Asymmetrie synthesis of 3-amino-δ-lactams and benzo [a] quinolizidines by catalytic cyclization reactions involving azlactones

Article abstract of DOI:10.1002/chem.200900814

The first asymmetric three-component formal [4+2] cycloaddition reaction of azlactones, cinnamaldehydes, and primary amines were disclosed. Anisidine 3, 100mg 4A, and catalyst 5d was added chloroform under argon to a tube charged with aldehyde 2. The solu

Full text of DOI:10.1002/chem.200900814

COMMUNICATION
DOI: 10.1002/chem.200900814
Asymmetric Synthesis of 3-Amino-d-lactams and Benzo[a]quinolizidines by
Catalytic Cyclization Reactions Involving Azlactones
Jun Jiang,[b, c] Jian Qing,[a] and Liu-Zhu Gong*[a]
3-Amino-d-lactams, 3-aminopiperidinones, and 3,4-dihy-
dropyridinone are important nitrogenous structural motifs
in organic synthesis. Benzo[a]quinolizidine structural motifs
have been found in numerous alkaloids that have shown
potent biological activity as exemplified by schulzeine A.[1]
Peptide mimic studies have found that the incorporation of
Currently, the synthesis of such structural motifs has been
restricted to chiral auxiliary-induced asymmetric synthesis
and to chiral resolution.[2–4,6] Catalytic enantioselective
methods to access these compounds would be highly valua-
ble in both pharmaceutical and organic chemistry, but
remain unknown.
Azlactones possessing three
reactive sites at C-2, C-4, and
C-5, of which both C-2 and C-5
are electrophilic, while C-4 is
nucleophilic, have been versa-
tile reactants for the develop-
ment of synthetically important
reactions.[7] For instance, these
azlactones could undergo cyclo-
d-lactams into peptides led to a family of conformationally
constrained surrogates that showed enhanced biological ac-
tivities in comparison with their parent molecules.[2] 3-Ami-
nopiperidine, which can be obtained from the reduction of
3-amino-d-lactams, has served as a core structural element
commonly appearing in biologically active molecules.[3–5] For
example, alogliptin can be used for the treatment of diabe-
tes,[4] and CP-690550 serves as a Janus kinase 3 (JAK3) in-
hibitor, an immunosuppressive agent exhibiting potent ef-
fects in preclinical transplantation and arthritis models.[5]
addition at C-4 and C-5 with 1,3-azabutadienes, directly pro-
viding racemic 3,4-dihydropyridinones.[8] However, no enan-
tioselective versions of this reaction have yet been disclosed.
In view of the synthetic significance of chiral 3,4-dihydropyr-
idinones and the unavailibility of enantioselective methods
to access them, we became interested in the asymmetric cy-
cloaddition of azlactones with 1,3-azabutadienes. Herein, we
report the first asymmetric catalytic three-component cycli-
zation reaction of cinnamaldehydes, primary amines, and
azlactones by using chiral Brønsted acid catalysts, which
yields dihydropyridinones with high enantioselectivity. The
use of this reaction in the facile synthesis of benzo[a]quinoli-
zidine derivatives with high optical purity is also described.
Inspired by elegant findings of Brønsted acid catalysis,[9]
we have established a cyclization reaction of 1,3-dicarbonyls
with 1,3-azadiene catalyzed by phosphoric acids.[10] The
phosphoric acid was considered to protonate 1,3-azadiene,
generating an active iminium species and thereby lowering
the LUMO of 1,3-azadiene, as indicated in asymmetric
counteranion directed catalysis.[11] Additionally, the Brønst-
ed acid is also presumably able to activate the azlactone
through a hydrogen bond. This presumed dual activation
strategy (Scheme 1, I) prompted us to consider that chiral
phosphoric acids might be able to control the stereochemis-
try of the cycloaddition of 1,3-azabutadienes with azlactones
[a] J. Qing, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
Fax : (+86)551-3606266
E-mail: gonglz@ustc.edu.cn
[b] J. Jiang
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences (CAS)
Chengdu, 610041 (China)
[c] J. Jiang
Graduate School of Chinese Academy of Sciences, Beijing (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900814.
Chem. Eur. J. 2009, 15, 7031 – 7034
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7031

