Conformationally Restricted Trans Peptide Isostere
J . Org. Chem., Vol. 66, No. 11, 2001 3751
The reaction mixture was quenched with saturated aqueous
NaCl (25 mL), and the resulting mixture was concentrated
under reduced pressure. The residue was extracted with CH2-
Cl2 (4 × 40 mL), and the combined organic layers were dried
over MgSO4 and then concentrated to afford a yellow oil.
Crystallization from hexane/EtOAc (4:1) 17 as white needles
reaction mixture was filtered through a short silica plug,
washing with additional ethanol. The solvent was removed
under reduced pressure to afford 21 as a colorless oil (126 mg,
100%).1H NMR (300 MHz, CDCl3): δ, 1.18 (s, 9H), 2.01-2.13
(m, 1H), 2.62 (d, 2H, J ) 7.8 Hz), 3.37 (dd, 2H, J ) 7.5, 9.0
Hz), 3.55 (dd, 1H, J ) 3.9, 9.0 Hz) 3.60 (dd, 1H, J ) 6.9, 10.8
Hz), 3.66-3.76 (m, 2H), 7.17-7.31 (m, 5H); 13C NMR (75 MHz,
CDCl3): δ, 27.2, 34.4, 42.2, 65.0, 65.9, 73.2, 125.8, 128.1, 128.9,
140.0.
1
(4.62 g, 74%), mp 100-102 °C (lit.17 92-95 °C). H NMR (300
MHz, CDCl3): δ, 2.70-2.79 (m, 2H), 3.00-3.06 (m, 2H), 3.23-
3.33 (m, 3H), 4.14-4.18 (m, 2H), 7.15-7.35 (m, 10H).
(4S)-4-Ben zyl-3-[2-b en zyloxym et h yl-3-p h en yl-1-oxo-
p r op yl]-2-oxa zolid in on e (18). TiCl4 (0.15 mL, 1.36 mmol)
was added to a solution of 17 (400 mg, 1.29 mmol) in dry CH2-
Cl2 (5 mL) at 0 °C. After stirring the reaction mixture for 5
min, diisopropylethylamine (0.225 mL, 1.29 mmol) was added,
and the reaction mixture was stirred for 1 h. Benzyl chloro-
methyl ether (0.36 mL, 2.59 mmol) was added, and the reaction
mixture was stirred at 0 °C for a further 5 h and then
quenched with saturated aqueous NH4Cl (4 mL). The mixture
was extracted with CH2Cl2 (2 × 10 mL) and diethyl ether (2
× 10 mL), and the combined organic layers were dried over
MgSO4 and then concentrated under reduced pressure. The
yellow oil was purified by column chromatography (hexane/
EtOAc 4:1) to afford 18 as a colorless oil (508 mg, 92%). 1H
NMR (300 MHz, CDCl3): δ, 2.69 (dd, 1H, J ) 9.3, 13.5 Hz),
2.89 (dd, 1H, J ) 6.9, 13.8 Hz), 2.99 (dd, 1H, J ) 8.4, 13.8
Hz), 3.19 (dd, 1H, J ) 3.3, 13.5 Hz), 3.67 (dd, 1H, J ) 4.8, 9.3
Hz), 3.83-3.93 (m, 2H), 4.03 (dd, 1H, J ) 3.0, 9.0 Hz), 4.48-
4.64 (m, 4H), 7.16-7.34 (m, 15H); 13C NMR (75 MHz, CDCl3):
δ, 34.9, 37.3, 44.9, 54.9, 65.5, 70.3, 72.8, 126.2, 127.0, 127.3,
127.4, 128.1, 128.2, 128.6, 128.9, 129.2, 135.0, 137.9, 138.2,
152.8, 173.8. HRMS (EI) calcd for C20H20NO4 [M+ - C6H5CH2]
338.13939, found 338.13923.
ter t-Bu t yld im et h ylsilyl-(2RS,6S)-6-[N-(b en zyloxyca r -
bon yl)a m in o]-2-ben zyl-5-oxo-7-p h en yl-3-h ep ten yl Eth er
(22). To a solution of 14 (3.0 g, 9.72 mmol) in dry toluene (75
mL) at -90 °C was added dropwise a 1.0 M solution of
DIBALH in toluene (10.0 mL, 10 mmol). The reaction was
stirred for 1.5 h at -80 to -90 °C and then quenched with
saturated aqueous sodium potassium tartrate (30 mL). The
reaction mixture was warmed to room temperature and
extracted with diethyl ether (2 × 50 mL) and EtOAc (30 mL).
