8494 J . Org. Chem., Vol. 61, No. 24, 1996
Hoye and Renner
2H), 0.19** (d, 3H, J ) 7 Hz), 0.16 (m, 1H), and 0.05 (m, 1H).
HRMS (FAB): calcd for C27H42F3NO2 (M + H+) 470.3246, found
470.3227.
Exp er im en ta l Section
In the 1H NMR data (δ values are in ppm) for 8-11
resonances associated with the major amide rotamer are
indicated with * and those for the minor amide rotamer with
**; resonances comprising protons from both rotamers bear
no asterisk. Proton assignments were consistent with DQ-
COSY experiments for 8, 9, 10, 11, and 15 and DQ-COSY and
NOESY spectra for 16 and 17.
(3S,5S)-3,5-Dih yd r o-3,5-d im et h yl-4H -d in a p h t h [2,1-c:
1′,2′-e]a zep in e (R)-MTP A Am id e (14). Azepine 6 (4.7 mg,
0.15 mmol) and Hu¨nig’s base (2 mg, 0.16 mmol, 1.1 equiv) were
dissolved in methylene chloride (200 µL) and stirred slowly in
a tapered screw-capped vial under argon. (S)-MTPA-Cl (5.4
mg, 0.21 mmol, 1.5 equiv) was added, and the reaction mixture
was stirred at ambient temperature for 14 h. The solvent was
removed under reduced pressure, and the residue was purified
by flash chromatography (10:1 Hex:EtOAc) to give a white
solid (5.2 mg, 67%). 1H NMR (CDCl3, 500 MHz): δ 7.95 (d,
1H, J ) 8.5 Hz), 7.93 (br d, 2H, J ) 8.5 Hz), 7.87 (br d, 1H, J
) 8.5 Hz), 7.67 (br d, 2H, J ) 7.5 Hz), 7.56 (d, 1H, J ) 8.5
Hz), 7.52 (d, 1H, J ) 8.5 Hz), 7.48 (ddd, 1H, J ) 1.5, 7, and 7
Hz), 7.34-7.43 (m, 4H), 7.24-7.30 (m, 2H), 7.15 (br d, 2H, J
) 3.5 Hz), 5.90 (q, 1H, J ) 6.5 Hz), 5.52 (q, 1H, J ) 6.5 Hz),
3.71 (q, 3H, J ) 1.5 Hz), 0.91 (d, 3H, J ) 7 Hz), and -0.34 (d,
3H, J ) 7 Hz). IR (thin film): 1737 (w), 1642 (s), 1254 (m),
1181 (s), and 1163 (s) cm-1. MS (EI): m/ z 539 (21), 525 (5),
524 (20), 350 (30), 307 (42), 291 (20), 280 (57), 265 (41), 189
(2S,6S)-2-(Ca r beth oxym eth yl)-6-m eth ylp ip er id in e (R)-
MTP A Am id e (8). (Carbethoxymethyl)methylpiperidine 3
(3.9 mg, 0.021 mmol) and Hu¨nig’s base (6.7 mg, 0.052 mmol,
2.5 equiv) were dissolved in deuteriochloroform (200 µL) and
stirred slowly in a tapered screw-capped vial under argon. (S)-
MTPA-Cl (13.5 mg, 0.053 mmol, 2.5 equiv) was added, and
the mixture was stirred at ambient temperature for 96 h. The
solvent was evaporated, and the resulting residue was taken
up in 1 M NH4Cl and stirred vigorously for 30 min. The
mixture was extracted with methylene chloride (4 × 1 mL),
dried over MgSO4, and flashed through a short plug of silica.
The resulting oil was purified by preparative HPLC (90:10
Hex:EtOAc) to give 8 as a clear oil (5.1 mg, 61%). 1H NMR
(CDCl3, 500 MHz, 2.5:1 ratio of rotamers): δ 7.56-7.53 (m,
4H), 7.41-7.37 (m, 6H), 5.10* (m, 1H), 5.05** (m, 1H), 4.47*
(m, 1H), 4.34** (m, 1H), 4.19* (dq, 1H, J ) 11 and 7 Hz), 4.15*
(dq, 1H, J ) 11 and 7 Hz), 4.14** (dq, 1H, J ) 11 and 7 Hz),
4.10** (dq, 1H, J ) 11 and 7 Hz), 3.76* (q, 3H, J ) 1.5 Hz),
3.70** (q, 3H, J ) 2 Hz), 2.83** (dd, 1H, J ) 11 and 16 Hz),
2.59* (dd, 1H, J ) 10 and 15 Hz), 2.54* (dd, 1H, J ) 4 and 15
Hz), 2.43** (br d, 1H, J ) 16 Hz), 1.8-1.4 (m, many H’s), 1.29*
(t, 3H, J ) 7.5 Hz), 1.26** (t, 3H, J ) 7.5 Hz), 1.24** (d, 3H,
J ) 7.5 Hz), 1.05** (br d, 1H, J ) 13.5 Hz), 0.52** (m, 1H),
and 0.26* (d, 3H, J ) 7 Hz). HRMS (FAB): calcd for C20H26F3-
NO4 (M + H+) 402.1892, found 402.1884.
