5688 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
preparative TLC (hexane:ethyl acetate, 1:2 v:v; Rf ) 0.12) to give
a colorless oil (0.0125 g, 82% yeild). Spectral data were identical
to that described above.
procurement of catalytic antibodies utilizing hapten 2 will
be forthcoming.
3â-((Ben zyloxyca r bon yl)oxy)-8-(ben zyloxyca r bon yl)-8-
a za b icyclo[3.2.1]oct a n e-2â-ca r b oxylic Acid N-(5-Ca r -
bom eth oxyp en tyl)a m id e (11). N-Norcocaine (6) (0.289 g, 1.0
mmol) was dissolved in 0.8 N HCl (10 mL) and refluxed
overnight to generate N-norecgonine. The solution was allowed
to cool to room temperature and extracted with diethyl ether
(20 mL) to remove benzoic acid. The aqueous layer was treated
with Na2CO3 (solid) to adjust the pH to 10. Benzyl chloroformate
(0.428 mL, 3.0 mmol) was added to the aqueous solution and
stirred at room temperature for 3 h. Ethyl acetate (15 mL) was
added to the reaction mixture followed by the addition of HCl
(concd) to adjust the pH to 2. The aqueous layer was extracted
twice with ethyl acetate. The organic layers were combined,
dried over Na2SO4, and concentrated in vacuo to give a yellow
oil. The crude mixture was purified by flash silica gel chroma-
tography (hexane:ethyl acetate, 2:1, v:v; Rf ) 0.15) to give 10 as
a pale yellow oil. The bis-O,N-CBZ-carboxylic acid 10 was
observed to decompose readily and was therefore used im-
mediately in the subsequent reaction. The carboxylic acid 10
(0.054 g, 0.123 mmol) was dissolved in CH2Cl2 (1.5 mL) at room
temperature, followed by the addition of TEA (0.021 mL, 0.147
mmol) and methyl 6-aminocaproate (0.027 g, 0.147 mmol). DCC
was dissolved in CH2Cl2 (0.5 mL), added to the reaction mixture,
and allowed to stir overnight. The reaction was filtered twice,
concentrated to an oil, and purified by flash chromatography
(hexane:ethyl acetate, 1:1 v:v; Rf ) 0.12) to give the product as
a clear oil (0.022 g, 31% yeild). 1H NMR (CDCl3): δ 1.24 q, 2H,
J ) 7.2; 1.34 q, 2H, J ) 7.3; 1.53 m, 2H; 1.68 d, 2H, J ) 7.3;
1.88-2.02 m, 3H; 2.23 t, 2H, J ) 7.5; 2.36 dt, 1H, J ) 2.9, 12.2;
2.85 d, 1H, J ) 6.8; 3.05-3.14 m, 2H; 3.63 s, 1H; 4.52 s, 1H;
4.65 d, 1H, J ) 6.6; 4.99-5.14 m, 5H; 5.83 s, 1H; 7.27-7.34 m,
10H. MS (FAB): m/ z 567 (M + H).
Exp er im en ta l Section
Gen er a l P r ocd u r es. All solvents used in reactions were
distilled prior to use. All other reagents were used as supplied
unless otherwise stated. Ecgonine and N-norcocaine were
obtained from NIDA. All chromatography was performed with
silica gel unless specified otherwise. 1H and 31P NMR spectra
were recorded on a Varian VXR 300. 1H NMR chemical shifts
are relative to TMS (δ ) 0.00 ppm) or CDCl3 (δ ) 7.24 ppm).
31P NMR chemical shifts are relative to H3PO4 (δ ) 0.00 ppm).
3â-Hyd r oxy-8-m et h yl-8-a za b icyclo[3.2.1]oct a n e-2â-ca r -
boxylic Acid N-(5-Ca r bom eth oxyp en tyl)a m id e (4). To a
stirred suspension of ecgonine‚HCl (1.0 g, 4.51 mmol) in CH2-
Cl2 (40 mL) at 0 °C was added pyridine (0.365 mL, 4.51 mmol)
followed by oxalyl chloride (1.57 mL, 18.04 mmol). The reaction
was allowed to warm to room temperature for 3 h, at which time
the solution became pale pink in color. The solvent was
evaporated and dried overnight in vacuo at room temperature
to give the crude acid chloride of ecgonine. A solution of methyl
6-aminocaproate (1.23 g, 6.76 mmol) and pyridine (1.46 mL,
18.04 mmol) in CH2Cl2 was added to the crude ecgonine acid
chloride at 0 °C and the reaction was allowed to stir for 1 h.
