Organocatalytic enantioselective aza-Michael addition of purine bases to α,β-unsaturated ketones

Article abstract of DOI:10.1002/adsc.201200488

The first organocatalytic enantioselective aza-Michael addition of purine bases to α,β-unsaturated ketones has been developed, affording Michael adducts in moderate to high yields (up to 96% yield) and high to excellent enantioselectivities (up to >99% ee). A wide range of α,β-unsaturated ketones including aliphatic and aromatic enones are tolerated in this process, generally demonstrating good reactivity, regioselectivity and enantioselectivity. The aromatic α,β-unsaturated ketones showing quite low reactivity in the reported catalytic systems, were first successfully employed as Michael acceptors in this transformation, yielding high enantioselectivities (up to 94% ee). The utility of this method was also applied for the synthesis of enantioenriched non-natural nucleoside analogues with potential biological activities. Copyright

Full text of DOI:10.1002/adsc.201200488

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DOI: 10.1002/adsc.201200488
Organocatalytic Enantioselective Aza-Michael Addition of Purine
Bases to a,b-Unsaturated Ketones
Hao Wu,a Zhiqing Tian,a Lili Zhang,b Yaodong Huang,b,* and Yongmei Wanga,*
a
State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University, Tianjin 300071,
Peopleꢀs Republic of China
Fax : (+86)-22-2350-4439; e-mail: ymw@nankai.edu.cn
Key Laboratory of Systems Bioengineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin
b
300072, Peopleꢀs Republic of China
Fax : (+86)-22-2789-0166; e-mail: huangyaodong@tju.edu.cn
Received: June 3, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200488.
Abstract: The first organocatalytic enantioselective
aza-Michael addition of purine bases to a,b-unsatu-
rated ketones has been developed, affording Mi-
chael adducts in moderate to high yields (up to
96% yield) and high to excellent enantioselectivities
(up to >99% ee). A wide range of a,b-unsaturated
ketones including aliphatic and aromatic enones are
tolerated in this process, generally demonstrating
good reactivity, regioselectivity and enantioselectiv-
ity. The aromatic a,b-unsaturated ketones showing
quite low reactivity in the reported catalytic sys-
tems, were first successfully employed as Michael
acceptors in this transformation, yielding high enan-
tioselectivities (up to 94% ee). The utility of this
method was also applied for the synthesis of enan-
tioenriched non-natural nucleoside analogues with
potential biological activities.
dicinal activities are known (Figure 1).[4] Notably, the
biological effect has an enantiospecific character in all
these compounds.[5] For example, (+)-(2S,3R)-EHNA
is the most potent isomer as an inhibitor of adenosine
deaminase whereas its enantiomer (À)-(2R,3S)-
EHNA is approximately 250-fold less active.[5a] The
remarkably different activities of respective enantio-
mers as well as the challenging issues of reactivity and
regioselectivity between two (N-7 H and N-9 H)
competitive tautomeric forms[6] make the develop-
ment of effective methods for synthesis of these inter-
esting chiral building blocks highly desirable.
In the past several years, however, most of those
methodologies for the preparation of chiral purine
bases relied on the introduction of a chiral side chain
to purines.[7] In contrast, considerably less attention
has been paid to the investigation of a catalytic enan-
À
À
Keywords: aza-Michael addition; organocatalysis;
purine bases; a,b-unsaturated ketones
An aza-Michael reaction of a nitrogen-centered
source is a convenient and important way to prepare
pharmacologically and synthetically useful b-amino
carbonyl compounds, including b-amino acids and b-
lactams.[1] Over the last decade, tremendous progress
has been achieved by employing numerous attractive
nitrogen nucleophiles for this important organic trans-
formation.[2] The purine scaffold as the structural core
of the nucleobases, is a ubiquitous feature in both bio-
logical systems and synthetic compounds, finding ap-
plications as biologically active drugs and fluorescent
probes.[3] A great number of purine-based compounds
for chemotherapy belonging to open chain acyclic
Figure 1. Structures of some typical chiral purine bases with
sugar analogues with chiral carbons with various me- various biological activities.
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Hao Wu et al.
