Highly enantioselective Biginelli reaction using a new chiral ytterbium catalyst: Asymmetric synthesis of dihydropyrimidines

Article abstract of DOI:10.1021/ja056092f

The highly enantioselective three-component Biginelli condensation catalyzed by a recyclable chiral ytterbium triflate with a novel hexadentate amine phenol ligand containing a pyridyl group has been developed. A wide range of optically active dihydropyrimidines with remarkable pharmacological interest was obtained in high yields with good to excellent enantioselectivities under mild conditions. Copyright

Full text of DOI:10.1021/ja056092f

Published on Web 11/08/2005
Highly Enantioseletive Biginelli Reaction Using a New Chiral Ytterbium
Catalyst: Asymmetric Synthesis of Dihydropyrimidines
Yijun Huang,† Fengyue Yang,† and Chengjian Zhu*,†,‡
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing
UniVersity, Nanjing 210093, China, and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received September 4, 2005; E-mail: cjzhu@netra.nju.edu.cn
Multicomponent reactions (MCRs) occupy an outstanding posi-
tion in organic and medicinal chemistry for their high degree of
atom economy, applications in combinatorial chemistry, and
diversity-oriented synthesis.1 The venerable Biginelli reaction, one-
pot cyclocondensation of aldehyde, 1,3-ketoester, and urea or
thiourea, is inarguably one of the most useful MCRs.2 Polyfunc-
tionalized dihydropyrimidines (DHPMs) represent a heterocyclic
system of remarkable pharmacological efficiency, and many exhibit
Figure 1. Dihydropyrimidine antagonists.
Scheme 1. Synthesis of the Hexadenate Chiral Ligands
antiviral, antitumor, antibacterial, and antiinflammatory properties.3
Notably, monastrol is the only cell-permeable molecule currently
known to specifically inhibit mitotic kinesis Eg5 and is considered
a lead for the development of new anticancer drugs,4 while the
(R)-SQ 32,926 has been identified as potent orally active antihy-
pertensive agent (Figure 1).3a Several marine natural products
containing the dihydropyrimidine-5-carboxylate core were found
to be potent HIVgp-120-CD4 inhibitors.5 Pharmacological studies
concerning the absolute configuration at the C4 stereogenic center
were well documented, and in some cases, individual enantiomers
the novel hexadentate ligands. We were pleased to find that the
ligands 2a and 2b provided high yield and good enantioselectivity
with 90% and 83% ee, respectively. Accordingly, the evaluation
of La(OTf)3 and Sm(OTf)3 as their 2a complexes was carried out
in the catalyzed condensation, as shown in Table 1 (entries 1,2). A
further survey of solvents using 10 mol % of Yb-2a revealed that
dry THF was the most favorable solvent. The use of 5 mol % of
Yb-2a catalyst caused a slight decrease in the ee value (entry 7).
perform opposing biological activities.3 Nevertheless, only a few
examples of asymmetric synthesis of this heterocyclic target have
been reported.6 Chemical resolution and enzymatic strategies have
thus far been the methods of choice to obtain optically active
DHPMs.7 Access to highly enantiomerically pure DHPMs by
catalytic asymmetric synthesis is therefore of considerable current
interest and a formidable task.
Lanthanide triflates (Ln(OTf)3) are unique Lewis acids, which
A control experiment utilizing just the ligand provided no product.
are highly effective, water-compatible, and reusable catalysts in
Due to the good results obtained, we applied the optimal protocol
organic synthesis.8 Despite the synthetic utilities of Ln(OTf)3,
to a variety of aldehydes and 1,3-ketoesters, with urea or thiourea.
relatively few successful examples have been achieved in asym-
In most cases, the desired DHPM derivatives were obtained in good
metric syntheses using chiral lanthanide triflates as catalysts.9 This
yields with excellent enantioselectivities as shown in Table 2.
is intrinsically due to the large radius character and the high
Electronic variation on aryl aldehydes caused no appreciable
coordination number required by the lanthanide ion, while ordinary
changes in the efficiency and enantioselectivity of the condensations.
ligands cannot provide effective environments for asymmetric
This reaction also embodies high functional-group tolerance, since
induction. Herein, we describe the development of a novel chiral
nonaromatic conjugated (E)-cinnamaldehyde (entry 12), aliphatic
phenylacetaldehyde (entry 13), and electron-rich heteroaromatic
ytterbium catalyst and its application in enantioselective synthesis
of chiral DHPMs with excellent enantioselectivities by the three-
aldehyde furfural (entry 14) result in good enantioselectivity. High
component Biginelli reaction.
selectivities were obtained at room temperature to ensure a practical
In the efforts to develop an efficient catalyst for the Biginelli
and highly efficient process for the synthesis of optically active
reaction, hexadentate chiral ligands bearing tertiary amine, phenol,
C4-aryl dihydropyrimidinones.