The mixture was treated with Na2CO3 (10% w/v) and extracted
twice with CH2Cl2. The organic layers were combined and dried
over MgSO4, and the solvent was evaporated in vacuo overnight
to remove excess pyridine. The crude mixture was purified by
flash silica chromatography (MeOH:CHCl3, 25:75; Rf ) 0.15) to
give the product as a pale yellow semisolid (0.788 g, 56% yield).
1H NMR (CDCl3): δ 1.31-1.39 m, 2H; 1.48-1.55 m, 3H; 1.58-
1.65 m, 2H; 1.76 dd, 1H, J ) 4.1, 19.2; 1.86 t, 1H, J ) 9.3; 2.13
t, 2H, J ) 7.4; 2.33 s, 3H; 2.56 d, 1H, J ) 16.8; 3.22 s, 1H; 3.28
q, 2H, J ) 6.9; 3.64 s, 3H; 3.68 d, 1H, J ) 5.3; 5.71 s, 1H br;
6.23 s, 1H. MS (FAB): m/ z 313 (M + H).
8-(Ben zyloxyca r bon yl)-3â-(m eth oxyp h en ylp h osp h in yl)-
8-a za b icyclo[3.2.1]oct a n e-2â-ca r b oxylic Acid N-(5-Ca r -
bom eth oxyp en tyl)a m id e (9). F r om 8. Tetrazole (0.0021 g
0.03 mmol) and 8 (0.141 g, 0.326 mmol) were dissolved in
benzene and stirred under Ar(g) at 4 °C. N,N-Diisopropylethy-
lamine (0.13 mL, 0.730 mmol) was added via syringe followed
by the addition of phenylphosphonic dichloride (0.048 mL, 0.338
mmol). The reaction was allowed to warm to room temperature
for 1 h, followed by the dropwise addition of methanol (0.040
mL, 0.905 mmol), and the mixture was allowed to stir an
additional 30 min. The solvent was removed in vacuo, and the
product was purified by flash chromatography (MeOH:ethyl
acetate 5:95 v:v, Rf ) 0.2) to give a colorless oil (0.110 g, 58%
yield). 1H NMR (CDCl3): δ 1.14-1.74 m, 8H; 1.80-2.05 m, 3H;
2.14-2.31 m, 2H; 2.55 ddt, 1H, J ) 48.0, 12.1, 2.6; 2.77 ddd,
1H, J ) 48.6, 6.5, 2.0; 2.91-3.10 m, 2H; 3.61-3.68 m, 6H; 4.37-
4.45 m, 1H; 4.60 d, 1H, J ) 6.1; 4.64-4.82 m, 1H; 5.06 d, 2H, J
) 5.4; 5.89 dt, 1H, J ) 73.0, 5.3; 7.25-7.33 m, 5H; 7.37-7.58
m, 3H; 7.74 dd, 2H, J ) 13.6, 6.9. 31P NMR: δ 20.67, 21.01.
MS (FAB): m/ z 587 (M + H) Anal. Calcd for C16H19NO5: C,
60.62; H, 6.84; N, 4.88. Found: C, 60.95; H, 6.77; N, 4.81. F r om
12, P a th A. A benzene (3 mL) solution of N-CBZ-norecgonine
(7) (100 mg, 0.33 mmol), diisopropylamine (0.23 mL, 1.32 mmol),
and tetrazole (2 mg, 0.03 mmol) under Ar(g) was cooled to 5 °C
and treated with phenylphosphonic dichloride (0.047 mL, 0.33
mmol). The ice bath was removed, and the reaction was stirred
for 1 h. Methyl 6-aminocaproate hydrochloride (60 mg, 0.33
mmol) was added and stirring was continued for 1 h. Saturated
ammonium chloride solution (10 mL) and dichloromethane (30
mL) were added. The organic layer was separated, dried over
sodium sulfate, and evaporated to give 13 as a pale yellow oil.
