Ho et al.
1
Hz), 3.54 (dd, 1H, J ) 14.0, 4.1 Hz), 3.73 (m, 1H), 3.75 (s, 3H),
4.40 (d, 1H, J ) 5.2 Hz), 7.75 (s, 1H); 13C NMR δ -4.9, -4.7,
17.9, 25.6, 53.2, 54.0, 55.5, 72.2, 116.9, 159.7. Anal. Calcd for
mp 105-107 °C; H NMR δ 2.14 (dd, 2H, J ) 15.5, 5.7 Hz,
2.59 (quintet, 1H, J ) 5.1 Hz), 2.99 (dd, 1H, J ) 11.0, 4.8 Hz),
3.16 (dd, 1H, J ) 11.0, 4.8 Hz), 3.62 (s, 3H), 7.15-7.85 (m,
13H); 13C NMR δ 37.8, 51.1, 51.9, 64.7, 72.7, 120.4, 125.3,
125.5, 126.2, 126.4, 127.6, 128.2, 128.5, 128.7, 128.8, 128.9,
C
12H23N5O2Si: C, 48.48; H, 7.74; N, 23.57. Found: C, 48.48;
H, 7.74; N, 23.57.
140.4, 140.9, 145.2, 150.0, 150.2, 173.2. Anal. Calcd for C24H23
NO3: C, 77.21; H, 6.22; N, 3.75. Found: C, 76.95; N. 6.21; N,
3.77.
-
4-[(1R)-2-Azid o-1-[(ter t-bu tyld im eth ylsilyl)oxy]eth yl]-
1-cyclop en t yl-5-[d im et h yla m in om et h ylen e]a m in o]im -
id a zole (11). A solution of imidate 5b (297 mg, 1 mmol) and
cyclopentylamine (80 µL, 69 mg, 0.81 mmol) in 2,2,2-trifluo-
roethanol (1 mL) and 1,2-dichloroethane (10 mL) was stirred
at 80 °C for 4 h to yield 10. An analytical sample was obtained
by flash chromatography (EtOAc:Et3N ) 99:1): 1H NMR δ 0.01
(s, 3H), 0.20 (s, 3H), 0.09 (s, 9H), 1.6-2.20 (m, 8H), 3.30-3.45
(m, 4H), 4.25-4.30 (m, 1H), 4.97 (t, J ) 4.2 Hz, 1H), 7.13 (s,
1H). Anal. Calcd for C16H30N6OSi: C, 54.82; H, 8.63; N, 23.97.
Found: C, 55.11; H, 8.76; N, 24.01.
A solution of oxalyl chloride (2.0 M, 23 mL, 46 mmol) in
CH2Cl2 (60 mL) was cooled at -78 °C as DMSO (7 mL in 17
mL of CH2Cl2) was added via a syringe pump at such a rate
(1 mL/min) that the temperature remained below -60 °C. The
mixture was cooled to -78 °C for 1 h, freshly prepared 14 in
CH2Cl2 (ca. 40 mL) was added slowly, and stirring was
continued at -78 °C for 1 h. Et3N (25 mL, 180 mmol) was
added, the resulting mixture was stirred at -78 °C for 0.5 h,
and 1% aq HCl (150 mL) was added. The solution was warmed
to room temperature and extracted with CH2Cl2 (100 mL ×
3). The combined organic layers were washed with brine (100
mL), dried over Na2SO4, and filtered. The filtrate was concen-
trated to dryness, and the residue was immediately purified
by flash chromatography (EtOAc:hexane ) 15:85) to give the
aldehyde 15 (4.4 g, 61%): mp 105-107 °C; 1H NMR δ 2.21
(dd, 1H, J ) 11.9, 5.7 Hz), 2.51 (dd, 1H, J ) 11.9, 4.3 Hz),
2.82 (ddd, 1H, J ) 6.1, 5.7, 4.3 Hz), 3.46 (d, 1H, J ) 6.1 Hz),
3.65 (s, 3H), 7.20-7.43 (m, 11H), 7.69 (m, 2H), 9.44 (s, 1H);
13C NMR δ 36.6, 51.8, 58.7, 72.8, 120.0, 120.2, 125.2, 125.3,
126.1, 127.4, 128.0, 128.2, 128.4, 128.6, 128.7, 140.1, 144.2,
149.0, 149.3, 171.6, 201.7. Anal. Calcd for C24H21NO3: C, 77.60;
H, 5.71; N, 3.77. Found: C, 77.55; H, 5.95; N, 3.68.
