Asymmetric organocatalytic tandem reaction to chiral pyrimidinone derivatives using urea as dinitrogen source

Article abstract of DOI:10.1002/adsc.201000291

A facile method for the asymmetric synthesis of pyrimidinone derivatives was developed via an organocatalytic tandem aza-Michael addition- hemiaminal formation-dehydroxylation reaction, using N,N′-dialkyloxyurea as dinitrogen source (up to 97% ee). The transformations of hemiaminal intermediates to pyrimidinones with more complex structures have been also investigated.

Full text of DOI:10.1002/adsc.201000291

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DOI: 10.1002/adsc.201000291
Asymmetric Organocatalytic Tandem Reaction to Chiral
Pyrimidinone Derivatives using Urea as Dinitrogen Source
Zhao-Quan He,a Quan Zhou,a Li Wu,a and Ying-Chun Chena,b,*
a
Key Laboratory of Drug-Targeting and Drug Delivery System of Education Ministry, Department of Medicinal
Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, Peopleꢀs Republic of China
Fax : (+86)-28-8550-2609; phone: (+86)-28-8550-2609; e-mail: ycchenhuaxi@yahoo.com.cn
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Peopleꢀs Republic of China
b
Received: April 14, 2010; Revised: June 12, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000291.
Abstract: A facile method for the asymmetric syn-
thesis of pyrimidinone derivatives was developed
via an organocatalytic tandem aza-Michael addi-
tion–hemiaminal formation–dehydroxylation reac-
tion, using N,N’-dialkyloxyurea as dinitrogen source
(up to 97% ee). The transformations of hemiaminal
intermediates to pyrimidinones with more complex
structures have been also investigated.
Keywords: amines; asymmetric catalysis; organic
catalysis; pyrimidinones; tandem reactions
Enantiomerically enriched 1,3-diamines are key struc-
tural units in a number of natural products or phar-
macologically active molecules. For example, the bat-
zelladine alkaloids containing 1,3-diamine skeletons
are members of a growing class of guanidine alkaloids
Figure 1. Some natural products containing 1,3-diamine
structure.
Consequently, the significance of 1,3-diamine com-
that exhibit a broad spectrum of biological activity. pounds has attracted increasing attention in the devel-
Most of them could be used to treat autoimmune dis- opment of a number of protocols to access such
orders and, therefore, are potential leads for AIDS motifs. However, most of these processes are func-
therapy. It is worthy of note that chiral 1,3-diamines tional group transformations of optically active com-
are important intermediates in the total synthesis of pounds to prepare 1,3-diamines.[6] Only a few direct
batzelladines A, B and F.[1] Saxitoxin (Figure 1), the asymmetric syntheses of 1,3-diamines have been de-
paralytic agent of the Alaska butter clam Saxidomas scribed[7] in comparison with the analogous 1,2-di-
giganteus, is one of the most toxic non-protein poisons
amines.[8] It remains indispensable to find new effec-
ACHTUNGTRENNUNG
known and has also found widespread applications in tive approaches to prepare structurally diverse chiral
the studies of various nerve disorders.[2] In addition, 1,3-diamines. We envisaged that an tandem asymmet-
1,3-diamine structures are always key moieties of ric aza-Michael addition[9]–intramolecular hemiaminal
some aminoglycosides, most of which are important formation from readily available N,N’-dialkyloxyureas
antibiotics with a broad antibacterial spectrum, partic- 2 and a,b-unsaturated aldehydes 3 would afford chiral
ularly against Gram-negative bacteria.[3] 1,3-Diamines, heterocyclic intermediates 4 under the catalysis of a
especially chiral ones, are of great interest in medici- chiral secondary amine 1, which could be smoothly
nal chemistry, for example, in cancer research.[4] On converted to 1,3-diamine derivatives, pyrimidinones 5,
the other hand, these compounds have also been effi- after a simple dehydroxylation. Moreover, the elec-
ciently applied as ligands in asymmetric catalysis.[5]
trophilic hemiaminal functionality should be further
attacked by some nucleophiles under suitable condi-
1904
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Adv. Synth. Catal. 2010, 352, 1904 – 1908

