Nornicotine Aqueous Aldol Reactions
DMSO to a solution of acetone (240 mM) and catalyst (2.4 mM)
in buffer (200 mM phosphate, pH 8.0). The reaction was
followed for no more than 5% of the reaction during which the
rate was linear (r2 > 0.990).
the stereoelectronic nature of individual catalyst struc-
tures, thereby guiding future synthetic efforts in the
production of viable aqueous aldol catalysts.
Com p u ta tion a l Stu d ies. All geometries and energies
presented in the present study were computed by using the
B3LYP density functional theory15 method as implemented in
the Gaussian98 program package.16 Geometry optimizations
were performed by using the triple-ú plus polarization basis
set 6-311G(d,p), followed by single point energy calculation
with the larger basis set 6-311+G(2d,2p). Hessians were
calculated at the HF/3-21G level of theory. Hessians provide
a control that the stationary points localized are correct, with
no imaginary frequencies for minima and one imaginary
frequency for transition states, and also allow evaluation of
the zero-point vibrational effects on energy. Electrostatic
solvent effects were modeled with use of the conductor-like
solvation model COSMO at the B3LYP/6-311G(d,p) level. In
this model, a cavity around the system is surrounded by
polarizable dielectric continuum.17 The dielectric constant for
the solvent is chosen to be ꢀ ) 80, a widely accepted standard
for water. To describe the simple aldol reaction in organic
solvent, ꢀ for THF was set at 7.6. All energies presented are
enthalpies to which solvation energies are added. Zero-point
effects are also included.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise stated, all reactions
were performed under an inert atmosphere with dry reagents
and solvents and flame-dried glassware. Analytical thin-layer
chromatography (TLC) was performed with 0.25 mm precoated
silica gel Kieselgel 60 F254 plates. Visualization of the chro-
matogram was by UV absorbance, iodine, dinitrophenylhy-
drazine, ceric ammonium molybdate, ninhydrin, or potassium
permanganate as appropriate. Preparative and semiprepara-
tive TLC was performed with Merck 1 mm or 0.5 mm coated
silica gel Kieselgel 60 F254 plates, respectively. Methylene
chloride and chloroform were distilled from calcium hydride.
Tetrahydrofuran (THF) was distilled from sodium/benzophe-
none. Methanol was distilled from magnesium. 1H and 13C
NMR spectra were recorded at 500 and 125 MHz, respectively,
unless otherwise noted.
2,3,3a ,4,5,9b -H exa h yd r o-1H -p yr r olo[3,2-h ]isoq u in o-
lin e (2). Nornicotine analogue 2 was prepared according to
published procedures11 with slight modifications: (a) the
oxidation of tetrahydroisoquinoline was performed at elevated
reaction temperatures (40 °C); (b) compounds were purified
on silica with flash chromatography (CHCl3:MeOH:NH4OH 85:
15:1.5) in higher yields to those previously reported; and (c)
the low yield of the Michael addition was improved by using
multiple equivalents (4-5) of nitroethylene.
Ack n ow led gm en t. This work was supported finan-
cially by The Scripps Research Institute, The Skaggs
Institute for Chemical Biology, the National Institutes
of Health (GM 43278 to L.N.), and the National Institute
on Drug Abuse (DA 15973 to T.J .D.).
2,3,3a ,4,5,9b-Hexa h yd r o-1H-p yr r olo[2,3-f]qu in olin e (3).
Nornicotine analogue 3 was prepared according to published
procedures11 with identical modifications as listed for the
synthesis of 2.
J O048894J
Aqu eou s Ald ol Rea ction Scr een in g. The assay was
initiated by the addition of a solution of 4-nitrobenzaldehyde
(100 mM in DMSO) to a solution of acetone (240 mM) and
catalyst (2.4 mM) in buffer (200 mM phosphate, pH 7.4). The
total assay volume was 1 mL and the assay was performed at
37 °C. At times throughout the assay, aliquots (10 µL) were
removed and diluted to a final volume of 0.5 mL with
phosphate buffer. Aliquots of these diluted solutions (20 µL)
were then removed and injected onto a RP-C18 HPLC column,
equipped with a guard-column (HPLC conditions: isocratic
mobile phase of acetonitrile:water (25:75) with 0.1% TFA;
solvent flow rate of 1 mL min-1 and detection at 254 nm). Aldol
addition product formation (retention time ) 6.2 min) was
determined by interpolation of peak height and area values
relative to standard curves.
(15) (a) Becke, A. D. Phys. Rev. 1988, A38, 3098-3100. (b) Becke,
A. D. J . Chem. Phys. 1993, 98, 1372-1377. (c) Becke, A. D. J . Chem.
Phys. 1993, 98, 5648-5652.
(16) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.9; Gaussian, Inc.: Pittsburgh, PA,
1998.
(17) (a) Miertus, S.; Scrocco, E.; Tomasi, J . J . Chem. Phys. 1981,
114, 117-129. (b) Miertus, S.; Tomasi, J . J . Chem. Phys. 1982, 65,
239-245. (c) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J . Chem. Phys.
Lett. 1996, 255, 327-335. (d) Barone, V.; Cossi, M. J . Phys. Chem. A
1998, 102, 1995-2001.
Ra te Con sta n t Deter m in a tion . The rate constant for each
catalyst was determined by the method of initial rates under
pseudo-first-order conditions. The assay was initiated by the
addition of a solution of 4-nitrobenzaldehyde (1-8 mM) in
J . Org. Chem, Vol. 69, No. 20, 2004 6609