Dihydromotuporamine Derivatives
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 11 3837
purified by flash column chromatography on silica gel or used
in the next step without further purification: yield 95%; Rf )
0.5, 50% CHCl3/hexane; 1H NMR (CDCl3) δ 5.71-5.88 (m, 2H,
CH), 4.86-5.04 (m, 4H, CH2), 3.02-3.27 (bm, 4H, NCH2), 2.05
(q, 4H, CH2), 1.34-1.58 (m, 16H, CH2), 1.30 (br s, 9H, CH3);
13C NMR (CDCl3) δ 156.0, 139.4, 138.8, 114.7, 114.3, 79.1, 47.3,
47.1, 34.2, 33.8, 29.8, 29.7, 29.4, 29.3, 28.8, 27.2, 26.5; HRMS
(FAB) calcd for C21H40NO2 (M + H)+ 338.3059, found 338.3085.
Azacyclopentadec-6-ene-1-carboxylic Acid tert-Butyl
Ester (13). Separate solutions of 12 (600 mg, 1.78 mmol) and
Grubb’s catalyst (48 mg, 0.060 mmol, 3.37 mol %) each in dry
CH2Cl2 (75 mL) were simultaneously added dropwise to a
refluxing solution of dry CH2Cl2 (550 mL) over a period of 6 h
under an Ar atmosphere. After the addition was complete, the
reaction mixture was allowed to reflux for 12 h. After the
consumption of 12 was checked by 1H NMR (CDCl3), the
solvent was removed and the residue was purified by column
chromatography (50% CHCl3/hexane). The pale-yellow oil 13
was isolated in 72% yield (mixture of E and Z isomers): Rf )
0.5, 50% CHCl3/hexane; 1H NMR (CDCl3) δ 5.30 (m, 2H, CH),
3.10-3.23 (m, 4H, NCH2), 2.07 (m, 4H, CH2), 1.22-1.61 (m,
25H, 8 × CH2, 3 × CH3); 13C NMR (CDCl3) δ 154.4, 131.68,
131.65, 131.9, 130.8, 79.1, 49.6, 49.5, 47.9, 32.3, 32.21, 31.5,
31.3, 29.98, 28.97, 28.8 (3C), 28.6, 28.5, 28.4, 28.0, 27.7, 27.6,
27.2, 27.1, 26.9, 26.7, 26.4; HRMS (FAB) calcd for C19H36NO2
(M + H)+ 310.2746, found 310.274.
Azacyclopentadecane-1-carboxylic Acid tert-Butyl Es-
ter (14). Pd on charcoal (20 wt %, 74 mg) was added to a
stirring solution of alkene 13 (354 mg, 1.14 mmol) in ethanol
(5 mL). The flask was briefly evacuated, and H2 gas was
admitted via a balloon. The reaction mixture was allowed to
stir overnight under a H2 atmosphere at room temperature.
The black suspension was then filtered through a layer of
Celite and washed with MeOH. The combined filtrates were
evaporated. Compound 14 was obtained as a pale-yellow
viscous oil in 99% yield: 1H NMR (CDCl3) δ 3.18 (m, 4H,
NCH2), 1.58 (m, 4H, CH2), 1.21-1.49 (m, 29H, 10 × CH2, 3×
CH3); 13C NMR (CDCl3) δ 156.0, 79.7, 48.3, 28.4, 28.0, 27.4,
26.5, 26.1, 26.0, 25.1.
Azacyclopentadecane Hydrochloride Salt (15). A solu-
tion of Boc-protected azacyclopentadecamine 14 (352 mg,
1.13 mmol) was dissolved in absolute ethanol (12 mL) and
stirred at 0 °C for 10 min. A 4 N HCl (18 mL) solution was
added dropwise, and stirring was continued at 0 °C for 20 min
and then at room temperature overnight. The solution was
concentrated in vacuo to give 15 as a white solid in 99% yield:
1H NMR (CDCl3) δ 3.06 (t, 4H, NCH2), 1.74 (q, 4H, CH2), 1.40-
1.52 (m, 20H, CH2); 13C NMR (CDCl3) δ 44.7, 26.8, 26.52, 26.48,
25.0, 23.67; HRMS (FAB) calcd for C14H29N·HCl (M - Cl)+
212.2378, found 212.2372.