Asymmetric Organocatalytic Tandem Reaction to Chiral Pyrimidinone Derivatives
tions, thus pyrimidinones 6 with more molecular com- (BA, 10 mol%).[10] The reaction proceeded very
plexity would be generated (Scheme 1).
slowly and poor conversion was observed after 72 h
We first investigated the reaction of N,N’-dibenzyl- (Table 1, entry 1). Urea substrate 2a could be con-
ACHTUNGTRENNUNG
structure were crucial (entry 12).
Scheme 1. Proposed organocatalytic reaction sequence to
chiral pyrimidinones.
Having established the optimal reaction conditions,
the substrate scope of the tandem aza-Michael addi-
tion–hemiaminal
formation–dehydroxylation
se-
bient temperature catalyzed by chiral a,a-diphenyl- quence to access pyrimidinones 5 was investigated
prolinol O-TMS ether 1a (10 mol%) and benzoic acid with urea 2a and a number of a,b-unsaturated alde-
Table 1. A survey of reaction conditions for pyrimidinone construction.[a]
Entry
1
Acid
Solvent
t [h]
Yield[b] [%]
ee[c] [%]
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1a
BA
BA
toluene
toluene
toluene
toluene
toluene
THF
MeCN
DCM
PhCF3
PhCF3
PhCF3
PhCF3
72
140
59
60
35
72
72
44
16
22
96
144
<10
81
93
90
93
<10
<10
93
95
85
–
2[d]
3
65
95
93
94
–
OFBA
PNBA
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
4
5
6
7
8
9
10
11
12[e]
–
94
95
94
92
71
60
59
[a]
Unless otherwise noted, reactions were performed with 0.1 mmol of 2a, 0.15 mmol of 3a, 0.01 mmol of catalyst 1 and acid
in 1 mL solvent at room temperature. Then Et3SiH/BF3·Et2O (0.3 mmol/0.3 mmol) were directly added to conduct the de-
hydroxylation reaction at 08C.
Isolated yield for two steps.
Determined by chiral HPLC analysis.
At 408C.
[b]
[c]
[d]
[e]
2b was used, ee for 5b.
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Zhao-Quan He et al.
Table 2. Tandem aza-Michael addition–hemiaminal formation–dehydroxylation to access pyrimidinones.[a]
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Entry
R
t [h]
Product
Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
Ph
16
10
10
9
19
15
18
34
13
6
5a
5c
5d
5e
5f
5g
5h
5i
95
92
90
83
86
90
85
83
82
95
93
82
95
93
94
95
97
95
94
93
93
83
86
95
p-Cl-C6H4
m-Cl-C6H4
p-Br-C6H4
o-Br-C6H4
p-CF3-C6H4
m-Me-C6H4
p-MeO-C6H4
2-thienyl
Me
9
5j
5k
5l
10[d,e]
11[d]
12[d]
n-Pr
i-Pr
8
88
5m
[a]
Unless otherwise noted, reactions were performed with 0.1 mmol of 2a, 0.15 mmol of 3a, 0.01 mmol of 1a and AcOH in
1 mL PhCF3 at room temperature. Then Et3SiH/BF3·Et2O (0.3 mmol/0.3 mmol) were directly added to conduct the dehy-
droxylation reaction at 08C.
Isolated yield for two steps.
Determined by chiral HPLC analysis.
[b]
[c]
[d]
[e]
0.2 mmol of enal was used.
The absolute configuration of 5k was determined after conversion to a known compound, see the Supporting Informa-
tion. The other products were assigned by analogy.
hydes 3. The results are summarized in Table 2. The tricyclic product 6a was gratifyingly isolated in excel-
electronic characteristics of aryl-substituted a,b-unsa- lent enantio- and diastereoselectivity. similar
A
turated aldehydes seemed to have limited effects on tandem sequence could be applied for the reaction of
the enantioselectivity. Excellent ee values were ob- urea 2d and cinnamaldehyde. Although a poor dr
tained for a diversity of a,b-unsaturated aldehydes ratio was observed, both diastereomers 6b and 6b’
bearing electron-withdrawing or electron-donating could fortunately be separated by a simple flash
aryl groups, and good to excellent isolated yields were column chromatography, also with high ee values
obtained (Table 2, entries 1–8). In addition, a hetero- (Scheme 2).
aryl-substituted enal could be successfully utilized,
In addition, we were pleased to find that the diaste-
and excellent enantioselectivity was also attained reoselective allylation of hemiaminal 4a could be
(entry 9). Linear alkyl-substituted a,b-unsaturated al- smoothly performed with allyltrimethylsilane under
dehydes exhibited high reactivity while the enantiose- the catalysis of BF3·Et2O at À608C.[14] As outlined in
lectivity was slightly lower (entries 10 and 11). The re- Scheme 3, a pyrimidinone compound 6c bearing a ver-
action of an a,b-unsaturated aldehyde bearing a satile terminal olefinic functionality was attained in
branched b-isopropyl group was quite sluggish, but high yield with a good dr.
good yield and excellent enantioselectivity could be
provided by extending the reaction time (entry 12).
In conclusion, we have presented a facile protocol
to access chiral pyrimidinones via an aminocatalytic
Since the attempted intramolecular Friedel–Crafts tandem aza-Michael addition–intramolecular hemi-
reaction of 4a was unsuccessful under various condi- aminal formation–dehydroxylation reaction from
AHCTUNGTRENNUNG
tions, we designed two new ureas 2c and 2d with readily available N,N’-dialkyloxyureas and a,b-unsa-
more electron-rich 3,4-dimethoxybenzyl and (1- turated aldehydes. This process exhibited good effi-
methyl-1H-indol-2-yl)methyl
group,
respectively. ciency and excellent enantiocontrol under environ-
After the aminocatalytic domino aza-Michael addi- mentally friendly and mild conditions. In addition,
tion–hemiaminal formation of 2c and cinnamaldehyde some synthetic transformations with chiral hemiami-
finished, the solvent was removed and a catalytic nal intermediates could be conducted to afford pyri-
amount of HCl in ethyl acetate (20 mol%) was added midinone derivatives with more molecular complexi-
in DCM at À788C.[13] After an additional 30 min, the ty,[15] which might be useful for further applications in
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Adv. Synth. Catal. 2010, 352, 1904 – 1908

