M. Adamczyk, R. E. Reddy / Tetrahedron: Asymmetry 12 (2001) 1047–1054
1053
3.9. (R)-(+)-Methyl 3-amino-3-(5-hydroxy-2-
CH2Cl2 (50 mL) and water (15 mL). The organic layer
was separated, dried (MgSO4) and the solvent removed
on a rotary evaporator with the bath temperature kept
below 35°C. The crude product was purified by silica
gel column chromatography (40–60% EtOAc in hex-
anes) to afford the Mosher’s amide of (R)-(+)-b-amino
ester 2 as a colorless gummy material (0.022 g 65%). Rf:
0.41 (60% EtOAc in hexanes); 1H NMR (CDCl3): l
8.18 (d, 1H, J=8.1 Hz), 8.08 (d, 1H, J=2.7 Hz),
7.57–7.41 (m, 5H), 7.15 (d, 1H, J=8.4 Hz), 6.97 (dd,
1H, J=8.4, 3.0 Hz), 5.47–5.40 (m, 1H), 3.58 (s, 3H),
3.36–3.35 (m, 3H), 3.04–2.83 (m, 2H); 19F NMR
(CDCl3 and 2.0 mL of a,a,a-trifluorotoluene): l −5.98
(s, CF3); ESI-MS (m/z): 413 (M+H)+, 825 (2×M+H)+;
HRMS (FAB, m/z): calcd for C19H20N2O5F3, 413.1324,
observed 413.1327.
pyridinyl)propanoate 2
Trifluoroacetic acid (0.25 mL, 3.22 mmol, 5.0 equiv.)
was added to a 0°C cooled solution of (Ss,R)-(+)-
methyl 3-{5-[(4-methoxybenzyl)oxy]-2-pyridinyl}-3-{[(4-
methylphenyl)sulfinyl]amino}propanoate 9a (0.292 g,
0.643 mmol) and methanol (13 mL) under nitrogen and
the mixture was stirred for 5 h. After completion of the
reaction, as determined by TLC (60% EtOAc in hex-
anes), the solvent was removed on a rotary evaporator
at <35°C bath temperature. The residue was dissolved
in water (20 mL) and ether (20 mL). The aqueous layer
was separated and the organic layer was extracted with
water (15 mL). The combined aqueous layer was
washed with ether (2×20 mL) and concentrated on a
rotary evaporator. The residue was dried under vacuum
(0.1 mmHg) over 15 h to afford PMB ether (R)-methyl
3-amino-3-{5-[(4-methoxybenzyl)oxy]-2-
References
pyridinyl}propanoate 10 (0.271 g) along with small
amounts of (R)-(+)-methyl 3-amino-3-(5-hydroxy-2-
pyridinyl)propanoate 2. Analytical RP HPLC:
MeCN:0.1% aqueous trifluoroacetic acid/30:70, 2.0
mL/min at 225 nm, Rt: 4.13 min, 86%, (R)-10 and 1.29
min, 14% (R)-(+)-2; ESI-MS (m/z): 377 (M+H)+, 633
(2×M+H)+. The crude mixture of (R)-10 and (R)-(+)-2
was dissolved in CH2Cl2 (13 mL), and trifluoroacetic
acid (0.99 mL, 12.86 mmol, 20.0 equiv.) was added at
room temperature under nitrogen. The mixture was
stirred for 3 h and the resulting violet solution was
concentrated on a rotary evaporator. The colorless
residue was dissolved in MeCN–0.1% aq TFA (8:2
ratio, 30 mL) and purified by preparative RP HPLC
using MeCN:0.1% aqueous trifluoroacetic acid/15:85,
45 mL/min at 225 nm. Lyophilization of the product
afforded of (R)-(+)-methyl 3-amino-3-(5-hydroxy-2-
pyridinyl)propanoate 2 as its TFA salt (0.195 g, >95%).
[h]2D3=+3.4 (c 0.62, MeOH); analytical RP HPLC:
MeCN:0.1% aq TFA/5:95, 2.0 mL/min at 225 nm, Rt:
6.10 min, >99%; 1H NMR CD3OD): l 8.18 (d, 1H,
J=2.7 Hz), 7.30 (d, 1H, J=8.4 Hz), 7.20 (dd, 1H,
J=8.4, 3.3 Hz), 4.75–4.70 (m, 1H), 3.70 (s, 3H), 3.08–
2.93 (m, 2H); 13C NMR (CD3OD): l 171.8, 155.8,
146.2, 139.1, 124.4, 124.2, 52.7, 52.3, 38.7; ESI-MS
(m/z): 197 (M+H)+, 219 (M+Na)+, 393 (2×M+H)+, 415
(2×M+Na)+; HRMS (FAB, m/z): calcd for C9H13N2O3,
197.0926 (M+H)+, observed 197.0927.
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3.10. Preparation of Mosher’s amide of (R)-(+)-methyl
3-amino-3-(5-hydroxy-2-pyridinyl)propanoate 2
In an oven dried 10 mL round bottom flask equipped
with magnetic stir bar, nitrogen inlet and a rubber
septum,
(R)-(+)-methyl
3-amino-3-(5-hydroxy-2-
pyridinyl)propanoate 2 (0.031 g, 0.01 mmol) was dis-
solved in anhydrous CH2Cl2 (1.5 mL). Triethylamine
(0.140 mL, 1.0 mmol, 10.0 equiv.) and (S)-(+)-a-
methoxy-a-trifluoromethylphenylacetic acid chloride
(MTP-Cl, 0.018 mL, 0.1 mmol, 1.0 equiv.) were added
sequentially at room temperature and the mixture was
stirred for 2 h. The mixture was quenched with ice and
stirred for an additional 10 min, then diluted with
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