Otaka et al.
MHz, CDCl3) δ 0.95 (d, J ) 6.9 Hz, 3H), 1.01 (d, J ) 6.5 Hz,
3H), 1.34 (t, J ) 7.0 Hz, 3H), 1.43 (s, 9H), 2.02-2.19 (m, 1H),
4.10-4.25 (m, 1H), 4.31 (q, J ) 6.7 Hz, 2H), 4.69 (d, J ) 10.6
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 17.3, 22.8, 28.3,
56.5, 63.1, 80.1, 115.1, 155.2, 163.3; HRMS (FAB), m/z calcd
for C13H24F2NO4 (MH+) 296.1673, found 296.1678.
NH4Cl and brine and dried over MgSO4. Concentration under
reduced pressure followed by flash chromatography over silica
gel with EtOAc-n-hexane (1:3) gave 37 mg (82%) of a mixture
of diastereomers of the title compound 43 as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 0.96 (s, 1.5H), 1.10 (s, 3H), 1.21
(s, 1.5H), 1.25 (t, J ) 7.2 Hz, 1.5H), 1.27 (t, J ) 7.1 Hz, 1.5H),
1.40 (s, 4.5H), 1.41 (s, 4.5H), 2.86-3.02 (m, 1H), 3.42 (d, J )
7.1 Hz, 0.5 H), 3.44 (d, J ) 7.1 Hz, 0.5H), 4.07-4.22 (m, 2H),
4.50 (br, 1H), 4.69 (br, 1H), 4.86 (dd, J ) 35.6, 10.4 Hz, 0.5H),
4.89 (dd, J ) 35.6, 10.4 Hz, 0.5H), 7.14-7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 14.1, 26.2, 26.4, 28.2, 38.3, 50.5, 52.9, 60.9,
71.4, 79.9, 102.0, 128.1, 128.2, 129.0, 136.0, 154.2, 161.6, 171.6;
HRMS (FAB), m/z calcd for C22H33FNO5 (MH+) 410.2343, found
410.2353.
Eth yl (5R,3Z)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-eth -
oxyca r bon yl-4-flu or o-6- p h en ylh ex-3-en oa te (44) (Ta ble
3, en tr y 3). To a mixture containing the enoate 34 (80 mg,
0.217 mmol) and (EtOCO)2O (0.157 mL, 1.09 mmol) in THF
(2.0 mL) was added a solution of SmI2 in THF (0.1 M, 13.0
mL, 1.30 mmol) at 0 °C under argon. After 1 h, the reaction
mixture was quenched with saturated NH4Cl and extracted
with Et2O. The extract was washed with saturated NH4Cl and
brine and dried over MgSO4. Concentration under reduced
pressure followed by flash chromatography over silica gel with
Eth yl (5S,2E)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-4,4-d i-
flu or o-6-m eth ylh ep t-2-en oa te (29). By use of a procedure
similar to that described for the preparation of the enoate 15a ,
the ester 28 (290 mg, 0.982 mmol) was converted into the title
compound 29 (260 mg, 82% yield) as colorless crystals: mp
43-44 °C; [R]24 -5.0 (c 1.00, CHCl3); 1H NMR (270 MHz,
D
CDCl3) δ 0.94 (d, J ) 6.6 Hz, 3H), 100 (d, J ) 6.9 Hz, 3H),
1.30 (t, J ) 7.1 Hz, 3H), 1.44 (s, 9H), 2.08-2.22 (m, 1H), 3.85-
4.04 (m, 1H), 4.23 (q, J ) 7.0 Hz, 2H), 4.67 (d, J ) 10.6 Hz,
1H), 6.30 (d, J ) 15.8 Hz, 1H), 6.82 (dt, J ) 15.8, 11.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 14.3, 17.0, 22.8, 28.3, 58.2,
61.1, 80.1, 120.0, 122.5, 137.9, 155.5, 164.6. Anal. Calcd for
C
15H25F2NO4: C, 56.06; H, 7.84; N, 4.36. Found: C, 55.86; H,
7.74; N, 4.35.
