7584 J . Org. Chem., Vol. 64, No. 20, 1999
Dexter et al.
was flushed with nitrogen. Dry DMF (0.5 mL) and 1,2-
dibromoethane (19 µL, 0.225 mmol) were added, and the
mixture was stirred vigorously. The mixture was heated on a
hot water bath for 20 min before being allowed to attain
ambient temperature. Trimethylsilyl chloride (6 µL, 0.046
mmol) was added to the mixture, which was stirred for a
further 30 min. Iodide 3, 6, or 7 (0.75 mmol) was dissolved in
dry DMF (0.5 mL) under nitrogen. The iodide solution was
transferred by syringe to the zinc mixture and stirred at room
temperature. TLC (petroleum ether-ethyl acetate, 2:1) showed
complete consumption of starting material within 15 min.
P r ep a r a tion of P r otected 4-Ar yl â-Am in o Acid s (12a -
l). Gen er a l P r oced u r e. The electrophile (1.0 mmol), tris-
(dibenzylideneacetone)dipalladium (0.0228 g, 0.025 mmol,
0.025 equiv) and tri-o-tolylphosphine (0.0304 g, 0.10 mmol,
0.10 equiv) were added successively to the reaction mixture
as solids. The reaction mixture was stirred at room temper-
ature for 3 h and was subsequently diluted with ethyl acetate
(50 mL), washed with brine, dried, and evaporated to dryness.
Flash column chromatography over silica with an appropriate
petroleum ether-ethyl acetate gradient furnished the pro-
tected 4-aryl-â-amino acid 12.
Meth yl 3(R)-[(ter t-Bu toxyca r bon yl)a m in o]-4-p h en yl-
bu ta n oa te (12a ). Treatment with iodobenzene yielded 12a
(0.161 g, 73%), isolated as a white solid, mp 48-50 °C (lit. 51-
52 °C).31 Found C, 65.28; H, 8.05; N, 4.77. C16H23NO4 requires
C, 65.51; H, 7.90; N, 4.77. νmax 3378, 1738, 1714, 1513, and
1168; δH 1.46 (9 H, s), 2.49 (1 H, dd, J ) 5.8 and 15.9), 2.56 (1
H, dd, J ) 5.5 and 15.9), 2.86 (1 H, J ) 8.0, 13.5), 2.96-2.98
(1 H, m), 3.73 (3 H, s), 5.12 (1 H, br d, J ) 6.7), and 7.23-7.38
(5 H, m); δC 28.17, 37.46, 40.30, 48.72, 51.53, 79.26, 126.51,
128.44, 129.30, 137.65, 155.05, and 172.06; m/z (EI) 220.0976
(36, M+ - C4H9O; C12H14NO3 requires 220.0974) 202 (62), 176
(46), and 146 (77). [R]D +11.4 (c 1.34 in CH2Cl2). [R]D +20.8 (c
1.28 in MeOH) (lit.31 +19.9 (c 1.29 in MeOH)).
172.06; m/z 201.1002 (2.5, M+- C4H8; C9H15NO4 requires
201.1001). [R]D +20.8 (c 1.06 in CH2Cl2).
Meth yl 3(R)-[(ter t-Bu toxyca r bon yl)a m in o]-h ep t-5,6-d i-
en oa te (20). Treatment with propargyl chloride yielded 20
(0.1375 g, 69%), isolated as a colorless oil. νmax 3363, 2978,
1956, 1738, 1715, 1520, 1366, 1249, and 1168; δH 1.44 (9 H,
s), 2.23-2.30 (2 H, m), 2.58 (2 H, br d, J ) 5), 3.67 (3 H, s),
3.97-4.04 (2 H, dt, J ) 2.8 and 6.4), and 5.02-5.08 (2 H, m);
δC 28.58, 33.74, 38.33, 47.68, 51.90, 75.20, 79.59, 85.99, 155.41,
172.20, and 209.79; m/z 199.0845 (7, M+ - C4H8; C9H17NO4
requires 199.0845), 146 (31), 108 (13), 102 (72), 82 (17), and
57 (100). [R]D -7.9 (c 1.24 in CH2Cl2).
