Notes
J . Org. Chem., Vol. 61, No. 2, 1996 815
for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62. Found: C, 57.66;
H, 4.33; N, 5.47.
purified by chromatography on silica gel eluting with 4:4:92
methanol:triethylamine:dichloromethane. Although the dia-
steromers were largely separable, they were collected together
in order to establish the true overall reaction yield. After
concentration of appropriate fractions, the product residue was
concentrated from toluene (2 × 150 mL) and then chloroform (2
× 150 mL) to remove residual triethylamine. The product 7 was
isolated as a very thick oil (11.6 g, 92%). The diastereoselectivity
of the reaction was determined by removing a small sample of
the crude reaction product (prior to chromatography) and
subjecting it to aqueous alkaline hydrolysis conditions (see
below), followed by acidification of the aqueous hydrolysis
mixture to pH 6 with concd H3PO4 and analysis on a chiral
HPLC column (see General Experimental). TLC Rf major
diasteromer ) 0.52, minor diasteromer ) 0.65 (5:5:90 MeOH:
NEt3:CH2Cl2); IR (neat) 3352, 3062, 2980, 1634, 1480, 1454,
1379, 1205, 1177, 1093, 1024, 868, 755, 738, 702 cm-1; 1H NMR
(approximately 1:1 rotamer ratio, CDCl3) δ 8.10 (d, 0.5H, J )
4.2 Hz), 8.09 (d, 0.5H, J ) 2.7 Hz), 7.83 (d, 2H, J ) 7.2 Hz), 7.69
(t, 1H, J ) 7.4 Hz), 7.55 (t, 2H, J ) 7.9 Hz), 7.16-7.41 (m, 7H),
4.71 (d, 0.5H, J ) 8.4 Hz), 4.60 (d, 0.5H, J ) 9.3 Hz), 4.33 (dd,
0.5H, J ) 6.8, 4.8 Hz), 4.16-4.26 (m, 1H), 4.12 (dd, 0.5H, J )
7.0, 5.7 Hz), 3.44 (dd, 0.5H, J ) 14.5, 4.7 Hz), 3.12 (dd, 0.5H, J
) 14.5, 7.0 Hz), 2.94 (s, 1.5H), 2.90 (s, 1.5H), 2.83-2.99 (m, 1H),
1.5-3.0 (s(br), 3H), 1.01 (d, 1.5H, J ) 6.9 Hz), 0.97 (d, 1.5H, J
) 6.7 Hz); 13C NMR (CDCl3) δ 175.3, 174.6, 157.6, 156.9, 144.9,
143.0, 142.8, 142.1, 141.5, 134.9, 134.5, 130.2, 130.1, 129.8, 128.5,
128.3, 128.2, 128.1, 127.6, 127.1, 126.6, 124.8, 124.7, 75.4, 75.3,
59.0, 58.0, 51.6, 51.2, 42.9, 42.7, 32.5, 26.9, 15.7, 14.1. HRMS
for C24H28N3O5S (MH+) requires 470.1750, found 470.1737.
Anal. Calcd for C24H27N3O5S: C, 61.39; H, 5.80; N, 8.95.
Found: C, 59.96; H, 5.81; N, 8.64.
5-(Ben zen esu lfon yloxy)-2-(br om om eth yl)p yr id in e (5). A
mixture of 4 (33.48 g, 134.3 mmol, 1 equiv) and N-bromosuc-
cinimide (33.47 g, 188.0 mmol, 1.40 equiv) in deoxygenated
carbon tetrachloride (300 mL) was heated to reflux. 2,2′-Azobis-
(2-methylpropiononitrile) (2.00 g, 11.6 mmol, 0.09 equiv) was
added to the refluxing mixture and heating was continued.
