Syntheses of Azabicycloalkanes
J . Org. Chem., Vol. 64, No. 17, 1999 6317
0.47 (10% MeOH/CHCl3); mp 175-176 °C; 1H NMR (CDCl3) δ
7.89 (2 H, dd, J ) 1.3, 11.9 Hz), 7.87 (2 H, dd, J ) 1.5, 12.0
Hz), 7.48 (6 H, m), 4.59 (1 H, m), 3.05 (1 H, m), 2.97 (3 H, s),
2.74 (1 H, dd, J ) 6.0, 10.0 Hz), 2.20 (2 H, d, J ) 12.7 Hz),
2.11 (2 H, d, J ) 12.7 Hz), 1.57 (2 H, qd, J ) 3.3, 12.8 Hz),
1.39 (2 H, qd, J ) 3.1, 12.7 Hz); 13C NMR (CDCl3) δ 132.9 (d,
J ) 139.5 Hz), 132.2 (d, J CP ) 9.5 Hz), 128.8 (d, J CP ) 12.3
Hz), 79.9, 49.1, 38.9, 33.8 (d, J CP ) 5.1 Hz), 31.5; 31P NMR
(CDCl3) δ 24.25; IR (KBr) νmax 3137, 1438, 1351, 1198, 1112
cm-1; EIMS m/z (relative intensity) 394 (M + H, 100)+, 298
(79), 201 (52); HRMS (M + H)+ calcd for C19H25NO4PS
394.1242, found 394.1246.
Gen er a l P r oced u r e for P r ep a r a tion of Bicyclic Su b-
str a tes 3-5. A solution containing mesylate (10-12) in 1:1
DMF-benzene at 0 °C was treated under argon with potas-
sium tert-butoxide (3.0 equiv). The reaction mixture was
stirred for 3 h and then added to 8 volumes of water and 1
volume of additional benzene. The organic layer was washed
with brine and dried over Na2SO4. The solvent was concen-
trated under diminished pressure to afford a residue, which
was purified by flash chromatography on a silica gel column.
(7-Aza bicyclo[2.2.1]h ep t-7-yl)p h osp h on ic Acid Dieth yl
Ester (3). Elution with 9:1 ethyl acetate-petroleum ether
afforded 3 as a colorless oil: yield 1.24 g (74%); Rf 0.71 (9:1
chloroform-methanol); 1H NMR (CDCl3) δ 4.05 (6 H, m),
1.75 (4 H, d, J ) 6.8 Hz), 1.39 (4 H, d, J ) 6.8 Hz), 1.30 (6 H,
t, J ) 7.1 Hz); 13C NMR (CDCl3) δ 62.6 (d, J CP ) 5.8 Hz), 57.8
(d, J CP ) 2.2 Hz), 31.0 (d, J CP ) 5.9 Hz), 16.4 (d, J CP ) 6.8
Hz); 31P NMR (CDCl3) δ 6.46; IR (thin film) νmax 1275, 1256,
1028 cm-1; EIMS m/z (relative intensity) 233 (M+, 28), 204
(100), 148 (90); HRMS calcd for C10H20NO3P 233.1181, found
233.1171.
relative humidity for biotransformation. After 168 h, the cells
were removed from the cultures by vacuum filtration and the
filtrate was extracted with methylene chloride. The combined
organic layer was washed with brine and dried over Na2SO4.
The solvent was concentrated under diminished pressure to
afford a residue which was purified by flash chromatography
on a silica gel column. Elution with 9:1 chloroform-methanol
afforded 13 as a colorless oil: yield 186.3 mg (43%); Rf 0.24
(95:5 chloroform-methanol); [R]25 +2.7° (c ) 1.0, CHCl3); 1H
D
NMR (CDCl3) δ 4.33 (1H, m), 4.04 (4 H, quint, J ) 7.3 Hz),
3.91 (2 H, td, J ) 1.9, 4.8 Hz), 3.52 (1 H, br s), 2.19 (2 H, m),
1.79 (1 H, m), 1.67-1.49 (2 H, series of m), 1.30 (6 H, t, J )
7.1 Hz), 1.04 (1 H, dt, J ) 3.8, 12.3 Hz); 13C NMR (CDCl3) δ
71.7 (d, J CP ) 10.1 Hz), 62.7 (d, J CP ) 6.5 Hz), 61.4, 58.9, 39.7
(d, J CP ) 5.8 Hz), 31.1 (d, J CP ) 4.4 Hz), 21.9 (d, J CP ) 4.4
Hz), 16.3 (d, J CP ) 6.5 Hz); 31P NMR (CDCl3) δ 6.10; IR (thin
film) νmax 3364 (br), 1236, 1024 cm-1; EIMS m/z (relative
intensity) 249 (M+, 20), 205 (86), 112 (100); HRMS calcd for
C
10H20NO4P 249.1130, found 249.1148.
