Highly enantioselective organocatalytic Biginelli and Biginelli-like condensations: Reversal of the stereochemistry by tuning the 3,3′-disubstituents of phosphoric acids

Article abstract of DOI:10.1021/ja905320q

Organocatalytic enantioselective Biginelli and Biginelli-like reactions by chiral phosphoric acids derived from 3,3′-disubstituted binaphthols have been investigated. The size of 3,3′-substituents of the catalysts is able to control the stereochemistry of

Full text of DOI:10.1021/ja905320q

Published on Web 09/28/2009
Highly Enantioselective Organocatalytic Biginelli and
Biginelli-Like Condensations: Reversal of the Stereochemistry
by Tuning the 3,3′-Disubstituents of Phosphoric Acids
Nan Li,†,‡ Xiao-Hua Chen,§ Jin Song,§ Shi-Wei Luo,*,§ Wu Fan,§ and
Liu-Zhu Gong*,†,§
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, China, Chengdu
Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China, and
Graduate School of Chinese Academy of Sciences, Beijing, China
Received July 6, 2009; E-mail: gonglz@ustc.edu.cn; luosw@ustc.edu.cn
Abstract: Organocatalytic enantioselective Biginelli and Biginelli-like reactions by chiral phosphoric acids
derived from 3,3′-disubstituted binaphthols have been investigated. The size of 3,3′-substituents of the
catalysts is able to control the stereochemistry of the Biginelli reaction. By tuning the 3,3′-disubstituents of
the phosphoric acids, the stereochemistry of the Biginelli reaction can be reversed. This organocatalytic
Biginelli reaction by Brønsted acids 12b and 13 is applicable to a wide range of aldehydes and various
ꢀ-keto esters, providing a highly enantioselective method to access DHPMs. 3,3′-Di(triphenylsilyl) binaphthol-
derived phosphoric acid afforded Biginelli-like reactions of a broad scope of aldehydes and enolizable
ketones with benzylthiourea, giving structurally diverse dihydropyrimidinethiones with excellent optical purity.
Theoretical calculations with the ONIOM method on the transition states of the stereogenic center forming
step showed that the imine and enol were simultaneously activated by the bifunctional chiral phosphoric
acid through formation of hydrogen bonds. The effect of the 3,3′-substituents in phosphoric acids on the
stereochemistry of the Biginelli reaction was also theoretically rationalized. The current protocol has been
applied to the synthesis of some pharmaceutically interesting compounds and intermediates, such as chiral
thioureas, dihydropyrimidines, guanidines, and the precursor of (S)-L-771688.
of Eg 5 ATPase than (R)-monastrol.6 (S)-L-771688 (3) is a more
potent and selective R1a receptor antagonist for the treatment
Introduction
Chiral dihydropyrimidinethiones (DHPMs) have found in-
creasing applications to the synthesis of pharmaceutically
relevant substances exhibiting a wide range of important
pharmacological properties,1 including calcium channel modula-
tion,2 R1a-adrenergicreceptor antagonism,3 and mitotic kinesin
inhibition.4 It has been reported that the individual enantiomers
have been found to exhibit different or even opposite pharma-
ceutical activities.1 For example, the (R)-enantiomer of SQ
32926 (1), a calcium channel blocker, exhibits >400-fold more
potent antihypertensive activity in vitro than the other enanti-
omer.5 (S)-Monastrol (2) is 15-fold more potent in the inhibition
of benign prostatic hyperplasia (BPH) than the (R)-enantiomer.7
In addition, chiral thioureas readily available from the reduction
of dihydropyrimidinethiones have been widely employed in
asymmetric catalysis as ligands.8 Moreover, dihydropyrimidi-
nethiones can be converted into either 1,3-diamines or guanidines,
which are core structural elements commonly present in natural
products exemplified by the batzelladine family of polycyclic
(3) (a) Nagarathnam, D.; et al. J. Med. Chem. 1999, 42, 4764. (b) Dhar,
T. G. M.; et al. J. Med. Chem. 1999, 42, 4778. (c) Lagu, D.; et al.
J. Med. Chem. 1999, 42, 4794. (d) Wong, W. C.; et al. J. Med. Chem.
1999, 42, 4804. (e) Lagu, B.; Tian, D.; Chiu, G.; Nagarathnam, D.;
Fang, J.; Shen, Q. R.; Forray, C.; Ransom, R. W.; Chang, R. S. L.;
Vyas, K. P.; Zhang, K. Y.; Gluchowski, C. Bioorg. Med. Chem. Lett.
2000, 10, 175. (f) Barrow, J. C.; Glass, K. L.; Selnick, H. G.;
Freidinger, R. M.; Chang, R. S. L.; O’Malley, S. S.; Woyden, C.
Bioorg. Med. Chem. Lett. 2000, 10, 1917.
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
‡ Graduate School of Chinese Academy of Sciences.
§ University of Science and Technology of China.
(1) (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043. (b) Kappe, C. O.
In Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-
VCH: Weinheim, 2005; p 95.
(4) (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971. (b) Deres,
K.; et al. Science 2003, 299, 893.
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Khim.-Farm. Zh. 1978, 12, 72. (b) Kastron, V. V.; Vitolin, R. O.;
Khanina, E. L.; Duburs, G.; Kimenis, A. Khim.-Farm. Zh. 1987, 21,
948. (c) Cho, H.; et al. J. Med. Chem. 1989, 32, 2399. (d) Atwal,
K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.;
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M. F. J. Med. Chem. 1990, 33, 2629. (e) Atwal, K. S.; Moreland, S.
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9
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A R T I C L E S
Li et al.