Methanesulfonic Acid 3-tert-Butoxycarbonylamino-
propyl Ester (19a). To a solution of the alcohol 18a (9.91 g,
57 mmol) and triethylamine (39.1 mL, 280 mmol) in CH2Cl2
(130 mL) at 0 °C, methanesulfonyl chloride (32.42 g, 28 mmol)
was added dropwise over 30 min under a N2 atmosphere. The
reaction mixture was stirred at 0 °C for 1 h and was slowly
warmed to room temperature and stirred overnight under
N2. The reaction mixture was then cooled to 0 °C, and a 4 M
NaOH solution (50 mL) was added slowly with vigorous
stirring. The organic phase was separated and washed with
water (2 × 70 mL). The organic phase was separated, dried
over anhydrous Na2SO4, filtered, and concentrated to give the
product 19a as a clear oil (95%) that was used in the next step
without further purification: Rf ) 0.5 (40% acetone/hexane);
1H NMR (CDCl3) δ 5.06 (br s, 1H, NH), 4.27 (t, 2H, OCH2),
3.21 (m, 2H, NCH2), 3.01 (s, 3H, CH3), 1.88 (quin, 2H, CH2),
1.43 (s, 9H, CH3).
Methanesulfonic Acid 4-tert-Butoxycarbonylamino-
butyl Ester (19b). Compound 19b was prepared by the same
procedure as for 19a using 18b as the starting alcohol. 19b:
yield 95% Rf ) 0.5 (40% acetone/hexane); 1H NMR (CDCl3)
δ 4.85 (br s, 1H, NH), 4.27 (t, 2H, OCH2), 3.16 (m, 2H, NCH2),
3.01 (s, 3H, CH3), 1.78 (quin, 2H, CH2), 1.59 (quin, 2H, CH2),
1.43 (s, 9H, CH3).
[3-(3-Hydroxypropylamino)propyl]carbamic Acid tert-
Butyl Ester (20a). The mesylate 19a (3.26 g, 13 mmol) and
3-aminopropanol (3.87 g, 52 mmol) were dissolved in aceto-
nitrile (20 mL). The mixture was then stirred at 75 °C under
a N2 atmosphere overnight. After the confirmation of the
disappearance of the mesylate by TLC, the solution was
concentrated under reduced pressure. The residue was dis-
solved in CH2Cl2 (20 mL) and washed three times with
aqueous sodium carbonate. The organic layer was separated,
dried with anhydrous Na2SO4, filtered, and concentrated under
vacuum. Flash column chromatography of the residue gave
20a as a light-yellow oil: yield 68%; Rf ) 0.35 (1:10:89
NH4OH/MeOH/CHCl3); 1H NMR (CDCl3) δ 5.05 (br t, 1H, NH),
3.77 (t, 2H, OCH2), 3.16 (q, 2H, BocNCH2), 2.83 (t, 2H, NCH2),
2.67 (t, 2H, NCH2), 1.69 (quin, 4H, CH2), 1.43 (s, 9H, CH3).
[4-(4-Hydroxybutylamino)butyl]carbamic Acid tert-
Butyl Ester (20b). Compound 20b was prepared in 65% yield
by the same procedure as for 20a using 4-aminobutanol and
19b as the starting materials. 20b: Rf ) 0.35 (1:10:89
NH4OH/MeOH/CHCl3); 1H NMR (CDCl3) δ 5.05 (br s, 1H,
NHCO), 3.54 (t, 2H, OCH2), 3.07 (m, 2H, BocNCH2), 2.61
(m, 4H, NCH2), 1.64 (quin, 4H, CH2), 1.55 (quin, 4H, CH2),
1.42 (s, 9H, CH3).