Additional 2.00-g portions of 2,2′-Azobis(2-methylpropiononitrile)
were added to the refluxing reaction mixture at 30 min intervals
over a a total reaction period of 2 h. Heating was discontinued
after 2 h, and the reaction mixture was allowed to cool. The
crude reaction mixture was concentrated in vacuo to remove the
bulk of the carbon tetrachloride, and the resulting slurry was
diluted with ethyl acetate (500 mL) and washed with water (400
mL). The organic layer was washed with a mixture of saturated
aqueous sodium bicarbonate solution (250 mL) and saturated
aqueous sodium thiosulfate solution (100 mL). The aqueous
layers were extracted with a second portion of ethyl acetate (250
mL). The combined organic layers were dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by chromatography on silica gel eluting with a
gradient of 4:1 dichloromethane:hexanes to dichloromethane to
10:1 dichloromethane:ethyl acetate to provide 5 (23.08 g, 52%)
as a white solid: mp 103-108 °C; IR (KBr) 3022, 1584, 1480,
1376, 1368, 1023, 1180, 1087, 1022, 854, 812, 766, 734, 689, 620,
603, 579, 548 cm-1; 1H NMR (CDCl3) δ 8.12 (s, 1H), 7.86 (d, 2H,
J ) 7.4 Hz), 7.72 (t, 1H, J ) 7.5 Hz), 7.57 (t, 2H, J ) 7.9 Hz),
7.45 (d(obs), 2H, J ) 1.5 Hz), 4.51 (s, 2H); 13C NMR (CDCl3) δ
155.6, 145.5, 143.4, 134.8, 134.6, 131.0, 129.4, 128.4, 124.2, 32.5.
Anal. Calcd for C12H10BrNO3S: C, 43.92; H, 3.07; N, 4.27.
Found: C, 43.72; H, 3.01; N, 4.16.
[S]-2-Am in o-3-(5-h yd r oxyp yr id yl)p r op a n oic Acid (L-
Aza tyr osin e, 1). A suspension of 7 (27.22 g, 57.97 mmol, 1
equiv, 97% de) in aqueous sodium hydroxide solution (0.500 M,
464 mL, 232 mmol, 4.00 equiv) was heated at reflux for 6 h.
The resulting homogeneous solution was then cooled to 23 °C
and extracted with two portions of dichloromethane (500 mL,
250 mL). The organic layers were combined and extracted with
water (200 mL) and then dried over anhydrous potassium
carbonate. Concentration of the organic layers provided 8.61 g
(90%) of recovered pseudoephedrine. The combined aqueous
layers were acidified with aqueous hydrochloric acid solution
(1.00 M, 232 mL, 232 mmol, 4.00 equiv) producing a slightly
acidic solution (pH ) 3). The volume of the aqueous solution
was reduced to approximately 100 mL in vacuo, and the
concentrate was applied to an ion exchange resin (100 g, Dowex
50WX4, 50-100 mesh). The resin was flushed with water until
the eluent was neutral (pH ) 6). The product was then eluted
with 0.25 M aqueous ammonium hydroxide solution (Note: on
occasion the product will begin to precipate on the column. In
this case, the column contents are transferred to a large sintered-
glass funnel and the product is eluted with 0.25 M aqueous
ammonium hydroxide solution). The ninhydrin-positive frac-
tions were combined and concentrated to provide 9.73 g of a pale
yellow solid. The solid was recrystallized from water (400 mL)
to afford 4.358 g (41%) of L-azatyrosine as a pale solid. Con-
centration and crystallization of the mother liquors provided two
additional crops of product (3.399 g, 32%). If desired, the mother
liquors may be decolorized by the addition of activated charcol
and filtration through Celite prior to recrystallization. All three
crops of amino acid were g99% ee and all passed CHN
5-(Ben zen esu lfon yloxy)-2-(iod om eth yl)p yr id in e (6). So-
dium iodide (5.48 g, 36.6 mmol, 2.00 eqiuv) was added to a
solution of 5 (6.00 g, 18.3 mmol, 1 equiv) in acetone (75 mL),
