3 × CH, Ph), 64.5 (OCH₂), 45.5 (PhCH), 30.4, 18.9 (2 × CH₂), 18.4 (MeCH), 13.6 (MeCH₂). HRMS: m/z [M⁺] calcd for C₁₃H₁₈O₂: 206.1299; found: 206.1301.

9

Using racemic lithium 1-(4-methoxyphenyl)ethoxide, epimerisation of esters such as (S,S)-anti-24 and (S,R)-syn-24, has been shown to occur at a significantly faster rate than simple transesterification.

10 Boyd E. Chavda S. Coulbeck E. Coumbarides GS. Dingjan M. Eames J. Flinn A. Krishnamurthy AK. Namutebi M. Northen J. Yohannes Y. Tetrahedron: Asymmetry  2006,  17:  3406 ; and references therein

11

Measured by ¹H NMR (400 MHz) spectroscopy; for rac,anti-17, the methyl doublets appear at δ = 1.43 (d, J = 7.2 Hz, 3 H, MeCH) and 1.42 (d, J = 6.6 Hz, 3 H, MeCH), whereas for rac,syn-17, the methyl doublets appear at δ = 1.41 (d, J = 7.2 Hz, 3 H, MeCH) and 1.35 (d, J = 6.6 Hz, 3 H, MeCH).

12

For active esters: R _f [light PE (40-60 °C)-Et₂O, 9:1] 0.69 [for (R)-11] and 0.50 [for (S)-12]. For further information see ref. 10.

13

For a representative procedure, see ref. 7d.

For representative reviews, see:

14a Fu G. Acc. Chem. Res.  2000,  33:  412 

14b Miller SJ. Acc. Chem. Res.  2004,  37:  601 

14c France S. Guerin DJ. Miller SJ. Lectka T. Chem. Rev.  2003,  103:  2985 

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For a review, see:

15a Ghanem A. Aboul-Enein HY. Chirality  2005,  17:  1 

For comprehensive examples, see:

15b Morgan B. Oehlschlager AO. Stokes TM. J. Org. Chem.  1992,  57:  3231 

15c Brown SM. Davies SG. de Sousa JAA. Tetrahedron: Asymmetry  1993,  4:  813 

15d Naemura K. Murata M. Tanake R. Yano M. Hirose K. Tobe Y. Tetrahedron: Asymmetry  1996,  7:  1581 

15e Naemura K. Murata M. Tanake R. Yano M. Hirose K. Tobe Y. Tetrahedron: Asymmetry  1996,  7:  3285 

15f Cordova A. Tremblay MR. Clapham B. Janda KD. J. Org. Chem.  2001,  66:  5645 

15g Swaleh SM. Hungerhoff B. Sonnenschein H. Theil F. Tetrahedron  2002,  58:  4085 

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16 Eames J. Synthesis by Resolution and Inversion, In Science of Synthesis   36:  Thomas EJ. Clayden JC. Georg Thieme Verlag; Stuttgart: 2007.  p.341-421  