(3-tert-Butoxycarbonylaminopropyl)-(3-hydroxypro-
pyl)carbamic Acid tert-Butyl Ester (21a). A solution of 20a
(1.27 g, 5.5 mmol) in triethylamine/MeOH (1:7 v/v, 150 mL)
was stirred at 0 °C for 10 min. A solution of di-tert-butyl
dicarbonate (1.79 g, 8.2 mmol) in MeOH (50 mL) was added
dropwise over 10 min. The mixture was stirred for 1 h at
0 °C. The temperature was then allowed to gradually rise to
room temperature, and the solution was stirred overnight
under an N2 atmosphere. The solution was then evaporated
under reduced pressure, and the residue was dissolved in
CH2Cl2 and washed with deionized water several times. The
organic layer was separated, dried with anhydrous Na2SO4,
filtered, and concentrated to give 21a as a colorless oil (90%)
that was used in the next step without further purification:
Rf ) 0.7 (1:10:89 NH4OH/MeOH/CHCl3); 1H NMR (CD3OD)
δ 3.55 (t, 2H, OCH2), 3.28 (t, 2H, NCH2), 3.24 (t, 2H, NCH2),
3.04 (q, 2H, NCH2), 1.62-1.81 (m, 4H, CH2), 1.44 (s, 9H, CH3),
1.42 (s, 9H, CH3).
(3-Hydroxypropyl)carbamic Acid tert-Butyl Ester (18a).
A solution of 3-aminopropanol (17a, 5 g, 66 mmol) in triethyl-
amine/MeOH (1:7 v/v, 150 mL) was stirred at 0 °C for 10 min.
A solution of di-tert-butyl dicarbonate (21.8 g, 99 mmol) in
MeOH (50 mL) was added dropwise over 10 min. The mixture
was stirred for 1 h under a N2 atmosphere. The temperature
was allowed to gradually rise to room temperature, and the
solution was stirred overnight. The solution was evaporated
under reduced pressure, and the residue was dissolved in
CH2Cl2 and washed with deionized water. The organic layer
was separated, dried over anhydrous Na2SO4, filtered, and
concentrated to give a clear oil 18a (90%) that was used in
the next step without further purification: Rf ) 0.4 (40%
acetone/hexane); 1H NMR (CDCl3) δ 5.20 (br s, 1H, NH), 3.62
(m, 2H, OCH2), 3.11 (m, 2H, NCH2), 1.64 (t, 2H, CH2), 1.41
(s, 9H, CH3).
(4-tert-Butoxycarbonylaminobutyl)-(4-hydroxybutyl)-
carbamic Acid tert-Butyl Ester (21b). Compound 21b was
prepared in 92% yield by the same procedure as for 21a using
20b as the starting alcohol. 21b: Rf ) 0.7 (1:10:89 NH4OH/
MeOH/CHCl3); 1H NMR (CDCl3) δ 4.67 (m, 1H, NH), 3.59
(t, 2H, OCH2), 2.98-3.22 (m, 6H, NCH2), 1.30-1.52 (m, 26H,
4 × CH2, 6 × CH3).
(4-Hydroxybutyl)carbamic Acid tert-Butyl Ester (18b).
Compound 18b was prepared by the same procedure as for
18a using 4-aminobutanol (17b). 18b: yield 90%; Rf ) 0.4 (40%
1
acetone/hexane); H NMR (CDCl3) δ 4.96 (bs, 1H, NH), 3.62
(m, 2H, OCH2), 3.11 (m, 2H, NCH2), 2.49 (m, 1H, OH), 1.55
(m, 4H, CH2), 1.41 (s, 9H, CH3).
Methanesulfonic Acid 3-[tert-Butoxycarbonyl-(3-tert-
butoxycarbonylaminopropyl)amino]propyl Ester (22a).