Figure 1. Biologically significant compounds containing DHPM and related structural motifs.
marine alkaloids,9 of which batzelladine A and B (4 and 5) were
reported to inhabit the binding of HIV-gp120 to the CD4 cell
surface receptor protein on T-cells to be potentially useful in
the treatment of AIDS.10 Therefore, an efficient method for the
preparation of optically pure DHPMs is in a great demand.
Biginelli and Biginelli-like reactions that assemble aldehydes,
urea/thiourea, and enolizable carbonyls into dihydropyrimidi-
nethiones provide robust tools for the creation of these structural
motifs.1a,11 Since the first description of the Biginelli reaction
over a century ago,11a the research interest has long been focused
on seeking new catalysts for efficiently producing racemic
DHPMs.1a In contrast, the asymmetric catalytic Biginelli reac-
tions, although they provide access to optically active DHPMs
in a straightforward manner, have been a long-standing chal-
lenge. As such, the preparation of optically pure DHPMs in
the pharmaceutical research laboratory mainly relies on resolu-
tion and chiral auxiliary-assisted asymmetric synthesis.12 Juaristi
and Mun˜oz-Mun˜iz reported the use of a chiral amide, in
combination with CeCl3, to catalyze the Biginelli reaction of
benzaldehyde, urea, and methyl acetoacetate with up to 40%
ee.13 Zhu and co-workers described an asymmetric catalytic
Biginelli reaction with a chiral ytterbium catalyst providing
DHPMs in high yields with excellent enantioselectivities ranging
from 80 to >99% ee.14 Schaus and co-workers introduced an
elegant asymmetric access to DHPMs starting with the orga-
nocatalytic Mannich reaction.15 Recently, we reported the first
organocatalytic Biginelli reaction using Brønsted acids as
catalysts, giving DHPMs with up to 97% ee.16 Subsequent to
our reports, Feng and Juaristi independently described an
organocatalytic asymmetric Biginelli reaction using a combined
catalyst system consisting of chiral secondary amine and
Brønsted acid.17 Despite these elegant examples, a catalytic
enantioselective protocol that tolerates a broad scope of ꢀ-keto
esters for Biginelli reactions and enolizable ketones for Biginelli-
like reactions has remains unknown. In this paper, we report
the full results of our studies on the Brønsted acid-catalyzed
enantioselective Biginelli and Biginelli-like reactions, which
provided a highly efficient method to access DHPMs with
structural diversity and excellent levels of enantioselectivity
(>99% ee).
General Consideration of the Brønsted Acid Catalyzed
Enantioselective Biginelli and Biginelli-like Reactions
Either a Biginelli or Biginelli-like reaction is initiated with
the condensation of an aldehyde with urea or thiourea in the
presence of a Brønsted acid, generating an activated N-
acyliminium, which is subsequently attacked by enolizable
carbonyls, including acetoacetates (Biginelli reaction) and
ketones (Biginelli-like reaction), to undergo a Mannich reaction,
and ultimately followed by cyclization and dehydration reactions
to afford the DHPMs.18 The nucleophilic addition of the
enolizable carbonyls to N-acyliminium is the stereogenic center
forming step (Scheme 1). Consequently, an optically active
Brønsted acid would afford an enantioselective Biginelli or
Biginelli-like reaction.
(9) (a) Heys, L; Moore, C. G.; Murphy, P. J. Chem. Soc. ReV. 2000, 29,
57. (b) Berlinck, R. G. S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat.
Prod. Rep. 2008, 25, 919.
(10) (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J.; Brosse, C. D.; Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.;
Breen, A. L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.; Potts,
B. C. M. J. Org. Chem. 1995, 60, 1182. (b) Olszewski, A.; Weiss,
G. A. J. Am. Chem. Soc. 2005, 127, 12178.
Results and Discussion
(11) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Dondoni, A.;
Massi, A. Acc. Chem. Res. 2006, 39, 451. (c) Kappe, C. O. Acc. Chem.
Res. 2000, 33, 879. (d) Saini, A.; Kumar, S.; Sandhu, J. S. J. Indian
Chem. Soc. 2007, 959.
Summary of Previous Studies on the Evaluation of Chiral
Brønsted Acids. Chiral phosphoric acids provide sufficient
(12) For a review, see: (a) Gong, L.-Z.; Chen, X.-H.; Xu, X.-Y. Chem.sEur.
J. 2007, 13, 8920. For selected examples, see: (b) Dondoni, A.; Massi,
A.; Sabbatini, S.; Bertolasi, V. J. Org. Chem. 2002, 67, 6979. (c)
Dondoni, A.; Massi, A.; Sabbatini, S. Tetrahedron Lett. 2002, 43, 5913.
(d) 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. 2002, 80, 646.
(e) Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.; Kappe, C. O.
Tetrahedron: Asymmetry 2000, 11, 1449. (f) Schnell, B.; Krenn, W.;
Faber, K.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 1 2000, 4382.
(13) Mun˜oz-Mun˜iz, O.; Juaristi, E. ArkiVoc 2003, xi, 16.
(15) (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc.
2005, 127, 11256. (b) Goss, J. M.; Schaus, S. E. J. Org. Chem. 2008,
73, 7651.
(16) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem.
Soc. 2006, 128, 14802.
(17) (a) Xin, J. G.; Chang, L.; Hou, Z. R.; Shang, D. J.; Liu, X.-H.; Feng,
X.-M. Chem.sEur. J. 2008, 14, 3177. (b) Gonza´lez-Olvera, R.;
Demare, P.; Regla, I.; Juaristi, E. ArkiVoc 2008, Vi, 61.