To our delight, the condensation of m-hydroxybenzaldehyde,
acetoacetate, and thiourea provided exclusively the (R)-enantiomer
and pyridine functional groups were first designed, as outlined in
Scheme 1. The chiral ligands 2a and 2b were easily synthesized
from corresponding salan compounds and 2-chloromethyl pyridine
of monastrol (entry 10). The product obtained from entry 3 could
in THF/DMF under sodium hydride in the respective yields of 85%
be easily transformed to (R)-SQ 32,926 by treatment with trichlo-
roacetyl isocyanate in THF and then by hydrolysis with methanol
and 76%.10 We assumed that the pyridyl groups could coordinate
with the central lanthanide ion on different sides, to afford favorable
and silica gel (Scheme 2).6d The enantiomeric excess of the obtained
stereochemical control in asymmetric catalytic process.
(R)-SQ 32,926 was over 99% ee, which indicates no racemization
Initially, we investigated the Biginelli condensation of ethyl
occurred during the transformation.
acetoacetate, benzaldehyde, and urea catalyzed by Yb(OTf)3 with
The catalyst could be recovered by pH-controlled extraction and
reused several times without evident loss of ee.12 The resulting
complex was identified as mononuclear formulation [YbL(OTf)],10b
† Nanjing University.
‡ Chinese Academy of Sciences.
9
16386
J. AM. CHEM. SOC. 2005, 127, 16386-16387
10.1021/ja056092f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantioselective One-Pot Biginelli Reaction Catalyzed by
Chiral Lanthanide Triflates under Different Conditionsa
entry
Lewis acid
solvent
yield, %b
ee, %c
config.d
1
2
3
4
5
6
7
La(OTf)3
Sm(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
THF
THF
THF
CH2Cl2
CH3CN
CH3OH
THF
83
81
87
80
86
88
84
81
85
90
83
82
80
85
R
R
R
R
R
R
R
Figure 2. (a) Molecular model of the chiral catalyst Yb-2a. (b) Proposed
working model for the asymmetric Biginelli reaction catalyzef by Yb-2a
(other groups omitted for clarity).
e
In conclusion, a new catalytic approach to highly enantioselective
multicomponent Biginelli condensation using a recyclable chiral
Yb triflate with a novel hexadentate chiral ligand has been
developed. A wide range of optically active dihydropyrimidines
with remarkable pharmacological interest was obtained in high
yields with good to excellent enantioselectivities (up to 99% ee)
using this practical method under mild conditions. Further studies
on the utility of this catalyst in other asymmetric syntheses are
underway.
Yb(OTf)3
a All reactions were carried out at room temperature with catalyst loading
of 10 mol % unless otherwise noted. b Isolated yields. c The ee’s were
determined by HPLC with a Daicel Chiralcel OD-H column. d The absolute
configuration was determined by the comparison of the characteristic CD
spectra with DHPMs of known absolute configuration.11 e Catalyst loading
of 5 mol %.
Table 2. Enantioselective Three-component Biginelli
Dihydropyrimidines Synthesis Catalyzed by Yb-2aa
Acknowledgment. We gratefully acknowledge the National
Natural Science Foundation of China (20332050, 20472028) for
generous financial support.
Supporting Information Available: A complete description of
experimental details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews, see: (a) Ramo´n, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005,
44, 1602. (b) Ramachary, D. B.; Barbas, C. F., III. Chem. Eur. J. 2004,
10, 5323. (c) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825.
(d) Andreana, P. R.; Liu, C. C.; Schreiber, S. L. Org. Lett. 2004, 6, 4231.
