(20 mL) was added under nitrogen via syringe. The reaction was
monitored by TLC (petrol–ethyl acetate, 1 : 1) and was com-
plete after 5 min. The precipitate was removed by filtration and
the filtrate washed with aqueous sodium thiosulfate solution
(1 M, 3 × 20 mL) and brine (50 mL), followed by drying
(MgSO4). The DCM was evaporated under reduced pressure
and the crude product purified by column chromatography on
silica with petrol–ethyl acetate (2 : 1) to give the iodide as white
crystals (5.87 g, 76%), mp 75–77 ЊC. νmax/cmϪ1 3277 (N–H);
1725 (C᎐O); 1702 (C᎐O); 1186 (C–O). Found C, 37.88; H, 3.06;
N, 3.21; I, 30.57. C13H13O3NF3I requires C, 37.61; H, 3.16; N,
3.37; I, 30.57%. δH (250 MHz, CDCl3) 2.75 (1H, dd, J 17.0 and
5.5), 2.95 (1H, dd, J 17.0 and 5.0), 3.30–3.50 (2H, m), 4.23–4.40
(1H, m), 5.17 (2H, s), 7.14 (1H, d, J 17.0) and 7.30–7.50 (5H,
m); δC (62.5 MHz, CDCl3) 7.1, 37.7, 47.7, 67.2, 115.7 (q, J 288),
128.4, 128.6, 128.7, 135.1, 156.8 (q, J 37), and 170.2; m/z (EI)
414.9906 (13%, Mϩ, C13H13O3NF3I requires 414.9892), 308(5),
266(7), 195(9), 154(3), 139(7), 108(100) and 107(32); [α]2D2.5 ϩ 7.0
(c 1.00 in CHCl3).
42%), mp 84–86 ЊC. νmax/cmϪ1 3357 (C–H); 3313 (O–H); 1687
(C᎐O); 1534 (N–H). Found C, 68.69; H, 6.96; N, 3.49.
᎐
C22H27NO5 requires C, 68.55; H, 7.06; N, 3.63%. δH (250 MHz,
CDCl3) 1.44 (9H, s), 2.59 (2H, br d, J 5), 2.60 (1H, m (signal
partially obscured)), 3.01–3.12 (1H, m), 3.83–4.01 (1H, m), 5.16
(2H, s), 5.53 (1H, br d, J 7.5), 6.79 (1H, t, J 7.5), 6.88 (1H, d,
J 7.6), 6.96 (1H, d, J 7.5), 7.13 (1H, t, J 7.5), 7.37 (5H, s) and
7.85 (1H, br s). δC (62.5 MHz, CDCl3) 28.2, 36.1, 36.7, 48.5,
66.6, 80.4, 116.3, 119.8, 123.2, 128.3, 128.4, 128.6, 130.8, 135.4,
155.4, 156.4, and 171.7 (one signal obscured); m/z (EIϩ)
385.1875 (3%, Mϩ, C22H27NO5 requires 385.1889), 385(3),
222(19), 178(64) and 91(100); [α]2D2.1 ϩ19.6 (c 1.02 in CHCl3).
᎐
᎐
3R-tert-Butoxycarbonylamino-4-(3-hydroxyphenyl)butanoic
acid benzyl ester (7b). This product was prepared following the
procedure outlined above, using 3-iodophenol as the aryl iodide
(172 mg, 0.78 mmol, 1.3 eq.) and the zinc reagent 1b. Purifi-
cation of the crude product by column chromatography on
silica with DCM–EtOAc (6 : 1) yielded a white solid (201 mg,
88%), mp 88–90 ЊC. νmax/cmϪ1 3384 (C–H); 1729 (C᎐O); 1691
᎐
(C᎐O); 1513 (N–H). Found C, 68.48; H, 7.02; N, 3.51.
