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M. Sebek et al.
LETTER
127.6, 127.8, 128.0 (arom. CH), 143.2 (arom. C), 144.6 (CH), 146.0
(arom. C), 147.6 (arom. C), 161.1 (C=O). Anal. Calcd for
C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C, 76.15; H, 6.02; N,
4.25. HRMS: m/z calcd for C22H21NO3Na [M + Na]+: 370.1414;
found: 370.1410.
dried over Na2SO4. Evaporation of ether yielded the (R)-tetrahydro-
furan-2-carboxylic acid (0.48 g, 86%).
Analytical Data of Compound (R)-4
[a]D23 +30.2 (c 1.0, CH2Cl2). 1H NMR (CDCl3): d = 1.75–1.90 (2 H,
m, CH2), 1.97 (1 H, m, CH2), 2.19 (1 H, m, CH2), 3.85 (2 H, m,
CH2O), 4.39 (1 H, dd, J = 5.3, 8.5 Hz, CH), 11.08 (1 H, br s, OH).
13C NMR (CDCl3): d = 24.9 (CH2), 29.9 (CH2), 69.2 (OCH2), 75.9
(OCH), 177.5 (C=O).
Tetrahydrofuran-2-yl-[(S)-2(hydroxydiphenylmethyl)pyrroli-
din-1-yl]-methanone (3f)
For HPLC analysis the diastereomerically pure reference substrates
(R,S)-3f and (S,S)-3f were prepared. To a solution of racemic tetra-
hydrofuran-2-carboxylic acid (0.49 g, 4.13 mmol) in THF (60 mL)
was added 1,1¢-carbonyldiimidazole (0.746 g, 4.60 mmol). After
stirring at ambient temperature for 45 min, (S)-a,a-diphenyl-2-pyr-
rolidinemethanol (1.046 g, 4.13 mmol) was added, and stirring was
continued for 24 h. The solvent was evaporated, and the residue was
dissolved in CH2Cl2 (50 mL). The organic phase was washed with
0.5 M HCl (3 × 15 mL), sat. aq NaHCO3 (3 × 15 mL), dried
(Na2SO4), and concentrated under reduced pressure. Purification by
column chromatography on SiO2 (hexane–EtOAc, 1:2) gave 27%
(R,S)-3f (0.39 g) and 28% (S,S)-3f (0.40 g).
Compound (R,S)-3f: Rf = 0.35 (hexane–EtOAc, 1:2); [a]D23 –147 (c
1.0, CHCl3). 1H NMR (CDCl3) d = 1.09 (1 H, m, CH2), 1.47 (1 H,
m, CH2), 1.70–2.17 (6 H, m, CH2), 2.98 (1 H, m, CH2), 3.47 (1 H,
m, CH2), 3.68 (2 H, m, CH2), 4.41 (1 H, m, CH), 5.05 (1 H, m, CH),
6.80 (1 H, s, OH), 7.14–7.27 (6 H, m, arom. H), 7.27–7.42 (4 H, m,
arom. H). 13C NMR (CDCl3): d = 23.6, 25.4, 28.4, 29.4 (CH2), 48.3
(CH2N), 67.9 (CH), 68.9 (CH2O), 77.4 (CH), 81.7 (C), 127.1, 127.2,
127.4, 127.7, 127.9, 128.0 (arom. CH), 143.0, 146.0 (arom. C),
174.3 (C=O). Anal. Calcd for C22H25NO3: C, 75.15; H, 7.17; N,
3.99. Found: C, 75.00; H, 7.10; N, 4.17. HRMS: m/z calcd for
C22H25 NO3Na [M + Na]+: 374.1727; found: 374.1725.
To determine the optical purity of the (R)-tetrahydrofuran-2-car-
boxylic acid, 50 mg of crude mixture was dissolved in MeOH (2
mL) and treated with SOCl2 (60 mg). After 2 h stirring, the solvent
was carefully evaporated, and (R)-tetrahydrofuran-2-carboxylic
acid methyl ester was obtained with 95% ee (analyzed by HPLC).
Analytical Data of (R)- and (S)-4-Methyl ester
1H NMR (CDCl3): d = 1.76–2.05 (3 H, m, CH2), 2.17 (1 H, m, CH2),
3.68 (3 H, s, OCH3), 3.85 (1 H, m, Ha of OCH2), 3.95 (1 H, m, Hb
of OCH2), 4.40 (1 H, dd, J = 5.2, 8.3 Hz, CH). 13C NMR (CDCl3):
d = 25.2 (CH2), 30.1 (CH2), 52.0 (OCH3), 69.1 (OCH2), 76.6
(OCH), 173.7 (C=O). HPLC analysis: Chiralcel OD-H (150 × 4.6
mm), hexane–2-PrOH (98:2), 1.2 mL/min, tR = 4.2 min for (S)-
tetrahydrofuran-2-carboxylic acid methyl ester and tR = 6.2 min for
(R)-tetrahydrofuran-2-carboxylic acid methyl ester.
Acknowledgment
We appreciate financial support by the Ministry of Economy of
Mecklenburg-Vorpommern (Germany) and the Leibniz-Gemein-
schaft (Pakt für Innovation und Forschung).
Compound (S,S)-3f: Rf = 0.25 (hexane–EtOAc, 1:2); [a]D23 –128 (c
1.0, CHCl3). 1H NMR (CDCl3): d = 1.16 (1 H, m, CH2), 1.52 (2 H,
m, CH2), 1.68–2.05 (5 H, m, CH2), 2.79 (1 H, m, CH2), 3.48 (1 H,
m, CH2), 3.76 (1 H, m, CH2), 3.92 (1 H, m, CH2),4.41 (1 H, m, CH),
5.05 (1 H, m, CH), 6.96 (1 H, s, OH), 7.13–7.28 (6 H, m, arom. H),
7.28–7.43 (4 H, m, arom. H). 13C NMR (CDCl3): d = 23.7, 25.3,
29.0, 29.6 (CH2), 47.9 (CH2N), 68.2 (CH), 69.2 (CH2O), 76.3 (CH),
81.7 (C), 127.1, 127.2, 127.3, 127.7, 127.8, 127.9 (arom. CH),
143.0, 145.7 (arom. C), 174.2 (C=O). Anal. Calcd for C22H25NO3:
C, 75.15; H, 7.17; N, 3.99. Found: C, 74.97; H, 7.12; N, 4.14.
HRMS: m/z calcd for C22H25NO3Na [M + Na]+: 374.1727; found:
374.1721.
References
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Optimized Procedure for the Asymmetric Hydrogenation of
Substrate 2f to Product 3f
The hydrogenation was performed in a 250 mL autoclave (Parr In-
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1.5 mL/min, tR = 5.7 min for (R,S)-3f and tR = 15.7 min for (S,S)-3f.
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Removal of the Chiral Auxiliary in 3f
A solution of diastereomerically pure (R,S)-3f (1.70 g, 4.84 mmol)
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Synlett 2009, No. 3, 461–465 © Thieme Stuttgart · New York