and the resulting heterogeneous mixture was stirred for 2.5 h
at 23 °C. Acetone was removed by concentration in vacuo. The
residue was diluted with ethyl acetate (100 mL), and the
resulting mixture was washed with water (100 mL). The organic
layer was extracted with a mixture of saturated aqueous sodium
bicarbonate solution (30 mL) and saturated aqueous sodium
thiosulfate solution (10 mL). The aqueous layers were extracted
with a second portion of ethyl acetate (75 mL). The combined
organic layers were dried over anhydrous sodium sulfate, filtered
and concentrated in vacuo to produce a yellow-brown solid. The
product was recrystallized from a mixture of ethyl acetate (15
mL) and ether (30 mL) to provide 5.18 g of 6 as a stable, light
brown crystalline solid. Concentration of the mother liquors and
recrystallization provided an additional 1.19 g of 6 (total 6.37 g,
93%). Larger scale preparations of this compound (20 g of 6)
provided yields of 75-82%: mp 111-113 °C; IR (KBr) 3032,
1584, 1475, 1450, 1375, 1299, 1203, 1179, 1087, 1020, 946, 853,
808, 763, 733, 689, 611, 583, 568, 545 cm-1; 1H NMR (CDCl3) δ
8.06 (dd, 1H, J ) 1.0, 2.2 Hz), 7.85 (dd, 2H, J ) 1.0, 8.2 Hz),
7.72 (t, 1H, J ) 6.3 Hz) 7.57 (t, 2H, J ) 7.4 Hz), 7.39 (m, 2H),
4.47 (s, 2H); 13C NMR (CDCl3) δ 157.1, 144.9, 143.3, 134.7, 134.4,
130.8, 129.4, 128.3, 123.5, 4.5. Anal. Calcd for C12H10INO3S:
C, 38.42; H, 2.69; N, 3.73. Found: C, 38.51; H, 2.85; N, 3.47.
[[R,R]-2S]-N-(2-Hydr oxy-1-m eth yl-2-ph en yleth yl)-N-m eth -
yl 2-a m in o-3-(2-(5-b en zen esu lfon yloxy)p yr id yl)p r op ion -
a m id e (7). A solution of n-butyllithium in hexanes (2.64 M,
29.5 mL, 78.0 mmol, 2.93 equiv) was added to a solution of
diisopropylamine (11.2 mL, 80.0 mmol, 3.00 equiv) in deoxy-
genated tetrahydrofuran (50 mL) at 0 °C. After 15 min, the
resulting solution of lithium diisopropylamide was transferred
via cannula over 5 min to a stirred slurry of anhydrous 2 (8.89
g, 40.0 mmol, 1.50 equiv) and flame-dried lithium chloride (10.2
g, 240 mmol, 9.00 equiv) in deoxygenated tetrahydrofuran (100
mL) at 0 °C. After 20 min, the bright yellow suspension was
cooled to -78 °C and a solution of 6 (10.0 g, 26.7 mmol, 1 equiv)
in tetrahydrofuran (40 mL with a 10-mL wash) was added slowly
to the reaction mixture. The reaction mixture was stirred for 3
h at -78 °C and was then warmed to -45 °C and stirred for an
additional 3 h. Water (400 mL) was added, and the resulting
two-phase mixture was warmed to 23 °C and extracted with one
400-mL and two 200-mL portions of dichloromethane. The
combined organic layers were dried over anhydrous potassium
carbonate, filtered, and concentrated in vacuo. The residue was
analysis: mp 253-256 °C dec, lit.4 262-263 °C dec; [R]20
)
D
+59.3 (c ) 1.08, 1 N HCl), lit.4 +55 (c ) 1.1, 1 N HCl); IR (KBr)
3084, 2988, 1625, 1597, 1571, 1489, 1410, 1347, 1294, 1255,
1150, 850, 692, 525 cm-1; 1H NMR (D2O) δ 8.05 (d, 1H, J ) 2.5
Hz), 7.28 (dd, 1H, J ) 8.5, 2.8 Hz), 7.21, (d, 1H, J ) 8.4 Hz),
4.03 (dd, 1H, J ) 7.9, 5.1 Hz), 3.29 (dd, 1H, J ) 15.1, 5.1 Hz),
3.15 (dd, 1H, J ) 15.1, 7.9 Hz). Anal. Calcd for C8H10N2O3: C,
52.74; H, 5.53; N, 15.38. Found: C, 52.57; H, 5.65; N, 15.00.
Ack n ow led gm en t. This research was generously
supported by the National Science Foundation and the
National Institutes of Health. J .L.G. acknowledges
postdoctoral fellowship support from the National In-
stitutes of Health.
J O9515079