tocol was shown to tolerate a
wide scope of cinnamaldehydes.
All reactions of the cinnamal-
dehydes bearing electronically
deficient substituents provided
3-amino-3,4-dihydropyridinones
in high yields and enantioselec-
tivities (Table 2, entries 1–8 and
10–12). Electronically rich 2-
methoxy-cinnamaldehyde un-
derwent a smooth cyclization
reaction but with a moderate
Scheme 1. Brønsted acid catalyzed formal [4+2] cycloaddition.
Table 1. Optimization of the cyclization reaction.[a]
via the proposed pathway shown in Scheme 1. However, the
amidation of azlactones with an amine, which subsequently
proceeded via intermediates I’ and II’ to generate 4’, com-
peted with the cyclization reaction. Moreover, the uncata-
lyzed cyclization reaction of 1,3-azadienes with azlactones
also occurred,[8] eroding the enantioselectivity. Therefore,
we initially believed that developing highly enantioselective
three-component cyclization reactions would be a challeng-
ing task.
As we anticipated, the three-component reaction of 4-
methyl-2-phenyloxazolone with p-nitrocinnamaldehyde (2a)
and p-anisidine (3a) progressed smoothly to afford 4a in
38% yield, along with an amidation product 4a’ in 33%
yield, in the absence of any promoter (Table 1, entry 1).
However, adding catalyst 5a accelerated the amidation reac-
tion to furnish 4a’ in 79% yield, while affording a small
amount of 4a (Table 1, entry 2). Moreover, even the use of
Entry
Catalyst
Solvent
Temp.
[oC]
Yield of
Yield of
ee of 4
4 [%][b,c]
4ꢀ [%][b]
[%][e]
1
2
3
4
5
6
7
8
none
5a
5a
5a
5b
5c
5d
5d
5d
5d
5d
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
toluene
THF
25
25
25
0
0
0
0
0
0
0
38[d]
7[d]
44
27
40
44
80
60
58
51
71
33
79
28
38
20
10
–
–
4
3
–
–
–
24
28
70
55
80
70
67
73
90[f]
9
10
11
CHCl3
0
[a] A solution of p-nitrocinnamaldehyde (0.26 mmol), p-anisidine (3a)/m-
anisidine (3b) (0.2 mmol), 4-methyl-2-phenyloxazolone (0.3 mmol), 4ꢁ
sieves (100 mg), and a catalyst in a solvent (2 mL) was stirred for 72 h.
[b] Yield of isolated product. [c] Single diastereomer was obtained.
[d] The reaction was conducted in the absence of 4ꢁ sieves for 12 h.
[e] The ee was determined by HPLC. [f] The data were observed for 4b.
the preformed 1,3-azadiene was unable to inhibit the amida-
tion side reaction.[12] Gratifyingly, removal the trace amount
of water generated from the initial condensation and the
solvent were found to be beneficial to the cyclization reac-
tion. As such, the addition of 4 ꢁ molecular sieves facilitat-
ed the generation of 4a in 44% yield with 24% ee (Table 1,
entry 3). An enhanced ee was obtained for 4a at 08C but at
the expense of the yield (Table 1, entry 4). An evaluation of
different phosphoric acids indicated that not only did 5d
provide the best results in terms of yield and stereochemical
outcome, but also nearly entirely inhibited the amidation
side reaction (Table 1, entries 4–7). A preliminary survey of
the solvents found that chloroform was most suitable for
this reaction (Table 1, entries 7–10). The use of m-anisidine
as a reaction component led to formation of 4b in 71%
yield and with 90% ee (Table 1, entry 11).
enantiomeric excess (Table 2, entry 9). 1-Naphthalenylacry-
laldehyde also participated in a good cyclization (Table 2,
entry 13). The reaction of 4-ethyl-2-phenyloxazolone (1b)
afforded 3-amino-3,4-dihydropyridinones in high yields and
enantioselectivities (Table 2, entries 14 and 15). Notably,
other 2-phenyloxazolones bearing a sterically bulkier sub-
stituent at C-4, for example, 1c–e, could also participate in
the three-component reaction with high enantioselectivities
(Table 2, entries 16–18). The expansion of the protocol to
other anilines gave the desired products in ee values ranging
from 84–91% ee (Table 2, entries 19–21). Unfortunately, ali-
phatic enals failed to give the desired products. The stereo-
chemistry of 4m was confirmed by an X-ray structure analy-
sis (Figure 1).
More importantly, we found that substituted aryl ethyla-
mines were good reaction partners. For example, the aryl
ethylamine 6 participated in smooth cyclization reactions