(18) For mechanistic studies on Biginelli reaction, see:Kappe, C. O. J. Org.
Chem. 1997, 62, 7201.
(14) Huang, Y.; Yang, F.; Zhu, C. J. Am. Chem. Soc. 2005, 127, 16386.
9
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Organocatalytic Biginelli and Biginelli-Like Condensations
A R T I C L E S
Scheme 1. Biginelli and Biginelli-Like Reactions
acidity required for the activation of imines leading to many
new asymmetric procedures.19 In particular, they afforded
Mannich reactions with high enantioselectivities.19d,e In the light
of these successes as well as the mechanism of the Biginelli
reaction, we believed that chiral phosphoric acids 12 and 13
and their structural analogues would effectively catalyze the
asymmetric Biginelli reaction.
chemistry were considerably dependent on the size of the
substituents on the catalysts. Increasing the size of 3,3′-
substituents usually diminished the yield and enantioselectivity
as shown in the reactions catalyzed by phosphoric acids.16
Interestingly, the stereochemistry of the Biginelli reaction can
be reversed by tuning the 3,3′-disubstituents of the phosphoric
acids. For example, using the phosphoric acid 12b,20 which has
highly bulky 3,3′-substituents, as the catalyst gave (S)-9a with
the highest enantioselectivity (96% ee), whereas the structurally
similar phosphoric acid 12a bearing less sterically hindered
substituents favored the formation of (R)-9a with 80% ee (eq
1). The enantioselectivity of (R)-9a could be improved to 85%
ee by the replacement of 12a with H8-BINOL based phosphoric
acid 13.16
Our previous evaluation of the BINOL- and H8-BINOL-
based phosphoric acids 12 and 13 and their derivatives to
catalyze the Biginelli reaction of 4-nitrobenzaldehyde (6a),
thiourea (7a), and ethyl acetoacetate (8a) revealed that the 3,3′-
substituents on the phosphoric acids considerably impacted the
reaction performance.16 Both reaction conversion and stereo-
(19) For chiral phosphoric acid catalysis, see recent excellent reviews:(a)
Akiyama, T. Chem. ReV 2007, 107, 5744. (b) Doyle, A. G.; Jacobsen,
E. N. Chem. ReV. 2007, 107, 5713. (c) Terada, M. Chem. Commun.
2008, 4097. Leading references: (d) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356. (e) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43, 1566. Selected recent
examples: (f) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008,
130, 9246. (g) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem.,
Int. Ed. 2008, 47, 2411. (h) Guo, Q.-S.; Du, D.-M.; Xu, J.-X. Angew.
Chem., Int. Ed. 2008, 47, 759. (i) Wang, X.-W.; List, B. Angew. Chem.,
Int. Ed. 2008, 47, 1119. (j) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.-
M.; Ding, K.-L. Angew. Chem., Int. Ed. 2008, 47, 2840. (k) Sickert,
M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631. (l) Itoh, J.;
Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016.
(m) Terada, M.; Soga, K.; Momiyama, N. Angew. Chem., Int. Ed.
2008, 47, 4122. (n) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew.
Chem., Int. Ed. 2008, 47, 5079. (o) Rueping, M.; Antonchick, A. P.
Angew. Chem., Int. Ed. 2008, 47, 5836. (p) Hu, W.-H.; Xu, X.-F.;
Zhou, J.; Liu, W.-J.; Huang, H.-X.; Hu, J.; Yang, L.-P.; Gong, L.-Z.
J. Am. Chem. Soc. 2008, 130, 7782. (q) Li, G.-L.; Fronczek, F. R.;
Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216. (r) Kang, Q.; Zheng,
X.-J.; You, S.-L. Chem.sEur. J. 2008, 14, 3539. (s) Enders, D.;
Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem., Int. Ed.
2008, 47, 5661. (t) Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008,
130, 14452. (u) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem.
Soc. 2009, 131, 3430. (v) Akiyama, T.; Katoh, T.; Mori, K. Angew.
Chem., Int. Ed. 2009, 48, 4226. (w) Rueping, M.; Antonchick, A. P.;
Sugiono, E.; Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908. (x)
Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J.-P. J. Am.
Chem. Soc. 2009, 131, 4598.
Scope of the Organocatalytic Asymmetric Biginelli Reac-
tion by 12b and 13. The generality of the asymmetric Biginelli
reaction catalyzed by 13 has been investigated and reported
previously.16 This protocol is applicable to a wide range of
aldehydes and provided a highly enantioselective method to
access DHPMs with 88 to 96% ee. The variation of the R3
substituent of ꢀ-keto esters 8 could be tolerated, and generally,
high enantioselectivities were achieved for the reactions related
to the substrates.16
Basically, the asymmetric Biginelli reaction using 12b as the
catalyst always generated DHPMs with stereochemistry opposite
to those obtained with 13,16 regardless of the substrate used
(Table 1). Notably, 12b provided generally higher levels of
(20) For the first use of 12b as catalyst, see:Storer, R. I.; Carrera, D. E.;
Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.
9
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A R T I C L E S
Li et al.