The crude phosphonic acid 13 was taken up in dichloromethane
and treated with sodium carbonate (100 mg) and dimethyl
sulfate (0.032 mL, 0.50 mmol). After the solution was stirred
overnight at room temperature, solvent was removed under
vacuum and the residue was purified by flash chromatography
(CH2Cl2:methanol 95:5 v:v) to give 9 (46 mg, a 24% yield) as a
pale yellow oil. The spectral data for this product were identical
to that descibed above. F r om 12, P a th B. In situ formation of
12 from 7 was identical to the procedure described above from
12, path A with the exception that all amounts were doubled.
The synthetic intermediate 12 was then treated with MeOH
(0.066 mL, 1.5 mmol) to form 14. The solvent was removed in
8-(Ben zyloxyca r b on yl)-3â-h yd r oxy-8-a za b icyclo[3.2.1]-
octa n e-2â-ca r boxylic Acid (7). N-Norcocaine (6) (0.5 g, 1.73
mmol) was dissolved in 0.8 N HCl (10 mL) and refluxed
overnight to generate N-norecgonine. The solution was allowed
to cool to room temperature and extracted with diethyl ether
(20 mL) to remove benzoic acid. The aqueous layer was treated
with Na2CO3 (solid) to adjust the pH to 10. Benzyl chloroformate
(0.271 mL, 1.90 mmol) was added to the aqueous solution and
stirred at room temperature for 3 h. Ethyl acetate (15 mL) was
added to the reaction mixture followed by the addition of HCl
(concd) to adjust the pH to 2. The aqueous layer was extracted
once with ethyl acetate and twice with CH2Cl2. The organic
layers were combined, dried over Na2SO4, and concentrated in
vacuo to a yellow oil. The crude mixture was purified by flash
silica gel chromatography (MeOH:CH2Cl2 10:90, v:v; Rf ) 0.25)
to give 7 as a pale yellow oil (0.235 g, 44% yield). 1H NMR
(CDCl3): δ 1.64-1.67 m, 2H; 1.88-1.97 m, 2H; 1.99-2.09 m,
2H; 2.96 s, 1H; 4.04-4.08 m, 1H; 4.44 s, 1H; 4.86 s, 1H; 5.12 s,
2H; 7.33 s, 5H.
8-(Ben zyloxyca r b on yl)-3â-h yd r oxy-8-a za b icyclo[3.2.1]-
oct a n e-2â-ca r b oxylic Acid N-(5-Ca r b om et h oxyp en t yl)-
a m id e (8). F r om 7. N-CBZ-norecgonine (7) (0.249 g, 0.86 mmol)
was dissolved in CH2Cl2 (8 mL) at room temperature followed
by the addition of DCC (0.185 g, 0.898 mmol). The mixture was
stirred for 10 min, after which a white precipitate formed.
6-Aminocaproic acid methyl ester hydrochloride (0.178 g, 0.980
mmol) along with TEA (0.137 mL, 0.980 mmol) was dissolved
in CH2Cl2 (2 mL) and added to the above reaction mixture. The
mixture was allowed to stir overnight at room temperature, after
which it was filtered twice. The filtrate was concentrated in
vacuo and purified by flash silica gel chromatography (ethyl
acetate; Rf ) 0.3) to give the desired product as a colorless oil
(0.281 g, 80% yield). 1H NMR (CDCl3): δ 1.23-1.33 m, 2H;
1.39-1.41 m, 2H; 1.57-1.74 m, 5H; 1.89-2.04 m, 3H; 2.29 t,
2H J ) 7.4; 2.74 s, 1H; 3.15-3.17 m, 2H; 3.66 s, 3H; 4.11-4.13
m, 1H; 4.49 s, 1H; 4.65 s, 1H; 5.11 s, 2H; 7.33 s, 5H. F r om 11.
Amide 11 (0.020 g, 0.035 mmol) was dissolved in MeOH (2 mL)
at room temperature, Na2CO3 (0.015 g, 0.142 mmol) was added,
and the reaction was allowed to stir until complete consumption
of starting material was observed by TLC (3 h). The solvent
was evaporated in vacuo, and the product was purified by