᎐
General procedure for the coupling reactions of iodides with aryl
iodides
C22H27NO5 requires C, 68.55; H, 7.06; N, 3.63%. δH (250 MHz,
CDCl3) 1.40 (9H, s), 2.49 (1H, dd, J 16.5 and 6), 2.56 (1H, dd,
J 16.5 and 6), 2.73 (1H, dd, J 13 and 7.9), 2.85 (1H, dd, J 13.5
and 6.5), 4.07–4.26 (1H, m), 5.09 (1H, d, J 12), 5.10 (1H, signal
partially obscured), 5.17 (1H, d, J 12), 5.85 (1H, s), 6.58–6.78
(3H, m), 7.11 (1H, t, J 8) and 7.36 (5H, s). δC (62.5 MHz,
CDCl3) 28.3, 37.6, 40.2, 48.7, 66.5, 79.7, 113.7, 116.2, 121.2,
128.3, 128.5, 129.5, 135.5, 139.0, 155.4, 156.3 and 171.6 (one
signal obscured); m/z (EIϩ) 385.1888 (5%, Mϩ, C22H27NO5
requires 385.1889), 278(62), 222(62) and 178(100); [α]2D2.1 ϩ6.9
(c 1.02 in CHCl3).
Zinc dust (0.236 g, 3.6 mmol, 6.0 eq.) was placed in a dry 25 mL
round bottom flask, with sidearm, containing a rugby ball
shaped stirrer. The flask was flushed with nitrogen and dry
DMF (0.75 mL) and TMSCl (100 µL, 0.8 mmol) were added
under nitrogen via syringe. The solution was observed to effer-
vesce and the mixture was vigorously stirred at room temper-
ature for 5 min (the DMF occasionally changes to a yellow
colour during this period). The zinc was allowed to settle and
the supernatant solution was removed via syringe, followed by
drying of the zinc under vacuum by heating with a hot air
gun. A solution of the zinc reagent precursor iodide (0.6 mmol,
1.0 eq.) was dissolved in DMF (0.75 mL) under nitrogen and
transferred to the zinc via syringe. The solution was stirred at
room temperature and the insertion judged to be complete by
TLC within 5 min. Pd2(dba)3 (17.9 mg, 0.02 mmol), P(o-tol)3
(23.8 mg, 0.08 mmol) and the aryl iodide (1.3 eq. relative to the
iodide) were added to the flask. The flask was covered with
aluminium foil and left at room temperature overnight. The
reaction was diluted with EtOAc (50 mL), filtered and evapor-
ated under reduced pressure. The residue was warmed at 40 ЊC
under high vacuum to remove the DMF. The crude product was
purified by column chromatography.
3R-tert-Butoxycarbonylamino-4-(4-hydroxyphenyl)butanoic
acid benzyl ester (7c). This product was prepared following the
procedure outlined above, using 4-iodophenol as the aryl iodide
(172 mg, 0.78 mmol, 1.3 eq.) using zinc reagent 1b. Purification
of the crude product by column chromatography on silica with
DCM–EtOAc (10 : 1) yielded a white solid (194 mg, 85%), mp
124–126 ЊC. νmax/cmϪ1 3358 (C–H); 1702 (C᎐O); 1686 (C᎐O);
᎐
᎐
1529 (N–H). Found C, 68.32; H, 6.96; N, 3.41. C22H27NO5
requires C, 68.55; H, 7.06; N, 3.63%. δH (400 MHz, (CD3)2CO)
1.40 (9H, s), 2.58 (2H, d, J 6.5), 2.75 (1H, dd, J 13.5 and 7), 2.83
(1H, dd, J 13.5 and 7), 4.07–4.23 (1H, m), 5.06–5.20 (2H, m),
5.95 (1H, br d, J 7.5), 6.79 (2H, d, J 8), 7.07 (2H, d, J 8), 7.27–
7.54 (5H, m) and 8.19 (1H, s). δC (100 MHz, (CD3)2CO) 28.7,
39.4, 40.4, 50.7, 66.7, 78.9, 116.0, 128.9, 129.0, 129.4, 130.0,
131.3, 137.5, 156.0, 156.9 and 171.9; m/z (EIϩ) 385.1887 (3%,
Mϩ, C22H27NO5 requires 385.1889), 268(56), 222(42), 178(82)
and 91(100); [α]2D2.1 ϩ6.9 (c 1.02 in CHCl3).
