(15 cm3) under nitrogen at room temperature. The flask was
covered with foil and the mixture stirred at room temperature
for 3 h. Methanol (15 cm3) was added and the reaction left to
stir for a further 15 minutes. The reaction mixture was poured
into water (75 cm3) and extracted with ether (2 × 50 cm3). The
combined organic fractions were washed with water (2 × 75
cm3), 5% NaOH (25 cm3), water (3 × 50 cm3) and dried
(MgSO4). Concentration under reduced pressure gave a pale
yellow oil. Flash chromatography on silica gel using petrol–
ethyl acetate (20:1) gave 3a as a pale yellow oil (1.14 g, 2.72
νmax/cmϪ1 (cap. film) 1394, 1506, 1725, 3034, 3348; δH (500
MHz, CDCl3) 1.50 (9H, s), 1.81 (3H, d, J 7), 4.37 (1H, dq, J 3
and 7), 4.46 (1H, dd, J 3 and 8), 5.12 (2H, s), 5.65 (1H, d, J 8),
7.30–7.40 (5H, m); δC (125 MHz, CDCl3) 23.0, 28.0, 50.0, 60.0,
67.3, 83.5, 128.1, 128.2, 128.6, 136.1, 155.6, 167.4. m/z (EI) 315
(Mϩ Ϫ tBu, 70%), 272 (11), 264 (13), 191 (100) 91 (100), 57 (31).
Preparation of protected ꢀ-methylarylalanines (10a/b–13a/b).
General procedure
Zinc dust (0.294 g, 4.5 mmol, 6.0 eq.) was weighed into a 50 cm3
round bottom flask that was repeatedly evacuated and flushed
with nitrogen. Dry DMF (0.5 cm3) and 1,2-dibromoethane (19
µL, 0.225 mmol) were added via syringe and the mixture was
stirred vigorously. The mixture was then heated until ethane
was evolved before being allowed to attain room temperature.
Trimethylsilylchloride (15 µL, 0.115 mmol) was added to the
mixture and stirred for 30 min. Iodide 3a or 3b (0.314 g, 0.75
mmol) was dissolved in dry DMF (0.5 cm3) under nitrogen. The
iodide solution was added to the activated zinc at room tem-
perature in a water bath via syringe. After 2 minutes aryl iodide
(1.0 mmol), Pd2(dba)3 (0.0228 g, 0.025 mmol, 0.025 eq.) and
tri-o-tolyl-phosphine (0.0304 g, 0.10 mmol, 0.10 eq.) were
added in that order to the reaction mixture. The reaction
mixture was left to stir at room temperature for 3 h and then
diluted with ethyl acetate (50 cm3). The organic extract was
washed with brine (50 cm3), water (50 cm3) and dried (MgSO4).
ϩ
mmol, 54%). (Found: [MHϩ Ϫ C4H9], 362.9972. C12H14NO4
requires 362.9968); [α]2D2 40.2 (c. 1.05, CH2Cl2); νmax/cmϪ1 (cap.
film) 1394, 1504, 1724, 2978, 3033; δH (500 MHz, CDCl3) 1.51
(9H, s), 1.99 (3H, d, J 7), 4.19 (1H, dd, J 8 and 3.5), 4.44
(1H, dq, J 7 and 3.5), 5.12 (2H, m), 5.61 (2H, d, J 8), 7.31–7.39
(5H, s); δC (125 MHz, CDCl3) 25.3, 28.1, 60.7, 67.2,
83.6, 128.1, 128.3, 128.6, 129.6, 136.1, 155.6, 167.6; m/z (EI) 363
t
(MHϩ Ϫ Bu, 30%), 318 (42), 292 (9), 236 (40), 107 (33), 91
(100), 57 (40).
tert-Butyl (2S,3S )-2-(benzyloxycarbonyl)amino-3-formyloxy-
butanoate (6)
Isolated as a pale yellow oil from the above reaction (33 mg,
ϩ
0.1 mmol, 2%). (Found: [MHϩ Ϫ C4H9] 281.0907. C13H15NO6
requires 281.0899); [α]3D0 5.9 (c. 1.5, CH2Cl2); νmax/cmϪ1 (cap.
