C O M M U N I C A T I O N S
Table 2. Organocatalytic Enantioselective Biginelli Reaction with
Phosphoric Acid 8a
reactions of urea (2b) with various aldehydes and â-keto esters
were carried out to give corresponding DHPMs with up to 97% ee
a
(entries 22-24).
Individual enantiomers of monastrol show distinct pharmaceutical
properties.5b The enantioenriched monastrol could be readily
prepared in high optical purity (91% ee), commencing with the
Biginelli reaction of meta-TBSO-benzaldehyde (1q) with thiourea
(2a) and ethyl acetoacetate (3a) (See Supporting Information).
In summary, we have discovered the first organocatalytic
asymmetric Biginelli reaction. The optimal chiral phosphoric acid,
entry
4
R1
2
R2
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
3-FC6H4
3-NO2C6H4
2-ClC6H4
3-ClC6H4
2-NO2C6H4
3-BrC6H4
3,5-Br2C6H3
3,5-(CF3)2C6H3
4-MeO2CC6H4
1-BrC10H6
c-C6H11
PhCHdCH
3-MeOC6H4
3-BrC6H4
3,5-Br2C6H3
3-BrC6H4
3-FC6H4
3-BrC6H4
3-FC6H4
2-FC6H4
2-FC6H4
3-NO2C6H4
3,5-Br2C6H3
3,5-F2C6H3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
86
80
77
73
52
85
66
56
67
64
40
44
83
85
51
65
70
64
65
86
84
75
51
84
91
88
91
90
90
91
96
97
90
91
92
88
90
91
96
92
94
92
94
91
92
8
derived from H -binol, afforded the reaction in high yields with
excellent enantioselectivities of up to 97% ee. A wide variety of
substrates, including aldehydes and â-keto esters, could be tolerated.
This reaction has an advantage of avoiding the contamination of
transition metals in the manufacture of the medicinally relevant
chiral 3,4-dihydropyrimidin-2-(1H)-ones.
4ja
4ka
4la
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4ma
4na
4gb
4hb
4gc
4bc
4jd
4bd
4oc
4od
4cb
4hc
4pb
Acknowledgment. We are grateful for financial support from
NSFC (20472082, 203900505, and 20325211).
Et
Me
Me
i-Pr
i-Pr
t-Bu
t-Bu
i-Pr
t-Bu
i-Pr
Et
Supporting Information Available: Experimental details and
characterization of new compounds and complete ref 5c. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
d
(1) For reviews, see: (a) Multicomponent Reactions; Zhu, J., Bienaym e´ , H.,
Eds.; Wiley-VCH: Weinheim, Germany, 2005. (b) Ram o´ n, D. J.; Yus,
M. Angew. Chem., Int. Ed. 2005, 44, 1602. (c) Burke, M. D.; Schreiber,
S. L. Angew. Chem., Int. Ed. 2004, 43, 46.
90
97
d
d
Me
93
(
(
(
2) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
3) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
4) For reviews, see: (a) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39,
a
The reaction was carried out on a 0.2 mmol scale, and the ratio of
b
c
1
/2/3 is 1/1.2/3. Isolated yield based on aldehyde. Determined by HPLC.
The ratio of 1/2/3 is 1/1.2/5.
d
4
51. (b) Kappe, C. O. In Multicomponent Reactions; Zhu, J., Bienaym e´ ,
H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; p 95. (c) Kappe, C.
based phosphoric acid 8a replaced 7a as a catalyst (entries 1 and
). A survey of solvents revealed that dichloromethane is a better
solvent than the others examined (see Supporting Information).
Importantly, the water generated from the condensation steps of
forming N-acyliminium intermediate 5 and the final product 4aa
O. Acc. Chem. Res. 2000, 33, 879.
5
(5) For examples, see: (a) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.;
Cucinotta, G.; DiMarco, J. D.; Gougoutas, J.; Hedberg, A.; Malley, M.;
McCarthy, J. P.; Zhang, R.; Moreland, S. J. Med. Chem. 1995, 38, 119.
