M. Mroczkiewicz, R. Ostaszewski / Tetrahedron 65 (2009) 4025–4034
4031
J¼6.8 Hz, 1H), 5.08 (s, 2H), 5.74 (t, J¼4.3 Hz, 1H), 6.54 (t, J¼5.2 Hz,
1H), 6.85 (d, J¼8.4 Hz, 2H), 7.08 (d, J¼8.4 Hz, 2H), 7.20–7.40 (m, 5H);
(d, J¼2.4 Hz, 2H), 5.75 (br s, 1H), 6.81 (br s, 1H), 6.87 (d, J¼8.8 Hz,
2H), 7.11 (d, J¼8.4 Hz, 2H), 7.28–7.38 (m, 5H); 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3)
d
15.2, 22.3, 22.7, 25.0, 37.1, 41.6, 43.3,
CDCl3) d 22.4, 22.6, 25.1, 37.0, 42.4, 43.3, 47.9, 55.3, 56.9, 61.8, 67.1,
47.5, 55.2, 56.6, 62.5, 62.6, 66.8, 100.3, 114.2, 127.4, 127.9, 128.1,
128.4, 136.2, 156.1, 159.0, 170.4; IR (film in CHCl3) nmax: 3328, 2957,
1723, 1648, 1514, 1455, 1249, 1176, 1128, 1058, 755, 698 cmꢀ1. Anal.
Calcd for C30H43N3O7: C, 64.61; H, 7.77; N, 7.53. Found: C, 64.55; H,
7.42; N, 7.58.
114.4, 127.5, 128.0, 128.1, 128.2, 128.5, 136.1, 156.8, 159.1, 171.1, 171.2;
IR (film in CHCl3) nmax: 3329, 2957, 1726, 1650, 1514, 1455, 1368,
1249, 1177, 1051, 753, 698 cmꢀ1
.
4.4.7.2. Method 2. To a solution of 20 (150 mg, 0.28 mmol) in THF
(2 mL), calcium chloride (62 mg, 0.56 mmol), lithium chloride
(24 mg, 0.56 mmol), and sodium borohydride (53 mg, 1.4 mmol)
were added. The reaction mixture was heated to 35 ꢁC for 20 h,
cooled to room temperature, and methanol (5 mL) was added.
Then, the reaction mixture was filtered and filtrate was evaporated
to dryness. The residue was dissolved in DCM (5 mL), washed with
an aqueous solution of hydrochloric acid (10 mL, 1 M), dried
(MgSO4), and solvent was evaporated. Product was purified by
column chromatography (silica gel, 70–325 mesh, 2.5 g, hexane/
EtOAc, 7:3, v/v). Yield: 93%, 126 mg (0.26 mmol) of a colorless oil;
4.4.4. {[(4-Methoxybenzyl)-(3-methyl-1-propylcarbamoylbutyl)-
carbamoyl]methyl}carbamic acid benzyl ester (19). General
procedure A
Yield: 89%, 471 mg (0.89 mmol) of a colorless oil; Rf¼0.36
(hexane/EtOAc, 4:6, v/v). 1H NMR (CDCl3, 400 MHz)
d 0.85 (dd,
J¼6.4, 8.4 Hz, 6H), 1.40–1.52 (m, 2H), 1.82–1.93 (m, 1H), 2.03 (s, 3H),
3.41 (q, J¼5.5 Hz, 2H), 3.78 (s, 3H), 3.98 (dd, J¼4.8, 12.0 Hz, 2H),
4.02–4.10 (m, 1H), 4.10–4.18 (m, 1H), 4.51 (s, 2H), 4.92 (t, J¼4.8 Hz,
1H), 5.09 (s, 2H), 5.71 (br s, 1H), 6.70 (br s, 1H), 6.86 (d, J¼8.4 Hz,
2H), 7.09 (d, J¼8.4 Hz, 2H), 7.28–7.38 (m, 5H); 13C NMR (100 MHz,
Rf¼0.23 (CHCl3/MeOH, 95:5, v/v). 1H NMR (CDCl3, 400 MHz)
d 0.86
CDCl3)
d
20.8, 22.3, 22.6, 25.1, 36.9, 38.5, 43.3, 47.6, 55.2, 56.9, 62.8,
(dd, J¼6.2, 11.4 Hz, 6H), 1.45–1.56 (m, 2H), 1.84–1.95 (m, 1H), 3.20–
3.32 (m,1H), 3.34–3.43 (m,1H), 3.60–3.65 (m, 2H), 3.79 (s, 3H), 3.83
(dd, J¼5.3, 16.8 Hz, 1H), 3.99 (dd, J¼5.1, 17.0 Hz, 1H), 4.50 (d,
J¼17.2 Hz, 1H), 4.57 (d, J¼17.2 Hz, 1H), 4.70 (s, 1H), 4.96 (t, J¼7.1 Hz,
1H), 5.09 (d, J¼2.2 Hz, 2H), 5.78 (t, J¼4.7 Hz, 1H), 6.80 (m, 1H), 6.87
(d, J¼8.4 Hz, 2H), 7.12 (d, J¼8.4 Hz, 2H), 7.29–7.38 (m, 5H); 13C NMR
66.9, 114.3, 127.4, 128.0, 128.1, 128.5, 136.2, 156.2, 159.0, 170.4, 170.8,
171.1; IR (film in CHCl3) nmax: 3329, 2957, 1726, 1650, 1514, 1455,
1368, 1249, 1177, 1051, 754, 698 cmꢀ1
; HRMS calcd for
C28H37N3O7Na [MþNa]þ: 550.2524; found: 550.2502.
