Synthesis of R-Amino Acids
J. Am. Chem. Soc., Vol. 119, No. 4, 1997 669
1.39 (m, 1H), 0.97 (d, 3H, J ) 6.8), 0.91-0.99* (m, 6H), 0.87 (t, 3H,
J ) 7.4); 13C NMR (CDCl3) δ 176.3, 175.5*, 142.2*, 142.1, 128.2*,
128.0, 127.7*, 127.3, 126.6*, 126.4, 75.0, 74.4*, 57.3*, 56.4, 52.6*,
52.4, 30.6, 27.8*, 27.7, 26.8, 15.3*, 14.2, 10.0*, 9.8. Anal. Calcd for
C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found: C, 66.80; H, 8.77;
N, 11.19.
9H), 0.03 (s, 9H); 13C NMR (CDCl3) δ 177.9, 177.2*, 142.2*, 142.1,
128.3, 128.0, 127.8*, 127.3, 126.6, 126.4, 75.3, 74.7*, 57.4*, 56.5,
48.9*, 48.6, 30.6, 26.9*, 23.2*, 22.9, 15.4*, 14.0, -0.9*, -1.0. Anal.
Calcd for C16H28N2O2Si: C, 62.29; H, 9.15; N, 9.08. Found: C, 62.64;
H, 8.75; N, 9.08.
(S,S)-Pseudoephedrine D-Pipecolinamide (11). A solution of (S,S)-
(+)-1 (511 mg, 2.30 mmol, 1 equiv) in tetrahydrofuran (10 mL with a
8-mL wash) was transferred via cannula to a flask containing anhydrous
lithium chloride (585 mg, 13.8 mmol, 6.00 equiv). The resulting slurry
was cooled to -78 °C. A solution of n-butyllithium in hexanes (2.85
M, 1.57 mL, 4.48 mmol, 1.95 equiv) was added slowly to the inner
edge of the flask such that it was cooled before mixing with the reaction
slurry. After 20 min, the dark yellow suspension was transferred to
an ice bath. After stirring for 20 min at 0 °C, 1-chloro-3-iodopropane
(404 µL, 3.22 mmol, 1.40 equiv) was added to the bright yellow reaction
suspension. After 100 min, 1 M aqueous hydrochloric acid solution
(30 mL) was added to the reaction mixture, followed by ethyl acetate
(75 mL). The organic layer was separated and extracted with a second
portion of aqueous hydrochloric acid solution (1 M, 30 mL). The
aqueous extracts were combined, and the resulting solution was cooled
in an ice bath and was carefully basified to pH 14 by the addition of
50% aqueous sodium hydroxide solution. The basic aqueous solution
was extracted with four 40-mL portions of dichloromethane. The
combined organic extracts were dried over potassium carbonate, filtered,
and concentrated in vacuo to provide an oily residue. The residue was
dissolved in chloroform (20 mL), and the resulting solution was warmed
to 48 °C. After stirring at 48 °C for 5 h, the solution was cooled and
diluted with 0.5 M aqueous sodium hydroxide solution (25 mL) and
the layers were separated. The aqueous layer was extracted with two
30-mL portions of dichloromethane, and the combined organic layers
were dried over anhydrous potassium carbonate, filtered, and concen-
trated in vacuo. The residue was purified by chromatography on silica
gel eluting with 4% methanol, 4% triethylamine, and 92% dichlo-
romethane to afford the product 11 (457 mg, 76%) as an oil. The
diastereomeric excess of the product was determined by capillary GC
analysis as described in the general procedures (220 °C, major Rt )
14.6 min, minor Rt ) 16.9 min). The product was found to be 96%
Pseudoephedrine D-â-[6-Chloro-5-[(methoxymethyl)oxy]-2-py-
ridyl]alaninamide (7j). A solution of n-butyllithium in hexanes (2.60
M, 1.47 mL, 3.83 mmol, 2.73 equiv) was added slowly to the inner
edge of a flask containing a slurry of anhydrous (S,S)-(+)-1 (437 mg,
1.96 mmol, 1.40 equiv) and flame-dried lithium chloride (500 mg, 11.8
mmol, 8.43 mmol) in tetrahydrofuran (12 mL) at -78 °C. After stirring
for 20 min at -78 °C, the reaction flask was transferred to an ice bath.