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Scheme 1. Synthetic route to chiral purine bases via organocatalytic aza-Michael addition and three challenges of the strat-
egy.
tioselective synthesis of these compounds with achiral zoic acid as cocatalyst (Table 1, entries 1–7). The uti-
starting materials via an asymmetric aza-Michael ad- lization of chloropurine in the model reaction may
dition catalyzed by a chiral catalyst.[8] Jacobsen firstly
Table 1. Screening of the optimal reaction conditions.[a]
reported the successful use of [(salen)Al] complexes
in the conjugate addition of purine to a, b-unsaturat-
ed ketones and imides, opening a new entry to the
synthesis of non-nature nucleosides.[8a] Qu demon-
strated an organocatalytic method for the synthesis of
optically active acyclonucleosides by employing a,b-
unsaturated enals.[8b] These two methods both gave
adducts with high enantioselectivities, but their appli-
cation were restricted by the spectrum of a,b-unsatu-
rated carbonyl compounds (no reactions when sub-
strates bearing aromatic b-substituents),[8] harsh reac-
tion conditions[8b] and not well-developed regioselec-
tivity between two competitive tautomeric forms[8a] as
well as employment of expensive organometallic com-
plexes that were difficult to prepare.[8a] These limita-
tions promoted us to develop a new method for the
enantioselective synthesis of chiral purine bases by
the aza-Michael addition (Scheme 1).
During the last decade, organocatalysis has been
one of the most rapidly growing and competitive
Entry
Catalyst
Time [h]
Yield[%][b]
ee [%][c]
fields in asymmetric catalysis, and has developed to
a third pillar beside metal catalysis and biocatalysis.[9]
It offers several advantages, such as mild reaction
conditions, simple operation, and easily accessible cat-
alyst systems. We envisioned that the extension of Ja-
cobsenꢀs chemistry to the aza-Michael addition of pu-
rines to a,b-unsaturated ketones using suitable orga-
nocatalysts would provide an efficient asymmetric
synthetic route to chiral purine bases (Scheme 1).
Herein, to the best of our knowledge, we report the
first organocatalytic aza-Michael addition of purine
bases to a broad spectrum of a,b-unsaturated ketones
ranging from aliphatic to aromatic enones for the
highly enantioselective synthesis of chiral purine
bases with exclusive N-9 addition regioselectivity
under mild reaction conditions (up to 96% yield, up
to >99% ee).
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
3g
3d
3d
3d
24
48
48
48
24
24
48
48
48
48
96
86
46
87
90
89
92
90
88
80
64 (S)[d]
47 (R)[d]
53 (R)[d]
79 (R)[d]
75 (S)[d]
74 (R)[d]
37 (R)[d]
92 (R)[d]
94 (R)[d]
96 (R)[d]
8[e]
9[f]
10[f,g]
[a]
Unless otherwise noted, reactions were carried out by
using 6-chloro-9H-purine 1a (0.1 mmol, 1.0 equiv.) and 3-
hepten-2-one 2a (0.15 mmol, 1.5 equiv.) in toluene
(1 mL) with 20 mol% catalyst and 40 mol% PhCO2H at
room temperature.
[b]
[c]
[d]
Isolated yields.
Determined by HPLC analysis.
To begin our initial investigation, several bifunc-
tional catalysts 3 (20 mol%) were screened to evalu-
ate their ability to promote the aza-Michael addition
of 6-chloro-9H-purine 1a to 3-hepten-2-one 2a at
room temperature in toluene in the presence of ben-
The absolute configuration was determined by compari-
son with the literature.
10 mol% catalyst and 40 mol% PhCO2H were used.
10 mol% catalyst and 30 mol% PhCO2H were used.
Reaction was conducted at 08C.
[e]
[f]
[g]
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Organocatalytic Enantioselective Aza-Michael Addition of Purine Bases
prove especially noteworthy, as relatively facile nucle- lent enantioselectivity and good yield (entry 10, 80%
ophilic substitution of chloride enables the prepara- yield, 96% ee).
