The Journal of Organic Chemistry
Note
extracted with EtOAc (3 × 40 mL). The combined organic layers were
washed with brine (75 mL), dried over MgSO4, and concentrated
under reduced pressure. The resulting residue was purified by flash
column chromatography (1:1 EtOAc/hexanes with 1% Et3N) to
provide ( )-esermethole (13) (1.22 g, 87% yield) as a brown oil. Rf
0.2 (1:9 MeOH/CH2Cl2); 1H NMR (500 MHz, C6D6) δ 6.73 (d, J =
2.5, 1H), 6.70 (t, J = 2.5, 1H), 6.29 (d, J = 2.5, 1H), 3.96 (s, 1H), 3.44
(s, 3H), 2.61 (s, 3H), 2.54−2.56 (m, 2H), 2.36 (s, 3H) 1.77−1.85 (m,
2H), 1.32 (s, 3H); 13C NMR (125 MHz, C6D6) 153.4, 146.9, 138.1,
112.2, 109.7, 107.4, 98.0, 55.1, 52.7, 52.5, 41.1, 37.5, 37.2, 27.2.
Spectral data match those previously reported.16
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 10, 12, 13, and
1, in addition to SFC traces for 13 and 1. This material is
AUTHOR INFORMATION
■
Corresponding Author
(+)-Esermethole (13). To a solution of ( )-esermethole (13)
(312 mg, 1.35 mmol) in THF (1.3 mL) was added (−)-ditolyl-L-
tartaric acid (623 mg, 1.62 mmol) in 1.3 mL of THF. After 1 h, the
resulting salt was heated to 80 °C with vigorous stirring for 40 min
until the mixture became homogeneous. The solution was cooled to
room temperature, while maintaining vigorous stirring for 15 h. A solid
precipitate formed, which was collected by filtration and washed with
THF (3 × 2 mL) to afford the tartaric salt of (+)-esermethole (13).
The resulting tartaric salt was suspended in EtOAc (30 mL) and
washed with satd aq K2CO3 (30 mL) to afford (+)-esermethole (13)
(131 mg, 33% yield, 94% ee). SFC (CHIRALPAK OD-H, CO2/
MeOH = 19:20 with 0.1% Et2NH, flow 1.5 mL/min, 23 °C, detection
at 254 nm) tR 5.63 min (minor) and tR 6.14 min (major); Rf 0.2 (1:9
MeOH/CH2Cl2); 1H NMR (500 MHz, C6D6) δ 6.73 (d, J = 2.5, 1H),
6.70 (t, J = 2.5, 1H), 6.29 (d, J = 2.5, 1H), 3.96 (s, 1H), 3.44 (s, 3H),
2.61 (s, 3H), 2.54−2.56 (m, 2H), 2.36 (s, 3H) 1.77−1.85 (m, 2H),
1.32 (s, 3H); 13C NMR (125 MHz, C6D6) δ 153.4, 146.9, 138.1, 112.2,
ACKNOWLEDGMENTS
■
The authors are grateful to the National Science Foundation
(CHE-0955864 and graduate fellowship DGE-0707424 to
G.C.), Boehringer Ingelheim, DuPont, Eli Lilly, Amgen,
AstraZeneca, and the University of California, Los Angeles
for financial support. We thank Professor Harran (UCLA) for
pertinent discussions and Dr. Liansuo Zu for experimental
assistance.
REFERENCES
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+130.0 (c 0.35, C6H6). Spectral data match those previously
reported.17
(+)-Phenserine (1). To a solution of (+)-esermethole (13) (74.2
mg, 0.32 mmol) in CH2Cl2 (4 mL) was added BBr3 (0.15 mL, 1.60
mmol) as a solution in CH2Cl2 (1.60 mL) over 3 min. The reaction
was stirred for 1.5 h and concentrated by purging the reaction with N2.
The residue was dissolved in 5 mL of MeOH, and the resulting
solution was stirred for 5 min and was then concentrated. The
resulting residue was diluted with H2O (5 mL) and satd aq NaHCO3
(15 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL).
The combined organic layers were washed with brine (20 mL), dried
over Na2SO4, and concentrated under reduced pressure. The crude
product was used in the subsequent step without further purification.
To a solution of the crude residue in THF (1.4 mL) was added
NaH (1.1 mg, 0.03 mmol). The reaction was purged with N2 for 1
min, and then phenylisocyanate (38 μL, 0.35 mmol) was added
dropwise over 5 s. After stirring for 14 h, the reaction was quenched
with satd aq NaHCO3 (15 mL), and the aqueous layer was extracted
with EtOAc (3 × 15 mL). The combined organic layers were washed
with brine (50 mL), dried over Na2SO4, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (1:1 EtOAc/hexanes with 1% Et3N) to afford
(+)-phenserine (1) (79 mg, 81% yield) as a pink foam. Rf 0.3 (1:9
MeOH/CH2Cl2); 1H NMR (500 MHz, C6D6) δ 7.37 (d, J = 8.0, 2H),
7.07−7.10 (m, 2H), 6.93−7.01 (m, 1H), 6.89 (s, 1H), 6.81−6.84 (m,
2H), 6.18 (d, J = 3.0, 1H), 3.99 (s, 1H), 2.53 (s, 3H), 2.44−2.50 (m,
2H), 2.30 (s, 3H), 1.71−1.80 (m, 2H), 1.24 (s, 3H); 13C NMR (125
MHz, C6D6)) δ 152.2, 150.0, 143.0, 138.2, 137.6, 128.8, 128.8, 123.0,
120.6, 118.5, 116.4, 106.3, 97.7, 52.7, 52.3, 40.9, 40.9, 37.5, 36.4, 26.9;
[α]23.8D +70.0 (c 0.005, CHCl3); mp 138−140 °C. Spectral data match
those previously reported.2g
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̈
( )-Phenserine (1) was also prepared from ( )-esermethole (13)
using the above procedure (74% yield). The racemic mixture was
resolved by Supercritical Fluid Chromotography (SFC). SFC
conditions: CHIRALPAK OJ-H (2 cm × 25 cm), CO2/MeOH
(85:15) with 1% Et2NH, flow 50 mL/min, detection at 220 nm.
Analatical detection was conducted under the same conditions, except
at a flow rate of 3 mL/min on a 15 cm × 0.46 cm column: tR 2.26 min
((−)-phenserine (1)) and tR 3.00 min ((+)-phenserine (1)).
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