Highly enantioselective Biginelli reaction catalyzed by SPINOL-phosphoric acids

Article abstract of DOI:10.1039/c2ob25663k

A highly enantioselective Biginelli reaction promoted by chiral spirocyclic SPINOL-phosphoric acids has been developed. Under the optimized conditions with 5 mol% catalyst loading, a wide range of optically active dihydropyrimidinethiones (DHPMs) were obtained in high yields (up to 98%) with good to excellent enantioselectivities (up to 99% ee). The synthetic utility of this method was demonstrated by the synthesis of chiral precursors of three drugs, including (S)-Monastrol, (S)-L-771688 and (S)-SQ 32926.

Full text of DOI:10.1039/c2ob25663k

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 4467
www.rsc.org/obc
PAPER
Highly enantioselective Biginelli reaction catalyzed by SPINOL-phosphoric
acids†
Fangxi Xu, Dan Huang, Xufeng Lin* and Yanguang Wang*
Received 12th January 2012, Accepted 4th April 2012
DOI: 10.1039/c2ob25663k
A highly enantioselective Biginelli reaction promoted by chiral spirocyclic SPINOL-phosphoric acids has
been developed. Under the optimized conditions with 5 mol% catalyst loading, a wide range of optically
active dihydropyrimidinethiones (DHPMs) were obtained in high yields (up to 98%) with good to
excellent enantioselectivities (up to 99% ee). The synthetic utility of this method was demonstrated by the
synthesis of chiral precursors of three drugs, including (S)-Monastrol, (S)-L-771688 and (S)-SQ 32926.
reactions has received much attention.9,10 Zhu and co-workers
Introduction
described the first highly enantioselective synthesis of DHPMs
by using a chiral ytterbium Lewis acid catalyst.10a Gong and co-
Enantioselective organocatalysis has been recognized as an
environmentally benign and practical methodology for asym-
metric synthesis.1 Chiral cyclic phosphoric acids, which contain
both a Brønsted acidic site and Lewis basic site, represent an
important and widely applicable class of organocatalysts for a
variety of enantioselective transformations.2 Since the pioneering
works of BINOL-phosphoric acids reported independently by
the groups of Akiyama and Terada in 2004,2a,b a number of
chiral diol-based phosphoric acids have been developed for
widespread applications as metal-free chiral catalysts.2c–f
Recently, we reported the chiral spirocyclic SPINOL-phosphoric
acids as a novel skeleton of Brønsted acids, which effectively
promoted the asymmetric Friedel–Crafts reaction of various
indoles with imines3a and the highly enantioselective Pictet–
Spengler reaction of Nb-α-naphthylmethyl tryptamines with
aldehydes.3b The groups of List, Hu and Zhou also indepen-
dently reported SPINOL-phosphoric acid-promoted enantio-
selective transformations.4
The Biginelli reaction is one of the most useful multicompo-
nent reactions, it allows straightforward access to the functiona-
lized 3,4-dihydropyrimidin-2(1H)-ones and -thiones (DHPMs)
via a one-pot condensation of an aldehyde, urea or thiourea, and
acetoacetate.5 Chiral DHPMs have exhibited a wide range of
important pharmaceutical activities and have become the key
structural units in many drugs,6,7 such as (S)-Monastrol,7a,b (S)-
L-771688,7c SNAP-79417d and SQ 329267e (Fig. 1), as well as
in some natural alkaloids.8 Consequently, the approach to access
optically active DHPMs via asymmetric catalytic Biginelli
workers reported the first organocatalytic Biginelli reaction using
BINOL-phosphoric acids with excellent enantiocontrol.10b The
asymmetric synthesis of DHPMs via the chiral secondary
amines,10c–g primary amines,10h bifunctional primary amine-
thioureas,10i and NbCl5/primary amines10j catalyzed enantio-
selective Biginelli reactions were also reported. Despite these
elegant examples, the development of new organocatalysis with
high enantiocontrol for this important reaction remains highly
valuable. As a continuation of our work on SPINOL catalysts,3
we herein report the first chiral SPINOL-phosphoric acid-cata-
lyzed enantioselective Biginelli reaction.
Results and discussion
Initially, a series of SPINOL-phosphoric acids (S)-1a–f bearing
different 6,6′-substituents were evaluated for their capacity to
catalyze the model reaction of 4-nitrobenzaldehyde (2a), thiourea
(3a), and ethyl acetoacetate (4a) (Table 1). The reaction was per-
formed at 50 °C in the presence of 10 mol% catalyst in toluene.