Eth yl (5S,3Z)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-flu -
or o-6-m eth ylh ep t-3- en oa te (30). By use of a procedure
similar to that described for SmI2-mediated reduction of γ,γ-
difluoro-R,â-enoate 15a (Table 2, entry 3), the enoate 29 (50
mg, 0.156 mmol) was converted into the title compound 30
EtOAc-n-hexane (1:6) gave the title compound 44 (70 mg, 76%
1
yield) as a colorless oil: [R]20 -8.2 (c 0.86, CHCl3); H NMR
(40 mg, 85% yield) as a colorless oil: [R]21 -30.5 (c 1.02,
D
D
CHCl3); 1H NMR (270 MHz, CDCl3) δ 0.94 (d, J ) 2.0 Hz, 3H),
0.96 (d, J ) 2.0 Hz, 3H), 1.26 (t, J ) 7.1 Hz, 3H), 1.45 (s, 9H),
1.83-1.98 (m, 1H), 3.09-3.17 (m, 2H), 3.90-4.07 (m, 1H), 4.14
(q, J ) 7.0 Hz, 2H), 4.72 (d, J ) 9.2 Hz, 1H), 4.98 (dt, J )
36.6, 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 18.3,
19.4, 21.1, 28.3, 29.4, 57.3, 60.4, 79.7, 99.2, 155.0, 158.8, 170.8;
HRMS (FAB), m/z calcd for C15H27FNO4 (MH+) 304.1924, found
304.1935.
(270 MHz, CDCl3) δ 1.24 (t, J ) 7.1 Hz, 3H), 1.26 (t, J ) 6.6
Hz, 3H), 1.39 (s, 9H), 2.95 (d, J ) 5.9 Hz, 2H), 4.11-4.23 (m,
4H), 4.40 (d, J ) 9.6 Hz, 1H), 4.55 (br, 1H), 4.68 (d, J ) 8.9
Hz, 1H), 5.07 (dd, J ) 35.3, 9.6 Hz, 1H), 7.14-7.33 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 14.1, 28.4, 38.5, 47.8, 52.3, 61.8,
61.9, 80.0, 99.4, 126.7, 128.3, 129.2, 135.9, 154.4, 159.7, 166.9,
167.1; HRMS (FAB), m/z calcd for C22H31FNO6 (MH+) 424.2135,
found 424.2141.
Eth yl (5R,3Z)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-flu -
or o-6-p h en ylh ex-3- en oa te (35): colorless crystals; mp 60-
61 °C; [R]20D -8.8 (c 0.80, CHCl3); 1H NMR and 13C NMR same
as compound 23a . Anal. Calcd for C19H26FNO4: C, 64.94; H,
7.46; N, 3.99. Found: C, 64.69; H, 7.40; N, 3.77.
Eth yl (5R,3Z)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-flu -
or o-2-h yd r oxym eth yl- 6-p h en ylh ex-3-en oa te (45) (Ta ble
3, en tr y 4). To a solution of 2,6-diphenylphenol (800 mg, 3.25
mmol) in CH2Cl2 (8 mL) was added a solution of Me3Al in
n-hexane (1.02 M, 1.59 mL, 1.62 mmol) at room temperature
under argon. After 1 h, a solution of s-trioxane (48 mg, 0.541
mmol) in CH2Cl2 (2 mL) was added to the reaction mixture at
0 °C. After 1 h, to the reaction mixture were successively added
a solution of the enoate 34 (100 mg, 0.271 mmol) in THF (2
mL) and a solution of SmI2 in THF (0.1 M, 8.1 mL, 0.812 mmol)
at 0 °C. After being stirred for 1 h at the same temperature,
the reaction mixture was quenched with saturated NH4Cl and
extracted in the usual manner. Purification by flash chroma-
tography over silica gel with EtOAc-n-hexane (1:2) gave the
title compound (mixture of diastereomer) 45 (67 mg, 65% yield)
as a colorless oil: 1H NMR (600 MHz, CDCl3) δ 1.24 (t, J )
7.1 Hz, 1.5H), 1.25 (t, J ) 7.1 Hz, 1.5H), 1.40 (s, 4.5H), 1.42
(s, 4.5H), 2.86-3.00 (m, 2H), 3.52-3.63 (m, 2H), 3.65-3.68
(m, 0.5H), 3.71-3.76 (m, 0.5H), 4.08-4.20 (m, 2H), 4.46 (br,
1H), 4.63-4.76 (br, 1H), 4.70 (dd, J ) 37.0, 9.3 Hz, 0.5H), 4.76
(dd, J ) 36.4, 9.6 Hz, 0.5H), 7.17 (d, J ) 7.2 Hz, 2H), 7.21-
7.32 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 14.1, 28.2, 38.4,
43.4, 53.0, 61.0, 63.0, 79.9, 101.6, 126.6, 128.1, 128.2, 135.8,
153.8, 157.3, 171.9; HRMS (FAB), m/z calcd for C20H29FNO5
(MH+) 382.2030, found 382.2023.
