488 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 1
Dong et al.
CHCl3 (10 mL) was added isonipecotic acid (129 mg, 1.0 mmol).
The resulting mixture was stirred at rt for 16.5 h before removal
of the solvents. The residue was crystallized from 1:1 EtOH/
water to afford 34 (179 mg, 82%) as a colorless solid. Mp
159-161 ꢀC; 1H NMR (CDCl3) δ 1.18-1.35 (m, 2H),
1.58-2.06 (m, 25H), 2.24 (d, J=6.8 Hz, 2H), 2.60 (tt, J=10.7,
3.9 Hz, 1H), 2.86 (t, J=11.2 Hz, 1H), 3.14 (t, J=11.2 Hz, 1H),
3.85 (d, J=13.7 Hz, 1H), 4.44 (d, J=13.6 Hz, 1H); 13C NMR
(CDCl3) δ 26.48, 26.86, 27.72, 28.33, 30.27, 33.37, 34.06, 34.79,
36.39, 36.80, 39.23, 40.46, 40.93, 44.96, 108.62, 111.34, 170.53,
178.19. Anal. (C24H35NO6) C, H, N.
cis-Adamantane-2-spiro-30-80-[[[40-(aminocarbonyl)-10-piperi-
dinyl]carbonyl]methyl]-10,20,40-trioxaspiro[4.5]decane (35). To a
solution of 2 (220 mg, 0.5 mmol) in CHCl3 (10 mL) and EtOH
(10 mL) was added isonipecotamide (128 mg, 1.0 mmol). The
resulting mixture was stirred at rt for 4 h before removal of the
solvents. The residue was crystallized from 2:1 EtOH/water to
afford 35 (164 mg, 76%) as a colorless solid. Mp 149-151 ꢀC; 1H
NMR (CDCl3) δ 1.16-1.32 (m, 2H), 1.58-2.06 (m, 25H), 2.22
(d, J=6.8 Hz, 2H), 2.39 (tt, J=11.2, 3.9 Hz, 1H), 2.69 (t, J=11.5
Hz, 1H), 3.06 (t, J=11.7 Hz, 1H), 3.92 (d, J=13.7 Hz, 1H), 4.60
(d, J=13.2 Hz, 1H), 5.54 (s, 2H); 13C NMR (CDCl3) δ 26.46,
26.84, 28.60, 29.02, 30.25, 30.30, 33.31, 34.05, 34.77, 36.37,
36.78, 39.24, 41.04, 42.37, 45.15, 108.61, 111.31, 170.39,
176.16. Anal. (C24H36N2O5) C, H, N.
cis-adamantane-2-spiro-30-80-(20-carboxyethyl)-10,20,40-trioxas-
piro[4.5]decane (13.2 g, 95%) as a colorless solid. Mp 144-
146 ꢀC; 1H NMR (CDCl3) δ 1.12-1.26 (m, 2H), 1.27-1.38 (m,
1H), 1.57 (dt, J=7.8, 7.1 Hz, 2H), 1.62-2.04 (m, 20H), 2.36 (t,
J=7.6 Hz, 2H), 11.58 (br s, 1H); 13C NMR (CDCl3) δ 26.47,
26.86, 29.72, 30.80, 31.71, 34.02, 34.76, 34.78, 35.44, 36.37,
36.79, 108.76, 111.25, 180.06. Step 3. A solution of the above
ozonide acid (0.5 g, 1.5 mmol), HOSu (0.21 g, 1.79 mmol), and
EDCI (0.34 g, 1.79 mmol) in DMF (20 mL) under Ar was stirred
at rt for 24 h before being quenched with water (25 mL) at 0 ꢀC.