1a and 1b showed much lower catalytic activity (Table 1, entries
1 and 2), while 1c–e could promote the reaction in 64–88%
yields with an ee of 64–84% (Table 1, entries 3–5). Interestingly,
Department of Chemistry, Zhejiang University, Hangzhou 310027,
China. E-mail: lxfok@zju.edu.cn, orgwyg@zju.edu.cn
†Electronic supplementary information (ESI) available: Experimental
procedure, 1H, 13C NMR and HPLC spectra for all compounds. See
DOI: 10.1039/c2ob25663k
Fig. 1 Examples of biologically active DHPMs.
Org. Biomol. Chem., 2012, 10, 4467–4470 | 4467
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Screening of the catalysts for the enantioselective Biginelli
Table 3 Substrates scope of the enantioselective Biginelli reactiona
reactiona
Entry
R1 (2)
R2 (4)
5
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-NO2C6H4 (2a)
3-NO2C6H4 (2b)
2-NO2C6H4 (2c)
4-BrC6H4 (2d)
3-BrC6H4 (2e)
3-FC6H4 (2f)
2-ClC6H4 (2g)
4-MeC6H4 (2h)
3-MeOC6H4 (2i)
Piperonyl (2j)
1-Naphthyl (2k)
2-Furyl (2l)
Cyclohexyl (2m)
3-NO2C6H4 (2b)
3-NO2C6H4 (2b)
3,4-F2C6H3 (2o)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Et (4a)
Me (4b)
i-Pr (4c)
Me (4b)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
92
86
81
92
82
89
88
96
90
84
98
80
40
94
94
90
94
97
99
90
92
94
97
91
94
94
99
90
84
91
95
93
Entry
Catalyst, R
Time (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
1a, Ph
6
6
3
3
3
2
47
30
64
80
88
91
38
34
70
64
84
90
1b, 4-PhC6H4
1c, 4-ClC6H4
1d, 3,5-(CH3)2C6H3
1e, 3,5-(CF3)2C6H3
1f, 1-Naphthyl
9
10
11
12
13
14
15
16
a Reactions were carried out with 2a (0.10 mmol), 3a (0.12 mmol), 4a
(0.30 mmol) and 10 mol% of catalyst in toluene (1 mL) at 50 °C.
b Isolated yield. c Determined by chiral HPLC analysis.
a Reactions were carried out with 2 (0.10 mmol), 3 (0.12 mmol), 4
(0.30 mmol) and 5 mol% of 1f in xylene (1 mL) at 50 °C for 3 days.
b Isolated yield. c Determined by chiral HPLC analysis.
Table 2 Optimization of the reaction conditions with catalyst 1fa
revealed that the operation with 5 mol% of 1f at 50 °C was
optimal for the synthesis of 5a with the highest 94% ee (Table 2,
entries 8–11).
Yieldb
T(°C) Time (d) (%)
eec
(%)
With the optimal conditions in hand, the enantioselective Bigi-
nelli reactions of a variety of aldehydes with thiourea and ethyl
acetoacetate were then investigated. As shown in Table 3, a
variety of substituted benzaldehydes 2a–j could undergo the
reactions to afford DHPMs in high yields with excellent enan-
tioselectivities ranging from 90% ee to 99% ee (Table 3, entries
1–10). In general, the electronic effect slightly influences the
results, whereas the steric effect plays an important role on con-
trolling the enantioselectivity, as demonstrated by that the ortho-
substituted benzaldehydes afforded higher enantio-selectivities
(Table 3, entries 3 and 7). Excellent yield (98%) and enantio-
selectivity (99% ee) was obtained when sterically hindered 1-
naphthaldehyde 2k was employed (Table 3, entry 11). Hetero-
aromatic aldehyde 2l also underwent the reaction with 80% yield
and 90% ee (Table 3, entry 12). However, aliphatic aldehydes
were much less reactive. For example, cyclohexyl aldehyde (2m)
afforded poor yield (40%) and lower enantioselectivity (84% ee)
(Table 3, entry 13). For alkyl acetoacetates 4, both methyl and
iso-propyl gave similar yields and enantioselectivity (Table 3,
entries 14–16).
Entry 1f (mol%) Solvent
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
5
Benzene
Toluene
Xylene
1,4-Dioxane
CH3CN
50
50
50
50
50
3
2
1.5
6
6
3
6
6
3
90
91
96
48
55
82
63
56
92
85
71
92
90
93
87
76
91
93
90
94
91
91
ClCH2CH2Cl 50
CH2Cl2
Xylene
Xylene
Xylene
Xylene
rt
rt
50
70
70
9
10
11
5
2
1.5
3
a Reactions were carried out with 2a (0.10 mmol), 3a (0.12 mmol), 4a
(0.30 mmol) and catalyst 1f in solvent (1 mL). b Isolated yield.
c Determined by chiral HPLC analysis.
catalyst 1f, which provided excellent enantioselectivity in our
previous reports,3 was also the best catalyst for the present reac-
tion, affording the desired DHPM 5a in 91% yield with 90% ee
(Table 1, entry 6).