(e) Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600. (f)
Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Acc. Chem. Res. 1996, 29, 123. (g) Burke, M. D.; Schreiber, S. L.
Angew. Chem., Int. Ed. 2004, 43, 46.
(2) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Kappe, C. O. Acc.
Chem. Res. 2000, 33, 879. (c) Lusch, M. J.; Tallarico, J. A. Org. Lett.
2004, 6, 3237.
(3) (a) Dihydropyrimidine calcium channel modulators. Atwal, K. S.; Swan-
son, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.;
O’Reilly, B. C. J. Med. Chem. 1991, 34, 806. (b) Kappe C. O. Eur. J.
Med. Chem. 2000, 35, 1043. (c) Kappe C. O. QSAR Comb. Sci. 2003, 22,
630.
(4) (a) Mayer, T. M.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber,
S. L.; Mitchison, T. J. Science 1999, 286, 971. (b) Kappe, C. O.; Shishkin,
O. V.; Uray, G.; Verdino, P. Tetrahedron 2000, 56, 1859.
(5) (a) Heys, L.; Moore, C. G.; Murphy, P. J. Chem. Soc. ReV. 2000, 29, 57.
(b) Barluenga, J.; Tomas, M.; Rubio, V.; Gotor, V. J. Chem. Commun.
1995, 1369. (c) Aron, Z. D.; Overman, L. E. Chem. Commun. 2004, 253.
(6) (a) Mun˜oz-Mun˜iz, O.; Juaristi, E. ArkiVoc 2003, xi, 16. (b) Lou, S.; Taoka,
B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005, 127, 11256.
(7) (a) Dondoni, A.; Massi, A.; Sabbatini, S.; Bertolasi, V. J. Org. Chem.
2002, 67, 6979. (b) Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.;
Kappe, C. O. Tetrahedron: Asymmetry 2000, 11, 1449. (c) Dondoni, A.;
Massi, A.; Sabbatini, S. Tetrahedron Lett. 2002, 43, 5913. (d) Schnell,
B.; Krenn, W.; Faber, K.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 1
2000, 4382.
a All reactions were performed on 0.5 mmol scale of substrates with 10
mol % of Yb-2a at room temperature. b Isolated yields. c The ee’s were
determined by HPLC with a Daicel Chiralcel OD-H or AD-H column.
d Determined by the comparison of the optical rotation values with
literature.7c,d e Assigned by the comparison of the characteristic CD spectra
with DHPMs of known absolute configuration.11
Scheme 2. Synthesis of (R)-SQ 32,926
(8) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. ReV.
2002, 102, 2227.
(9) (a) Hamada, T.; Manabe, K.; Ishikawa, S.; Nagayama, S.; Shiro, M.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 2989. (b) Evans, D. A.;
Fandrick, K. R.; Song, H. J. J. Am. Chem. Soc. 2005, 127, 8942. (c) For
other kinds of lanthanide complexes as chiral catalysts, see: Shibasaki,
M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(10) (a) Albanese, D.; Landini, D.; Penso, M.; Spano`, G.; Trebicka, A.
Tetrahedron 1995, 51, 5681. (b) Setyawati, I. A.; Liu, S.; Rettig, S. J.;
Orvig, C. Inorg. Chem. 2000, 39, 496.
(11) (a) Krenn, W.; Verdino, P.; Uray, G.; Faber, K.; Kappe, C. O. Chirality
1999, 11, 659. (b) Uray, G.; Verdino, P.; Belaj, F.; Kappe, C. O.; Fabian
W. M. F. J. Org. Chem. 2001, 66, 6685.
(12) See Supporting Information for a graphic illustration. Hashizume, T.;
Yonehara, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2000, 65, 5197.
(13) Molecular modeling calculation was performed using the MM+ force field
in the HyperChem 6.0 from Hypercube Inc., Gainesville, Florida.
and the possible structure of Yb-2a with molecular mechanics
computation is shown in Figure 2a.13 We propose a transition-state
model which explains the absolute configiration of the favored
enantiomer in the Biginelli reaction, as shown in Figure 2b. The in
situ generated acylimine intermediate could coordinate to the Yb
atom. The si-face of the coordinated acylimine was schielded by
the pyridyl group, allowing nucleophilic attack of the enol ester
from the re-face.
JA056092F
9
J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005 16387