2836 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 12
PlouVier et al.
HN+), 7.58-7.24 (m, 4H, Ar), 4.44-1.14 (m, 22H, aliph); 13C
NMR (75 MHz, APT, CDCl3) δ 137.3 (+), 131.7 (-), 131.3 (-),
128.6 (+), 126.4 (-), 126.2 (+), 125.8 (-), 72.5 (-), 67.6 (-),
67.5 (+), 63.8 (+), 63.3 (+), 50.5 (+), 49.3 (+), 32.6 (+), 27.3
(+), 24.6 (+), 20.7 (+), 18.6 (+); HRMS (EI) mass calcd for
C19H26F3NO2, 357.19156; found, 357.19160 (11.7%); Anal. (C19H27F3-
NO2Cl) C, H, N.
Methods E and F. (1R,2R)/(1S,2S)-1-(1-Naphthalenethoxy)-
2-(3-(R/S)-hydroxypyrrolidinyl)cyclohexane Monohydrochloride
(50) and (1R,2R)/(1S,2S)-1-(1-Naphthalenethoxy)-2-(3-(R/S)-
acetoxypyrrolidinyl)cyclohexane Monohydrochloride (36). To
a solution of 26 (1.4 g, 3.7 mmol) in i-PrOH (30 mL) was added
portion-wise at room-temperature NaBH4 (0.5 g, 13.2 mmol). The
resultant mixture was stirred at room temperature for 16 h. The
reaction mixture was quenched with 1 M aq HCl (∼2 mL) for 40
min and then concentrated in vacuo. The residue was taken up with
CH2Cl2 (20 mL), the insoluble material was filtered and washed
with CH2Cl2 (20 mL), and the combined filtrates were dried and
split in two equal parts.
One part was treated with ethereal HCl (20 mL). The solvents
were evaporated in vacuo and the residual oil was triturated in Et2O
(80 mL) to yield 50 (0.55 g, 79% yield) as a hygroscopic solid. 1H
NMR (400 MHz, CDCl3) δ 8.10-7.35 (m, 7H, Ar), 4.20-1.10
(m, 22H, aliph); 13C NMR (75 MHz, APT, CDCl3) δ 135.0 (+),
133.7 (+), 132.0 (+), 128.6 (-), 126.9 (-), 126.8 (-), 125.8 (-),
125.4 (-), 123.7 (-), 79.5 (-), 79.3 (-), 70.9 (-), 70.7 (-), 68.7
(+), 68.6 (+), 63.3 (-), 63.2 (-), 59.6 (+), 59.3 (+), 48.6 (+),
48.4 (+), 34.3 (+), 34.1 (+), 33.8 (+), 29.1 (+), 29.0 (+), 27.0
(+), 23.5 (+), 23.4 (+), 23.1 (+), 23.0 (+); HRMS (EI) mass calcd
for C22H29O2N, 339.21983; found, 339.21962 (100%); HPLC
(Supelco ODP-50 150 × 4.6 mm, 5 µ; 50 mM phosphate buffer
(pH 11)-acetonitrile (50:50)) 98.9% ; CE 98.9%.
Aminoether 31 (Table 3) was prepared using the procedure
described above.
Method D. (1R,2S)/(1S,2R)-1-(1-Naphthalenethoxy)-2-(3-ke-
topyrrolidinyl) Cyclohexane Monohydrochloride (46). To a flask
containing Mg(ClO4)2 (2.14 g, 0.95 mmol) vacuum flame-dried,
cooled, and charged with argon was added via cannula a solution
of 3b (21.6 g, 125.0 mmol) in CH3CN (15 mL). The resultant
mixture was refluxed until all material had dissolved and then
cyclohexene oxide (1.0 g, 10.0 mmol) was added over a period of
2.5 h. The reaction mixture was then refluxed for 16 h, cooled to
room temperature, and partitioned between water (150 mL),
saturated aq NaHCO3, (50 mL) and Et2O (100 mL). The aqueous
layer was collected and extracted twice with Et2O (2 × 100 mL).