film) 1155, 1522, 1726, 2938, 2980 3350; δH (500 MHz, CDCl3)
1.32 (3H, d, J 6.5), 1.48 (9H, s), 4.56 (1H, dd, J 8 and 3),
5.11 (2H, s), 5.30–5.35 (1H, m), 5.56 (1H, d, J 8), 7.17–7.36
(5H, m), 8.01 (1H, s); δC (125 MHz, CDCl3) 16.9, 30.0, 57.3,
67.2, 70.6, 83.3, 128.2 (×2), 128.5, 136.1, 155.9, 160.2, 167.9.
m/z (EI) 281 (Mϩ Ϫ C4H8, 9%), 236 (4), 107 (9), 91 (100), 57
(31).
tert-Butyl (2S,3R/S )-2-(benzyloxycarbonyl)amino-3-(p-nitro-
phenyl)butanoate (10a/b)
Treatment with p-iodonitrobenzene (0.249 g, 1.0 mmol)
followed by flash chromatography on silica gel using petrol–
ethyl acetate (8:1) yielded (2S,3R) diastereoisomer 10a (52 mg,
0.13 mmol, 17%) as a thick dark oil. (Found: Mϩ 414.1799.
tert-Butyl (2R,3R)-2-(benzyloxycarbonyl)amino-3-iodo-
butanoate (3b)
C22H26N2O6 requires 414.1791); [α]2D2 16.3 (c. 0.27, CH2Cl2);
ϩ
νmax/cmϪ1 (cap. film) 1347, 1521, 1724, 2935, 2978, 3340. δH (500
MHz, CDCl3) 1.33 (3H, d, J 7), 1.35 (9H, s), 3.33 (1H, pent,
J 6.5), 4.51 (1H, dd, J 6 and 9), 4.99 (1H, d, J 12), 5.09 (1H, d,
J 12), 5.37 (1H, d, J 9), 7.28–7.40 (7H, m), 8.12 (2H, m); δC (125
MHz, CDCl3) 16.1, 27.9, 42.8, 59.1, 67.1, 82.9, 123.9, 128.2,
128.4, 128.6, 128.9, 137.9, 147.0, 149.6, 155.9, 169.9. m/z (EI)
414 (Mϩ, 15%), 358 (10), 313 (45), 151 (6), 91 (100), 57 (9%).
(2S,3S) Diastereoisomer 10b (63 mg, 0.15 mmol, 20%).
Iodide 3a (3.06 g, 7.3 mmol) was added to a stirred solution of
sodium iodide (3.29 g, 20 mmol, 2.7 eq.) in acetone (200 cm3)
under nitrogen at room temperature then heated at reflux for
24 h. The reaction mixture was concentrated under reduced
pressure. Residue was extracted into ethyl acetate (200 cm3),
washed with brine (250 cm3), 1 M sodium thiosulfate solution
(100 cm3) and water (250 cm3). Concentration of the organic
layer gave a 2:1 mixture of the (2R,3R)- and (2R,3S)-diastereo-
isomers as a pale yellow oil. Flash chromatography on silica gel
using petrol–ethyl acetate gave 3b (0.37 g, 0.88 mmol, 12%) and
a 1:1 mixture of 3a/b (1.824 g, 4.35 mmol, 60%). (Found: Mϩ,
419.0594. C16H22NO4Iϩ requires 419.0593); [α]2D2 Ϫ14.4 (c. 1.2,
CH2Cl2); νmax/cmϪ1 (cap. film) 1394, 1507, 1728, 2978; δH (500
MHz, CDCl3) 1.49 (9H, s), 1.92 (3H, d, J 7), 4.17 (1H, dd, J 2.5
and 9.5), 4.69 (1H, dq, J 7 and 2.5), 5.14 (2H, s), 5.44 (1H, d,
J 9.5), 7.26–7.40 (5H, m); δC (125 MHz, CDCl3) 26.0, 28.0, 29.6,
60.2, 67.3, 83.2, 128.1, 128.2, 128.5, 136.1, 156.6, 168.5; m/z
(EI) 419 (Mϩ, 28%), 363 (40), 318 (28), 236 (5), 192 (65), 107
(13), 91 (100), 57 (30).