(2-en d o-Hyd r oxy-7-a za bicyclo[2.2.1]h ep t-7-yl)p h osp h o-
n ic Acid Dip h en yl Ester (14) a n d (2-en d o-Hyd r oxy-7-
a za bicyclo[2.2.1]h ep t-7-yl)p h osp h on ic Acid P h en yl, p-
H yd r oxyp h en yl E st er (16). A solution containing (7-
azabicyclo[2.2.1]hept-7-yl)phosphonic acid diphenyl ester 4
(1.00 g, 3.04 mmol) in 1:1 ethanol-DMF (5 mL) was equally
distributed among ten stage II preparative scale liquid cultures
of B. bassiana (prepared as described above). All flasks were
then placed on an orbital shaker at 250 rpm, 29-30 °C, and
50% relative humidity for biotransformation. After 168 h, the
cells were removed from the cultures by vacuum filtration and
the filtrate was extracted with methylene chloride. The
combined organic layer was washed with brine and dried over
Na2SO4. The solvent was concentrated to afford a residue
which was purified by flash chromatography on a silica gel
column. Elution with 9:1 chloroform-methanol afforded 14 as
(7-Aza bicyclo[2.2.1]h ep t-7-yl)ph osp h on ic Acid Dip h en -
yl Ester (4). Elution with 4:6 ethyl acetate-petroleum ether
afforded 4 as a white, crystalline solid: yield 2.06 g (81%); Rf
0.73 (9:1 chloroform-methanol); mp 75-76 °C; 1H NMR
(CDCl3) δ 7.31 (4 H, t, J ) 7.5 Hz), 7.25 (4 H, d, J ) 7.6 Hz),
7.14 (2 H, t, J ) 7.0 Hz), 4.25 (2 H, s), 1.72 (4 H, d, J ) 6.5
Hz), 1.41 (4 H, d, J ) 6.3 Hz); 13C NMR (CDCl3) δ 151.4 (d,
J CP ) 8.0 Hz), 129.7, 124.8, 120.3 (d, J CP ) 5.1 Hz), 58.5 (d,
J CP ) 2.1 Hz), 31.0 (d, J CP ) 5.8 Hz); 31P NMR (CDCl3) δ -4.75;
IR (KBr) νmax 3050, 1279, 1222, 1095 cm-1; EIMS m/z (relative
intensity) 329 (M+, 35), 300 (100), 77 (46). Anal. Calcd for
a pale yellow oil: yield 78 mg (7%); Rf 0.43 (9:1 chloroform-
1
methanol); [R]25 +3.5° (c ) 1.0, CHCl3); H NMR (CDCl3) δ
D
7.31 (4 H, t, J ) 7.8 Hz), 7.22 (4 H, d, J ) 7.6 Hz), 7.15 (2 H,
t, J ) 7.2 Hz), 4.24 (1 H, m), 4.14 (1 H, td, J ) 2.0, 4.7 Hz),
4.09, (1 H, td, J ) 1.6, 4.5 Hz), 2.34 (1 H, s), 2.20 (1 H, m),
2.10 (1 H, m), 1.73 (1 H, m), 1.55 (2 H, m), 1.03 (1 H, dt, J )
3.8, 12.5 Hz); 13C NMR (CDCl3) δ 151.3 (d, J CP ) 6.5 Hz), 129.9,
125.1, 120.3 (dd, J CP ) 3.6, 5.1 Hz), 72.0 (d, J CP ) 9.3 Hz),
C
18H20NO3P: C, 65.65; H, 6.12; N, 4.25. Found: C, 65.64; H,
61.9 (d, J CP ) 2.1 Hz), 59.7 (d, J CP ) 2.2 Hz), 40.1 (d, J CP )
6.26; N, 4.15.
5.1 Hz), 31.3 (d, J CP ) 3.7 Hz), 22.0 (d, J CP ) 3.6 Hz); 31P NMR
(CDCl3) δ -5.07; IR (thin film) νmax 3404 (br), 1591, 1489, 1190,
937 cm-1; EIMS m/z (relative intensity) 345 (M+, 17), 300 (27),
112 (100), 77 (75); HRMS calcd for C18H20NO4P 345.1130,
found 345.1131.