tion of various derivatives.[6] To our delight, the reac-
With the established optimal reaction conditions in
tion proceeded smoothly to provide the desired hand, the scope of the asymmetric transformation was
adduct 4a in moderate to good yields (46–96%) with examined by employing a variety of a,b-unsaturated
moderate enantioselectivities (Table 1, entries 1–4, ketones and purine bases. The process proved to be
47–79% ee). A promising result was obtained with the a general strategy for enantioselective aza-Michael
chiral thiourea–primary amine 3d, affording 87% addition with significant structural variations. Exclu-
yield and 79% ee (Table 1, entry 4). On this basis, sev- sive formation of the N-9 regioisomers was observed
eral commonly used bifunctional chiral thiourea–pri- in all cases. As revealed in Table 2, all a,b-unsaturat-
mary amines were investigated. However, disappoint- ed aliphatic ketones gave the aza-Michael adducts in
ing results without any improvement were obtained high yields and excellent enantioselectivities both at
albeit with somewhat better yields (Table 1, entries 5– room temperature and at 08C (Table 2, entries 1–9,
7). Therefore, catalyst 3d was chosen as the best cata- 70–91% yield, 91–97% ee). Generally, better ee values
lyst. Further reaction optimization focused on the cat- were realized when reactions were carried out at 08C
alyst and additive loadings. Gratifyingly, when the albeit with lower yields. Increasing the length of the
amount of catalyst 3d was decreased to 10 mol%, side chains had a limited effect on both yield and
a great improvement in enantioselectivity was imple- enantioselectivity. Notably, when an aromatic b-sub-
mented (entry 8, 92% ee). Further changing the load- stituted enone showing no reactivity in the literature
ings of benzoic acid from 10 mol% to 60 mol% was used,[8] the reaction gave a satisfactory enantiose-
showed that the enantioselectivity could increase to lectivity and moderate yield (entry 10, 52–67% yield,
the apex when 30 mol% of PhCO2H was added 88–89% ee). To the best of our knowledge, this is the
(Table 1, entry 9, 88% yield, 94% ee; TS-1 in the Sup- first successful example showing that the asymmetric
porting Information). Lowering the temperature to aza-Michael reaction of aromatic b-substituted a,b-
08C, the reaction gave the desired product with excel- unsaturated ketones to purine bases could proceed
easily with high enantioselectivity. Other purine bases
Table 2. Substrate scope for organocatalytic aza-Michael of a, b-unsaturated aliphatic ketones 2 with purine bases 1.[a]
Entry
X
Y
R1
R2
Product
Yield [%][b,d]
ee [%][c,d]
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OBn
SMe
NHBoc
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
Me
n-Pr
i-Pr
n-Bu
n-pentyl
n-hexyl
BnOCH2
Me
Me
Ph
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Me
Me
Me
Me
Me
Me
Me
Et
nBu
Me
Me
Me
Me
Me
Me
Me
4b
4a
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
85 (79)
88 (80)
84 (77)
87 (76)
86 (79)
89 (85)
91 (83)
82 (73)
83 (70)
67 (52)
84 (73)
92 (83)
69 (52)
89 (78)
96 (90)
82 (76)
93 (96)
94 (96)
92 (96)
95 (97)
91 (93)
94 (95)
96 (96)
95 (97)
94 (96)
88 (89)
93 (93)
95 (93)
>99 (98)
96 (97)
80 (82)
92 (90)
9
10
11
12
13
14
15
16
Cl
H
[a]
Unless otherwise noted, reactions were carried out by using purine bases 1 (0.1 mmol, 1.0 equiv.) and enones 2
(0.15 mmol, 1.5 equiv.) in toluene (1 mL) with 10 mol% catalyst 3d and 30 mol% PhCO2H for 48 h at room temperature.
Isolated yields.
Determined by HPLC analysis.
The value in parentheses indicates the yields and ee when reactions were carried out at 08C.
[b]
[c]
[d]
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Hao Wu et al.
Table 3. Screening of the optimal reaction conditions.[a]
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also displayed good to excellent reactivities and enan-
tioselectivities in the aza-Michael addition to enones
(Table 2, entries 11–16, 52–96% yield, 80–>99% ee).
