Identification of β-Prochiral Protons to the Ether Oxygen of Chiral Esters of 2-Arylethan-1-ols with d-Yb(hfc)₃ Shift Reagents

Abstract

The prochiral H_S and H_R of the N-(4-nitrophenylsulfonyl)-l-phenylalanyl ester of 2-phenyl, 2-p-methylphenyl- and 2-m-methoxyphenyl-ethan-1-ol are differentiated and defined in the ¹H NMR spectrum by shift studies with ytterbium d-3-heptafluoro­butyrylcamphorate. In each case, 4a-c, H_S is more sensitive than H_R to the addition of the shift reagent.

Key words

chirality - asymmetric synthesis - enantiomeric resolution - esters - lanthanides

References

• 1a Coxon JM. Cambridge JRA. Nam SGC. Org. Lett.  2001,  3:  4225 
• 1b

  At the concentration of d- and l-Eu(hfc)₃ necessary to separate the β-prochiral protons, a broad signal of the shift reagent appeared with the β-protons and made integration inaccurate. This does not occur with d-Yb(hfc)₃ and so, even though the proton signals are somewhat broader than with the europium shift reagent, integration of the β-protons is more accurate.

2

Conversion of the alcohol to a chiral ester results in the α- and β-protons becoming magnetically non-equivalent. For the chiral esters 4a, the β-prochiral hydrogens were not distinguishable in the NMR spectra in the absence of shift reagent and, while the α-prochiral protons showed some non-equivalence, incomplete resolution makes population analysis difficult.

3

The shift of the prochiral α- and β-protons is the same whether l- or d-Eu(hfc)₃ is used, showing that the asymmetry of the ligand for the diastereomeric complexes was not measurably transmitted to these protons.