Asymmetric Organocatalytic Tandem Reaction to Chiral Pyrimidinone Derivatives
Scheme 2. Tandem aza-Michael addition–hemiaminal formation–intramolecular Friedel–Crafts reaction to access polycyclic
frameworks.
15:1–10:1) to give pyrimidinone 5a; yield: 36.8 mg (95%).
95% ee, determined by chiral HPLC analysis (Daicel chiral-
pak IC, 30% 2-propanol/n-hexane, 1 mLminÀ1, UV 220 nm):
t
minor =19.91 min, tmajor =22.43 min; [a]2D0:+6.2 (c 1.81 in
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.50–7.48 (m, 2H),
7.39–7.32 (m, 6H), 7.29–7.25 (m, 5H), 7.13–7.12 (m, 2H),
5.05–5.00 (m, 3H), 4.58 (d, J=9.6 Hz, 1H), 4.44 (dd, J=
4.8 Hz, J=7.2 Hz, 1H), 3.32–3.20 (m, 2H), 2.18–2.05 (m,
2H); 13C NMR (50 MHz, CDCl3): d=159.8, 139.7, 136.0,
135.6, 129.5, 128.6, 128.5, 128.4, 128.2, 128.0, 126.9, 77.8,
77.2, 63.8, 47.2, 29.2; ESI-HR-MS: m/z=411.1684, calcd. for
[C24H24N2O3 +Na]: 411.1685.
Scheme 3. Diastereoselective allylation of hemiaminal inter-
mediate 4a.
medicinal chemistry or other fields. More investiga-
tion is underway in our laboratory and the results will
be reported in due course.
Deprotection Procedure
The N-benzyloxy moeity of 5a could be easily removed (see
also the Supporting Information). To a solution of 5a
(46 mg, 012 mmol) in methanol (4 mL) was added Raney Ni
(30 mol%) at room temperature. The reaction mixture was
kept under a hydrogen atmosphere (1 bar) for 8 h. Then the
mixture was filtered through celite. The celite was washed
with methanol and the filtrate was concentrated under
vacuum. The residue was washed with petroleum ether/ethyl
acetate (10:1, 20 mL) to afford the debenzyloxylated pyrimi-
Experimental Section
General Procedure for the One-Pot, Tandem Aza-
Michael Addition–Intramolecular Hemiaminal
Formation–Dehydroxylation Reaction
Urea 2a (27.2 mg, 0.1 mmol) was added to a mixture of cata-
lyst 1a (3.2 mg, 0.01 mmol), acetic acid (0.6 mL, 0.01 mmol)
and cinnamaldehyde 3a (19.8 mg, 0.15 mmol) in PhCF3
(1 mL) at room temperature. The reaction mixture was
stirred until complete consumption of 2a (monitored by
TLC). Then the solution was cooled to 08C and Et3SiH
(48 mL, 0.3 mmol) and BF3·OEt2 (38 mL, 0.3 mmol) were
added. After 5 min, the mixture was purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate,
1
done 6d; yield: 72%; [a]2D0: À22.2 ( c 0.46, CHCl3); H NMR
(400 MHz, CDCl3): d=7.38–7.34 (m, 5H), 4.97–4.91 (m, 2
H), 4.58 (brs, 1 H), 3.36–3.28 (m, 2H), 2.16–2.14 (m, 1H),
1.94–1.91 (m, 1H); 13C NMR (100 MHz, CDCl3): d=166.0,
128.9, 128.0, 126.1, 55.1, 38.5, 30.4; ESI-HR-MS: m/z=
177.1022, calcd. for [C10H12N2O+H]: 177.1028.
Adv. Synth. Catal. 2010, 352, 1904 – 1908
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Zhao-Quan He et al.
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We are grateful for the financial support from NSFC
(20772084), PCSIRTC (IRT0846) and National Basic Re-
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1904 – 1908