Lowering the temperature to 08C did not show any
great improvement in enantioselectivity. It is notewor-
thy that the N-Boc-protected purine underwent the
aza-Michael addition with 3-hepten-2-one smoothly at
room temperature, thus providing the product 4m
with greater than 99% ee (Table 2, entry 13). Unfortu-
nately, in the case of 2,6-dichloro-9H-purine, the
enantioselectivity decreased as compared with the 6-
monosubstituted purine bases (Table 2, entry 15). Sur-
prisingly, the exclusive N-9 substituted product was
observed when purine was employed with high yield
and enantioselectivity (Table 2, entry 16, 92% ee).[8a]
Although recent progress on the asymmetric aza-
Michael reaction of purine bases has been remark-
able, one challenge that the reaction is highly sub-
strate-dependent continues to limit the application of
this transformation. Only a,b-unsaturated aliphatic
carbonyl compounds could be employed as good sub-
strates, giving good yields and high enantioselectivi-
ties while a,b-unsaturated aromatic aldehydes or ke-
tones afforded only traces of the Michael adducts.[8] It
is also noteworthy that some chiral purine bases with
aromatic substituents, for example, (R)-HMBA, were
found to exhibit more potent inhibition of adenosine
deaminase than the corresponding enantiomer (Fig-
ure 1).[5c] In order to further demonstrate the generali-
ty and use of our organocatalyzed aza-Michael reac-
tion between purine bases and a,b-unsaturated
enones, other enones such as a,b-unsaturated aromat-
ic enones were chosen as substrates in the developed
reaction. With all these considerations, we turned our
Entry
Catalyst
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
3a
3d
3e
3f
3a
3a
3a
3a
3a
72
96
96
96
72
72
72
72
72
49
38
42
39
53
49
53
59
52
52 (S)[d]
46 (R)[d]
59 (S)[d]
26 (R)[d]
70 (S)[d]
67 (S)[d]
73 (S)[d]
77 (S)[d]
87 (S)[d]
5[e,f]
6[e,g]
7[e,h]
8[e,i]
9[e,i,j]
[a]
Unless otherwise noted, reactions were carried out by
using 6-chloro-9H-purine 1a (0.1 mmol, 1.0 equiv.) and
chalcone 5a (0.15 mmol, 1.5 equiv.) in toluene (1 mL)
with 20 mol% catalyst and 40 mol% PhCO2H at room
temperature.
Isolated yields.
Determined by HPLC analysis.
The absolute configuration was determined by compari-
son with the literature.
10 mol% catalyst was used.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
40 mol% Boc-l-proline was used.
10 mol% Boc-l-proline was used.
20 mol% Boc-l-proline was used.
30 mol% Boc-l-proline was used.
[j]
Reaction was conducted at 08C.
attention to the possibility of employing trans-chal- loading revealed that the enantioselectivity climbed
cone 5a in an aza-Michael reaction with 6-chloro-9H- to the summit when 30 mol% Boc-l-proline was
purine 1a catalyzed by the chiral amines 3 (Table 3). added (Table 3, entry 8, 77% ee, TS-2 in the Support-
Gratifyingly, the desired aza-Michael reaction oc- ing Information). On lowering the temperature to
curred, affording moderate yields and enantioselectiv- 08C, a great improvement in enantioselectivity was
ities (Table 3, entries 1–4, 38–49% yield, 26–59% ee). observed albeit with lower yield (Table 3, entry 9,
The catalyst 3d which was the optimal catalyst for 52% yield, 87% ee).
aza-Michael addition of aliphatic enones, however,
Subsequent study probed the generality of the aza-
gave only 38% yield and 46% ee (entry 2). Poor re- Michael addition focusing upon variation of chalcones
gioselectivity was obtained when catalyst 3e was used, (5) and purine bases (1). Table 4 shows that a wide
although a much better ee was afforded (entry 3, 59% range of aromatic a,b-unsaturated enones with elec-
ee).[10] So quinine-derived chiral primary amine 3a tron-donating and electron-withdrawing groups were
giving exclusively the N-9 adduct, was chosen for fur- compatible under the optimized reaction conditions,
ther optimization of the reaction. Then the catalyst affording high to excellent enantioselectivities and
loading and acidic additives as co-catalysts were in- moderate yields (Table 4, entries 1–8, 46–58% yield,
vestigated. When the catalyst loading was decreased 80–93% ee). The substitution pattern of R1 at the
to 10 mol%, fortunately, a significant improvement in ortho, meta or para position was observed to have no
enantioselectivity was seen (TS-2 in the Supporting significant effect on the enantioselectivity (entries 4–
Information, 64% ee). After testing several acidic ad- 6). Purine bases containing electron-donating or elec-
ditives able to enhance both reactivity and selectivity, tron-withdrawing substituents at C-6 were also readily
Boc-l-proline as a chiral acid was employed with the tolerated, thus giving exclusively N-9 adducts in good
best results in terms of stereoselectivity (Table 3, yields and high enantioselectivities (entries 9–12, 51–
entry 5, 70% ee). Further investigation of the additive 63% yield, 83–94% ee). Despite moderate yields in
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Organocatalytic Enantioselective Aza-Michael Addition of Purine Bases
Table 4. Substrate scope for organocatalytic aza-Michael of a, b-unsaturated aromatic ketones 5 with purine bases 1.[a]
Entry
X
R1
R2
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OBn
SMe
NHBoc
Br
H
H
H
H
H
H
H
4-Cl
4-OMe
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
52
49
53
55
46
50
58
52
60
63
51
59
87
83
83
80
81
82
93
85
94
88
85
83
4-Me
4-F
4-Cl
2-Cl
3-Cl
H
H
H
H
H
9
10
11
12
H
H
H
6j
6k
6l
H
[a]
Unless otherwise noted, reactions were carried out by using purine bases 1 (0.1 mmol, 1.0 equiv.) and enones 5
(0.15 mmol, 1.5 equiv.) in toluene (1 mL) with 10 mol% catalyst 3a and 30 mol% Boc-l-proline for 72 h at 08C.