(b) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber,
S. L.; Mitchison, T. J. Science 1999, 286, 971. (c) Deres, K.; et al. Science
2003, 299, 893.
(
Scheme 1) has little effect on the reaction since the addition of 5
(
6) (a) Dondoni, A.; Massi, A.; Sabbatini, S.; Bertolasi, V. J. Org. Chem.
2002, 67, 6979. (b) Dondoni, A.; Massi, A.; Sabbatini, S. Tetrahedron
Lett. 2002, 43, 5913. (c) Sidler, D. R.; Barta, N.; Li, W.; Hu, E.; Matty,
L.; Ikemoto, N.; Campbell, J. S.; Chartrain, M.; Gbewonyo, K.; Boyd,
R.; Corley, E. G.; Ball, R. G.; Larsen, R. D.; Reider, P. J. Can. J. Chem.
Å molecular sieves did not enhance the yield (entry 8). Further
improvement in the yield without sacrificing the stereochemistry
could be achieved by prolonging the reaction time (entry 9).
However, increasing reaction temperature slightly eroded the
enantioselectivity, albeit with 93% yield (entry 10).
After we established the optimal conditions, we explored the
generality of the phosphoric acid-catalyzed asymmetric Biginelli
reaction (Table 2). The scope of the aldehyde component was first
investigated by reaction with thiourea (2a) and ethyl acetoacetate
2
002, 80, 646. (d) Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.;
Kappe, C. O. Tetrahedron: Asymmetry 2000, 11, 1449. (e) Schnell, B.;
Krenn, W.; Faber, K.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 1 2000,
4382.
(
(
(
7) Mu n˜ oz-Mu n˜ iz, O.; Juaristi, E. ArkiVoc 2003, xi, 16.
8) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386.
9) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005,
127, 11256.
(
3a) (entries 1-13). A variety of aromatic aldehydes bearing various
(10) For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 1520. (b) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45,
types of substituents underwent the reaction to afford high enan-
tioselectivities ranging from 88 to 97% ee. The reaction conversion
and enantiochemical outcome depend, to some degree, on the
substituent on the aldehydes (entries 1-10). The reaction of meta-
substituted benzaldehydes and ortho-chlorobenzaldehyde proceeded
in high yields (entries 1-4 and 6). meta-Disubstituted benzalde-
hydes resulted in excellent enantioselectivities (96-97% ee), albeit
with a slight decrease in the yields (entries 7 and 8). An aliphatic
aldehyde was less reactive but afforded high enantioselectivity of
3
909. (c) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (d) Bolm, C.;
Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44,
758. (e) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289.
1
(
11) (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (b)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed.
2004, 43, 1566.
(12) (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2004,
1
26, 11804. (b) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett.
2
005, 7, 2583. (c) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005,
127, 15696. (d) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (e) Hoffmann, S.; Seayad, A. M.;
List, B. Angew. Chem., Int. Ed. 2005, 44, 7424. (f) Storer, R. I.; Carrera,
D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84. (g)
Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.
(h) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005,
9
2% ee (entry 11). The electron-rich 3-anisaldehyde and cinnam-
aldehyde provided 90 and 88% ee, respectively (entries 12 and 13).
The scope of â-keto ester components in the organocatalytic
asymmetric Biginelli reaction was examined next (Table 2, entries
127, 9360. (i) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem.,
Int. Ed. 2006, 45, 2254. (j) Rueping, M.; Sugiono, E.; Azap, C. Angew.
Chem., Int. Ed. 2006, 45, 2617. (k) Mayer, S.; List, B. Angew. Chem.,
Int. Ed. 2006, 45, 4193.
1
4-21). Primary experimental results indicated that variation of
the R substituent of â-keto esters 3 could be tolerated, and generally
high enantioselectivities (91-96% ee) were provided for the
reactions related to these substrates (entries 14-21). Biginelli
2
(13) Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
JA065267Y
J. AM. CHEM. SOC.
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