t
ϩ
(Found Mϩ
Ϫ CO2 Bu 313.1193. C17H17N2O4 requires
313.1188); [α]2D2 15.9 (c. 0.27, CH2Cl2); νmax/cmϪ1 (cap. film)
1346, 1718, 2935, 2978, 3342; δH (500 MHz, CDCl3) 1.40 (9H,
s), 1.80 (3H, d, J 7), 3.43 (1H, pent, J 6.5), 4.51 (1H, dd, J 5.5
and 8.5), 5.05 (1H, d, J 12), 5.09 (1H, d, J 12), 5.26 (1H, d, J 9),
7.25–7.45 (7H, m), 8.14 (2H, m); δC (125 MHz, CDCl3) 16.6,
28.0, 42.4, 59.1, 67.1, 82.9, 123.4, 128.0, 128.3, 128.5, 128.8,
136.0, 146.9, 149.1, 156.0, 169.6; m/z (EI) 358 (MHϩ Ϫ Bu,
t
0.3%), 313 (1), 223 (1), 151 (6), 107 (30), 91 (100).
tert-Butyl (2S,3R/S )-2-(benzyloxycarbonyl)amino-3-
(p-methoxyphenyl)butanoate (11a/b)
Using iodide 3a (0.98 g, 2.34 mmol) to generate the organozinc
reagent 2a/b and p-methoxyiodobenzene (0.73 g, 3.12 mmol)
followed by flash chromatography on silica gel using petrol–
ethyl acetate 8:1 gave (2S,3S) diastereoisomer 11a (221 mg, 0.55
mmol, 24%) as a dark red oil. [α]2D1 16.3 (c. 0.27, CH2Cl2).
νmax/ cmϪ1 (cap. film) 1514, 1726, 3344. δH (500 MHz, CDCl3)
1.33 (3H, d, J 7), 1.41 (9H, s), 3.30 (1H, pent, J 6.5), 3.76 (3H,
s), 4.44 (1H, dd, J 9 and 5), 5.07 (2H, s), 6.81 (2H, m), 7.11 (2H,
m), 7.25–7.30 (5H, m); δC (125 MHz, CDCl3) 17.9, 27.9, 41.3,
55.2, 59.8, 66.8, 81.6, 113.7, 128.0, 128.1 (×2), 128.8, 133.0,
136.4, 156.2, 158.6, 170.5. m/z (EI) 400 (MHϩ, 0.1%), 344 (0.5),
327 (0.1), 298 (1.3), 248 (5), 135 (100), 91 (52), 57 (12%).
tert-Butyl (2R,3S )-2-(benzyloxycarbonyl)amino-3-bromo-
butanoate (12)
Carbon tetrabromide (0.958 g, 2.89 mmol) and triphenyl-
phosphine (0.758 g, 2.89 mmol) were dissolved in anhydrous
toluene (16 cm3) in a dry flask under nitrogen at room temper-
ature. Ester 5 (0.618 g, 2.00 mmol) was added in four portions
over 30 minutes. The reaction was stirred at room temperature
for 3 hours, then filtered and the solid washed with toluene
(20 cm3). The filtrate was concentrated under reduced pressure
to give a pale yellow oil. Flash chromatography on silica gel
using petrol–ethyl acetate (3:1) gave tert-butyl (2R,3S)-2-
(benzyloxycarbonyl)amino-3-bromobutanoate 12 as a yellow
oil (0.373 g, 1.00 mmol, 50%); (Found MHϩ Ϫ C4H9 315.0091,
C12H14NO4Brϩ requires 315.0106); [α]2D2 31.0 (c. 1.05, CH2Cl2);
Also (2S,3R) diastereoisomer 11b (190 mg, 0.48 mmol, 20%)
ϩ
as a dark red oil. (Found Mϩ 399.2022. C23H29NO5 requires
399.2046); [α]2D1 16.3 (c. 0.27, CH2Cl2); νmax/ cmϪ1 (cap. film)
2848
J. Chem. Soc., Perkin Trans. 1, 2002, 2845–2850