After stirring for 20 min at 0 °C, the reaction flask was cooled to -78
°C. After stirring for 5 min at -78 °C, a precooled (-78 °C) solution
of 2-chloro-3-[(methoxymethyl)oxy]-6-(iodomethyl)pyridine (440 mg,
1.40 mmol, 1 equiv) in tetrahydrofuran (3 mL, with a 3 mL wash) was
added to the pale yellow suspension. After stirring for 5 h at -78 °C,
the reaction was terminated by the addition of 1 M aqueous hydrochloric
acid solution (30 mL). The resulting mixture was warmed to 23 °C
and extracted with ethyl acetate (50 mL). The organic layer was washed
with a second portion of 1 M aqueous hydrochloric acid solution (30
mL). The combined aqueous extracts were cooled in an ice bath and
basified to pH 14 by the addition of 50% aqueous sodium hydroxide
solution. The resulting alkaline aqueous solution was extracted with
four 25-mL portions of dichloromethane. The combined organic layers
were dried over anhydrous potassium carbonate, filtered, and concen-
trated. A small amount (34 mg) of the crude residue was reserved for
chiral HPLC analysis, and the remaining crude residue (607 mg) was
purified by chromatography on silica gel eluting with 4% methanol,
4% triethylamine, and 92% dichloromethane to afford 480 mg (89%)
of the alkylation product as an oil. The diastereomeric excess of the
crude product was estimated by hydrolysis (2 mL of 0.5 M aqueous
sodium hydroxide solution, reflux 4 h), followed by extraction of the
aqueous mixture with dichloromethane (3 × 10 mL), and acidification
of the aqueous layer to pH 1 with concentrated perchloric acid followed
by chiral HPLC analysis (pH 2.0 HClO4, 0.8 mL/min, 220 nm, major
Rt ) 7.0 min, minor Rt ) 10.4 min), indicating a de of 93%: TLC Rf
) 0.51 (5% MeOH, 5% NEt3, 90% CH2Cl2); 1H NMR (1.2:1 rotamer
ratio, CDCl3) (J in hertz) δ 7.50 (d, 0.5H, J ) 7.1), 7.22-7.42 (m,
5.5H), 7.10 (d, 0.5H, J ) 8.2), 7.04 (d, 0.5H, J ) 8.2), 5.22 (s, 1H),
5.20 (s, 1H), 4.62 (d, 0.5H, J ) 9.2), 4.52-4.57 (m, 1H), 4.29 (m,
0.5H), 4.13 (m, 1H), 3.49 (s, 1.5H) 3.48 (s, 1.5H), 3.40 (dd, 0.5H, J )
14.0, 3.0), 2.94 (s, 1.5H), 2.92 (s, 1.5H), 2.88-2.94 (m, 1H), 2.77 (dd,
0.5H, J ) 14.0, 7.4), 0.94 (d, 1.5H, J ) 6.7), 0.91 (d, 1.5H, J ) 6.2);
13C NMR (CDCl3) δ 175.7, 174.7, 151.3, 150.8, 147.7, 147.6, 142.0,
141.4, 140.3, 128.5, 128.2, 128.1, 127.5, 127.2, 126.5, 124.1, 124.0,
123.5, 123.4, 95.0, 94.9, 75.3, 57.7, 56.3, 51.7, 51.4, 42.2, 42.1, 31.3,
26.7, 15.5, 14.2; HRMS calcd for C20H27ClN3O4 (M + H) 408.1690,
found 408.1682.
1
de: TLC Rf ) 0.45 (5% MeOH, 5% NEt3, 90% CH2Cl2); H NMR
(4:1 rotamer ratio, the asterisk denotes minor rotamer peaks, CDCl3)
(J in hertz) δ 7.22-7.36 (m, 5H), 4.61 (d, 1H, J ) 8.0), 4.53* (d, 1H,
J ) 8.7); 4.40 (m, 1H), 4.12* (m, 1H), 3.68 (dd, 1H, J ) 10.9, 2.2),
3.11 (d, 1H, J ) 12.1), 2.90* (s, 3H), 2.84 (s, 3H), 2.64 (m, 1H), 1.87
(m, 1H), 1.29-1.60 (m, 5H), 1.07 (d, 3H, J ) 6.9), 0.95* (d, 3H, J )
6.5); 13C NMR (CDCl3) δ 173.8*, 173.6, 142.0, 128.3*, 128.0, 127.7*,
127.3, 126.7*, 126.6, 75.4*, 74.8, 57.7*, 57.0, 56.5, 45.6*, 44.5, 31.0,
29.6*, 28.4, 26.4*, 25.4, 24.1*, 23.5, 15.3*, 14.2; HRMS calcd for
C16H25N2O2 (M + H) 277.1916, found 277.1907.