Encouraged by these results, we further optimized the reaction
conditions by using 1f as catalyst. With 10 mol% catalyst
loading, a brief survey of solvent effect was carried out, and ee
values of 76–93% were obtained in all cases (Table 2, entries
1–7). Accordingly, xylene was chosen to be the most favorable
solvent, in terms of both yield (96%) and enantioselectivity
(93%). Subsequent temperature and catalyst loading survey
It is a remarkable fact that DHPMs 5i and 5p may be the
chiral precursors of two drugs, including (S)-Monastrol and (S)-
L-771688,10k,11 respectively. The absolute configurations of
DHPMs 5 were correlated to the absolute configuration of 5a,
which was confirmed to be S by comparison of the optical
rotation with the literature.10k
The Biginelli reaction involving urea instead of thiourea was
revealed to be much less reactive even with 10 mol% of 1f,
4468 | Org. Biomol. Chem., 2012, 10, 4467–4470
This journal is © The Royal Society of Chemistry 2012

View Article Online
General procedure for the enantioselective Biginelli reaction
Under nitrogen atmosphere, aldehyde 2 (0.1 mmol), thiourea 3a
(0.12 mmol) and catalyst (S)-1f (0.005 mmol) were dissolved in
1 mL xylene. After being stirred at room temperature for
2 hours, acetoacetate 4 (0.3 mmol) was added, and the resulting
mixture was stirred at 50 °C for 3 days as monitored by TLC.
Then the reaction was cooled to room temperature, diluted with
ethyl acetate and added some silica gel. The organic solvents
were removed under vacuum and the residue was purified by
flash column chromatography on silica gel (ethyl acetate/pet-
roleum ether = 1/4–1/2) to afford the corresponding DHPM
product 5.
(S)-Ethyl-6-methyl-4-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (5a). This product was obtained in
92% yield after chromatography and 94% ee as determined by
HPLC [Daicel Chiralpak AS-H, n-hexane/i-propanol = 70/30,
1.0 mL min−1, λ = 254 nm, t (minor) = 17.84 min, t (major) =
22.50 min]. [α]2D0 = +223.6° (c = 0.6, EtOAc); 1H NMR
(400 MHz, DMSO-d6) δ 1.12 (t, J = 6.8 Hz, 3H), 2.33 (s, 3H),
4.03 (q, J = 6.8 Hz, 2H), 5.33 (d, J = 3.6 Hz, 1H), 7.51 (d, J =
9.2 Hz, 2H), 8.25 (d, J = 8.8 Hz, 2H), 9.76 (s, 1H), 10.49 (s,
1H); 13C NMR (100 MHz, DMSO-d6) δ 14.4, 17.7, 54.1, 60.2,
100.2, 124.4, 128.3, 146.4, 147.4, 150.8, 165.3, 175.0; MS
(ESI) m/z 320.1 ([M − H]−).
Scheme 1 Highly enantioselective synthesis of dihydropyrimidinone
5q.
affording dihydropyrimidinone 5q with a significant drop of
both yield and enantioselectivity (Scheme 1). Alternatively, treat-
ment of the corresponding dihydropyrimidinethione 5o (Table 3,
entry 15) with hydrogen peroxide afforded 5q in 81% yield with
a maintained enantioselectivity of 95% ee (Scheme 1). Further
conversion of 5q will lead to (S)-SQ 32926, whose enantiomer
has been identified as potent orally active antihypertensive
agent.12
Synthesis of dihydropyrimidinone 5q
Conclusions
To a solution of 5o (28.9 mg, 0.086 mmol) in ethyl acetate
(1.6 mL) was added ammonia (0.7 mL) and 30% aqueous H2O2
(0.7 mL). After stirring at 50 °C for 1 hour in open air, the reac-
tion mixture was quenched with 1 mL water and extracted with
ethyl acetate. The organic layer was dried over Na2SO4, concen-
trated in vacuo, and the residue was purified by silica gel column
chromatography (ethyl acetate/petroleum ether = 2/1).
In summary, we have identified SPINOL-phosphoric acids as
highly efficient organocatalysts for the enantioselective Biginelli
reaction, providing a variety of optically active DHPMs in good
yields with excellent ee values. The synthetic utility of this
method was demonstrated by the synthesis of chiral precursors
of three drugs, including (S)-Monastrol, (S)-L-771688 and (S)-
SQ 32926. Further applications of the novel chiral spirocyclic
SPINOL-phosphoric acids in asymmetric catalysis are currently
underway.