4.4.5. {2-[(2-Benzyloxycarbonylaminoacetyl)-(4-methoxybenzyl)-
amino]-4-methylpentanoylamino}acetic acid ethyl ester (20).
General procedure A
(100 MHz, CDCl3) d 22.4, 22.6, 25.1, 37.0, 42.2, 43.3, 47.9, 55.3, 56.9,
61.8, 67.1, 114.4, 127.5, 128.0, 128.1, 128.2, 128.5, 136.1, 156.8, 159.1,
171.1, 171.2; IR (film in CHCl3) nmax: 3322, 2956, 1719, 1648, 1514,
1456, 1351, 1249, 1176, 1053, 754, 698 cmꢀ1; HRMS calcd for
C26H35N3O6Na [MþNa]þ: 508.2418; found: 508.2414.
Yield: 71%, 750 mg (1.42 mmol) of a colorless oil; Rf¼0.46
(hexane/EtOAc, 5:5, v/v). 1H NMR (CDCl3, 200 MHz)
d 0.78 (t,
J¼5.7 Hz, 6H), 1.19 (t, J¼7.1 Hz, 3H), 1.28–1.58 (m, 2H), 1.60–1.94 (m,
1H), 3.72 (s, 3H), 3.83 (t, J¼5.8 Hz, 2H), 3.93 (br s, 2H), 4.11 (q,
J¼7.2 Hz, 2H), 4.44 (s, 2H), 4.97 (br s,1H), 5.03 (s, 2H), 5.64 (br s,1H),
6.78 (d, J¼7.8 Hz, 2H), 6.87 (br s, 1H), 7.04 (d, J¼7.4 Hz, 2H), 7.10–
7.40 (m, 5H); IR (film in CHCl3) nmax: 3330, 2958, 1724, 1649, 1514,
1465, 1418, 1249, 1200, 1178, 1030, 755, 698 cmꢀ1. Anal. Calcd for
C28H37N3O7: C, 63.74; H, 7.07; N, 7.96. Found: C, 63.62; H, 7.46; N,
7.57.
4.4.8. ({(4-Methoxybenzyl)-[3-methyl-1-(2-oxoethylcarbamoyl)-
butyl]-carbamoyl}-methyl)-carbamic acid benzyl ester (22)
4.4.8.1. Method 1. To a solution of alcohol 21 (63 mg, 0.13 mmol)
in DCM (3 mL), water (1 mL), 2,2,6,6-tetramethyl (1.4 mg,
0.013 mmol), and sodium bromide (1.3 mg, 0.013 mmol) were
added. The reaction mixture was cooled to 0 ꢁC and an aqueous
solution of sodium hypochlorite (0.5 mL, 0.2 M solution saturated
with sodium bisulfate) was added dropwise for 30 min. After
additional 20 min, the reaction mixture was diluted with DCM
(10 mL) and water (10 mL). The layers were separated and the
aqueous layer was extracted with DCM (10 mL). The organic
layers were combined, washed with an aqueous solution of
hydrochloric acid (10 mL, 1 M) containing potassium iodide
(166 mg, 1 mmol), an aqueous solution of sodium thiosulfate
(10 mL, 10%) and water, and dried (MgSO4). The solvent was
evaporated and the product was purified by column chroma-
tography (silica gel, 70–325 mesh, 1 g, hexane/EtOAc, 8:2, v/v).
