4774 J . Org. Chem., Vol. 65, No. 15, 2000
Notes
(s, 3H); 13C NMR (90 MHz, CDCl3) δ 209.5, 75.6, 67.8, 64.7, 61.5,
58.6, 51.5, 40.8, 26.5, 26.4, 26.0, 18.4, -5.4; HRMS (M+ - C4H9)
calcd for C12H22NO3Si 256.1369, found 256.1357.
Sch em e 2
(+)-(1S,2R,5R,1′S)-2-[(2′-ter t-Bu tyld im eth ylsiloxy-1′-tr i-
isop r op ylsiloxy)eth yl]-8-m eth yl-8-a za bicyclo[3.2.1]octa n -
3-on e (9). To a solution of 8 (0.50 g, 1.60 mmol) and 2,6-lutidine
(0.86 g, 8.0 mmol) in CH2Cl2 (4 mL) was added dropwise at 0 °C
triisopropyl trifluoromethanesulfonate (0.54 g, 1.76 mmol). The
mixture was stirred for 7 h at room temperature and quenched
with water. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2. The combined organic extracts
were washed with brine, dried over MgSO4, and concentrated
in vacuo. Purification by column chromatography (4:1 hexanes-
EtOAc) afforded 9 (0.72 g, 96%) as a colorless oil: [R]23D ) +23.0
(c 0.8, CHCl3); IR (film) 1709, 1464 cm-1 1H NMR (360 MHz,
;
CDCl3) δ 4.26 (ddd, J ) 6.0, 5.6, 5.3 Hz, 1H), 3.82 (dd, J ) 10.2,
6.0 Hz, 1H), 3.64 (dd, J ) 10.2, 5.3 Hz, 1H), 3.43 (br d, J ) 6.6
Hz, 1H), 3.28 (m, 1H), 2.75 (dd, J ) 16.4, 4.7 Hz, 1H), 2.34 (d,
J ) 5.6 Hz, 1H), 2.28 (s. 3H), 2.22-2.03 (m, 2H), 2.13 (d, J )
16.4 Hz, 1H), 1.60-1.40 (m, 2H), 1.03 (s, 21H), 0.85 (s, 9H), 0.01
(s, 3H), 0.00 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 210.4, 74.7,
66.0, 63.7, 61.6, 61.3, 50.3, 41.3, 27.3, 26.6, 25.9, 18.1, 17.7, 12.7,
12.3, 4.9, 4.8; HRMS (M+ - C3H7) calcd for C22H44NO3Si2
426.2680, found 426.2867.
conversion was accomplished in a one-pot operation by
9
sequential treatment with HF, followed by RuCl3-NaIO4
and subsequent methylation with TMSCHN210 to furnish
(-)-(1S,2R,5R,1′S)-2-[(2′-ter t-Bu tyld im eth ylsiloxy-1′-tr i-
isop r op ylsiloxy)et h yl]-3-h yd r oxy-8-m et h yl-8-a za b icyclo-
[3.2.1]octa n e (10). Lithium (0.4 g) was added to 30 mL of
anhydrous ammonia at -78 °C. To the resulting blue solution
was added a solution of 9 (0.8 g, 1.7 mmol) in THF (10 mL).
After the mixture was stirred for 30 min at -78 °C, methanol
(2.5 mL) was added dropwise. Additional 0.12 g of lithium wire
was added at -78 °C. The reaction mixture was stirred for an
additional 30 min and quenched by cautious addition of solid
NH4Cl. Ammonia was allowed to evaporate slowly, and the
residue was extracted with ether. The extracts were dried over
MgSO4 and concentrated in vacuo. Purification by column
chromatography (10:1 CH2Cl2-MeOH) afforded 10 (0.78 g, 97%)
(S)-(+)-cocaine (2), [R]25 ) +15.0 (c 0.48, CHCl3) [lit.11d
D
[R]25D ) -16.0 (c 4.0, CHCl3) for 1] in 78% overall yield.12
Thus, the enantiomeric purity of synthetic (+)-2 was
∼90% ee and identical to that of 8, which can be improved
to 100% by a single recrystallization.