N -(D ip h e n y lp h o s p h in o y l)-7-a za b ic y c lo [2.2.1]h e p -
ta n e (5). Elution with 1:1 ethyl acetate-petroleum ether and
then 7:3 ethyl acetate-petroleum ether afforded 5 as a white,
crystalline solid: yield 882 mg (88%); Rf 0.58 (9:1 chloroform-
methanol); mp 184-185 °C; 1H NMR (CDCl3) δ 7.92 (2 H, dd,
J ) 1.3, 11.6 Hz), 7.90 (2 H, dd, J ) 1.4, 11.6 Hz), 7.44 (6 H,
m), 3.82 (2 H, m), 1.92 (4 H, d, J ) 6.5 Hz), 1.42 (4 H, d, J )
6.9 Hz); 13C NMR (CDCl3) δ 133.6 (d, J ) 131.5 Hz), 132.4 (d,
J CP ) 8.7 Hz), 131.6 (d, J CP ) 2.9 Hz), 128.6 (d, J ) 12.4 Hz),
58.5, 31.5 (d, J CP ) 6.5 Hz); 31P NMR (CDCl3) δ 22.63; IR (KBr)
Further elution with 9:1 chloroform-methanol afforded 16
as a pale yellow oil: yield 403 mg (37%); Rf 0.30 (9:1
chloroform-methanol); [R]25D +4.7° (c ) 1.0, MeOH); 1H NMR
((CD3)2SO) δ 7.39 (2 H, t, J ) 7.8 Hz), 7.22 (3 H, dd, J ) 1.0,
5.2 Hz), 7.02 (2 H, dd, J ) 1.0, 3.5 Hz), 6.73 (2 H, d, J ) 9.0
Hz), 5.03 (1 H, d, J ) 4.1 Hz), 4.01 (1 H, br s), 3.94 (1 H, m),
3.87 (1 H, br s), 2.09 (1 H, m), 1.87 (1 H, m), 1.60-1.30 (4 H,
series of m), 0.89 (1 H, dt, J ) 3.8, 12.1 Hz); 13C NMR ((CD3)2-
SO) δ 154.3, 150.8 (d, J CP ) 7.2 Hz), 142.9 (d, J CP ) 8.0 Hz),
129.8, 124.7, 120.4 (dt, J CP ) 4.4, 82.8 Hz), 115.8, 79.2, 70.5
(d, J CP ) 9.1 Hz), 61.2, 58.7, 30.7 (d, J CP ) 3.6 Hz), 21.5 (d,
J CP ) 3.7 Hz); 31P NMR (CDCl3) δ -4.34; IR (cast film) νmax
3266 (br), 1186, 940 cm-1; EIMS m/z (relative intensity) 361
(M+, 20), 161 (89), 112 (100); HRMS calcd for C18H20NO5P
361.1079, found 361.1088.
2-en do-Hydr oxy-7-(diph en ylph osph in oyl)-7-azabicyclo-
[2.2.1]h ep ta n e (15). A solution containing 7-(diphenylphos-
phinoyl)-7-azabicyclo[2.2.1]heptane 5 (103 mg, 0.35 mmol) in
5:7 ethanol-DMF (1.2 mL) was added to one stage II prepara-
tive scale liquid culture of B. bassiana (prepared as described
above) inside a sterile laminar flow hood. The flask was placed
on an orbital shaker at 250 rpm, 29-30 °C, and 50% relative
humidity for biotransformation. After 168 h, the cells were
removed from the culture by vacuum filtration and the filtrate
was extracted with methylene chloride. The combined organic
layer was washed with brine and dried over Na2SO4. The
ν
max 1438, 1215, 1060 cm-1; EIMS m/z (relative intensity) 297
(M+, 59), 268 (63), 201 (100); HRMS calcd for C18H20NOP
297.1283, found 297.1292.
Gen er a l Biotr a n sfor m a tion P r oced u r e. Details describ-
ing the maintenance of cultures and biotransformation protocol
are provided elsewhere.11 Medium A: 20 g of D-glucose, 5 g of
yeast extract (Difco), 5 g of soybean meal (Victoria Feed Co.),
5 g of NaCl, and 5 g of K2HPO4 per liter of water, pH adjusted
to 5.0 prior to autoclaving. Medium B: 20 g of corn steep liquor
(Sigma), 10 g of D-glucose per liter of water, pH adjusted to
5.0 prior to autoclaving. Media were sterilized for 15 min (125
mL DeLong flasks) or 20 min (1 L DeLong flasks) and allowed
to cool to room temperature prior to inoculation.
(2-en do-Hydr oxy-7-a za bicyclo[2.2.1]h ep t-7-yl)p h osph o-
n ic Acid Dieth yl Ester (13). A solution containing (7-
azabicyclo[2.2.1]hept-7-yl)phosphonic acid diethyl ester 3 (404.0
mg, 1.73 mmol) in ethanol (2 mL) was equally distributed
among four stage II preparative scale liquid cultures of B.
bassiana (prepared as described above). All flasks were then
placed on an orbital shaker at 250 rpm, 29-30 °C, and 50%