P. A. Procopiou et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
instrument optimised at 1400 cmÀ1. The IR spectrum of CD3CN was
also measured using the same cell. The baseline of the IR spectra
were corrected by subtracting the IR of the solvent from those of
the samples, and the baseline corrected VCD spectrum of each
sample was obtained by subtracting the VCD of the enantiomer
from that of each sample and then divided by two.
49.0 (s, 1C), 44.6–44.2 (m, 1C), 35.7–34.7 (m, 1C), 28.4 (s, 3C),
21.8 (s, 1C); [
20 = +61 (c 1.27, MeOH); Analytical Chiral HPLC
a]
D
RT = 7.58 min, 90%, and RT = 9.53 min, 10% on a Chiralpak AD col-
umn (250 mm  4.6 mm), eluting with 10% EtOH–heptane, flow
rate = 1 mL/min, detecting at 215 nm. A 50 mg portion of this sam-
ple was further purified on a silica cartridge (20 g) eluting with 0–
25% EtOAc–cyclohexane over 20 min. The appropriate fraction was
evaporated under reduced pressure to give an analytically pure
sample (30 mg) of (R)-tert-butyl 3-fluoro-3-(((R)-1-phenylethyl)-
carbamoyl)pyrrolidine-1-carboxylate (7) LCMS RT = 1.16 min,
100%, ES+ve m/z 337 (M+H)+ and 354 (M+NH4)+ and ESÀve m/z
4.4. VCD Calculations
A conformational search was carried out using MOE with
Amber12:EHT force field and a dielectric constant of 10 for both
the molecule and external filed. The conformational search
resulted 12 conformers. Geometry optimisation, frequency, and
IR and VCD intensity calculations of the conformers resulted from
the conformational search were carried out at the DFT level (B3LYP
functional/ dgdzvp2 basis set) with Gaussian 09 (Gaussian Inc.,
Wallingford, CT). The calculated frequencies were scaled by 0.979
and the IR and VCD intensities were converted to Lorentzian bands
with 6-cmÀ1 half-width for comparison to experiment. The popu-
lations of the conformers were adjusted using the solver function
in Excel to obtain the best fit between the experimental and the
calculated VCD spectra.
The confidence level in this study was evaluated using Com-
pareVOATM (BioTools, Inc.), an automated tool for quantifying the
level of agreement between calculated and observed VCD data.
The confidence level was determined from the absolute values of
two parameters from CompareVOATM: total neighbourhood similar-
ity (TNS (VCD)) and the enantiomeric similarity index (ESI).7 Com-
pareVOATM results for the current study:
335 (MÀH)À; [
a]
20 = +63 (c 0.933, MeOH).
D
The second compound eluting from the first column (more
polar diastereomer) (1.2 g, 28%) was crystallised from diethyl ether
to give white crystals of (S)-tert-butyl 3-fluoro-3-(((R)-1-
phenylethyl)carbamoyl)pyrrolidine-1-carboxylate 6: mp = 113–
115 °C (diethyl ether); LCMS RT = 1.16 min, 100%, ES+ve m/z 337
(M+H)+; 1H NMR (500 MHz, CDCl3) d 7.40–7.27 (m, 5H), 6.73 (br
s, 1H), 5.14 (quin, J = 7.1 Hz, 1H), 3.87–3.56 (m, 3H), 3.55–3.46
(m, 1H), 2.70–2.44 (m, 1H), 2.26–2.14 (m, 1H), 1.54 (d, J = 7.0 Hz,
3H), 1.48–1.43 (m, 9H); 13C NMR (CDCl3,126 MHz) 167.7–167.4
(m, 1C), 154.1–154.0 (m, 1C), 142.3–142.2 (m, 1C), 128.8 (s, 2C),
127.7 (s, 2C), 126.1–125.9 (m, 1C), 103.5–101.0 (m, 1C), 80.0–
79.7 (m, 1C), 55.4–54.9 (m, 1C), 49.1–48.9 (m, 1C), 44.6–44.2 (m,
1C), 35.5–34.8 (m, 1C), 28.4 (s, 3C), 21.9–21.7 (m, 1C); [a]
20 = +73
D
(c 0.876, MeOH); Analytical Chiral HPLC RT = 9.50 min, 100% on a
Chiralpak AD column (250 mm  4.6 mm) eluting with 10%
EtOH–heptane, flow rate = 1 mL/min, detecting at 215 nm. The
absolute configuration of this diastereomer was established from
an X-ray diffraction study.