Yield: 46%, 28 mg (0.06 mmol) of a colorless oil; Rf¼0.38 (hexane/
4.4.6. Synthesis of compound 16. General procedure A
The product 16 was not obtained. The substrates were recovered
as p-methoxybenzylammonium N-benzyloxycarbonylaminoacetate
monohydrate; mp 134–137 ꢁC. 1H NMR (CD3OD, 400 MHz)
d
3.73 (s,
2H), 3.79 (s, 3H), 4.02 (s, 2H), 5.07 (s, 2H), 6.96 (d, J¼8.4 Hz, 2H), 7.20–
7.40 (m, 7H); 13C NMR (CD3OD,100 MHz)
44.7, 45.5, 56.6, 68.4,116.3,
d
127.2, 129.7, 129.8, 130.3, 132.4, 139.1, 159.7, 162.7, 176.5. Anal. Calcd
for C18H22N2O5þH2O: C, 59.33; H, 6.64; N, 7.69. Found: C, 59.57; H,
6.51; 7.60.
4.4.7. {[(1-(2-Hydroxyethylcarbamoyl)-3-methylbutyl)-(4-methoxy-
benzyl)-carbamoyl]-methyl}-carbamic acid benzyl ester (21)
EtOAc, 4:6, v/v). 1H NMR (CDCl3, 200 MHz)
d 0.60–1.05 (m, 6H),
1.30–1.64 (m, 2H), 1.68–2.00 (m, 1H), 3.78 (s, 3H), 4.02 (d,
J¼3.6 Hz, 4H), 4.51 (s, 2H), 5.07 (br s, 1H), 5.09 (s, 2H), 5.65–5.90
(m, 1H), 6.85 (d, J¼8.4 Hz, 2H), 7.05 (br s, 1H), 7.10 (d, J¼8.4 Hz,
4.4.7.1. Method 1. To a solution of 19 (196 mg, 0.38 mmol) in
methanol (2 mL), an aqueous solution of sodium hydroxide (375 mL,
1.50 mmol, 4 M) was added. After 30 min, the reaction mixture was
diluted with EtOAc (10 mL) and washed with an aqueous solution
of hydrochloric acid (10 mL, 1 M). Layers were separated and the
aqueous layer was extracted with EtOAc (10 mL). The combined
organic layers were dried (MgSO4) and solvent was evaporated.
Product was used to the next step without further purification.
Yield: 96%, 177 mg (0.36 mmol) of a colorless oil; Rf¼0.13 (hexane/
2H), 7.34 (s, 5H), 9.54 (s, 1H); 13C NMR (50 MHz, CDCl3)
d 22.8,
23.0, 25.5, 37.3, 43.8, 48.1, 50.3, 55.6, 56.9, 67.4, 114.7, 127.9, 128.3,
128.5, 128.8, 136.6, 156.6, 159.4, 171.3, 194.6.
4.4.8.2. Method 2. To a solution of 17 (54.2 mg, 0.1 mmol) in THF
(3 mL) cooled to ꢀ50 ꢁC, lithium aluminum hydride (4.8 mg,
0.125 mmol) was added. The reaction mixture was stirred for
10 min at ꢀ10 ꢁC and for 90 min at 0 ꢁC. Then, an aqueous solution
of sodium bisulfate (0.15 mL, 0.15 mmol, 1 M) and water (10 mL)
were added. The layers were separated and the aqueous layer was
extracted with diethyl ether (10 mL). The combined organic layers
were washed with an aqueous solution of hydrochloride acid
EtOAc, 4:6, v/v). 1H NMR (CDCl3, 400 MHz)
d
0.86 (dd, J¼6.2,
12.0 Hz, 6H), 1.42–1.55 (m, 2H), 1.83–1.95 (m, 1H), 3.20–3.32 (m,
1H), 3.33–3.43 (m, 1H), 3.60–3.66 (m, 2H), 3.79 (s, 3H), 3.83 (dd,
J¼5.2, 16.8 Hz, 1H), 3.99 (dd, J¼5.2, ¼17.2 Hz, 1H), 4.50 (d, J¼17.2 Hz,
1H), 4.57 (d, J¼17.2 Hz, 1H), 4.70 (s, 1H), 4.96 (t, J¼7.0 Hz, 1H), 5.09