Table 1. Organocatalytic Enantioselective Biginelli Reaction with
Phosphoric Acid 12b and 13a
Table 2. Asymmetric Biginelli-Like Condensation of Benzaldehyde,
Thiourea, and Cyclohexanone Catalyzed by 12 and 13a
entry
R1 (6)
R2, R3 (8)
DHMPs (9) yield (%)b ee (%)c
7
temp.
yield ee
(%)b (%)c
entry
catalyst, Ar
solvent
11
1
2
3
4
5
6
7
8
9
3-FC6H4 (6b)
3-NO2C6H4 (6c)
2-ClC6H4 (6d)
3-ClC6H4 (6e)
2-NO2C6H4 (6f)
3-BrC6H4 (6g)
4-MeO2CC6H3 (6h) Me, Et (8a)
3-MeOC6H4 (6i)
2-MeC6H4 (6j)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
9s
82
95
91
94
72
95
97
94
95
96
96
95
98
96
94
92
(R) (°C)
1
2
3
4
5
6
7
8
9
13
H
H
25 CH2Cl2
25 CH2Cl2
11a <5% ND
11a <5% ND
11b 75 40
11b 53 24
11b 66 99
11b 21 74
12a, Ph
12a, Ph
13
Bn 50 toluene
Bn 50 toluene
Bn 50 toluene
Bn 50 toluene
Bn 50 toluene
Bn 50 toluene
12b, SiPh3
12c, 3,5-(CF3)2C6H3
12d, 2,4,6-(iPr)3C6H2
12e, 9-phenanthrenyl
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Et (8a)
Me, Me (8b)
Me, i-Pr (8c)
Me, t-Bu (8d)
Et, Me (8e)
Et, Me (8e)
Et, Me (8e)
11b 82
1
87 (81) 91 (88)
98 (84) 90 (75)
96 (88) 93 (76)
11b 34 64
11b 50 87
11b 94 93
10 4-MeC6H4 (6k)
11 4-tBuC6H4 (6l)
12 3,5-Br2C6H3 (6m)
13 1-BrC10H6 (6n)
14 c-C6H11 (6o)
15 PhCHdCH2 (6p)
16 3-BrC6H4 (6g)
17 3-BrC6H4 (6g)
18 3-BrC6H4 (6g)
19 3-FC6H4 (6b)
20 3,5-F2C6H3 (6q)
21 3-BrC6H4 (6g)
12f, 4-(2,4,6-Me3C6H2)C6H4 Bn 50 toluene
54d
92
91
94
90
30
96
96
97
10 12b, SiPh3
11 12b, SiPh3
12 12b, SiPh3
13 12b, SiPh3
Bn 50 CHCl3
Bn 50 m-xylene 11b 63 97
Bn 50 Cl(CH2)2Cl 11b 61 59
54e
44
Bn 50 toluene
11b 69 99d
83
82
80
a Reaction was carried out on a 0.1 mmol scale, the ratio of 6r/7/10a
was 1.5/1.0/5.0 and the reaction time was 5 days. b Isolated yield. c ee
was determined by HPLC. d Reaction time was 6 days.
9t
9u
9v
53g (67)f 87 (85)
26g (51)f 69 (92)
58g (56)f 90 (85)
ature. This was also indicated by our initial studies on the
Biginelli-like reaction of cyclohexanone with thiourea and
benzaldehyde using phosphoric acid catalyst 13 or 12a, which
failed to proceed under conditions that were used for either the
Biginelli reaction16 or the Mannich reaction (Table 2, entries 1
and 2).22 To our delight, the use of benzylthiourea to replace
thiourea as a reaction component gave 75% yield and 40% ee
by employing 12a as the catalyst (entry 3). Encouraged by this
primarily promising result, we performed the optimization
studies to improve the stereoselectivity by varying catalysts and
solvents. A series of BINOL-based phosphoric acids were
screened by conducting the reaction in toluene at 50 °C (entries
4-9), of which the catalyst 12b gave the highest levels of
enantioselectivity (99% ee, entry 5). The investigation of the
solvent effect concluded that the nonpolar solvents were suitable
media for controlling the enantioselectivity (entries 10-13).
Accordingly, considerably higher enantiomeric excesses were
obtained using either toluene or m-xylene as a solvent (entries
9, 11 and 13).
After establishing the optimal conditions, we examined the
scope of the aldehyde component by reactions with cyclohex-
anone (Table 3). A wide spectrum of aromatic aldehydes could
be tolerated and underwent smooth Biginelli-like condensations.
Significantly, unlike most phosphoric acid-catalyzed nucleophilic
additions to imines wherein the stereoselectivity is highly
dependent on the electron density of the imines,19 the Biginelli-
like reaction afforded excellent levels of enantioselectivity for
electronically poor, neutral, and rich benzaldehydes (92-99%
ee). Moreover, the position of the substituent on the benzalde-
hydes had little effect on the stereoselectivity as demonstrated
by reactions involving bromo- (entries 1-3), cyano- (entries 6
and 8), and methylbenzaldehydes (entries 10 and 12). The
number of the substituent on the benzaldehydes also had little
influence on the stereoselection (96-99% ee, entries 1-16),
with the exception of 3,4,5-trifluorobenzaldehyde, which de-
livered a comparably lower enantioselectivity (92% ee, entry
a Condition A: the reaction was carried out on a 0.2 mmol scale in
toluene at 50 °C catalyzed by 10 mol % of 12b for 60 h and the ratio of
6/7a/8 was 1/1.2/3. Condition B: the reaction was carried out on a 0.2
mmol scale in CH2Cl2 at room temperature catalyzed by 10 mol % of
13 for 6 days and the ratio of 6/7a/8 was 1/1.2/3. b Isolated yield based
on aldehyde, and the data in parentheses was obtained under condition
B. c Determined by HPLC, and ee of the opposite enantiomer in
parentheses was obtained under condition B. d Reaction time was 96 h.
e Ratio of 6/7a/8 was 2/1/3. f Ratio of 6/7a/8 was 1/1.2/5 and the
reaction time was 8 days. g Ratio of 6/7a/8 was 1/1.2/5 and the reaction
time was 96 h.
enantioselectivity than 13 in most cases16 with the exception
of reactions involving either 3,5-dibromobenzaldehyde, aliphatic,
or unsaturated aldehydes (entries 12, and 14-15). Moreover,
12b delivered excellent enantioselectivity ranging from 90 to
93% ee for electronically rich benzaldehydes 6j-l whereas 13
afforded much lower enantioselectivity ranging from 75 to 88%
ee (entries 9-11). In addition, the phosphoric acid 12b exhibited
higher enantioselectvity than 13 for the Biginelli reactions of
propionylacetate (entries 19 and 21) except for the reaction with
3,5-difluorobenzaldehyde (entry 20).