(2S,6S)-2-(Ca r beth oxym eth yl)-6-m eth ylp ip er id in e (S)-
MTP A Am id e (9). Amide 9 was prepared from amine 3 and
(R)-MTPA-Cl using a procedure analogous to that used for the
preparation of 8 from 3. 1H NMR (CDCl3, 500 MHz, 2:1 ratio
of rotamers): δ 7.56-7.51 (m, 4H), 7.39-7.36 (m, 2H), 7.36-
7.33 (m, 4H), 5.34** (m, 1H), 4.87* (m, 1H), 4.84* (m, 1H),
4.16** (dq, 1H, J ) 11 and 7.5 Hz), 4.12** (dq, 1H, J ) 11
and 7.5 Hz), 4.08** (m, 1H), 3.85* (q, 2H, J ) 7.5 Hz), 3.79*
(q, 3H, J ) 1.5 Hz), 3.74** (q, 3H, J ) 2 Hz), 2.68** (dd, 1H,
J ) 7 and 15 Hz), 2.64** (dd, 1H, J ) 8 and 15 Hz), 2.38* (dd,
1H, J ) 12 and 17 Hz), 1.7-1.4 (m, many H’s), 1.28** (t, 3H,
J ) 7.5 Hz), 1.25** (d, 3H, J ) 7.5 Hz), 1.17* (d, 3H, J ) 7
Hz), 1.16* (br d, 1H, J ) 17 Hz), 1.14* (t, 3H, J ) 7 Hz), 0.88**
(br d, 1H, J ) 15 Hz), and 0.55** (m, 1H). HRMS (FAB): calcd
for C20H26F3NO4 (M + H+) 402.1892, found 402.1893.
(2R,6R)-6-Meth yl-2-p r op ylp ip er id in e (S)-MTP A Am id e
(10). epi-Dihydropinidine hydrochloride (4) (4.2 mg, 0.024
mmol) was suspended in deuteriochloroform (100 µL). Hu¨nig’s
base (6.7 mg, 0.052 mmol, 2.2 equiv) and (R)-MTPA-Cl (8.8
mg, 0.035 mmol, 1.5 equiv) were added, and the mixture was
stirred overnight at ambient temperature. The solvent was
evaporated, and the residue was taken up in 1 M NH4Cl. The
mixture was extracted with methylene chloride (6 × 2 mL),
dried over MgSO4, and concentrated to yield a yellow oil, which
was purified by preparative HPLC (96:4 Hex:EtOAc) to give
10 as a clear oil (3.4 mg, 40%). 1H NMR (CDCl3, 500 MHz,
6:5 ratio of rotamers): δ 7.60-7.57 (m, 4H), 7.39-7.35 (m, 6H),
4.37** (m, 1H), 4.07-4.01* (m, 2H), 3.90** (m, 1H), 3.75 (s,
6H), 1.96-1.45 (m, many H’s), 1.43* (d, 3H, J ) 6.5 Hz), 1.38*
(m, 1H), 1.26** (m, 1H), 0.96** (t, 3H, J ) 7.5 Hz), 0.79** (m,
1H), 0.39* (t, 3H, J ) 7 Hz), 0.20** (d, 3H, J ) 6.5 Hz), and
0.17-0.10 (m, 2H). HRMS (FAB): calcd for C19H26F3NO2 (M
+ H+) 358.1994, found 358.2006.
(2R,6R)-6-Meth yl-2-u n decylpiper idin e (S)-MTP A Am ide
(11). Amide 11 was prepared from (-)-solenopsin A hydro-
chloride (5) using a procedure analogous to that used for the
preparation of 10 from 4 (7.3 mg, 62%). 1H NMR (CDCl3, 500
MHz): δ 7.60-7.57 (m, 4H), 7.38-7.35 (m, 6H), 4.37** (m, 1H),
4.05* (m, 1H), 4.03* (m, 1H), 3.88** (m, 1H), 3.75* (s, 3H),
3.74** (s, 3H), 2.0-1.4 (m, many H’s), 1.43* (d, 3H, J ) 6.5
Hz), 1.4-1.2 (m, many H’s), 1.10 (m, 2H), 0.94 (m, 2H), 0.892*
(t, 3H, J ) 7.5 Hz), 0.885** (t, 3H, J ) 7.5 Hz), 0.8-0.6 (m,
(75), and 105 (100). HRMS (EI): calcd for C34
539.2072, found 539.2054.