(S)-Isopropyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (5q). This product was obtained
in 81% yield and 95% ee as determined by HPLC [Daicel Chir-
alpak AD-H, n-hexane/i-propanol = 80/20, 1.0 mL min−1, λ =
254 nm, t (minor) = 9.30 min, t (major) = 13.19 min]. [α]D20
=
+90.8° (c = 0.6, EtOAc); 1H NMR (400 MHz, DMSO-d6) δ 1.00
(d, J = 6.4 Hz, 3H), 1.19 (d, J = 6.4 Hz, 3H), 2.30 (s, 3H),
4.81–4.88 (m, 1H), 5.32 (s, 1H), 7.66–7.74 (m, 2H), 7.91 (s,
1H), 8.11–8.16 (m, 2H), 9.37 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 18.3, 21.9, 22.2, 54.2, 67.1, 99.1, 121.6, 122.7,
130.6, 133.5, 147.6, 148.2, 149.7, 152.3, 165.0; MS (ESI) m/z
317.9 ([M − H]−).
Experimental section
General information
Unless otherwise noted, all reagents were purchased from com-
mercial supplies and used without further purification. Solvents
were used without dryness. H NMR spectra were recorded on
1
400 MHz spectrometer. The chemical shifts were reported rela-
tive to internal standard TMS (0) in CDCl3 or 2.5 in DMSO-d6.
The following abbreviations were used to describe peak patterns
where appropriate: br = broad, s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. Coupling constants were
reported in Hertz (Hz). 13C NMR spectra were recorded on
100 MHz spectrometer, referred to the internal solvent signals
(77.0 for CDCl3 or 40.0 for DMSO-d6). Optical rotations were
determined using a Perkin Elmer Model 341 polarimeter at
20 °C. The enantiomeric excess (ee) values were determined by
chiral HPLC analysis on Daicel Chiralpak AS-H or AD-H
columns.
Acknowledgements
We thank the National Natural Science Foundation of China (no.
21032005) and the Fundamental Research Funds for the Central
Universities for financial support of this research.
Notes and references
1 For selected reviews on organocatalysis, see: (a) A. Dondoni and
A. Massi, Angew. Chem., Int. Ed., 2008, 47, 4638;
(b) D. W. C. MacMillan, Nature, 2008, 455, 304; (c) M. S. Taylor and
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4467–4470 | 4469

View Article Online
E. N. Jacobsen, Angew. Chem., Int. Ed., 2006, 45, 1520; (d) S. Bertelsen
and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178; (e) Asymmetric
Organocatalysis, ed. A. Berkessel and H. Gröger, Wiley-VCH,
Weinheim, 2005; (f) Enantioselective Organocatalysis, ed. P. I. Dalko,
Wiley-VCH, Weinheim, 2007; (g) Special issue on organocatalysis, ed.
B. List, Chem. Rev., 2007, 107(12).
2 (a) T. Akiyama, J. Itoh, K. Yokota and K. Fuchibe, Angew. Chem., Int.
Ed., 2004, 43, 1566; (b) D. Uraguchi and M. Terada, J. Am. Chem. Soc.,
2004, 126, 5356. For recent reviews on chiral phosphoric acids, see
(c) M. Terada, Synthesis, 2010, 1929; (d) A. Zamfir, S. Schenker,
M. Freund and S. B. Tsogoeva, Org. Biomol. Chem., 2010, 8, 5262;
(e) M. Rueping, A. Kuenkel and I. Atodiresei, Chem. Soc. Rev., 2011, 40,
4539; (f) D. Kampen, C. M. Reisinger and B. List, Top. Curr. Chem.,
2010, 291, 395.
3 (a) F.-X. Xu, D. Huang, C. Han, W. Shen, X.-F. Lin and Y.-G. Wang,
J. Org. Chem., 2010, 75, 8677; (b) D. Huang, F.-X. Xu, X.-F. Lin and
Y.-G. Wang, Chem.–Eur. J., 2012, 18, 3148.
4 (a) I. Čorić, S. Müller and B. List, J. Am. Chem. Soc., 2010, 132, 17370;
(b) C.-H. Xing, Y.-X. Liao, J. Ng and Q. S. Hu, J. Org. Chem., 2011, 76,
4125; (c) B. Xu, S.-F. Zhu, X.-L. Xie, J.-J. Shen and Q.-L. Zhou, Angew.