Meth yl (3S)-5-Meth oxyca r bon yl-3-[N-(9-p h en yl-9-flu o-
r en yl)a m in o]-4-p en ten oa te (16 a n d 17). A suspension of
NaH (60% suspension in mineral oil, 2.8 g, 70 mmol) in THF
(1500 mL) was stirred at 0 °C as trimethyl phosphonoacetate
(11 mL, 68 mL) was added, and the resulting mixture was
stirred at 0 °C for 2 h. The mixture was cooled to -40 °C, and
a solution of aldehyde 15 (8.6 g, 23.2 mmol) in THF (100 mL)
was added over 10 min. The resulting mixture was stirred at
-40 °C for 2 h. Aqueous KH2PO4 (1 M, 600 mL) and EtOAc
(400 mL) were added, and the particulates were filtered. The
aq phase was extracted with EtOAc (100 mL × 2), and the
combined organic layers were washed with water (200 mL ×
2) and brine (100 mL), dried (MgSO4), and filtered. The solvent
was evaporated, and the residue was purified by flash chro-
matography (EtOAc:hexane ) 15:85) to give a 10:1 mixture
(8.96 g, 92%) of trans olefin 16 and cis olefin 17. Analytical
samples were prepared by an additional chromatography
(EtOAc:hexane ) 10:90).
Without purification of 10, N,N-dimethylformamide dimeth-
yl acetal (0.5 mL, 3.77 mmol) was added, and the resulting
mixture was heated at reflux temperature for 13 h. Purification
by flash chromatography on SiO2 (EtOAc:hexane:Et3N ) 30:
70:0.1) gave imidazole 11 (220 mg, 67%): [R]D +68.5 (c 0.11,
1
CHCl3); H NMR δ -0.11 (s, 3H), -0.02 (s, 3H), 0.84 (s, 9H),
1.77 (m, 6H), 2.07 (m, 2H), 3.00 (s, 6H), 3.34 (dd, 1H, J ) 12.4,
4.9 Hz), 3.64 (dd, 1H, J ) 12.4, 8.5 Hz), 4.49 (quintet, 1H, J )
7.2 Hz), 4.76 (dd, 1H, J ) 8.5, 4.9 Hz), 7.22 (s, 1H), 7.79 (s,
1H); 13C NMR δ -4.9, -4.4, 18.4, 24.3, 26.2, 33.1, 33.4, 55.3,
56.0, 69.9, 123.9, 129.2, 139.1, 155.5. Anal. Calcd for C19H35N7-
OSi: C, 56.14; H, 8.78; N, 24.12. Found: C, 56.24; H, 8.68; N,
24.11.
(8R)-8-[(ter t-Bu t yld im et h ylsilyl)oxy]-3-cyclop en t yl-
3,6,7,8-tetr a h yd r oim id a zo[4,5-d ][1,3]d ia zep in e (12a ). A
solution of imidazole 11 (206 mg, 0.5 mmol), propanedithiol
(0.5 mL, 5 mmol), and triethylamine (1 mL, 7.2 mmol) in
methanol (5 mL) was heated at 50 °C. After 13 h, the solvent
was evaporated to give a yellow oil which was purified by flash
chromatography (EtOAc:hexane:Et3N ) 50:50:0.1) to afford
1
diazepine 12a (145 mg, 85%): [R]D +72.5 (c 0.12, CHCl3); H
NMR δ -0.10 (s, 3H), 0.14 (s, 3H), 0.85 (s, 9H), 1.70 (m, 6H),
2.13 (m, 2H), 3.40 (m, 1H), 4.73 (quintet, 1H, J ) 7.1 Hz),
5.20 (m, 1H), 5.43 (br s, 1H), 7.07 (d, 1H, J ) 4.2 Hz), 7.29
(s, 1H); 13C NMR δ -4.4, -4.1, 18.6, 24.1, 24.2, 26.1, 33.6,
50.2, 54.9, 69.2, 129.6, 130.4, 145.9. Anal. Calcd for C19H35N7-
OSi: C, 61.08; H, 8.98; N, 16.77. Found: C, 61.16; H, 8.75; N,
16.72.