Isolated yields.
Determined by HPLC analysis.
[b]
[c]
the presence of this catalyst system, to the best of our were respectively esterified with (S)-methoxyphenyl-
knowledge, it is the first successful example of the acetic acid [(S)-MPA] to furnish 12 and 13. The abso-
enantioselective aza-Michael reaction of purine bases
to aromatic a,b-unsaturated enones, which provides
a new direct method to design other chiral purine in-
hibitors with enhanced inhibitory properties.
With the successful strategy as described above, the
transformations of the target adducts into non-natural
nucleoside molecules that are similar to (+)-(2S,3R)-
EHNA and (R)-PMPA were performed. Aza-Michael
addition of 1a to 2f under the optimized conditions
provided 4f in 88% yield and 94% ee. Reduction of
4f by NaBH4 gave syn-(2S,4R)-7 (58% yield, 89% ee)
and anti-(2R,4R)-8. Finally ammonification of 7 led to
the (+)-(2S,3R)-EHNA analogue 9 (Scheme 2). Addi-
tion of 1a and 2b gave the adduct 4b in 88% yield
and 93% ee which was readily reduced by NaBH4, af-
fording syn-(2S,4R)-10 (50% yield, 86% ee) and anti-
(2R,4R)-11. The sequential esterification and ammo-
nification afforded the desired (R)-PMPA analogue
12 (Scheme 3). This is the unprecedently most suc-
cessful strategy for the highly enantioselective synthe-
sis of these chiral non-natural nucleoside analogues
employing achiral a,b-unsaturated ketones.
The assignment of the absolute configuration of the
diastereomeric pairs (7, 8 and 10, 11) was achieved by
the Trost model,[11] which is based on the chemical
shift differences in the NMR spectra between the two
diastereomers. Taking compounds 10 and 11, for in-
stance, after chromatographic separation, 10 and 11 Scheme 2. Synthesis of the (+)-(2S,3R)-EHNA analogue 9.
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Hao Wu et al.
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Table 5. Chemical shift data of the diastereomeric pair of 12
and 13.[a]
Entry
Group
d (12)[b]
d (13)[b]
Dd[b]
1
2
3
4
5
6
7
1-CH3
5-CH3
1.28
1.37
2.06-2.14
2.20-2.29
5.05
1.12
1.60
2.14-2.20
2.32-2.44
5.06
0.16
0.23
0.08
0.12
0.01
0.41
0.05
3-CH2(H1)
3-CH2(H2)
4-CH
8H-(adenine)
2H-(adenine)
7.68
8.70
8.09
8.75
[a] 1H NMR (400MHz, CDCl3).
[b]
d in ppm.
Scheme 3. Synthesis of the (R)-PMPA analogue 12.
lute configuration of 12, 13 and hence syn-10, anti-11
1
were deduced from the H NMR spectrum of the (S)-
MPA esters (Scheme 4, Table 5). The signals of the
substituents under the shielding cone are moved up-
field.[12] Accordingly, the combination of structural
analysis and chiral HPLC led to the conclusion that
the aza-Michael adducts reduced by NaBH4 gave the
chiral alcohol syn-(2S,4R)-10 and anti-(2R,4R)-11.
To account for the stereochemical outcomes of the
aza-Michael addition, two plausible transition state
models are proposed in Scheme 5. (i) When the chiral
Scheme 5. Proposed transition-states I and II.
bifunctional thiourea–primary amine 3d was used 3d yielded the ketiminium cation with enone 2. Mean-
(Scheme 5, TS-I), the primary amine of the catalyst while, the exclusive N-9 regioselectivity indicated that
Scheme 4. Determination of absolute configuration of syn-(2S,4R)-10 and anti-(2R,4R)-11.