Optimization of the Biginelli-Like Reaction. In contrast to
numerous protocols available for Biginelli reactions, Biginelli-
like reactions using enolizable ketones have been explored less
even in a racemic manner.21 To the best of our knowledge, there
have been no reports describing the asymmetric catalytic version
of Biginelli-like reactions. The inferior reactivity of ketones,
compared to that of ꢀ-keto esters, appears to be a key factor
hindering the Biginelli-like reaction from successfully proceed-
ing under the catalysis of relatively mild Lewis or Brønsted
acids. Most commonly, stronger Lewis or Brønsted acids were
exploited to afford a racemic reaction at the elevated temper-
(21) (a) Abelman, M. M.; Smith, S. C.; James, D. R. Tetrahedron Lett.
2003, 44, 4559. (b) Wang, Z.-T.; Xu, L.-W.; Xia, C.-G.; Wang, H.-
Q. Tetrahedron Lett. 2004, 45, 7951. (c) Sabitha, G.; Reddy, K. B.;
Srinivas, R.; Yadav, J. HelV. Chim. Acta 2005, 88, 2996. (d) Zhu,
Y.-L.; Huang, S.-L.; Pan, Y.-J. Eur. J. Org. Chem. 2005, 2354.
(22) Guo, Q.-X.; Liu, H.; Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z. J. Am.
Chem. Soc. 2007, 129, 3790.
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Organocatalytic Biginelli and Biginelli-Like Condensations
A R T I C L E S
Table 3. Scope of Aldehydes in the Biginelli-Like Reactiona
Table 4. Scope of Cyclic Ketones in the Biginelli-Like Reactiona
entry
11
R
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
11r
11s
11t
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-NO2C6H4
4-MeO2CC6H4
4-CNC6H4
4-CF3C6H4
3-CNC6H4
4-tBuC6H4
4-MeC6H4
86
76
65
55
61
74
67
76
56
63
60
64
72
68
58
86
55
51
65
75
98
98
98
97
97
98
98
98
98
98
98
98
97
99
96
96
92
98
98
90d
4-MeOC6H4
2-MeC6H4
4-Cl,3-FC6H3
2,3-Cl2C6H3
3,5-Br2C6H3
3,4-(MeO)2C6H3
3,4,5-F3C6H2
2-naphthyl
2-furanyl
11u
11v
4-NO2C6H4
a Reaction was carried out on a 0.1 mmol scale, the ratio of 6/7b/10a
was 1.5/1.0/5.0. b Isolated yield. c ee was determined by HPLC.
d Methylthiourea (7c) was used as reaction component.
17). 2-Naphthaldehyde and furanylaldehyde both furnished the
Biginelli-like products with excellent enantioselectivities (98%
ee, entries 18 and 19). The absolute configuration of product
11u was accessed by X-ray analysis (see Supporting Informa-
tion). Moreover, the replacement of benzylthiourea with me-
thylthiourea (7c) also gave high levels of enantioselectivity (90%
ee, entry 20).
We next studied the generality of cyclic enolizable ketones
in the Biginelli-like reaction (Table 4). Tetrahydropyran- and
tetrahydrothiopyran-4-one were both good reaction partners,
undergoing clean Biginelli-like reactions with 3-bromobenzal-
dehyde with excellent levels of enantioselectivity (97 and 98%
ee, respectively, entries 1 and 2). N-Boc-protected piperidin-
4-one was seemly less reactive, and thus gave the product in
only 39% yield, but with 98% ee (entry 3). Enantioselective
desymmetrization could be partially realized in the Biginelli-
like reactions with prochiral 4-alkylcyclohexanones. Although
the diastereoselectivity was moderate, perfect enantiomeric
excess was obtained for each individual diastereomer (>99%
ee, entries 4 and 5). Interestingly, the ring size of the cyclic
ketone had considerable impact on the reaction. Cycloheptanone
and cyclooctanone were both suitable substrates, affording
corresponding Biginelli-like products in good yields with 91
and 90% ee, respectively (entries 6 and 7). In contrast,
cyclopentanone showed low reactivity under the same condi-
tions.23
a Reaction was carried out on a 0.1 mmol scale, the ratio of 6/7b/10
was 1.5/1.0/5.0. b Isolated yield. c Determined by 1H NMR. d ee was
determined by HPLC and the ee in parentheses represents the minor
diastereomer. e Using 20 mol % 12b. f At 65 °C.
enolizable site of the unsymmetrical ketones, and interestingly,
the steric factor of the ketone had little influence on the
regiocontrol (entries 1-6). For the linear aliphatic ketones, high
yields and regioselection were obtained with enantioselectivity
ranging from 92 to 96% ee for the major regiomer (entries 1-4).