ꢀ Analysis range: 1550–1100 cmÀ1
ꢀ Region omitted: Carbonyl stretching
ꢀ Range of statistical analysis (minimum 400 cmÀ1): 450 cmÀ1
ꢀ Width of triangular weighting function: 20 cmÀ1
ꢀ TNS (VCD): 73.1 (absolute value)
4.6. Crystal data and refinement for 6
C18H25FN2O3; M = 336.40; colourless hexagonal prism;
0.20 Â 0.14 Â 0.14 mm; T = 150(2) K; orthorhombic; space group,
P212121 (no. 19); unit cell dimensions, a = 6.08015(9) Å,
b = 12.26945(19) Å, c = 24.2480(4) Å, V = 1808.90(5) Å3; Z = 4;
ꢀ ESI: 70.9 (absolute value)
The confidence level was >99% as the TNS (VCD) value was >70
and ESI >60.
dcalc = 1.235 Mg mÀ3
;
l
(Cu-K ,
k = 1.54178 Å) = 0.750 mmÀ1
;
a
11153 measured reflections (between 3.65° and 72.30° in h) of
which 3358 unique (Rint = 0.0332); R1 [I > 2 (I)] = 0.0275; wR2 (all
r
4.5. (S)-tert-Butyl 3-fluoro-3-(((R)-1-phenylethyl)carbamoyl)
pyrrolidine-1-carboxylate 6 and (R)-tert-butyl 3-fluoro-3-(((R)-
1-phenylethyl)carbamoyl)pyrrolidine-1-carboxylate 7
data) = 0.0756; absolute structure parameter = À0.02(11).
Crystallographic data for the structure of 6 have been deposited
with the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC-1487805. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
A solution of ( )-1-(tert-butoxycarbonyl)-3-fluoropyrrolidine-
3-carboxylic acid
5 (available from Wuxi App Tec) (3.00 g,
12.9 mmol) in THF (70 mL) was treated at room temperature with
solid CDI (2.5 g, 15 mmol) and then the mixture was heated to
80 °C for 1.5 h. (R)-(+)-
a
-Methylbenzylamine (1.6 g, 13 mmol)
4.7. (À)-(R)-(3-Fluoropyrrolidin-3-yl)methanol 8
was added at this temperature and then the mixture was heated
for a further 1.5 h at 80 °C. The mixture was diluted with ethyl
acetate and washed with dilute aqueous HCl, NaHCO3, brine, dried
(MgSO4), filtered and allowed to evaporate slowly at room temper-
ature. The mixture was finally concentrated under reduced pres-
sure as no solid crystallised out. The residue was purified by
chromatography on two silica cartridges (100 g each) eluting with
0–25% EtOAc–cyclohexane over 40 min. The compound eluting
A
solution of (À)-N-CBZ-3-fluoro-3-(hydroxymethyl)pyrro-
lidine, (À)-1 (4.0 g, 16 mmol) was hydrogenated over 10% Pd/C
(400 mg) in ethanol (150 mL) overnight. The catalyst was removed
by filtration through Celite and washed with ethanol. The filtrate
and washings were evaporated under reduced pressure to give a
yellow oil, which solidified into a waxy solid. The solid (2.0 g) con-
tained some ethanol by NMR and was further dried in a blow-
down unit under nitrogen at 40 °C to give 8 in quantitative yield:
LCMS RT = 0.22 min, ES+ve m/z 120 (M+H)+ and ESÀve m/z 118
first was obtained as
a white foam (1.54 g, 36%): LCMS
RT = 1.17 min, ES+ve m/z 337 (M+H)+; 1H NMR (500 MHz, CDCl3)
d 7.39–7.27 (m, 5H), 6.76–6.71 (m, 1H), 5.14 (quin, J = 7.1 Hz,
1H), 3.93–3.61 (m, 3H), 3.56–3.43 (m, 1H), 2.62–2.37 (m, 1H),
2.19–2.08 (m, 1H), 1.54 (d, J = 7.0 Hz, 3H), 1.49–1.43 (m, 9H), con-
tains about 10% of the more polar diastereomer; 13C NMR
(CDCl3,126 MHz) 167.7–167.3 (m, 1C), 154.2–154.0 (m, 1C),
142.5–142.3 (m, 1C), 128.8 (s, 2C), 127.8–127.5 (m, 1C), 126.0 (s,
2C), 103.5–101.0 (m, 1C), 79.9–79.8 (m, 1C), 55.4–54.9 (m, 1C),
(MÀH)À; [
a
]
D
20 = À4 (c 1.19, EtOH); 1H NMR (500 MHz, CDCl3) d
3.82 (dd, J = 18.7, 12.5 Hz, 1H), 3.73 (dd, J = 22.0, 12.2 Hz, 1H),
3.22–3.15 (m, 1H), 3.23–3.14 (m, 1H), 2.99–2.92 (m, 1H), 2.91
(dd, J = 29.1, 13.2 Hz, 1H), 2.66 (br s, 2H), 2.10–1.98 (m, 1H),
1.94–1.81 (m, 1H); 13C NMR (CDCl3,126 MHz) 106.2 (d,
J = 175.9 Hz, 1C), 65.6 (d, J = 26.6 Hz, 1C), 55.2 (d, J = 25.9 Hz, 1C),
46.1 (s, 1C), 35.4 (d, J = 22.7 Hz, 1C).