In summary, a concise (4-5 steps), stereoselective
synthesis of (S)-(+)-cocaine (2) was achieved from tropi-
none (3). The present work underscores the general
utility of enantioselective deprotonation of meso cyclic
ketones in asymmetric synthesis.
as a colorless oil: [R]23 ) -3.0 (c 0.5, CHCl3); IR (film) 3464,
D
Exp er im en ta l Section 13
1464 cm-1; 1H NMR (360 MHz, CDCl3) δ 4.36 (ddd, J ) 6.1, 5.7,
3.4 Hz, 1H), 4.12 (dd, J ) 10.1, 5.7 Hz, 1H), 3.94 (ddd, J ) 12.1,
6.2, 5.4 Hz, 1H), 3.70 (dd, J ) 10.1, 3.4 Hz, 1H), 3.19 (br d, J )
5.6 Hz, 1H), 3.08 (br s, 1H), 2.28-1.84 (m, 4H), 2.12 (s, 3H),
1.73 (ddd, J ) 12.1, 5.7, 3.0 Hz, 1H), 1.54-1.40 (m, 2H), 1.10 (s,
21H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (90 MHz, CDCl3) δ
75.1, 66.1, 65.9, 63.1, 61.4, 48.8, 41.2, 41.0, 29.7, 26.2, 25.9, 25.5,
18.2, 13.1, 5.0, 4.7; HRMS (M+ - C3H7) calcd for C22H46NO3Si2
428.3016, found 428.2990.
(+)-(1S,2R,5R,1′S)-2-[(2′-ter t-Bu tyld im eth ylsiloxy-1′-h y-
d r oxy)eth yl]-8-m eth yl-8-a za bicyclo[3.2.1]octa n -3-on e (8).
To a solution of (S,S)-bis(1-phenylethyl)amine hydrochloride
(2.19 g, 8.37 mmol) in THF (25 mL) was added dropwise n-BuLi
(10.4 mL of a 1.6 M solution in hexane) at 0 °C. The mixture
was stirred for 1.5 h at 0 °C and cooled to -78 °C. Tropinone (3)
(0.78 g, 5.6 mmol) in THF (5 mL) was added dropwise, and the
resulting solution was stirred for 3 h at -78 °C, followed by
addition of 2-(tert-Butyldimethylsiloxy)ethanal (7) (1.48 g. 8.49
mmol) in THF (5 mL) at -78 °C. After the reaction mixture was
stirred for 3.5 h, saturated aqueous NH4Cl was then added and
the mixture was stirred for an additional 0.5 h at room
temperature. The mixture was poured into Et2O and water. The
organic layer was separated, and the aqueous layer was ex-
tracted with Et2O. The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. Purification by column
chromatography (EtOAc) afforded the aldol product 8 (1.26 g,
(+)-(1S,2R,5R,1′S)-2-[(2′-ter t-Bu tyld im eth ylsiloxy-1′-tr i-
isopr opylsiloxy)eth yl]-3-ben zoyloxy-8-m eth yl-8-azabicyclo-
[3.2.1]octa n e (11). Benzoyl chloride (0.3 g, 2.2 mmol) was added
dropwise at 0 °C to a solution of 10 (0.73 g, 1.55 mmol),
4-(dimethylamino)pyridine (30 mg, 0.25 mmol), and triethy-
lamine (1.3 mL) in CH2Cl2 (1.5 mL). The resulting mixture was
stirred for 3 h at room temperature and quenched at 0 °C by
addition of 5% aqueous NaOH solution. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2.