The combined organic layers were dried over MgSO4 and
reduced to afford the aldehyde intermediate 8 as a colorless
oil (2.36 g, 87%) which was used in the subsequent reaction
1
without further purification. H NMR (300 MHz, CDCl3): δ,
0.036 (s, 3H), 0.043 (s, 3H), 0.894 (s, 9H), 2.62-2.72 (m, 1H),
2.83 (dd, 1H, J ) 8.4, 14.1 Hz), 3.06 (dd, 1H, J ) 6.0, 13.8
Hz)), 3.75 (dd, 1H, J ) 5.4, 10.2 Hz), 3.90 (dd, 1H, J ) 3.9,
10.2 Hz), 7.16-7.28 (m, 5H), 9.80 (d, 1H).
To a solution of phosphonate 7 (1.57 g, 4.16 mmol) and
aldehyde 8 (1.15 g, 4.13 mmol) in dry ethanol (75 mL) was
added anhyd potassium carbonate (575 mg, 4.16 mmol). The
reaction was stirred for 24 h, filtered, and acidified with acetic
acid. The solvent was removed under reduced pressure, and
the residue was dissolved in EtOAc (100 mL). The organic
layer was washed with saturated aqueous sodium bicarbonate
(20 mL) and saturated aqueous sodium chloride (20 mL) and
then dried over MgSO4. The solvent was removed under
reduced pressure to afford a yellow oil that was purified by
column chromatography (4:1 hexane/EtOAc) to afford 22 as a
colorless oil (1.30 g, 56%). 1H NMR (300 MHz, CDCl3): δ, 0.04
(s, 3/2 H), 0.05 (s, 3/2 H), 0.90 (s, 9/2 H), 0.91 (s, 9/2 H), 2.57-
2.72 (m, 2H), 2.86-2.96 (m, 2H), 3.03-3.14 (m, 1H), 3.54-
3.62 (m, 2H) 4.75-4.87 (m, 1H), 5.04-5.14 (m, 2H), 5.51 (d,
2h, J ) 6.9 Hz), 6.06 (d, 1H, J ) 15.6 Hz), 6.84-6.97 (m, 3H),
7.10-7.38 (m, 14 H); 13C NMR (75 MHz, CDCl3): δ, -5.5, 18.2,
25.8, 36.6,36.7, 37.8, 38.0, 47.0, 47.1, 58.5, 58.9, 64.1, 64.4, 66.6,
124.4, 126.0, 126.2, 126.8, 127.6, 127.8, 127.9, 128.0, 128.1,
128.3, 128.4, 129.0, 129.2, 129.4, 129.7, 135.6, 136.4, 138.9,
139.0, 142.5, 150.1, 150.1, 155.4, 155.6, 196.0, 196.3. HRMS
(FAB) calcd for C34H44NO4Si [MH+] 558.3040, found 558.3051.
(2RS,6S)-6-[N-(Ben zyloxyca r bon yl)a m in o]-2-ben zyl-5-
oxo-7-p h en yl-3-h ep ten -1-ol (23). The silyl ethers 22 was
stirred in acetic acid/THF/H2O (9 mL:3 mL:3 mL) for 72 h.
The reaction mixture was neutralized with saturated aqueous
sodium bicarbonate followed by the addition of EtOAc (3 × 80
mL). The combined organic layers were dried over MgSO4, and
the solvent was removed under reduced pressure to afford a
colorless oil that was purified by column chromatography on
silica gel (hexane/EtOAc 4:1) and dried under high vacuum to
afford 23 as a viscous colorless oil (460 mg, 46%). 1H NMR
(300 MHz, CDCl3): δ, 2.60-3.09 (m, 3H), 3.50-3.68 (m, 2H)
4.77-4.90 (m, 1H), 5.04-5.13 (m, 2H), 5.49-5.53 (m, 2H), 6.06
(d, 1/2H, J ) 16.2 Hz), 6.08 (d, 1/2H, J ) 15.9 Hz), 6.77-6.89
(m, 1H), 6.93-7.37 (m, 15 H); 13C NMR (75 MHz, CDCl3): δ,
13.9, 20.7, 36.3, 36.4, 37.3, 37.6, 46.8, 58.1, 58.8, 60.1, 63.8,
66.4, 126.0, 126.2, 126.5, 126.6, 127.6, 127.8, 128.0, 128.1,
128.6, 128.7, 129.1, 135.5, 136.1, 138.6, 149.7, 149.9, 155.5.