4-(4-Hydroxyphenyl)-3R-(2,2,2-trifluoroacetylamino)butanoic
acid methyl ester (6). This product was prepared following the
procedure outlined above, using 4-iodophenol as the aryl iodide
(172 mg, 0.78 mmol, 1.3 eq.) and the zinc reagent 1a. Purifi-
cation of the crude product by column chromatography on
silica with DCM–MeOH (10 : 1) yielded a white solid (151 mg,
4S-tert-Butoxycarbonylamino-5-(4-hydroxyphenyl)pentanoic
acid methyl ester (8). This product was prepared following the
procedure outlined above, using 4-iodophenol as the aryl iodide
(172 mg, 0.78 mmol, 1.3 eq.) and zinc reagent 2. Purification
of the crude product by column chromatography on silica with
DCM–EtOAc (10 : 1) yielded a white solid (108 mg, 64 %), mp
149–151 ЊC. νmax/cmϪ1 3370 (C–H); 1713 (C᎐O); 1683 (C᎐O);
66%), mp 156–159 ЊC. νmax/cmϪ1 3300 (C–H); 1698 (C᎐O); 1516
᎐
(N–H). Found C, 59.36; H, 4.67; N, 3.52. C19H18F3NO4 requires
C, 59.84; H, 4.76; N, 3.67. δH (400 MHz, CD3OD) 2.58 (1H, dd,
J 15.5 and 8.5), 2.64 (1H, dd, J 15.5 and 5.5), 2.69 (1H, dd,
J 13.5 and 8), 2.75 (1H, dd, J 14 and 6.5), 4.39–4.49 (1H, m),
5.04 (1H, d, J 12), 5.09 (1H, d, J 12), 6.69 (2H, d, J 8.5) and 6.96
(2H, d, J 8.5). δC (100 MHz, CD3OD) 39.0, 40.0, 50.5, 67.6,
116.2, 117.4 (q, J 287), 129.2, 129.3, 129.4, 129.5, 131.3, 137.3,
157.3, 158.3 (q, J 37) and 172.1; m/z (TOF MS ESϩ) 382.1262
(7%, MHϩ, C19H19F3NO4 requires 382.1266), 304(10) and
251(100).
᎐
᎐
1516 (N–H). Found C, 63.08; H, 8.13; N, 4.22. C17H25NO5
requires C, 63.14; H, 7.79; N, 4.33%. δH (400 MHz, CD3OD)
1.36 (9H, s), 1.50–1.64 (1H, m), 1.76–1.88 (1H, m), 2.29 (1H,
dd, J 16.5 and 7), 2.36 (1H, dd, J 16.5 and 6.5), 3.62 (4H, s (two
overlapping signals)), 6.68 (2H, d, J 8.5) and 7.00 (2H, d, J 8.5).
δC (100 MHz, CD3OD) 28.8, 30.6, 31.7, 41.8, 52.1, 53.1, 79.8,
116.0, 130.7, 131.3, 156.8, 158.1 and 175.6; m/z (EIϩ) 323.1731
(3%, Mϩ, C17H25NO5 requires 323.1733), 216(32), 160(17),
116(72) and 107(59); [α]2D2.5 ϩ1.0 (c 1.02 in MeOH).
3R-tert-Butoxycarbonylamino-4-(2-hydroxyphenyl)butanoic
acid benzyl ester (7a). This product was prepared following the
procedure outlined above, using 2-iodophenol as the aryl iodide
(172 mg, 0.78 mmol, 1.3 eq.) and the zinc reagent 1b. Purifi-
cation of the crude product by column chromatography on
silica with DCM–EtOAc (20 : 1) yielded a white solid (97 mg,
2S-tert-Butoxycarbonylamino-3-(4-hydroxyphenyl)propionic
acid methyl ester (9a). This product was prepared following the
procedure outlined above, using 4-iodophenol as the aryl iodide
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 1 0 – 1 1 3
112