(2S)-2-{(3R,1Z)-3-[N-(ter t-Bu t oxyca r b on yl)a m in o]-2-
flu or o-4-p h en ylbu t-1-en yl}p r op a n o-3-la cton e (47) a n d
Its (2R)-Dia ster eom er (48). To a solution of the enoate 45
(63 mg, 0.189 mmol) in THF (0.2 mL) was added 1 N LiOH
(0.182 mL, 0.182 mmol) at room temperature. After 3 h, the
reaction mixture was acidified with 1 N HCl and extracted
with EtOAc. The extract was washed with brine and dried over
MgSO4. Concentration under reduced pressure gave the oily
carboxylic acid 46. To a solution of Ph3P (43 mg, 0.167 mmol)
and 46 in THF (0.5 mL) was added a solution of DEAD in
toluene (40%, 0.075 mL, 0.167 mmol) at -78 °C under argon.
After 10 min of stirring at -78 °C, a solution of the above
carboxylic acid in THF (1 mL) was added to the mixture at
N-[(1R)-1-P h en yleth yl]-(5S,2E)-5-[N-(ter t-bu toxyca r bo-
n yl)a m in o]-4,4-d iflu or o-6-m eth ylh ep t-2-en a m id e (31). To
a solution of the enoate 29 (100 mg, 0.311 mmol) in THF (0.4
mL) was added 1 N LiOH (0.342 mL, 0.342 mmol) at room
temperature. The mixture was stirred for 1 h and extracted
with EtOAc after acidification with 1 N HCl. The extract was
washed with brine and dried over MgSO4. Concentration under
reduced pressure gave an oily residue, which was dissolved
in THF (2 mL). To the solution were added (R)-methylbenzyl-
amine (0.044 mL, 0.342 mmol), (i-Pr)2NEt (0.059 mL, 0.342
mmol), 1-hydroxybenzotriazole (52 mg, 0.342 mmol), and
1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.059 mL,
0.342 mmol) at room temperature. The mixture was stirred
overnight and extracted with EtOAc. The extract was washed
with saturated citric acid, saturated NaHCO3, and brine and
dried over MgSO4. Concentration under reduced pressure gave
solid materials. Recrystallization of the solid from EtOAc-n-
hexane gave the title compound 31 (60 mg, 48% yield) as
colorless crystals: mp 188-190 °C; [R]14D +13.3 (c 0.08, CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.91 (d, J ) 6.8 Hz, 3H), 0.98 (d,
J ) 6.8 Hz, 3H), 1.41 (s, 9H), 1.54 (s, 3H), 2.08-2.19 (m, 1H),
3.88-4.00 (m, 1H), 4.67 (d, J ) 11.0 Hz, 1H), 5.16-5.24 (m,
1H), 5.91 (d, J ) 7.3 Hz, 1H), 6.28 (d, J ) 15.6 Hz, 1H), 6.74
(dt, J ) 15.1, 11.5 Hz, 1H), 7.25-7.38 (m, 5H); HRMS (FAB),
m/z calcd for C21H31F2N2O3 (MH+) 397.2303, found 397.2292.
Eth yl (5R,3Z)-5-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-flu -
or o-2-(1-h ydr oxy-1-m eth yleth yl)-6-ph en ylh ex-3-en oate (43)
(Ta ble 3, en tr y 2). To a mixture containing the enoate 34
(40 mg, 0.106 mmol) and acetone (0.024 mL, 0.324 mmol) in
THF (1.5 mL) was added a solution of SmI2 in THF (0.1 M,
3.2 mL, 0.324 mmol) at 0 °C under argon. After 1 h, the
reaction mixture was quenched with saturated NH4Cl and
extracted with Et2O. The extract was washed with saturated
1644 J . Org. Chem., Vol. 69, No. 5, 2004