Synthesis of Natural (-)-Cocaine and Unnatural (+)-Cocaine
J . Org. Chem., Vol. 63, No. 12, 1998 4077
mmol) in H2O (40 mL). To this stirred mixture was added
ethyl chlorooximidoacetate (14.49 g, 95.56 mmol)18 in THF (40
mL) at 0.39 mL/h with a syringe pump, and stirring was
continued at room temperature for 16 h. The aqueous layer
was extracted with Et2O (5 × 60 mL), and the combined
organic layer was dried, filtered, and evaporated. The residue
was chromatographed, eluting with 1/2 EtOAc/hexanes, to give
(1R,2R,3S,5S)-8-(ter t-Bu tyloxycar bon yl)-3-(ben zoyloxy)-
8-a za bicyclo[3.2.1]octa n e-2-ca r boxa m id e ((-)-22). A solu-
tion of (+)-21 (1.85 g, 6.83 mmol), benzoic anhydride (3.09 g,
13.66 mmol) and DMAP (1.83 g, 15.03 mmol) in CH2Cl2 (16
mL) was stirred at room temperature for 12 h. The reaction
mixture was diluted with Et2O (300 mL), and the organic layer
was washed with H2O (2 × 230 mL), 10% aqueous NaHCO3
(80 mL), and then H2O (230 mL), dried, filtered, and evapo-
rated. Chromatography of the crude solid with 5% MeOH/
(-)-18 as a colorless oil (1.22 g, 78%): [R]22 -20° (c 1.0,
D
CHCl3); IR (CHCl3) 1740, 1685 cm-1; 1H NMR (CDCl3) δ 1.39
(t, J ) 7.2, 3H), 1.42 (s, 9H), 1.55-1.90 (m, 2H), 1.9-2.2 (bs,
4H), 3.4-3.6(m, 1H), 4.0-4.6 (m, 3H), 4.92 (bs, 1H), 5.24 (dd,
J ) 8.0, 18.2, 1H); 13C NMR (CDCl3) δ 13.8 (3), 27.3 (2), 28.0
(3), 29.1 (2), 30.3 (22), 36.0 (2), 49.6 (1), 50.5 (1), 51.2 (1), 53.3
(1), 62.3 (2), 76.7 (1), 77.7 (1), 79.7 (0), 151.6 (0), 152.4 (0),
153.0 (0), 160.3 (0). Anal. Calcd for C16H24NO25: C, 59.2; H,
7.4; N, 8.6. Found: C, 59.3; H, 7.3; N, 8.9.
CH2Cl2 gave (-)-22 (2.58 g, 96%): mp 207-208 °C; [R]22
D
1
-29.8° (c 1.0, CHCl3); H NMR (CDCl3, 58 °C) δ 1.43 (s, 3H),
1.73 (dd, 2H), 1.89-2.01 (m, 4H), 2.53 (ddd, 1H), 2.98 (dd, 1H),
4.45 (bs, 1H), 5.43 (m, 1H), 5.91 (bs, 1H), 6.40 (bs, 1H), 7.36
(t, 2H), 7.51 (t, 1H), 7.97 (d, 1H); 13C NMR (CDCl3) δ 27.3,
28.1, 28.2, 33.6, 49.0, 52.1, 54.8, 67.1, 79.6, 128.2, 129.5, 1290.7,
132.9, 152.9, 165.8, 171.6. Anal. Calcd for C20H26N2O5: C,
64.2; H, 7.0; N, 7.5. Found: C, 64.1; H, 7.0; N, 7.3.
En a n tiom er (+)-18 (str u ctu r e n ot sh ow n ): [R]25 +12°
D
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (-)-18.
En a n tiom er (+)-22 (str u ctu r e n ot sh ow n ): [R]22D +28.1°
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (+)-21.
