EnantioselectiVe Synthesis of SNAP-7941
SCHEME 6. Synthesis of SNAP-7941
trimethylsilyl isocyanate (0.346 g, 3.00 mmol), and THF (10 mL).
The solution containing the 10b and 3,5-dimethylbarbituic acid was
transferred via cannula to the palladium and isocyanate mixture.
The reaction mixture was stirred for 4 h. The solution was then
concentrated under reduced pressure, and a solution of 75% acetic
acid in ethanol (3 mL) was added. The solution was transferred to
a 10 mL microwave tube, and irradiated for 3 min at 30 °C. The
reaction mixture was concentrated under reduced pressure and the
resulting residue was purified by flash chromatography over silica
gel (elution with 80% to 100% EtOAc in hexanes) to afford the
dihydropyrimidone reaction product as a white solid.
General Procedure for the Chiral Phosphoric Acid-Catalyzed
Asymmetric Biginelli Reaction. An oven-dried 10-mL round-
bottomed flask equipped with stir bar was charged with urea 15
(0.012 g, 0.20 mmol), phosphoric acid catalyst (17a-c) (0.02
mmol), 3,4-difluorobenzaldehyde (16) (44 µL, 0.40 mmol), and
CH2Cl2 (3 mL). The flask was sealed with a Teflon cap (caplug),
and the solution was stirred for 2 h at room temperature. The
dicarbonyl compound (8a, 8b) (1.0 mmol) was slowly added, and
the solution was stirred for 6 days. Silica gel was added to the
reaction mixture, and the mixture was concentrated under reduced
pressure. The resulting solid was purified by flash chromatography
over silica gel (with 80-100% EtOAc in hexanes) to afford the
Biginelli reaction products as white solids.
Synthesis of SNAP-7941. A solution of 25 (0.050 g, 0.10 mmol),
24 (0.083 g, 0.30 mmol), DIPEA (0.078, 0.60 mmol), and anhydrous
CH2Cl2 (3 mL) was stirred at room temperature under argon
atmosphere for 24 h. The mixture was concentrated and the resulting
residue was purified by flash chromatography over silica gel (elution
with 1-5% methanol in ethyl acetate) to provide the desired final
compound as a yellow oil.
reaction time was obtained with Hu¨nig’s base, providing the
enantioenriched form of SNAP-7941 in 90% yield.
Conclusion
We have developed two organocatalytic enantioselective
approaches to SNAP-7941 that focus on the synthesis of the
chiral dihydropyrimidone core. The asymmetric Mannich reac-
tion catalyzed by Cinchona alkaloids and the asymmetric
Biginelli reaction catalyzed by chiral phosphoric acids were
equally effective at producing the desired heterocycle. The
additional steps required by the Mannich route are offset by
the time required for the enantioselective Biginelli reaction.
Despite the progress to date, some challenges still remain.
However, these approaches are the first highly enantioselective
routes to this important class of biologically and pharmaceuti-
cally relevant compounds. The development of effective syn-
thetic approaches will hopefully facilitate future efforts to
characterize the activity and biological properties of these chiral
heterocycles.
Characterization Data for Selected Compounds: (a) 2-[(R)-
Allyloxycarbonylamino-3,4-diflurophenylmethyl)-3-oxo-4-me-
thoxybutyric Acid Methyl Ester (10a). Clear viscous oil (0.25 g,
67% yield). 1H NMR (CDCl3, 400 MHz, both diastereomers
reported): δ 7.10 (m, 8H), 6.41 (d, J ) 9.2 Hz, 1H), 6.33 (d, J )
8.8 Hz, 1H), 5.86 (m, 2H), 5.53 (m, 1H), 5.43 (m, 1H), 5.30 (s,
1H), 5.27 (s, 1H), 5.23 (s, 1H), 5.20 (s, 1H), 4.50 (d, J ) 5.6 Hz,
4H), 4.32 (m, 2H), 4.08 (dd, J ) 7.2, 6.8 Hz, 2H), 3.87 (dd, J )
14.8, 6.0 Hz, 2H), 3.69 (s, 3H), 3.62 (s, 3H), 3.44 (s, 3H), 3.29 (s,
3H). 13C NMR (CDCl3, 75.0 MHz, both diastereomers reported):
δ 204.5, 202.2, 171.4, 169.0, 167.4, 156.0, 155.8, 151.7, 149.3 (d,
Experimental Section
General Procedure for Asymmetric Mannich Reaction of
r-Amido Sulfones. To an oven-dried 50-mL round-bottomed flask
equipped with a stir bar was added R-amido sulfone 11 (0.40 g,
1.00 mmol), (+)-cinchonine (0.029 g, 0.10 mmol), and CH2Cl2 (10
mL). The solution was cooled to -15 °C. The dicarbonyl compound
(8a-c) (3.00 mmol) and 10 mL of a solution of Na2CO3/NaCl were
sequentially added dropwise. The reaction was stirred for 24 h at
-15 °C and then diluted with CH2Cl2 (20 mL) and H2O (20 mL).