17

Experimental Procedure for 1-Phenylethyl 2-Phenylpropionate [( R , R )- anti -17] and 1-Phenylethyl 2-(6-Methoxynaphthalen-2-yl)propionate [( S , S )- anti -24] Derived from the Parallel Kinetic Resolution of 1-Phenylethanol ( rac -16) Using Active Esters ( R )-11 and ( S )-12: t-BuLi (1.81 mL, 1.7 M in pentane, 3.07 mmol) was added to a stirred solution of 1-phenylethanol (rac-16; 1.25 g, 1.24 mL, 10.25 mmol) in THF at -78 °C. A solution of ZnCl₂ (3.07 mL, 1 M in Et₂O, 3.07 mmol) was added and the resulting solution was stirred for 2 min. An equimolar combination of pentafluorophenyl 2-phenylpropionate [(R)-11; 0.16 g, 0.51 mmol] and pentafluorophenyl 2-(6-methoxynaphthalen-2-yl)propionate [(S)-12; 0.203 g, 0.51 mmol] in THF (20 mL) was added, and the resulting solution was stirred for 12 h. The reaction was quenched by the addition of sat. aq NH₄Cl (5 mL) and H₂O (10 mL). The organic layer was extracted with CH₂Cl₂ (3 × 50 mL), washed with H₂O (10 mL), dried (over MgSO₄) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with light PE (40-60 °C)-Et₂O (9:1) to give a pair of inseparable diastereomers (anti/syn, 93:7) of 1-phenylethyl 2-phenylpropionates (R,R)-anti-17 and (R,S)-syn-17 (0.10 g, 77%) as an oil {R _F [light PE (40-60 °C)-Et₂O (1:1)] 0.80} and a pair of inseparable diastereomers (anti/syn, 94:6) of 1-phenylethyl 2-(6-methoxynaphthalen-2-yl)propionates (S,S)-anti-24 and (S,R)-syn-24 (0.13 g, 76%) as an oil {R _f [light PE (40-60 °C)-Et₂O (1:1)] 0.62}. Pentafluorophenol, if present, can be removed by an aq NaOH extraction. All compounds synthesised had satisfactory ¹H and ¹³C NMR, IR and HRM spectra with >95% purity.
Characterisation data for:
1-Phenylethyl 2-Phenylpropionate [(R,R)-anti-17]: transparent solid; mp 81-83 °C; R _f [light PE (40-60 °C)-Et₂O, 1:1] 0.80; [α]_D ²⁰ +10.53 (c = 3.0, CHCl₃) {lit.¹⁹ [α]_D ²⁰ +9.9 (c = 0.87, CHCl₃)}. IR (CHCl₃): 1730 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.14-7.30 (m, 8 H, 8 × CH, Ph^A and Ph^B), 7.00-7.05 (m, 2 H, 2 × CH, Ph^A or Ph^B), 5.78 (q, J = 6.6 Hz, 1 H, PhCHMeO), 3.68 (q, J = 7.2 Hz, 1 H, PhCHMe), 1.43 (d, J = 7.2 Hz, 3 H, PhCHMe), 1.42 (d, J = 6.6 Hz, 3 H, PhCHMeO). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5 (C=O), 141.6 (i-C, PhCHMeO), 140.4 (i-C, PhCHMe), 128.5,² 128.3,² 127.6,² 127.5,¹ 127.0,¹ 125.6,² (10 × CH, Ph^A, Ph^B), 72.4 (PhCHMeO), 45.7 (PhCHMe), 22.3 (PhCHMeO), 18.3 (PhCHMe). HRMS: m/z [MNH₄ ⁺] calcd for C₁₇H₂₂NO₂: 272.1645; found: 272.1648. MS: m/z (%) = 254 (10) [M⁺], 105 (100) [PhCHMe⁺].
1-Phenylethyl 2-(6-Methoxynaphthalene-2-yl)propionate [(S,S)-anti-24]: white solid; mp 94-96 °C; R _f [light PE (40-60 °C)-Et₂O (1:1)] 0.62; [α]_D ²⁰ +26.6 (c = 3.2, CHCl₃). IR (CHCl₃): 1723 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (d, J = 8.4 Hz, 1 H, CH, Ar), 7.63 (d, J = 8.4 Hz, 1 H, CH, Ar), 7.55 (br s, 1 H, CH, Ar), 7.33 (dd, J = 1.8, 8.3 Hz, 1 H, CH, Ar), 7.08-7.19 (m, 7 H, 7 × CH, Ar, Ph), 5.86 (q, J = 6.6 Hz, 1 H, PhCHMeO), 3.90 (s, 3 H, OMe, Ar), 3.88 (q, J = 7.2 Hz, 1 H, ArCHMe), 1.56 (d, J = 7.2 Hz, 3 H, ArCHMe), 1.50 (d, J = 6.6 Hz, 3 H, PhCHCMeO). ¹³C NMR (100 MHz, CDCl₃): δ = 173.7 (C=O), 147.5 (i-CO, Ar), 141.6 (i-C, Ph), 135.6 (i-C, Ar), 133.6, 128.9 (2 × i-C, Ar), 129.3,¹ 127.0,¹ 126.4,¹ 126.0,¹ 118.8,¹ 105.5¹ (6 × CH, Ar), 128.2,² 127.5,¹ 125.7,² (5 × CH, Ph), 72.5 (PhCHMeO), 55.3 (OMe), 45.6 (ArCHMe), 22.3 (PhCHMeO), 18.4 (ArCHMe). HRMS: m/z [MNH₄ ⁺] calcd for C₂₂H₂₆NO₃: 352.1907; found: 352.1907. MS: m/z (%) = 334 (20) [M⁺], 185 (100) [ArCHMe⁺], 105 (60) [PhCHMe⁺].

18 Fu has reported the use of 2-methyl-2-butanol (t-amyl alcohol) as a solvent within the efficient resolution of 1-phenylethanol using a chiral DMAP equivalent. For additional information, see: Ruble JC. Tweddell J. Fu GC. J. Org. Chem.  1998,  63:  2794 

19 Yang H. Henke E. Bornscheuer UT. Tetrahedron: Asymmetry  1999,  10:  957