The precipitate was filtered, washed with 95% aq EtOH
(10 mL), and dried to afford the active ester (0.64 g, 100%) as
a colorless solid. Mp 144-146 ꢀC; 1H NMR (500 MHz, CDCl3)
δ 1.16-1.29 (m, 2H), 1.35-1.44 (m, 1H), 1.63-2.02 (m, 22H),
2.62 (t, J=7.6 Hz, 2H), 2.83 (br s, 4H). Step 4. To a solution of
the ozonide active ester (0.5 g, 1.15 mmol) in CHCl3 (25 mL) was
added in one portion a solution of 1,2-diamino-2-methylpro-
pane (0.20 g, 2.3 mmol) in CHCl3 (15 mL). The reaction mixture
was stirred at rt for 1 h before being quenched with water
(50 mL). After separation of the organic layer, the aqueous
layer was extracted with CHCl3 (2 ꢀ 25 mL). The combined
extracts were washed with water (3 ꢀ 50 mL), dried over MgSO4,
and filtered. To the filtrate was added a solution of p-toluene-
sulfonic acid monohydrate (0.22 g, 1.16 mmol) in EtOH
(10 mL). After evaporation of the solvents, the residue was treated
with ether (15 mL). The solid was collected by filtration, washed
with ether (30 mL), and dried to afford 37 (0.49 g, 74%) as a
colorless solid. Mp 114-118 ꢀC; 1H NMR (CDCl3) δ 0.86-1.02
(m, 3H), 1.33 (s, 6H), 1.34-1.58 (m, 6H), 1.62-2.06 (m, 18H), 2.39
(s, 3H), 3.42 (d, J=5.9 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.64 (br s,
1H), 7.67 (d, J=7.8 Hz, 2H), 7.78 (s, 3H); 13C NMR (CDCl3) δ
21.36, 23.85, 26.45, 26.85, 29.52, 31.53, 33.33, 33.98, 34.76, 35.58,
36.36, 36.77, 46.54, 56.17, 108.61, 111.11, 125.64, 129.32, 140.03,
cis-Adamantane-2-spiro-30-80-[[(20-amino-20-methylpropyl)-
amino]carbonyl]-10,20,40-trioxaspiro[4.5]decane p-Tosylate (36).
Step 1. A mixture of 712 (8.7 g, 28.3 mmol), HOBt (4.59 g,
34.0 mmol), and EDCI (6.52 g, 34.0 mmol) in DMF (70 mL) was
stirred at rt overnight before addition of water (70 mL). The
precipitate was collected by filtration and dried to afford the
ozonide active ester (11.0 g, 91%) as a colorless solid. Mp
153-154 ꢀC; 1H NMR (CDCl3) δ 1.64-2.16 (m, 20 H),
2.20-2.30 (m, 2H), 2.88-2.98 (m, 1H), 7.35 (d, J = 8.3 Hz,
1H), 7.43 (t, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 8.07 (d, J=
8.3 Hz, 1H). Step 2. A mixture of the above active ester (425 mg,
1 mmol) and 1,2-diamino-2-methylpropane (229 mg, 2.5 mmol)
in CHCl3 (10 mL) was stirred at rt for 4 h. The reaction mixture
was washed with water (10 mL) and brine (10 mL) and dried
over MgSO4. After filtration, a solution of p-toluenesulfonic
acid monohydrate (190 mg, 1 mmol) in MeOH (2 mL) was
added. The resulting mixture was concentrated and triturated
with EtOAc to afford 36 (360 mg, 65%) as a colorless solid. Mp
141.70, 175.48. Anal. (C30H46N2O7S 1.2H2O) C, H, N.
3
cis-Adamantane-2-spiro-30-80-[[[(20-amino-20-methylpropyl)-
amino]carbonyl]amino]-10,20,40-trioxaspiro[4.5]decane p-Tosy-
late (38). Step 1. To a solution of the free base of 1015 (0.70 g,
2.51 mmol) in CH2Cl2 (100 mL) was added pyridine (0.3 mL)
followed by a solution of the 4-nitrophenyl chloroformate (0.6 g,
2.98 mmol) in CH2Cl2 (50 mL) at 0 ꢀC. The resulting mixture
was stirred at rt for 24 h, then diluted with CH2Cl2 (100 mL),
washed with 1 M aq NaHCO3 (2 ꢀ 100 mL), water (2 ꢀ 100 mL),
and brine (100 mL), dried over MgSO4, and filtered. After
removal of solvent, the crude product was purified by crystal-
lization from EtOH to afford the cis-adamantane-2-spiro-
30-80-[[(40-nitrophenoxy)carbonyl]amino]-10,20,40-trioxaspiro-
[4.5]decane (1.0 g, 90%). Step 2. To a solution of 1,2-diamino-
2-methylpropane (0.40 g, 4.64 mmol) in CHCl3 (10 mL) was
added dropwise a solution of the above 4-nitrophenyl carba-
mate (0.4 g, 0.90 mmol) in CHCl3 (10 mL) and MeOH (20 mL).