4

Typical Experimental Procedure for the Sharpless Asymmetric Dihydroxylation. Synthesis of (1 R )-1-(4-Methylphenyl)-1,2-ethanediol-1- d ₁ .
4-Methylstyrene-α-d ₁ (1.00 g, 8.40 mmol) was added to a vigorously stirring solution of AD-mix-β (11.76 g) in tertiary butyl alcohol (42 mL) and H₂O (42 mL) at 0 °C. The solution was stirred for 48 h at 0 °C. Sodium metabisulphite (12.60 g) was added and the reaction mixture was stirred for 1 h, and allowed to warm to r.t. The reaction mixture was diluted with CH₂Cl₂, the organic layer separated and the aqueous layer extracted with EtOAc. The solvent was removed under reduced pressure and flash chromatography on silica gel (EtOAc/petroleum ether) gave (1R)-1-(4-methylphenyl)-1,2-ethanediol-1-d ₁ as white crystals (0.92 g, 71%). Mp 72-74 °C. [α]_D ²⁰ -70 (c 2.9, CHCl₃) [lit.4b [α]_D ²⁰ -67 (c 0.90, CHCl₃, ee >97%) for undeuterated material]. ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.3 Hz, 2 H), 7.16 (d, J = 7.8 Hz, 2 H), 3.71 (d, J = 11.2 Hz, 1 H), 3.63 (d, J = 11.7 Hz, 1 H), 2.34 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 137.4, 129.0, 126.0, 74.0 (t, J _CD = 21.3 Hz), 67.8, 21.0. (b) Moussou P., Archelas A., Baratti J., Furstoss R.; J. Org. Chem.; 1998, 63: 3532
(c) Typical Experimental Procedure for the Synthesis of Chloroethylacetate. Synthesis of a Mixture of (2 R )- and (2 S )-2-Chloro-2-(4-methylphenyl)-ethylacetate-2- d ₁ .
(1S)-1-(4-Methylphenyl)-1,2-ethanediol-1-d ₁ (0.116 g, 0.710 mmol) and (1R)-1-(4-methylphenyl)-1,2-ethanediol-1-d ₁ (0.252 g, 1.640 mmol) were dissolved in dry CH₂Cl₂ (10 mL) and the solution cooled to 0 °C. Trimethyl orthoacetate was added (359 µL, 2.82 mmol), followed by trimethylsilyl chloride (364 µL, 2.87 mmol). The solution was stirred for 2 h, slowly warming to r.t. The solvent was removed by evaporation under reduced pressure to give (2R)- and (2S)-2-chloro-2-(4-methylphenyl)-ethylacetate-2-d ₁ as a colorless liquid (0.144 g, 99%). ¹H NMR (500 MHz, CDCl₃): δ = 7.22 (d, J = 7.8 Hz, 2 H), 7.11 (d, J = 8.3 Hz, 1 H), 4.43 (m, 2 H), 2.28 (s, 3 H), 1.99 (s, 3 H).
(d) Typical Procedure for the Synthesis of 2-Arylethanol. Synthesis of a Mixture of (2 R )- and (2 S )-2-( p -Methyl-phenyl)ethanol-2- d ₁ .
The mixture of (2R)- and (2S)-2-chloro-2-(4-methylphenyl)-ethylacetate-2-d ₁ (144 mg, 2.4 mmol) from above was dissolved in Et₂O (10 mL) and LiAlH₄ was added (0.0910 g, 2.400 mmol). The solution was stirred at r.t. for 2 h. Sat. NH₄Cl was added dropwise until the LiAlH₄ residues formed a paste on the bottom of the flask. The solution was dried by the addition of anhyd MgSO₄, filtered and the solvent evaporated under reduced pressure to give a clear liquid. ¹H NMR (500 MHz, CDCl₃): δ = 7.12 (m, 4 H), 3.83 (d, J = 6.3 Hz, 2 H), 2.81 (m, 1 H), 2.33 (s, 3 H), 1.65 (br s, 1 H).
(e) Typical Procedure for the Synthesis of 2-Arylethyl ( N -4-Nitrophenylsulfonyl)-( S )-2-amino-3-phenyl-propanoates. Synthesis of 2-(4-Methyl)phenylethyl ( N -4-Nitrophenylsulfonyl)-( S )-2-amino-3-phenylpropanoate.
A 2:1 mixture of (2S)- and (2R)-2-(4-methyl)phenyl-ethanol (0.1065 g, 0.782 mmol) and dry pyridine (0.076 mL, 1.170 mmol) were added to a solution of N-(4-nitrophenyl-sulfonyl)-l-phenylalanyl chloride (0.242 g, 0.782 mmol) in dry CH₂Cl₂ (5 mL) under dry N₂. After 3 h the solution was washed with HCl (5 mL, 1 M), sat. Na₂CO₃ (5 mL), dried over anhyd Na₂SO₄ and the solvent removed under reduced pressure. The product was purified by flash chromatography on silica gel (EtOAc/petroleum ether) and gave 2-(4-methyl)phenylethyl (N-4-nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate as a white solid (0.322 g, 88%). ¹H NMR (500 MHz, CDCl₃): δ = 8.14 (dd, J = 2.4, 6.8 Hz, 2 H), 7.77 (dd, J = 2.0, 6.8 Hz, 2 H), 7.22-7.19 (m, 3 H), 7.13 (d, J = 7.8 Hz, 2 H), 7.02 (d, J = 8.3 Hz, 2 H), 6.96 (m, 2 H), 5.25 (d, J = 9.8 Hz, 1 H), 4.25-4.22 (m, 1 H), 4.12 (t, J = 6.8 Hz, 2 H), 3.04 (dd, J = 5.4, 13.7 Hz, 1 H), 2.93 (dd, J = 6.8, 13.7 Hz, 1 H), 2.77 (t, J = 6.8 Hz, 2 H), 2.33 (s, 3 H).
(f) Typical Procedure for the NMR Investigation of 2-(4-Methyl)phenylethyl ( N -4-Nitrophenylsulfonyl)-( S )-2-amino-3-phenylpropanoate by the Addition of Yb(hfc) ₃ Chiral Shift Reagent.
Aliquots of d-Yb(hfc)₃ were added to a solution of 2-(4-methyl)phenylethyl (N-4-nitrophenylsulfonyl)-(S)-2-amino-3-phenylpropanoate in CDCl₃ in a 3 mL NMR tube until the prochiral protons β to the ester linkage were resolved in an NMR spectrum. The integral of the downfield peak was half the integral of the upfield peak. Therefore it was demonstrated that in undeuterated material the more downfield of the methylene signals is H_S and the upfield signal is H_R.