HRMS (FAB) calcd for C28H30NO4 [MH+] 444.2175, found
444.2177.
Ben zyl (2S)-3-P h en yl-2-(h yd r oxym eth yl)p r op yl Eth er
(19). To a solution of 18 (1.73 g, 4.03 mmol) in dry THF (20
mL) and methanol (0.17 mL) at 0 °C was added LiBH4 (231
mg, 10.6 mmol). The reaction was stirred for 16 h and then
quenched with 1 M aqueous sodium potassium tartrate (50
mL). The reaction mixture was extracted with CH2Cl2 (3 × 70
mL), and the combined organic layers were dried over MgSO4
and then concentrated to afford a colorless oil which was
purified by column chromatography (hexane/EtOAc 4:1) to
1
afford 19 as a colorless oil (836 mg, 81%). H NMR (300 MHz,
CDCl3): δ, 2.10-2.23 (m, 1H), 2.50-2.62 (m, 1H), 2.69 (d, 2H,
J ) 7.5 Hz), 3.51 (dd, 1H, J ) 6.6, 9.0 Hz), 3.58-3.69 (m, 2H),
3.75 (dd, 1H, J ) 3.9, 10.8 Hz), 4.51 (dd, 2H, J ) 11.7, 15.6
Hz), 7.18-7.39 (m, 10H); 13C NMR (75 MHz, CDCl3): δ, 34.4,
42.5, 65.3, 72.8, 73.4, 126.0, 127.6, 127.7, 128.3, 128.4, 129.0,
137.5, 139.9. HRMS (EI) calcd for C17H20O2 [M+] 256.14705,
found 256.14633.
Ben zyl (2S)-3-P h en yl-2-(ter t-b u t yloxym et h yl)p r op yl
Eth er (20). To a solution of 19 (416 mg, 1.62 mmol) in dry
cyclohexane (3 mL) were added tert-butyl trichloroacetamidate
(393 mg, 1.80 mmol) and BF3‚Et2O (32 µL, 0.32 mmol). The
reaction mixture was stirred for 16 h. Solid NaHCO3 was
added and, after stirring for 5 min, the reaction mixture was
filtered through a short silica plug, eluting first with cyclo-
hexane and then with CH2Cl2. Concentration of the cyclo-
hexane fraction afforded 20 as a colorless oil (130 mg, 26%).
Concentration of the CH2Cl2 fraction afforded a white solid/
oil mixture that was further purified by column chromatog-
raphy (hexane/EtOAc 4:1) to afford 20 as a colorless oil (187
1
mg, 37%). H NMR (300 MHz, CDCl3): δ, 1.19 (s, 9H), 2.03-
2.16 (m, 1H), 2.70 (d, 2H, J ) 7.5 Hz), 3.34 (dd, 2H, J ) 2.4,
5.4 Hz), 3.44 (dd, 2H, J ) 1.5, 5.4 Hz), 4.48 (s, 2H), 7.20-7.36
(m, 10H); 13C NMR (75 MHz, CDCl3): δ, 26.8, 27.5, 34.6, 41.8,
61.1, 69.9, 72.3, 72.9, 125.6, 127.3, 127.5, 128.0, 128.2, 129.2,
138.7, 140.6. HRMS (EI) calcd for C17H19O2 [M+ - C4H8]
255.13851, found 255.13866.
ter t-Bu tyl (2RS,6S)-6-[N-(Ben zyloxyca r bon yl)a m in o]-
2-ben zyl-5-oxo-7-p h en yl-3-h ep ten yl Eth er (24). To a mix-
ture of alcohols 23 (56 mg, 0.127 mmol) in dry cyclohexane
(0.40 mL) were added tert-butyl trichloroacetamidate (30 mg,
0.138 mmol) and BF3‚Et2O (1 drop). The reaction mixture was
stirred for 16 h. Solid NaHCO3 was added, and, after stirring
for 5 min, the reaction mixture was filtered through a short
silica plug, eluting first with CH2Cl2. Removal of the solvent
ter t-Bu t yl
(2R)-3-P h en yl-2-(h yd r oxym et h yl)p r op yl
Eth er (21). To a solution of 20 (175 mg, 0.56 mmol) in dry
ethanol (2 mL) was added a catalytic amount of 10% Pd/C.
The reaction flask was flushed with hydrogen, and the reaction
mixture was stirred under a hydrogen atmosphere for 2 h. The
(17) Sanko Company Limited. Eur. Pat. 0383 635 A2, 1986.