Notably, R-branched aliphatic ketones such as 3-methyl-2-
pentanone and 3-methylbutanone could also participate in the
Biginelli-like reaction, which favorably took place at the more
substituted carbon with complete regioselective control and
provided greater than 96% ee (entries 5 and 6). These observa-
tions indicated that the regioselectivity might be thermodynami-
cally controlled. 3-Pentanone participated in a slower reaction,
but the stereochemical outcome remained excellent (entry 7).
Aromatic ketones such as 1-p-tolylethanone could undergo a
smooth Biginelli-like reaction but with only moderate enanti-
oselectivity (61% ee, entry 8). The absolute configuration of
product 15f was assigned by X-ray analysis (see Supporting
Information).
Most significantly, the extension of the reaction conditions
to acyclic ketones was also successful (Table 5).24 The Biginelli-
like condensation took place at the thermodynamically stable
(23) Less than 5% yield was isolated with no determination of enantiomeric
excess.
(24) Notably, enolizable acyclic ketones gave poor stereoselectivity in the
phosphoric acid-catalyzed direct Mannich reaction, see ref 22.
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A R T I C L E S
Li et al.
Table 5. Scope of Acyclic Ketones in the Biginelli-Like Reactiona
Figure 2. Computed structures of imine intermediates and relative energies
in enthalpy and free energy in parentheses.
and substrates, and the stereochemistry was controlled by
different steric interactions within the competing diastereomeric
transition states.25 We investigated the transition states with the
similar model by theoretical calculations to identify key factors
that control the enantioselectivity, particularly, the influence of
the size of 3,3′-substituents of the BINOL-phosphoric acid on
the stereochemistry. We observed that the use of N-methylth-
iourea as a reaction component afforded the desired product
with excellent enantioselectivity with configuration similar to
that observed for N-benzylthiourea (Table 3, entries 4 and 20).
To simplify the calculation, we employed the reaction involving
N-methylthiourea as a chemical model. The full DFT calculation
was performed on the key intermediates of imine using B3LYP
functional and 6-31+G* basis set,26 while the location of
transition state structures was established with the ONIOM27
method implemented in Gaussian03 program.28
The full optimized structures of the imine intermediates
formed by condensation of 4-nitrobenzaldehyde with thiourea
or N-methylthiourea, respectively, were shown in Figure 2. This
calculation indicated that E-imine was more stable by 6 kcal/
mol than Z-imine, arising from the steric repulsion between the
phenyl ring and sulfur atom, which makes the thiourea twist to
the phenyl ring and thereby partially destroys the conjugation
interaction in Z-imine. When a methyl group replaced the H
atom in the thiourea, the formed E-imine preferred the orienta-
tion of methyl group cis to sulfur atom. Thus, for both kinds of
imine intermediates, the calculations implied that the imine was
stabilized by the conjugated system formed with phenyl ring
and thiourea and preferentially generated a conformer with the
H atom of NH cis to the N atom of imine. Such an orientation
of the intermediate led to two possible pathways in the
a Reaction was carried out on a 0.1 mmol scale, the ratio of 6/ 7b/ 10
was 1.5/ 1.0/ 5.0. b Isolated yield. c rr refers to regiomeric ratio and was
determined by 1H NMR of the crude product. d ee was determined by
HPLC and the ee in parentheses is the minor regiomer. e Ratio of 6/ 7b/
10 was 1.5/ 1.0/ 20.0. f Ratio of 6/ 7b/ 10 was 1.5/ 1.0/ 10.0.
g Diastereomeric ratio was 63/37. h At 50 °C. i Scale: 0.2 mmol. j Using
12e as a catalyst.
Interestingly, enolizable aliphatic aldehydes could not par-
ticipate in the cross Biginelli-like reaction with ketones but could
more easily undergo a self-Biginelli-like reaction. For example,
the self-reaction of 3-methylbutanal (16) catalyzed by 12a
furnished 17 in a moderate yield and enantiomeric purity (eq
2).
(25) (a) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem.
Soc. 2007, 129, 6756. (b) Simo´n, L.; Goodman, J. M. J. Am. Chem.
Soc. 2008, 130, 8741. (c) Simo´n, L.; Goodman, J. M. J. Am. Chem.
Soc. 2009, 131, 4070. (d) Yamanaka, M.; Hirata, T. J. Org. Chem.
2009, 74, 3266.
Theoretical Explanation of the Stereochemistry. To under-
stand the origin of enantioselectivity and how the 3,3′-
substituents of BINOL-phosphoric acids control the stereo-
chemistry, theoretical calculations were performed on the
nucleophilic addition of enol to imine, the stereogenic center
forming step. For this Mannich-type reaction catalyzed by chiral
BINOL-phosphoric acid derivatives, a general mechanism has
been proposed that the catalyst may simultaneously activate both
nucleophile and electrophile by hydrogen bonds between catalyst
(26) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Gill, P. M. W.;
Johnson, B. G.; Pople, J. A.; Frisch, M. J. Chem. Phys. Lett. 1992,
197, 499. (c) Krishnan, R.; Binkley, J. S.; Seeger, R; Pople, J. A.
J. Chem. Phys. 1980, 72, 650.
(27) (a) Svensson, M.; Humbel, S.; Morokuma, K. J. Chem. Phys. 1996,
105, 3654. (b) Vreven, T.; Morokuma, K. J. Comput. Chem. 2000,
21, 1419. (c) Dapprich, S.; Koma´romi, I.; Byun, K. S.; Morokuma,
K.; Frisch, M. J. J. Mol. Struct. (Theochem) 1999, 461.
(28) Frisch, M. J.; et al. Gaussian 03, reVision C.02; Gaussian, Inc.:
Wallingford, CT, 2004.