The organic layer was quickly separated, and the aqueous phase
was extracted with CH2Cl2 (2 × 20 mL). The organic layers were
combined, dried over sodium sulfate, filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography over silica gel (elution with 30% to 40% ethyl
acetate in hexanes) to afford the Mannich reaction products as white
solids.
General Procedure for Conversion from Mannich Adduct
to Dihydropyrimidone. To an oven-dried 50-mL round-bottomed
flask equipped with stir bar was added 10b (0.34 g, 1.00 mmol),
3,5-dimethylbarbituric acid (0.156 g, 1.00 mmol), and THF (10
mL). To another oven-dried 50-mL round-bottomed flask equipped
with stir bar was added Pd(PPh3)4 (0.060 g, 0.050 mmol),
2
1JCF ) 212.0 Hz), 136.9, 132.7, 122.8 (d, JCF ) 80.0 Hz), 117.8
2
2
(d, JCF ) 60.0 Hz), 116.1 (d, JCF ) 72.0 Hz), 66.3, 60.1, 59.6,
57.5, 53.4, 53.2, 52.8, 51.9. IR (thin film, cm-1): 3425, 2956, 1722,
1612, 1519, 1503, 1437, 1345, 1284, 1222, 1118, 1059. High
resolution mass spectrum m/z 394.1095 [(M + Na+) calcd for
C17H19NO6NaF2+: 394.1078]. [R]23 -28.7 (c 4.0, CHCl3). 78:22
D
er; HPLC analysis, tr major (of single diastereomer) 9.7 min, tr
minor (of single diastereomer) 11.2 min [ChiralcelAD column,
hexanes:IPA 90:10, 1.0 mL/min].
(b) 2-[(R)-Allyloxycarbonylamino-3,4-diflurophenylmethyl)-
3-oxo-butyric Acid Methyl Ester (10b). White solid (0.97 g, 97%
yield). Mp: 97-100 °C. 1H NMR (CDCl3, 400 MHz, both
diastereomers reported): δ 7.12 (m, 6H), 6.99 (s, 2H), 6.41 (d, J )
8.8 Hz, 1H), 6.25 (d, J ) 9.2 Hz, 1H), 5.85 (m, 2H), 5.47 (m, 1H),
5.37 (dd, J ) 6.8, 2.0 Hz, 1H), 5.21 (m, 5H), 4.49 (d, J ) 1.6 Hz,
4H), 4.00 (d, J ) 5.6 Hz, 1H), 3.94 (d, J ) 4.0 Hz, 1H), 3.68 (s,
3H), 3.66 (s, 3H), 2.23 (s, 3H), 2.00 (s, 3H). 13C NMR (CDCl3,
75.0 MHz, both diastereomers reported): δ 202.0, 199.6, 170.5,
1
168.2, 166.6, 155.0, 154.8, 150.6 (d, JCF ) 220.0 Hz), 148.1 (d,
1JCF ) 220.0 Hz), 131.8, 121.6 (d, 2JCF ) 24.0 Hz), 117.2 (d, 2JCF
) 44.0 Hz), 115.2 (d, 2JCF ) 72.0 Hz), 65.4, 63.0, 59.7, 52.1, 51.7,
30.0, 29.5, 22.0. IR (thin film, cm-1): 3423, 2996, 1720, 1649, 1612,
1519, 1503, 1437, 1363, 1284, 1219, 1147, 1119, 1061. High
resolution mass spectrum m/z 364.0954 [(M + Na+) calcd for
(21) (a) Mizuno, T.; Fukamatsu, T.; Takeuchi, M.; Shinkai, S. J. Chem. Soc.,
Perkin Trans. 1 2000, 407–413. (b) Cowart, M.; Latshaw, S. P.; Bhatia, P.;
Daanen, J. F.; Rohde, J.; Nelson, S. L.; Patel, M.; Kolasa, T.; Nakane, M.; Uchic,
M. E.; Miller, L. N.; Terranova, M. A.; Chang, R.; Donnelly-Roberts, D. L.;
Namovic, M. T.; Hollingsworth, P. R.; Martino, B. R.; Lynch, J. J.; Sullivan,
J. P.; Hsieh, G. C.; Moreland, R. B.; Brioni, J. D.; Stewart, A. O. J. Med. Chem.
2004, 47, 3853–3864.
C16H17NO5NaF2+: 364.0972]. [R]23 -32.4 (c 4.0, CHCl3). 94:6
D
er; HPLC analysis, tr major (of single diastereomer) 23.7 min, tr
J. Org. Chem. Vol. 73, No. 19, 2008 7655