The combined Et2O extracts were back-washed with brine (50 mL),
dried, and concentrated in vacuo to yield 25.2 g of crude material,
which solidified upon standing. The excess 3b was recovered by
successive recrystallizations in Et2O-hexanes (1:1, v/v). The
resultant mother liquor (7.5 g) obtained after three recrystallizations
was purified by chromatography using a mixture of EtOAc-
hexanes (1:5, v/v, +0.5% v/v i-PrNH2) to provide 1.5 g (55% yield)
of crude (1R,2R)/(1S,2S)-2-(1-naphthalenethoxy)cyclohexan-1-ol,
which was used in the next step without further purification.
To a suspension of pyridinium chlorochromate or PCC (4. 8 g,
22.2 mmol) in CH2Cl2 (35 mL) was added at once a solution of
(1R,2R)/(1S,2S)-2-(1-naphthalenethoxy)cyclohexan-1-ol (1.5 g, 5.5
mmol) in CH2Cl2 (5 mL). The resultant dark brown mixture was
stirred at room temperature for 16 h and then filtered through a
plug of silica gel topped with Na2SO4. The plug was further rinsed
with Et2O (3 × 40 mL) and the filtrate was concentrated in vacuo
to yield 2.0 g of crude material. The crude material was applied to
a dry column of silica gel and eluted with a mixture of EtOAc-
hexanes (1:6, v/v, + 0.5% v/v i-PrNH2) to yield 1.0 g of (2R/2S)-
2-(1-naphthalenethoxy)cyclohexan-1-one (68% yield). 13C NMR (50
MHz, APT, CDCl3) δ 203.0 (+), 135.0 (+), 134.0 (+), 132.0 (+),
129.0 (-), 127.0 (-), 125.5 (-), 125.0 (-), 123.5 (-), 113.0 (-),
83.0 (-), 70.0 (+), 40.0 (+), 34.5 (+), 33.5 (+), 28.0 (+), 23.0
Aminoethers 47 and 50 (Table 3) were prepared by using the
procedure described above, method E.
The other part was concentrated in vacuo, taken up with Ac2O
(15 mL), and refluxed for 2 h. The excess Ac2O was removed in
vacuo, the residue was taken up with water (100 mL), and the pH
was adjusted to pH 1 with 1 M aq HCl. The resultant acidic aqueous
solution was extracted with Et2O (2 × 30 mL), basified to pH 8,
and extracted with Et2O (3 × 50 mL). The combined Et2O extracts
at pH 8 were dried, concentrated under reduced pressure to ∼20
mL volume, and then treated with ethereal HCl. The solvent was
evaporated in vacuo, the resultant sticky material was redissolved
in CH2Cl2 (5 mL) and addition of Et2O triggered crystallization of
36 (0.5 g, 65% yield) as a hygroscopic solid. 1H NMR (400 MHz,
free base, CDCl3) δ 8.10-7.35 (m, 7H, Ar), 5.10 (m, 1H, CH),
4.00-1.10 (m, 23H, aliph); 13C NMR (75 MHz, APT, free base,
CDCl3) δ 170.7 (+), 134.9 (+), 133.6 (+), 131.9 (+), 128.5 (-),
126.7 (-), 126.6 (-), 125.6 (-), 125.3 (-), 125.2 (-), 123.6 (-),
79.6 (-), 79.2 (-), 73.9 (-), 73.7 (-), 68.8 (+), 68.7 (+), 63.5
(-), 63.4 (-), 56.9 (+), 56.8 (+), 49.4 (+), 49.0 (+), 33.8 (+),
33.7 (+), 31.3 (+), 31.2 (+), 28.9 (+), 27.3 (+), 26.9 (+), 23.3
(+), 23.2 (+), 22.9 (+), 21.1 (-), 21.0 (-); HRMS (EI) mass calcd
for C24H31O3N, 381.23041; found, 381.23117 (62.2%); Anal.
(C24H32O3NCl) H, N. Anal. Calcd for C24H32O3NCl: C, 68.97.
Found: C, 67.52.