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Organocatalytic Biginelli and Biginelli-Like Condensations
A R T I C L E S
Figure 3. Activation models and possible reaction pathways of the stereogenic step in the phosphoric acid-catalyzed Biginelli reaction.
Figure 4. Located transition state structures with distance parameters in angstroms and relative energies in enthalpy and free energy in parentheses.
nucleophilic addition step, respectively, as shown in I and II
(Figure 3). In pathways Ia and Ib, the imine was activated by
the proton of phosphoric acid OH to generate a zwitterionic
iminium salt, accompanying an additional hydrogen bond
formed between the enol proton and oxygen atom on the
phosphoric acid OH.25d In pathways IIa and IIb, the bifunctional
phosphoric acid allows the activation of the imine with the
proton of OH and the enol by Lewis basic phosphoryl oxygen.
Both kinds of zwitterionic iminium salts might adapt the
nucleophilic addition of enol to either the Re- or Si-face of imine
with different steric interactions within the competing diaster-
eomeric transition states. Thus, further theoretical calculations
were performed on the transition states to identify the preferred
attacking pathway on the basis of these two pathways.
Goodman and Simons has shown that the ONIOM method
could be successfully used to calculate the large catalyst system
like BINOL-based phosphoric acids, leading to the discovery
of reasonable mechanism and the explanation of enantioselec-
tivity in transfer hydrogenation and Strecker reaction.25b,c
Inspired by these successes, we also performed DFT calculation
of the stereogenic step of Biginelli reaction using ONIOM
method. All atoms in the catalyst were included in the lower-
level layer except the phosphoric acid moiety, which was
included in the higher-level layer, together with the imine and
nucleophilic enol involved in reaction pathways I and II (Figure
3), according to a typical ONIOM scheme in Gaussian03. The
DFT functional of B3LYP combined with 6-31G* basis set was
used in the higher-level layer, and the UFF molecular mechanics
force field was used in the lower-level layer.
TS-1-R and TS-1-S were the located transition state structures,
as shown in Figure 4, illustrating the addition reaction of the
enol of acetacetate to the imine of (E)-(4-nitrobenzylidene)th-
iourea activated by 3,3′-diphenyl-H8-BINOL phosphoric acid
to offer Mannich-like reaction intermediates. Both structures
showed that the 3,3′-diphenyl groups of the catalyst created a
cave, large enough to allow the phosphoric acid activating the
enol nucleophile and the imine electrophile simultaneously by
triple hydrogen bonding interactions as indicated in model IIa
(Figure 3). In both cases, the TSs were stabilized by forming
HBs as indicated by the relatively shorter distance of HBs (O--H
distance: ca. 2 Å in the TSs). TS-1-R was predicted to be more
favored by about 2.5 kcal/mol than TS-1-S, because of: (1) The
earlier transfer of the OH proton of enol to phosphoryl oxygen
in TS-1-R causes the enol more nucleophilic than that in TS-
1-S and the longer distance of the forming C-C bond in TS-
1-R means an early transition state for TS-1-R rather than TS-
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A R T I C L E S
Li et al.
Figure 5. Located transition state structures with distant parameters in angstroms and relative energies in enthalpy and free energy in parentheses.
1-S as indicated by the computed distance parameters (2.686
vs 2.256 Å) in Figure 4; (2) the Si-face of the imine seems less
obstructive than Re-face and thereby the nucleouphilic attacking
on the Si-face of imine is easier than Re-face with respect to
steric consideration. After the formation of C-C bond through
TS-1-R and followed by an addition of N atom of the thiourea
to the carbonyl of acetacetate and a subsequent dehydration,
the experimentally observed major product with R-configuration
would be furnished. However, the TS located from the model
Ia (Figure 3) failed to be obtained.
Computed transition state structures of Biginelli and Biginelli-
like reactions catalyzed by 3,3′-di(triphenylsilyl) BINOL-
phosphoric acid (12b) were shown in Figure 5. The imines
formed from the condensation of 4-nitrobenzaldehyde with either
thiourea or N-methyl thiourea and the enol nucleophile formed
from the tautomerization of acetacetate or cyclohexanone. The
lowest energy transition state was obtained for each case when
the Re-face of imine was attacked by the Si-face of enol with a
OH of enol anti to the thiourea moiety of imine via the pathways
IIb, wherein the imine and enol were simultaneously activated
by the proton of phosphoric acid OH and the Lewis basic site
as shown in TS-2-Sa and TS-3-Sa, which correspond to the
major product with (S)-configuration observed experimentally.