5(R)-[(ter t-Bu toxyca r bon yl)a m in o]-2-m eth ylen e-h ep -
ta n ed ioic Acid 1-Eth yl-7-m eth yl Diester (21). Treatment
with ethyl bromomethylacrylate44 yielded 21 (0.686 g, 72%),
isolated as a colorless oil. νmax 3371, 2979, 1739, 1716, 1631,
1519, 1366, 1246, and 1172; δH 1.30 (3 H, t, J ) 7.1), 1.44 (9
H, s), 1.69 (2 H, m), 2.27-2.35 (1 H, m), 2.38-2.45 (1 H, m),
2.54 (2 H, d, J ) 5.2), 3.68 (3 H, s), 3.92 (1 H, m), 4.20 (2 H,
q, J ) 7.1), 4.98 (1 H, br s), 5.57 (1 H, br s), and 6.16 (1 H, br
s); δC 14.21, 28.38, 28.72, 33.39, 39.25, 47.32, 51.66, 60.68,
79.29, 125.28, 139.83, 155.35, 166.98, and 171.99; m/z (EI)
273.1219 (1.2, M+ - C4H8; C12H19NO6 requires 273.1212), 229
(24), 184 (22), 156 (47), 102 (100), and 57 (98). [R]D +8.5 (c
0.80 in CH2Cl2).
Meth yl 3(R)-[(ter t-Bu toxycar bon yl)am in o]-4-(cycloh ex-
1′-en -3′-on e) Bu ta n oa te (22). Treatment with 3-iodocyclohex-
2-enone yielded 22 (0.423 g, 56%), isolated as fine white
needles, mp 94-97 °C. Found C, 61.39; H, 8.09; N, 4.41. C16H25
-
NO5 requires C, 61.72; H, 8.09; N, 4.50. νmax 3350, 2986, 1745,
1683, 1688, 1531, 1366, 1258 and 1162; δH 1.39 (9 H, s), 1.95-
2.05 (2 H, m), 2.28 (1 H, dt, J ) 5.5 and 1.8), 2.35 (2 H, t, J )
6.7), 2.38-2.50 (3 H, m), 2.55 (1 H, dd, J ) 5.5 and 16.2), 2.60
(1 H, dd, J ) 5.5 and 16.2), 3.70 (3 H, s), 4.17-4.24 (1 H, m),
5.08 (1 H, br d, J ) 9.2), and 5.86 (1 H, br s); δC 22.71, 28.29,
29.15, 37.29, 38.74, 43.71, 45.37, 51.85, 79.67, 128.34, 155.20,
P r ep a r a tion of P r otected 5-Ar yl γ-Am in o Acid s (16a -
g). Gen er a l P r oced u r e. The same procedure as described
above for the preparation of the protected 4-aryl-â-amino acids
12 was used in the preparation of 5-aryl γ-amino acid deriva-
tives 16, starting from iodide 7 (0.268 g, 0.75 mmol).
161.97 (C(1′)), 171.69, and 199.59; m/z 311.1747 (M+; C16H25
-
NO5 requires 311.1733), 255 (2, M+ - C4H8), 238 (5, M+
-
C4H9O), 224 (6), 195 (12), 146 (27), 110 (75), 102 (100), and 57
(65). [R]D -13.8 (c 0.995 in CH2Cl2).
Meth yl 4(R)-[(ter t-Bu toxycar bon yl)am in o]-oct-7-en oate
(23). Treatment with allyl chloride yielded 23 (0.722 g, 87%),
isolated as a colorless oil. Found C, 62.47; H, 9.25; N, 5.18.
Asp a r tic Acid a n d Glu ta m ic Acid Der ived Zin c/Cop -
p er Rea gen ts (17 a n d 18). Zinc dust (1.136 g, 18.0 mmol)
was activated in dried DMF using the procedure described
above but scaled up by a factor of 4. A solution of iodide 4 or
5 (3.0 mmol) in DMF was transferred under nitrogen via
syringe to the reaction mixture at room temperature. The
reaction was judged to be complete by TLC analysis (petroleum
ether-ethyl acetate, 2:1) after approximately 20 min and was
cooled to -55 °C (cryostat temperature). A solution of CuCN‚
2LiCl, prepared by dissolving copper(I) cyanide (0.2687 g, 3.0
mmol) and rigorously dried lithium chloride (0.2543 g, 6.0
mmol) in dry DMF (4.0 mL), was transferred via syringe to
the reaction mixture, which was then allowed to warm to 0
°C for 10 min. After cooling to -55 °C again, the electrophile
was introduced, and then the mixture was allowed to warm
to -10 °C and stirred at this temperature for 3 h. The reaction
mixture was partitioned between ethyl acetate (100 mL) and
saturated aqueous ammonium chloride (40 mL) and then
filtered. The organic layer was washed with water (40 mL)
and brine (40 mL) and then dried, and the solvent was
removed under reduced pressure. Flash column chromatog-
raphy on silica gel, eluting with an appropriate petroleum
ether-ethyl acetate gradient yielded the unsaturated pro-
tected amino acids.