H28F3NO2
(3S,5S)-3,5-Dih yd r o-3,5-d im et h yl-4H -d in a p h t h [2,1-c:
1′,2′-e]a zep in e (S)-MTP A Am id e (15). Compound 15 was
prepared from azepine 6 using a procedure analogous to that
used for the preparation of 14 from 6 (9.2 mg, 88%). 1H NMR
(CDCl3, 500 MHz): δ 7.96 (d, 1H, J ) 7 Hz), 7.92 (br d, 1H, J
) 7.5 Hz), 7.80 (br d, 1H, J ) 8 Hz), 7.61 (tt, 1H, J ) 1.5, 1.5,
7.5, and 7.5 Hz), 7.58 (br d, 3H, J ) 8 Hz), 7.50 (d, 1H, J ) 8
Hz), 7.48 (br d, 2H, J ) 8 Hz), 7.44 (ddd, 1H, J ) 1, 7, and 7
Hz), 7.43 (ddd,1H, J ) 1, 7, and 7 Hz), 7.35 (br d, 1H, J ) 8
Hz), 7.25 (br d, 1H, J ) 8.5 Hz), 7.22 (ddd, 1H, J ) 1.5, 7, and
7 Hz), 7.21 (ddd, 1H, J ) 1.5, 7, and 7 Hz), 5.74 (q, 1H, J ) 7
Hz), 5.23 (d, 1H, J ) 8.5 Hz), 5.05 (q, 1H, J ) 7 Hz), 3.70 (q,
3H, J ) 1.5 Hz), 0.84 (d, 3H, J ) 7 Hz), and 0.71 (d, 3H, J )
7 Hz). IR (thin film): 1737 (w), 1641 (s), 1254 (m), 1181 (s),
and 1163 (s) cm-1. MS (EI): m/ z 539 (46), 525 (14), 524 (33),
350 (47), 307 (70), 291 (32), 280 (100), 265 (69), and 189 (52).
HRMS (EI): calcd for C34H28F3NO2 539.2072, found 539.2077.
Nor coca in e N-(R)-MTP A Am id e (16). Cocaine base (500
mg, 1.65 mmol) was dissolved in dry benzene (10 mL) over
anhydrous potassium carbonate (50 mg). 2,2,2-Trichloroethyl
chloroformate (385 mg, 1.82 mmol) was added to the stirred
mixture, and the mixture was heated to reflux for 36 h. The
reaction mixture was poured into ice water, the layers were
separated, and the aqueous layer was extracted with chloro-
form (3 × 20 mL). The combined organic layers were washed
with brine and dried over MgSO4. The solvent was evaporated
to give norcocaine N-(trichloroethyl)carbamate as an oil. The
carbamate (166 mg, 0.357 mmol) was dissolved in 95% acetic
acid (30 mL) and stirred at ambient temperature. Zinc dust
(250 mg, 3.82 mmol) was added slowly, and the mixture was
stirred for 48 h. The mixture was diluted with water (75 mL),
basified with solid sodium carbonate, and extracted with
methylene chloride (3 × 50 mL). The combined organic
extracts were dried over MgSO4 and concentrated under
reduced pressure to give norcocaine (7) as a clear oil (75 mg,
74%), which slowly decomposed upon standing in air. The oil
(18.5 mg, 0.064 mmol) and Hu¨nig’s base (18.5 mg, 0.14 mmol,
2.2 equiv) were dissolved in methylene chloride (500 µL) under
argon. (S)-MTPA-Cl (19 mg, 0.075 mmol, 1.2 equiv) was added
slowly to the stirred mixture, and the reaction mixture was
stirred overnight. The solvent was evaporated, and the
residue was taken up in 1 M NH4Cl. The mixture was
extracted into methylene chloride (3 × 2 mL), dried over
MgSO4, and concentrated under reduced pressure to give a
yellow oil (35 mg). The oil was purified by flash chromatog-
raphy (4:1 Hex:EtOAc) to provide 16 as a clear oil (22.4 mg,
70%), which solidified (mp 149-152 °C) upon standing. 1H
NMR (CDCl3, 500 MHz): δ 7.96 (dd, 2H, J ) 1 and 8.5 Hz),
7.56 (tt, 1H, J ) 1, 1, 7.5, and 7.5 Hz), 7.53 (m, 2H), 7.42 (dd,
2H, J ) 7.5 and 8 Hz), 7.35-7.39 (m, 3H), 5.36 (ddd, 1H, J )
6, 6, and 11.5 Hz), 5.23 (m, 1H, Σ J ’s ) 11 Hz), 4.33 (m, 1H, ∑
J ’s ) 12.5 Hz), 3.94 (q, 3H, J ) 2 Hz), 3.70 (s, 3H), 3.19 (dd,