In contrast, the TS structures that correspond to (R)-products
were located from reaction pathway Ib rather than IIb as
displayed in TS-2-Ra/Rs and TS-3-Ra/Rs. Moreover, the HB
interactions between catalyst and enol in the TS-Rs were weaker
than those in the TS-Ss as indicated by a longer hydrogen bond
distance between the oxygen of phosphoric acid OH and enol
(1.489 Å in TS-2-Rs vs 1.184 Å in TS-2-Ss, and 1.613 Å in
TS-3-Rs vs 1.595 Å in TS-3-Ss, respectively). As a result, the
enol in TS-Rs was less activated than that in TS-Ss, leading to
a kinetically less favored nucloephilic addition to the activated
imines. This finding suggested that even if the energy deference
between TS-2-Sa and TS-2-Ra is small in the Biginelli reaction
(ca. 1.08 kcal/mol), the high enantioselectivity (96% ee) was
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Organocatalytic Biginelli and Biginelli-Like Condensations
A R T I C L E S
Scheme 2. Plausible Reaction Mechanism of the Biginelli and Biginelli-Like Reactions Catalyzed by Chiral Phosphoric Acid
Scheme 3. Asymmetric Synthesis of Chiral Precursor of (S)-L-771688
Synthetic Applications of Biginelli and Biginelli-Like Reac-
tions. The practical utility of the asymmetric catalytic Biginelli
reaction has been demonstrated in the synthesis of a chiral
precursor of (S)-L-771688 (3), selective R1a receptor antagonist
(Scheme 3). The dihydropyrimidinethione 9w (84% yield, 91%
ee), obtained from Biginelli condensation involving 3,4-difluo-
robenzaldehyde catalyzed by 12b, was subjected to an oxidation
with hydrogen peroxide and followed by a bromination with
PhMe3N+Br3-, producing 19 in 73% yield with a maintained
enantiomeric excess. Methoxylation of 19 using sodium meth-
oxide under the refluxing condition rapidly afforded 20 in 81%
yield. This compound has been readily transformed into (S)-L-
771688 (3) by following a procedure developed by Schaus and
co-workers.15b
still obtained. On the basis of these theoretical calculations, the
calculated energy differences in the transition states of the
stereogenic center forming step confirmed that the Biginelli and
Biginelli-like reactions catalyzed by the 3,3′-di(triphenylsilyl)
BINOL-phosphoric acid (12b) proceeded via reaction pathway
IIb through simultaneously activating the imine by forming
6-membered cyclic hydrogen bonding structure with the OH
of phosphoric acid and the enol by Lewis basic phosphoryl
oxygen, giving (S)-product in agreement with that observed
experimentally.
Reaction Mechanism. A reaction mechanism was proposed
on the basis of the DFT calculation and relevant studies by
others18,25 (Scheme 2). The Biginelli reaction started with a
condensation of the aldehyde with thiourea/urea, accelerated by
Brønsted acid, to give an imine. The chiral phosphoric acid
catalyst activated the imine through forming a chiral iminium
species III, which was attacked by the ꢀ-keto ester or the
enolizable ketone to undergo an enantioselective Mannich
reaction via the intermediate IIb, as suggested by DFT calcula-
tion. The subsequent cyclization and dehydration reactions gave
the Bignelli product and released the phosphoric acid catalyst.
Diastereoselective reduction of dihydropyrimidinethione 15f
with triethylsilane in the presence of trifluoroborane generated
chiral thiourea 21 in 81% yield with >99/1 dr and 96% ee.
Oxidation of the 15f with hydrogen peroxide afforded chiral
dihydropyrimidinone 22 with maintained enantiomeric excess
(eq 3).
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A R T I C L E S
Li et al.
able to control the stereochemistry of Biginelli reaction. This
organocatalytic Biginelli reaction by Brønsted acids 12b and
13 is applicable to a wide range of aldehydes and various ꢀ-keto
esters, providing a highly enantioselective method to access
DHPMs. Biginelli-like reactions catalyzed by 3,3′-di(triphenyl-
silyl) binaphthol derived phosphoric acid tolerated a broad scope
of aldehydes and enolizable ketones. Theoretical calculations
with the ONIOM method on the transition states of the
stereogenic step showed that the imine and enol were both
activated by the bifunctional chiral phosphoric acid through the
formation of hydrogen bonds. In the case catalyzed by 3,3′-
diphenyl binaphthol-derived phosphoric acid, the dual activation
model existed in both Si-facial and Re-facial attacking TSs while
the Si-facial attacking TS was more favored and thereby gave
(R)-enantiomer in major. In contrast, in the reaction catalyzed
by 3,3′-di(triphenylsilyl) phosphoric acid, the dual activation
model stably existed in Re-facial attacking TS, whereas in the
Si-facial attacking TS the phosphoric acid forms an 8-membered
cyclic hydrogen bonding structure with imine and a weaker
hydrogen bond with the enol to thereby cause the enol less
reactive than that in the Re-facial attacking TSs, therefore the
(S)-enantiomer was preferentially produced. These procedures
provide new accesses to a wide spectrum of structurally diverse
dihydropyrimidinethiones and their pharmaceutically relevant
derivatives with high enantiomeric purity.
The treatment of 11d with methyl iodide in the presence of
K2CO3 furnished a 2-methylthio dihydropyrimidine 23 in 91%
yield (eq 4). The structural analogues of 23 have been found to
show antifilarial activity.29 In addition, the transformation of
compounds of type 23 into chiral guanidine compounds could
be achieved by reaction with amines. For example, treatment
of 23 with pyrrolidine under refluxing conditions furnished
guanidine 24 in good yield (eq 4). Thus, this method also
provides a facile access to chiral guanidine containing hetero-
cycles, which constitute a large family of biologically active
compounds.30
Conclusion
Acknowledgment. We are grateful for financial support from
NSFC (20732006), MOST (973 program 2009CB825300), Ministry
of Education, and CAS.
In summary we have developed highly enantioselective
Biginelli and Biginelli-like reactions using chiral phosphoric
acids derived from 3,3′-disubstituted binaphthols as catalysts.
The size of 3,3′-substituents of the catalysts was found to be
Supporting Information Available: Experimental details,
characterization of new compounds, selected NMR and HPLC
spectra, and complete refs 2c,3a-d,4b, 7 and 28. This material
is available free of charge via the Internet at http://pubs.acs.org.
(29) Singh, B. K.; Mishra, M.; Saxena, N.; Yadav, G. P.; Maulik, P. R.;
Sahoo, M. K.; Gaur, R. L.; Murthy, P. K.; Tripathi, R. P Eur. J. Med.
Chem. 2008, 43, 2717.
(30) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203.
JA905320Q
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