(R,R)-Pseudoephedrine N-Methyl-L-phenylalaninamide (12f). A
solution of n-butyllithium in hexanes (2.60 M, 1.20 mL, 3.12 mmol,
2.95 equiv) was added slowly to the inner edge of a flask containing
a slurry of anhydrous (R,R)-2 (250 mg, 1.06 mmol, 1 equiv),
N-methylethanolamine (85 µL, 1.06 mmol, 1.00 equiv), and anhydrous
lithium chloride (269 mg, 6.35 mmol, 6.00 equiv) in tetrahydrofuran
(10 mL) at -78 °C. The resulting yellow suspension was stirred at
-78 °C for 20 min, at which time the reaction flask was warmed to 0
°C. After stirring at 0 °C for 20 min, benzyl bromide (139 µL, 1.16
mmol, 1.1 equiv) was added to the colorless slurry. After stirring for
1 h at 0 °C, aqueous hydrochloric acid solution (1 M, 30 mL) was
added to the colorless solution, followed by ethyl acetate (50 mL). The
organic layer was separated and extracted with two 25-mL portions of
1 M aqueous hydrochloric acid solution. The aqueous extracts were
combined, and the resulting solution was cooled in an ice bath and
carefully basified to pH 14 by the addition of 50% aqueous sodium
hydroxide solution. The basic aqueous solution was extracted with
three 40-mL portions of dichloromethane. The combined organic
extracts were dried over anhydrous potassium carbonate, filtered, and
concentrated in vacuo to provide 372 mg of the crude alkylation product
as an oily residue. A small portion of the residue (37 mg) was reserved
for analysis, and the remaining residue (335 mg) was purified by
chromatography on silica gel eluting with 4% methanol, 4% triethyl-
amine, and 92% dichloromethane to afford 289 mg (93%) of 12f as an
oil which rapidly crystallized upon standing. The solid was recrystal-
(R,R)-Pseudoephedrine L-(Trimethylsilyl)alaninamide (7h). 7h
was prepared by alkylation of (R,R)-(-)-1 (10.6 g, 47.9 mmol, 1 equiv)
with (bromomethyl)trimethylsilane (10.0 g, 59.8 mmol, 1.25 equiv)
following the procedure outlined for 7f (alkylation time 22 h at 23
°C). The product was purified by chromatography on silica gel eluting
with 4% methanol, 4% triethylamine, and 92% dichloromethane to
afford 13.12 g of 7h as an oil which crystallized upon standing. The
product was recrystallized from butyl acetate (15 mL)-hexanes (15
mL) at -20 °C to afford 4.87 g of analytically pure 7h. Three
additional crops of product afforded an additional 3.72 g of product
(total 8.59 g, 57%). The diastereomeric excess of the product was
determined by capillary GC analysis as described in the general
procedures (220 °C, major Rt ) 11.6 min, minor Rt ) 9.6 min). The
chromatographed product was 90% de (the de of the crude product
could not be determined because the minor diastereomer and the starting
material coeluted), and the recrystallized product was g99% de: 1H
NMR (3:1 rotamer ratio, the asterisk denotes minor rotamer peaks,
CDCl3) (J in hertz) δ 7.24-7.36 (m, 5H), 4.62 (m, 1H), 4.52 (m, 1H),
3.97* (m, 1H), 3.77* (dd, 1H, J ) 10.3, 3.9), 3.63 (dd, 1H, J ) 9.0,
5.0), 2.90* (s, 3H), 2.81 (s, 3H), 1.20* (dd, 1H, J ) 15.0, 3.8), 0.98
(d, 3H, J ) 6.7), 0.93* (d, 3H, J ) 6.7), 0.85* (d, 1H, J ) 15.0, 10.3),
0.78 (dd, 1H, J ) 14.9, 4.8), 0.66 (dd, 1H, J ) 14.7, 9.2), 0.09* (s,