C
14H25NO4 requires C, 61.97; H, 9.29; N, 5.16. νmax 3356, 2977,
1740, 1713, 1690, 1522, 1366, and 1173; δH 1.43 (9 H, s), 1.45-
1.50 (1 H, m), 1.52-1.57 (1 H, m), 1.59-1.67 (1 H, m), 1.82-
1.89 (1 H, m), 2.04-2.15 (2 H, m), 2.37 (2 H, t, J ) 7.5), 3.64-
3.65 (1 H, m), 3.67 (3 H, s), and 4.29 (1 H, br s); δC 28.53,
30.30, 30.71, 30.95, 35.18, 50.14, 51.79, 79.25, 115.14, 138.03,
155.78, and 174.23; m/z (EI) 271.1790 (0.07; M+ C14H25NO4
requires 271.1784), 215 (4, M+ - C4H8), 198 (9, M+ - C4H9O),
170 (14), 160 (13), 116 (95), 84 (63), and 57 (100). [R]D +2.3 (c
1.35 in CH2Cl2).
Meth yl 4(R)-[(ter t-Bu toxyca r bon yl)a m in o]-oct-6,7-d i-
en oa te (24). Treatment with propargyl chloride yielded 24
(0.664 g, 82%), isolated as a colorless oil. νmax 3358, 2977, 1956,
1739, 1213, 1694, 1521, and 1172; δH 1.42 (9 H, s), 1.65-1.71
(1 H, m), 1.85-1.92 (1 H, m), 2.13-2.19 (2 H, m), 2.38 (2 H, t,
J ) 7.5), 3.66 (3 H, s), 4.10-4.12 (1 H, m), 4.68 (2 H, dt, J )
1.84 and 6.71), and 5.01-5.07 (2 H, m); δC 28.58, 31.06, 32.42,
34.81, 50.42, 51.87, 74.98, 79.42, 85.86, 155.77, 174.17, and
209.80; m/z (EI) 213.0991 (2, M+ - C4H8; C10H19NO4 requires
231.1001), 216 (7, M+ - C4H5), 160 (21), 116 (71), and 57 (100).
[R]D -29.2 (c 1.05 in CH2Cl2).
Mich a el Ad d ition s. The zinc/copper reagent 17 was gener-
ated from iodide 6 using the procedure described above. A
solution of the R,â-unsaturated ketone (4.0 mmol) and chlo-
rotrimethylsilane (504 µL, 4.0 mmol) in freshly distilled THF
(2.0 mL) was added at -55 °C to the reaction mixture, which
was then allowed to warm to -10 °C and stir overnight. The
reaction mixture was partitioned between ethyl acetate (100
mL) and saturated aqueous ammonium chloride (40 mL) and
Met h yl
3(R)-[(ter t-b u t oxyca r b on yl)a m in o]-h ep t -6-
en oa te (19). Treatment with allyl chloride yielded 19 (0.1375
g, 69%), isolated as a colorless oil. Found C, 59.99; H, 9.03; N,
5.29. C13H23NO4 requires C, 60.06; H, 9.01; N, 5.44. νmax 3360,
2978, 1739, 1715, 1521, 1366, 1247, 1171, and 1055; δH 1.44
(9 H, s), 1.57-1.63 (2 H, m), 2.06-2.16 (2 H, m), 2.51 (1 H,
dd, J ) 5.5 and 15.5), 3.68 (3 H, s), 3.92-3.93 (1 H, m), 4.98
(1 H and 1 H, dd and m, J ) 1.5 and 10.0), 5.03 (1 H, ddd, J
) 1.5, 3.5, and 17.0), and 5.75-5.84 (1 H, m); δC 28.34, 30.34,
33.71, 39.03, 47.10, 51.60, 79.20, 115.15, 137.55, 155.27, and
(44) Villieras, J .; Rambaud, M. Synthesis 1982, 924-925.