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Organocatalytic Enantioselective Aza-Michael Addition of Purine Bases
151.42, 151.14, 146.02, 132.27, 53.49, 46.75, 35.31, 30.24,
the N-9 and N-3 position in the tautomeric form (N-
7) of purine formed hydrogen bonds with the thiourea
moiety to orient the purine to attack the ketiminium
cation (Table 2, entry 16). (ii) When the chiral bifunc-
tional thiourea–primary amine 3a was used for the re-
action of chalcone (Scheme 5, TS-II), the ketiminium
cation formed between 3a and chalcone 5a might
adopt a trans conformation. Meanwhile, a hydrogen
bond could be formed from the bridgehead nitrogen
of 3a and the NH group of the tautomeric form (N-7)
of purine to produce concerted communication.
In conclusion, the unprecedented asymmetric orga-
nocatalytic aza-Michael addition of purine bases to a,
b-unsaturated ketones has been developed, affording
Michael adducts in moderate to high yields (up to
96% yield) and high to excellent enantioselectivities
(up to >99% ee). A wide range of a,b-unsaturated
enones ranging from aliphatic to aromatic enones
were both tolerated to this process, generally demon-
strating good reactivity, regioselectivity and enantio-
selectivity. The aromatic a,b-unsaturated ketones in-
cluding aromatic b-substituted enones were first suc-
cessfully employed as Michael acceptors in this aza-
Michael process. This methodology offers several ad-
vantages, such as mild reaction condition, no need to
use toxic and expensive organometallic complexes
and easily accessible catalyst system. Meanwhile, this
first successful protocol for highly enantioselective
synthesis of chiral acyclonucleosides analogues from
achiral a,b-unsaturated ketones provides a new access
to optical active non-natural nucleosides. Further
studies into expanding the application of this ap-
proach to synthesize more promising candidates for
acyclonucleosides as well as the biological evaluation
of these compounds are currently underway.
19.43, 13.35; HR-MS: m/z= 267.1005, calcd. for
C12H15ClN4O [M+H]+: 267.1007; HPLC (Chiralpack AD, 2-
propanol/hexane=6/94, flow rate 1.2 mLminÀ1, l=254 nm):
t
major =16.521 min, tminor =25.731 min.
General Procedure for Aza-Michael Addition of
Purine Bases to a,b-Unsaturated Aromatic Ketones
To a sample vial equipped with a magnetic stirring bar was
added catalyst 3a (0.01 mmol, 10 mol%), Boc-l-proline
(0.03 mmol, 30 mol%) and toluene (1.0 mL), and the solu-
tion was stirred for 5 min at 08C. After addition of aromatic
enone 5 (0.15 mmol), the mixture was stirred for another
10 min. Then purine base 1 (0.1 mmol) was then added at
08C. The reaction was monitored by TLC after 72 h and the
resulting residue was purified by flash column chromatogra-
phy on silica (eluent: 5% methanol in dichloromethane) to
afford the desired product 6.
Compound (S)-6a: ee=87%; [a]2D5: 8.3 (c 0.2 in chloro-
1
form). H NMR (400 MHz, CDCl3): d=8.72 (s, 1H), 8.25 (s,
1H), 7.95 (d, J=7.6 Hz, 2H), 7.59 (m, 1H), 7.54–7.43 (m,
4H), 7.37 (m, 3H), 6.40 (dd, J=8.7, 5.1 Hz, 1H), 4.78 (dd,
J=18.0, 9.1 Hz, 1H), 3.93 (dd, J=18.1, 5.0 Hz, 1H);
13C NMR (101 MHz, CDCl3): d=195.58, 151.70, 151.24,
145.42, 137.95, 135.90, 133.93, 132.23, 129.29, 128.96, 128.86,
128.13, 127.13, 56.92, 41.93; HR-MS: m/z=363.1010, calcd.
for C20H15ClN4O [M+H]+: 363.1007; HPLC (Chiralpack
AD, 2-propanol/hexane=10/90, flow rate 1.2 mLminÀ1, l=
254 nm): tmajor =31.993 min, tminor =26.491 min.
Acknowledgements
Generous financial support by the National Basic Research
Program of China (973 Program: 2010CB833300) and the
Key Laboratory of Elemento-Organic Chemistry is gratefully
acknowledged.
Experimental Section
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