Method G. (1R,2R)-1-(1-Naphthalenethoxy)-2-(3-ketopyrro-
lidinyl)cyclohexane Monohydrochloride (40) and (1S,2S)-1-(1-
Naphthalenethoxy)-2-(3-ketopyrrolidinyl)cyclohexane Mono-
hydrochloride (41). A warm solution of (1R,2R)/(1S,2S)-1-(1-
naphthalenethoxy)-2-(1,4-dioxa-7-azaspiro[4,4]non-7-
yl)cyclohexane (1.19 g, 3 mmol) in 2-butanone (15 mL) was mixed
with a warm solution of di-p-toluoyl-D-tartaric acid (1.20 g, 3.1
mmol) in 2-butanone (20 mL). The mixture was allowed to cool
down to room temperature and placed at -20 °C overnight. The
resultant precipitate (ee 73.7%) was recrystallized from MeOH-
butanone to yield (1R,2R)-1-(1-naphthalenethoxy)-2-(1,4-dioxa-7-
azaspiro[4,4]non-7-yl)cyclohexane tartrate (0.73 g, ee g 99%). The
residual mother liquor was concentrated in vacuo, and the residue
was partitioned between 10% aq NaOH and CH2Cl2. The combined
organic extracts were dried and the solvent was evaporated in vacuo.
The residue (0.61 g, 1.6 mmol) was dissolved in 2-butanone (8
mL) and mixed with a warm solution of di-p-toluoyl-L-tartaric acid
(0.63 g, 1.2 mmol) in 2-butanone (10 mL). The mixture was allowed
to cool down to room temperature overnight to yield (1S,2S)-1-
(1-naphthalenethoxy)-2-(1,4-dioxa-7-azaspiro[4,4]non-7-yl)cyclo-
hexane tartrate (0.89 g, ee 97.5%).
(+); IR (film) 1720 cm-1
.
(2R/2S)-2-(1-Naphthalenethoxy)cyclohexan-1-one (1.0 g, 3.7
mmol), 2e (1.2 g, 9.3 mmol), and PVP (0.4 g) in benzene (10 mL)
were refluxed in a Dean-Stark apparatus for 5 h. The cooled
reaction mixture was then quickly transferred to a Parr shaker
apparatus, Pd on activated carbon (0.2 g) was added, and the mixture
was hydrogenated for 16 h. The catalyst was removed by filtration,
the filtrate was concentrated in vacuo, and the resultant crude
material (cis/trans, 87:13, area %/GC) was purified by dry-column
chromatography with a mixture of EtOAc-hexanes (1:2, v/v, +
0.5% v/v i-PrNH2) to provide 1.0 g (70% yield) of (1R,2S)/(1S,2R)-
1-(1-naphthalenethoxy)-2-(1,4-dioxo-7-azaspiro[4.4]non-7-yl)cyclo-
hexane, which was refluxed with 6 M aq HCl (20 mL) in 2-butanone
(80 mL) for 16 h. The cooled reaction mixture was concentrated
in vacuo, and the residue was diluted with water (90 mL). The
aqueous solution was then extracted with Et2O (2 × 50 mL) and
CH2Cl2 (3 × 70 mL). The combined CH2Cl2 extracts were dried
and the solvent was evaporated in vacuo. Trituration in Et2O
provided 46 (0.82 g, 84% yield); mp 176-178 °C; 1H NMR (400
MHz, CDCl3) δ 12.53 (br s, 1H, HN+), 8.06-7.32 (m, 7H, Ar),
4.05-1.16 (m, 20H, aliph); 13C NMR (75 MHz, APT, CDCl3) δ
204.2 (+), 204.0 (+), 135.0 (+), 134.9 (+), 133.6 (+), 131.9 (+),
131.8 (+), 128.7 (-), 127.1 (-), 127.0 (-), 125.9 (-), 125.8 (-),
125.5 (-), 125.4 (-), 123.7 (-), 123.6 (-), 72.4 (-), 71.7 (-),
68.3 (+), 68.2 (+), 65.5 (-), 64.9 (-), 54.7 (+), 54.3 (+), 48.8
(+), 48.2 (+), 35.5 (+), 35.1 (+), 32.9 (+), 26.8 (+), 26.7 (+),
24.0 (+), 22.5 (+), 21.9 (+), 18.3 (+); Anal. (C22H28NO2Cl) C,
H, N.