(3a S ,3b R ,5a S ,6a S )-7-(t er t -Bu t yloxyca r b on yl)-7-a za -
bicyclo[3.2.1]octa n o[2,3-d ]isooxa zole-3-ca r boxylic Acid
((-)-19). To a solution of (-)-18 (795 mg, 2.45 mmol) in EtOH
at 0 °C was added 10% aqueous NaOH (35 mL) dropwise. The
reaction mixture was stirred at 0 °C for 1 h and then at room
temperature for 1.5 h. The resulting clear solution was cooled
to 0 °C, diluted with H2O (45 mL), and acidified to pH 5.0 by
dropwise addition of cold 10% HCl and then it was extracted
with 1/3 i-PrOH/CHCl3 (7 × 45 mL). The combined organic
phase was dried, filtered, and evaporated to give a hygroscopic
white foam ((-)-19, 700 mg, 96%): [R]22D -17.5° (c 1.0, CHCl3);
1H NMR (CDCl3) δ 1.44 (t, J ) 7.2, 3H), 1.50-2.10 (m, 6H),
3.40-3.60 (m, 1H), 4.14 and 4.35 (bs, 1H), 4.92 and 5.05 (bs,
1H), (5.16 (q, J ) 8.5, 1H); 13C NMR (CDCl3) δ 24.7 (3), 27.4
and 28.5 (2), 49.8 (1), 51.3 and 52.9 (1), 77.2 and 78.0 (1), 80.7
(0), 152.0 (0), 152.7 and 153.2 (0), 161.8 (0). Anal. Calcd for
(1R,2R,3S,5S)-3-(Ben zoyloxy)-8-azabicyclo[3.2.1]octan e-
2-ca r boxa m id e ((-)-23). To a solution of (-)-22 (374 mg,
1.0 mmol) in CH2Cl2 was added TFA (2.7 mL) dropwise, the
solution was stirred at room temperature for 1 h, and the
reaction mixture was evaporated to give a residue that was
partitioned between CH2Cl2 and saturated NaHCO3. The
aqueous phase was further extracted with CH2Cl2 (3 × 20 mL),
and the combined organic phase was dried, filtered, and
evaporated. Chromatography of the residue with 10% MeOH/
CH2Cl2 gave (-)-23 (247 mg, 90%): mp 163-164 °C; [R]22
D
1
-43.5° (c 1.0, CHCl3); H NMR (CDCl3) δ 1.74-2.12 (m, 6H),
2.88 (d, J ) 7.1, 1H), 3.09 (bs, 1H), 3.68 (d, J ) 2.5, 1H), 3.74
(d, J ) 5.0, 1H), 5.36 (m, 1H), 6.01 (bs, 1H), 7.38 (t, 2H), 7.52
(t, 1H), 7.97 (d, 1H); 13C NMR (CDCl3) δ 28.2, 29.2, 34.8, 49.2,
53.3, 56.3, 66.7, 128.2, 129.5, 129.9, 132.9, 165.8, 174.0. Anal.
Calcd for C15H18N2O3: C, 65.7; H, 6.6; N, 10.2. Found: C, 65.5;
H, 6.8; N, 10.1.
C
14H20N2O5‚H2O: C, 53.5; H, 7.0; N, 8.9. Found: C, 53.7; H,
7.0; N, 8.7.
En a n tiom er (+)-19 (str u ctu r e n ot sh ow n ): [R]22D +17.2°
(c 1.0, MeOH); spectral and chromatographic properties identi-
cal with (+)-19.
En a n tiom er (+)-23 (str u ctu r e n ot sh ow n ): [R]22D +36.0°
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (+)-21.
(1R,2R,3S,5S)-8-(ter t-Bu tyloxyca r bon yl)-2-cya n o-3-h y-
d r oxy-8-a za bicyclo[3.2.1]octa n e ((-)-20). Acid (-)-19 (5.96
g, 20.11 mmol) under N2 was heated in an oil bath at 105-
110 °C for 40 min. After being cooled to room temperature,
the solid residue was chromatographed (10% MeOH/CH2Cl2)
(1R,2R,3S,5S)-3-(Ben zoyloxy)-8-m et h yl-8-a za b icyclo-
[3.2.1]octa n e-2-ca r boxa m id e ((-)-24). To a solution of (-)-
23 (325 mg, 1.19 mmol) in CH3CN (25 mL) were added 37%
aqueous formaldehyde solution (0.49 mL, 6.13 mmol) and
NaBH3CN (0.123 g, 2.04 mmol), and the suspension was
stirred at room temperature for 1 h. The reaction mixture was
then acidified to pH 6 with glacial HOAc, stirred for 0.5 h,
basidifed to pH 8-9 with aqueous NH4OH, and partitioned
between CH2Cl2 (200 mL) and saturated aqueous NaHCO3 (50
mL). The aqueous phase was further extracted with CH2Cl2
(4 × 50 mL), and the organic layers were combined, dried,
filtered, and evaporated to give a yellowish oil. Chromatog-
raphy (gradient from 10%-20% MeOH/CH2Cl2 with 0.5%
to give (-)-20 as a white solid (4.06 g, 80%): mp 139-140 °C;
1
[R]23 -9.0° (c 1.0, CHCl3); H NMR (CDCl3, 58 °C) δ 1.50 (s,
D
3H), 1.58-1.65 (dd, 2H), 1.79-2.05 (m, 4H), 2.42 (bs, 1H), 3.07
(dd, 1H), 4.15 (m, 1H), 4.42 (m, 1H), 4.61 (m, 1H); 13C NMR
(CDCl3) δ 27.9, 28.3, 38.2, 41.9, 52.1, 54.0, 63.1, 80.5, 117.4,
152.5. Anal. Calcd for C13H20N2O3: C, 61.9; H, 8.0; N, 11.1.
Found: C, 61.6; H, 8.2; N, 11.2.