Chem., Int. Ed., 2011, 50, 11483; (d) S. Müller, M. J. Webber and
B. List, J. Am. Chem. Soc., 2011, 133, 18534.
R. S. L. Chang, S. S. O’Malley, T. V. Olah, J. D. Ellis, A. Barrish,
K. Kassahun, P. Leppert, D. Nagarathnam and C. Forray, J. Med. Chem.,
2000, 43, 2703; (d) B. Borowsky, M. M. Durkin, K. Ogozalek,
M. R. Marzabadi, J. Deleon, R. Heurich, H. Lichtblau, Z. Shaposhnik,
I. Daniewska, T. P. Blackburn, T. A. Branchek, C. Gerald, P. J. Vaysse
and C. Forray, Nat. Med. (N. Y.), 2002, 8, 825; (e) K. S. Atwal,
B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland, A. Hedberg and
B. C. O’Reilly, J. Med. Chem., 1991, 34, 806.
8 A. D. Patil, N. V. Kumar, W. C. Kokke, M. F. Bean, A. J. Freyer,
C. D. Brosse, S. Mai, A. Truneh, D. J. Faulkner, B. Carte, A. L. Breen,
R. P. Hertzberg, R. K. Johnson, J. W. Westley and B. C. M. Potts, J. Org.
Chem., 1995, 60, 1182.
9 G.-Z. Gong, X.-H. Chen and X.-Y. Xu, Chem.–Eur. J., 2007, 13, 8920.
10 (a) Y.-J. Huang, F.-Y. Yang and C.-J. Zhu, J. Am. Chem. Soc., 2005, 127,
16386; (b) X.-H. Chen, X.-Y. Xu, H. Liu, L.-F. Cun and L. Z. Gong,
J. Am. Chem. Soc., 2006, 128, 14802; (c) J.-G. Xin, L. Chang,
Z.-R. Hou, D.-J. Shang, X.-H. Liu and X.-M. Feng, Chem.–Eur. J., 2008,
14, 3177; (d) R. González-Olvera, P. Demare, I. Regla and E. Juaristi,
ARKIVOC, 2008, vi, 61; (e) Y.-Y. Wu, Z. Chai, X.-Y. Liu, G. Zhao and
S.-W. Wang, Eur. J. Org. Chem., 2009, 904; (f) J.-H. Sohn, H.-M. Choi,
S. Lee, S. Joung and H.-Y. Lee, Eur. J. Org. Chem., 2009, 3858;
(g) S. Saha and J. N. Moorthy, J. Org. Chem., 2011, 76, 396; (h) D. Ding
and C.-G. Zhao, Eur. J. Org. Chem., 2010, 3802; (i) Y.-Y. Wang, J.-P. Yu,
Z.-W. Miao and R.-Y. Chen, Org. Biomol. Chem., 2011, 9, 3050;
( j) Y.-F. Cai, H.-M. Yang, L. Li, K.-Z. Jiang, G.-Q. Lai, J.-X. Jiang and
L.-W. Xu, Eur. J. Org. Chem., 2010, 4986; (k) N. Li, X.-H. Chen,
J. Song, S.-W. Luo, W. Fan and L.-Z. Gong, J. Am. Chem. Soc., 2009,
131, 15301.
5 (a) P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360. For reviews, see
(b) C. O. Kappe, Acc. Chem. Res., 2000, 33, 879; (c) C. O. Kappe, in
Multicomponent Reactions, ed. J.-P. Zhu and H. Bienaymé, Wiley-VCH,
Weinheim, 2005, p. 95.
6 C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043.
7 (a) T. U. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King,
S. L. Schreiber and T. J. Mitchison, Science, 1999, 286, 971;
(b) Z. Maliga, T. M. Kapoor and T. J. Mitchison, Chem. Biol., 2002, 9,
989; (c) J. C. Barrow, P. G. Nantermet, H. G. Selnick, K. L. Glass,
K. E. Rittle, K. F. Gilbert, T. G. Steele, C. F. Homnick, R. M. Freidinger,
R. W. Ransom, P. Kling, D. Reiss, T. P. Broten, T. W. Schorn,
11 J. M. Goss and S. E. Schaus, J. Org. Chem., 2008, 73, 7651.
12 (a) K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland,
A. Hedberg and B. C. O’Reilly, J. Med. Chem., 1991, 34, 806;
(b) B. Schnell, W. Krenn, K. Faber and C. O. Kappe, J. Chem. Soc.,
Perkin Trans. 1, 2000, 4382.
4470 | Org. Biomol. Chem., 2012, 10, 4467–4470
This journal is © The Royal Society of Chemistry 2012