(8R)-3-Cyclop en t yl-8-h yd r oxy-3,6,7,8-t et r a h yd r oim i-
d a zo[4,5-d ][1,3]d ia zep in e (12b). A solution of silyl ether 12a
(132 mg, 0.4 mmol) in 1,4-dioxane (30 mL) in a Teflon
container was cooled in an ice bath as aq HF (49%, 10 mL)
was added slowly. The mixture was stirred at room temper-
ature for 3 h, diluted with CHCl3 (100 mL), and washed with
saturated aq Na2CO3 (200 mL). The aq phase was extracted
with CHCl3/isopropyl alcohol (3:1, 100 mL × 5), and the
combined organic layers were dried (Na2SO4) and concentrated
to a yellow oil. Purification was effected by flash chromatog-
raphy (IPA:CHCl3:Et3N ) 10:90:0.1) to give 12b (183 mg,
96%): [R]D +85.0 (c 0.14, CHCl3); 1H NMR δ 1.77 (m, 6H), 2.13
(m, 2H), 3.42 (m, 2H), 4.73 (quintet, 1H, J ) 7.5 Hz), 4.94 (br
s, 1H), 5.14 (m, 1H), 6.08 (br s, 1H), 7.09 (s, 1H), 7.41 (s, 1H);
13C NMR δ 23.3, 32.6, 54.9, 66.9, 72.1, 128.4, 135.5, 148.1,
148.2. Anal. Calcd for C19H35N7OSi: C, 55.44; H, 7.61; N, 23.51.
Found: C, 55.26; H, 8.00; N, 23.11.
Meth yl (3S)-3-[N-(9-P h en yl-9-flu or en yl)a m in o]-4-oxo-
bu ta n oa te (15). A stirred solution of 138 (7.0 g, 19 mmol) in
THF (60 mL) was cooled to -78 °C as BH3 (1.0 M solution in
THF, 45 mL, 4.5 mmol) was added. The solution was warmed
to 0 °C and stirred for 60 h. Aqueous NH4Cl (80 mL) was
added, and the mixture was extracted twice with CH2Cl2 (100
mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated to about 40 mL, which was im-
mediately used in the next step without purification. A small
amount of alcohol 14 was purified by flash chromatography
(EtOAc:hexane ) 30:70) in a cold room (<4 °C):
Data for 16 (E isomer): [R]D +43.0 (c 0.04, CHCl3); 1H NMR
δ 2.24 (dd, J ) 15.4, 5.1 Hz, 1H), 2.37 (dd, J ) 15.4, 7.5 Hz,
1H), 2.82 (br s, 1H), 3.15-3.20 (m, 1H), 3.59 (s, 3H), 3.65 (s,
3H), 5.15 (d, J ) 15.6 Hz, 1H), 6.37 (dd, J ) 15.6, 8.3 Hz, 1H),
7.28 (m, 11H), 7.60 (d, J ) 7.5 Hz, 1H), 7.69 (d, J ) 7.5 Hz,
1H); 13C NMR δ 40.4, 51.2, 51.6, 51.9, 72.5, 119.1, 119.7, 120.0,
125.1, 125.6, 126.0, 127.2, 127.7, 127.8, 128.3, 128.5, 140.3,
140.6, 144.9, 148.9, 150.0, 166.4, 171.4. Anal. Calcd for C27H25
NO4: C, 75.85; H, 5.91; N, 3.28. Found: C, 75.54; H, 6.03; N,
3.23.
Data for 17 (Z isomer): [R]D +36.0 (c 0.02, CHCl3); 1H NMR
δ 2.38 (m, 2H), 2.95 (br s, 1H), 3.39 (s, 3H), 3.68 (s, 3H), 4.24
(m, 1H), 4.98 (dd, J ) 10.6, 1.0 Hz, 1H), 5.73 (dd, J ) 10.6,
9.3 Hz, 1H), 7.28 (m, 11H), 7.56 (d, J ) 7.5 Hz, 1H), 7.61 (d,
J ) 7.5 Hz, 1H); 13C NMR δ 40.5, 48.3, 50.8, 51.6, 72.5, 116.6,
119.5, 119.7, 125.3, 125.6, 126.0, 127.1, 127.3, 127.8, 128.1,
128.2, 128.3, 140.5, 140.8, 144.9, 148.9, 150.7, 151.9, 165.7,
172.1. Anal. Calcd for C27H25NO4: C, 75.85; H, 5.91; N, 3.28.
Found: C, 76.05; H, 5.99; N, 3.20.
Dim eth yl (3R)-3-[N-(9-P h en yl-9-flu or en yl)a m in o]a d i-
p a te (18). A slurry of a 10:1 mixture of esters 16 and 17 (8.96
g, 21 mmol), EtOAc (100 mL), MeOH (50 mL), and 5% Pt/C (1
g) was hydrogenated in a Parr shaker under 20 psi of H2 at
room temperature for 30 h. The reaction mixture was filtered,
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112 J . Org. Chem., Vol. 68, No. 1, 2003