En a n tiom er (+)-20 (str u ctu r e n ot sh ow n ): [R]24D +7.2°
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (+)-19.
Et3N) gave (-)-24 as a hygroscopic foam (257 mg, 75%): [R]24
D
-19.5° (c ) 1.0, CHCl3); 1H NMR (CDCl3) δ 1.66-1.77 (m, 2H),
2.04-2.19 (m, 4H), 2.24 (s, 3H), 2.88 (d, J ) 7.4, 1H), 3.27 (bs,
1H), 3.36 (d, J ) 5.9, 1H), 5.32 (m, 1H), 6.44 (bs, 1H), 7.38 (t,
2H), 7.50 (t, 1H), 8.00 (d, 1H), 9.29 (bs, 1H); 13C NMR (CDCl3)
δ 24.6, 25.5, 35.4, 40.1, 51.0, 60.1, 62.8, 65.5, 127.9, 128.0,
129.4, 130.0, 132.6, 165.6, 173.6. Anal. Calcd for C16H22N2-
O4‚H2O: C, 62.73; H, 7.24; N, 9.14. Found: C, 62.47; H, 6.98;
N, 9.48.
(1R,2R,3S,5S)-8-(ter t-Bu tyloxyca r bon yl)-3-h yd r oxy-8-
a za bicyclo[3.2.1]oct a n e-2-ca r boxa m id e ((+)-21). To a
solution of (-)-20 (3.18 g, 12.60 mmol) in acetone (60 mL) were
added H2O (30 mL) and 10% Na2CO3 (60 mL). To the resulting
solution at 0 °C was added 30% aqueous H2O2 dropwise (30
mL), and the reaction mixture was stirred at room tempera-
ture for 24 h and then concentrated to about 100 mL. The
remaining aqueous phase was extracted with 1/3 i-PrOH/
CHCl3 (6 × 300 mL), and the combined organic phase was
dried, filtered, and evaporated. Recrystallization from THF/
En a n tiom er (+)-24 (str u ctu r e n ot sh ow n ): [R]22D +19.0°
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (+)-24.
hexanes gave (+)-21 (3.20 g, 94%): mp 153-154 °C; [R]22
(1R,2R,3S,5S)-3-(Ben zoyloxy)-8-m et h yl-8-a za b icyclo-
[3.2.1]octa n e-2-ca r boxylic Acid ((-)-25). To a solution of
(-)-24 (96 mg, 0.33 mmol) in a mixture of glacial HOAc and
Ac2O (1/2, 3.75 mL) at 0 °C was added NaNO2 (230 mg, 3.33
mmol). The suspension was stirred at 0 °C for 16 h and room
temperature for 8 h and then evaporated to dryness and
triturated with 20% MeOH/CH2Cl2. The resulting solution
was then concentrated, and the residue was chromatographed
with 20% MeOH/CH2Cl2 to give (-)-25 (89 mg, 93%): mp 191-
D
1
+18.4° (c 1.0, CHCl3); H NMR (CDCl3) δ 1.45 (s, 3H), 1.64-
2.02 (m, 6H), 2.79 (dd, 1H), 4.15 (bs, 1H), 4.38 (bs, 1H), 4.65
(bs, 1H), 5.63 (bs, 2H), 7.28 (bs, 1H); 13C NMR (CDCl3) δ 27.7,
28.2, 39.0, 49.5, 52.8, 54.1, 64.4, 80.1, 153.4, 175.7. Anal. Calcd
for C13H20N3O3: C, 57.8; H, 8.3; N, 10.4. Found: C, 58.0; H,
8.3; N, 10.6.
En a n tiom er (-)-21 (str u ctu r e n ot sh ow n ): [R]22D -18.0°
(c 1.0, CHCl3); spectral and chromatographic properties identi-
cal with (+)-21.
192 °C (lit.21 mp 196-197 °C, lit.25 mp 194-195 °C); [R]22
D