The resulting mixture was stirred at rt for 4 h and then quenched
with water (30 mL). After separation of the organic layer, the
aqueous layer was extracted with CHCl3 (2 ꢀ 30 mL). The
combined extracts were washed with 1 M aq NaHCO3 (2 ꢀ
20 mL), water (3 ꢀ 20 mL), and brine (20 mL), dried over
MgSO4, filtered, and concentrated. The residue was dissolved in
CHCl3 (20 mL) and then treated with a solution of p-toluene-
sulfonic acid monohydrate (0.17 g, 0.89 mmol) in EtOH
(10 mL). After evaporation of the solvent, the crude product
was purified by crystallization from 1:4 EtOH/CH2Cl2 to afford
38 (0.16 g, 31%) as a colorless solid. Mp 172-173 ꢀC; 1H NMR
(DMSO-d6) δ 1.13 (s, 6H), 1.27-1.39 (m, 2H), 1.59-1.93 (m,
20H), 2.28 (s, 3H), 3.10 (d, J=5.8 Hz, 2H), 3.44-3.54 (m, 1H),
6.01-6.11 (m, 2H), 7.10 (d, J=7.8 Hz, 2H), 7.47 (d, J=7.8 Hz,
2H), 7.65 (s, 3H); 13C NMR (DMSO-d6) δ 20.95, 23.31, 23.36,
25.95, 26.35, 30.04, 32.16, 34.41, 34.43, 35.87, 36.22, 46.37,
47.26, 54.51, 108.08, 110.87, 125.66, 128.20, 137.72, 145.97,
158.14. Anal. (C28H43N3O7S) C, H, N.
1
154-156 ꢀC; H NMR (CDCl3) δ 1.19-1.31 (m, 2H), 1.36 (s,
6H), 1.48-2.03 (m, 21H), 2.40 (s, 3H), 3.45 (d, J=6.3 Hz, 2H),
7.24 (d, J=8.3 Hz, 2H), 7.33 (d, J=6.6 Hz, 1H), 7.67 (d, J=8.3
Hz, 2H), 7.75 (s, 3H); 13C NMR (CDCl3) δ 21.33, 23.89, 26.43,
26.52, 26.85, 33.34, 34.74, 34.76, 36.36, 36.75, 43.04, 46.13,
56.44, 107.69, 111.15, 125.50, 129.39, 140.40, 141.67, 175.98.
Anal. (C28H42N2O7S) C, H, N.
cis-Adamantane-2-spiro-30-80-[20-[[(20-amino-20-methylpropyl)-
amino]carbonyl]ethyl]-10,20,40-trioxaspiro[4.5]decane p-Tosylate
(37). Step 1. A solution of 317 (22.35 g, 124.7 mmol) and methyl
3-(4-oxocyclohexyl)propionate18 (15.3 g, 83.1 mmol) in cyclo-
hexane (400 mL) and CH2Cl2 (80 mL) was treated with ozone
according to the method of Dong et al.12 After removal of
solvents, the crude product was purified by crystallization from
80% aq EtOH (150 mL) to afford adamantane-2-spiro-30-80-(20-
methoxycarbonylethyl)-10,20,40-trioxaspiro[4.5]decane (17.18 g,
59%) as a colorless solid. Mp 102-104 ꢀC; 1H NMR (CDCl3) δ
1.15-1.23 (m, 2H), 1.24-1.37 (m, 1H), 1.54-1.61 (m, 2H),
1.62-2.05 (m, 20H), 2.32 (t, J=7.8 Hz, 2H), 3.66 (s, 3H); 13
C
NMR (CDCl3) d 26.46, 26.86, 29.72, 31.10, 31.74, 34.04, 34.75,
34.77, 35.53, 36.36, 36.78, 51.49, 108.79, 111.20, 174.17. Step 2.
To a solution of the above ozonide ester (14.43 g, 41.2 mmol) in
95% aq EtOH (200 mL) was added NaOH (4.90 g, 123.7 mmol)
solution in water (100 mL). The mixture was stirred at 50 ꢀC for
4 h, cooled to 0 ꢀC, and treated with 1 M HCl (162 mL). The
precipitate was collected by filtration, washed with 50% aq
EtOH (150 mL), and dried in a vacuum oven at 40 ꢀC to give
cis-Adamantane-2-spiro-30-80-[[[[(20-amino-20-methylpropyl)-
amino]carbonyl]amino]methyl]-10,20,40-trioxaspiro[4.5]decane