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. Purification by column chromatography
(6:1 hexanes-EtOAc) afforded 11 (0.76 g, 85%) as a colorless
72%) as a white solid: mp 72-73 °C; [R]23 ) +77.0 (c 0.6,
D
CHCl3); IR (film) 3390, 1713, 1471 cm-1
;
1H NMR (360 MHz,
CDCl3) δ 7.02 (br s, 1H), 4.05 (ddd, J ) 6.9, 5.6, 2.2 Hz, 1H),
3.51 (dd, J ) 10.1, 5.6 Hz, 1H), 3.42 (dd, J ) 10.1, 6.9 Hz, 1H),
3.46-3.38 (m, 2H), 2.69 (ddd, J ) 16.1, 4.9, 1.9 Hz, 1H), 2.40 (s.
3H), 2.39 (d, J ) 2.2 Hz, 1H), 2.30 (d, J ) 16.1 Hz, 1H), 2.29-
2.10 (m, 2H), 1.67-1.55 (m, 2H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06
oil: [R]23 ) +18.0 (c 0.83, CHCl3); IR (film) 1723, 1471 cm-1
;
D
1H NMR (360 MHz, CDCl3) δ 8.02 (dd, J ) 7.4, 1.4 Hz, 2H),
7.54 (m, 1H), 7.40 (dd, J ) 7.8, 7.4 Hz, 2H), 5.41 (ddd, J ) 15.9,
11.1, 7.9 Hz, 1H), 4.17 (ddd, J ) 8.1, 4.4, 1.9 Hz, 1H), 4.10 (dd,
J ) 11.1, 1.9 Hz, 1H), 3.88 (dd, J ) 11.1, 8.1 Hz, 1H), 3.57 (br
d, J ) 7.2 Hz, 1H), 3.15 (m, 1H), 2.27 (ddd, J ) 7.9, 4.4, 2.1 Hz,
1H), 2.22-1.85 (m, 4H), 2.16 (s, 3H), 1.71-1.62 (m, 1H), 1.59-
1.50 (m, 1H), 1.04-0.98 (br s, 21H), 0.92 (s, 9H), 0.07 (s, 3H),
0.06 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 165.9, 132.8, 130.4,
129.6, 128.2, 74.5, 68.5, 68.2, 61.0, 60.6, 50.3, 40.7, 37.7, 26.3,
26.1, 25.2, 18.6, 18.2, 12.6, 4.7, 4.6; HRMS (M+ - C3H7) calcd
for C29H50NO4Si2 532.3278, found 532.3282.
(10) Shioiri, T.; Aoyama, T. J . Synth. Org. Chem., J pn. 1996, 54,
918.
(11) For previous syntheses of cocaine, see: (a) ref 1. (b) Bainova,
M. S.; Bazilevskaya, G. I.; Preobrazhenskii, N. A. Zh. Obshch. Khim.
1960, 30, 3258. (c) Tufariello, J . J .; Mullen, G. B.; Tegeler, J . J .;
Trybulski, E. J .; Wong, S. C.; Ali, S. A. J . Am. Chem. Soc. 1979, 101,
2435. (d) Lewin, A. H.; Naseree, T.; Caroll, F. I. J . Heterocycl. Chem.
1987, 24, 19. (e) Lin, R.; Castells, J .; Rapoport, H. J . Org. Chem. 1998,
63, 4069.
(12) Also isolated was a small (6%) amount of a byproduct, whose
structure was tentatively assigned to be as shown in 13.
(13) (a) For general procedures, see: Ha, J . D.; Cha, J . K. J . Am.
Chem. Soc. 1999, 121, 10012. (b) Unless noted otherwise, the OH
proton resonances are not reported in the 1H NMR spectral listings.
(S)-(+)-Coca in e (2). A solution of 11 (0.29 g, 0.5 mmol) in
acetonitrile (6 mL) was treated with 50% aqueous HF solution
(3 mL) at room temperature. The mixture was stirred for 1 h
and concentrated under reduced pressure. After the residue was
dissolved in 7 mL of 2:2:3 CCl4-CH3CN-H2O, NaIO4 (0.46 g,
2.15 mmol) and RuCl3‚3H2O (12 mg, 0.05 mmol) were then