with 4-methyl-2-phenyloxazolone (1a) and various cinna-
maldehydes (2) under the catalysis of 20 mol% of 5d, to
The generality of the cyclization reaction with respect to
either a,b-unsaturated aldehydes (2) or azlactones (1) was
explored under the optimized conditions (Table 2). The pro-
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Asymmetric Synthesis of 3-Amino-d-lactams and Benzo[a]quinolizidines
COMMUNICATION
Table 2. Scope of the cyclization reaction.[a]
Table 3. Synthesis of benzo[a]quinolizidine derivatives.[a]
Entry R1 (1)
R2 (2)
3
4
Yield
ee
[%][b,c] [%][d]
Entry Product (8), Yield,[b,c] %ee[d] Entry Product (8), Yield,[b,c] %ee[d]
1
2
3
4
5
6
7
8
Me (1a)
2-NO2C6H4 (2b)
2-NO2C6H4 (2b)
3-NO2C6H4 (2c)
2-CF3C6H4 (2d)
4-CF3C6H4 (2e)
2-BrC6H4 (2 f)
4-BrC6H4 (2g)
2-ClC6H4 (2h)
2-MeOC6H4 (2i)
3b 4c 80
3a 4d 81
3b 4e 71
3b 4 f 79
3b 4g 80
3b 4h 75
96
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
ethyl (1b)
ethyl (1b)
n-propyl (1c)
n-butyl (1d)
91[f]
84
88
85
84
80
1
2
4
5
3b 4i
3b 4j
73
72
80
9
3b 4k 76
81
62
10
11
12
13
14
15
16
17
18
19
20
21
2,4-(NO2)2C6H3 (2j) 3b 4l
94[g]
96
2,3-Cl2C6H3 (2k)
2,4-Cl2C6H3 (2l)
1-naphthyl (2l)
2-NO2C6H4 (2b)
2-NO2C6H4 (2b)
2-NO2C6H4 (2b)
2-NO2C6H4 (2b)
3b 4m 62
3b 4n 83
3b 4o 88
3b 4p 80
3a 4q 90
3b 4r 80
3b 4s 75
87
86
91[e]
85[e]
86[e]
85[e]
80[f,g]
84
MeS
N
(1e) 2-NO2C6H4 (2b)
3b 4t
62
Me (1a)
Me (1a)
Me (1a)
4-NO2C6H4 (2a)
2-NO2C6H4 (2b)
4-NO2C6H4 (2a)
3c 4u 73
3d 4v 81
3e 4w 71
90[f]
91
3
6
[a] Unless otherwise indicated,
a
solution of cinnamaldehyde
(0.26 mmol), anisidine (0.2 mmol), azlactone (0.3 mmol), 100 mg 4ꢁ
sieves, and 15 mol% 5d in CHCl3 (2 mL) was stirred at 08C for 72 h.
[b] Yield of isolated product. [c] A single diastereomer was obtained.
[d] The ee was determined by HPLC. [e] Using 20 mol% of 5d at 208C.
[f] Using 20 mol% of 5d at 08C. [g] The reaction mixture was stirred for
5 days.
[a] For the detailed Experimental Section, see Supporting Information.
[b] The yield refers to the overall isolated yield of two steps. [c] Unless
otherwise indicated, a single diastereomer was obtained. [d] Determined
by HPLC.
potent biological activity.[1] The utility of this methodology
was further demonstrated by the reduction of 4c with trie-
thylsilane in the presence of trifluoroacetic acid under mild
conditions, which yielded 3-amino-d-lactam 9 with 97% ee
(Scheme 2).
Scheme 2. Synthesis of 3-aminopiperidinones derivatives.
In conclusion, we have disclosed the first asymmetric
three-component formal [4+2] cycloaddition reaction of
azlactones, cinnamaldehydes, and primary amines.[14] Use of
a phosphoric acid derivative as the catalyst provided excel-
lent enantioselectivities of up to 96% ee for a wide range of
3-amino-3,4-dihydropyridinones. Importantly, this method is
highly useful in the synthesis of cyclic nitrogenous structural
motifs, such as benzo[a]quinolizidine derivatives, 3-amino-d-
lactams, and piperidinones, which appear in numerous natu-
ral and unnatural products that exhibit important biological
activities.
Figure 1. The X-ray crystal structure of 4m
give 7 in high yields. Treatment of these with trifluoroborane
led to clean Pictet Spengler type cyclization reactions, gener-
ating benzo[a]quinolizidine derivatives 8 in high overall
yields and with excellent enantioselectivities ranging from
90% to 97% ee (Table 3). Thus, this reaction provides an ef-
fective access to benzo[a]quinolizidine structural motifs,[13]
which would potentially be applicable in synthesizing impor-
tant analogues of numerous alkaloids that have shown
Chem. Eur. J. 2009, 15, 7031 – 7034
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www.chemeurj.org
7033

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Experimental Section
General procedure: To a tube charged with aldehyde 2 (0.26 mmol), ani-
sidine 3 (0.2 mmol), 100 mg 4ꢁ, and catalyst 5d was added chloroform
(1.5 mL) under argon. The solution was stirred for 30 min at room tem-
perature and then for another 10 min at 08C. Subsequently, azlactone 1
(0.3 mmol) in chloroform (0.5 mL) was added slowly at 08C. The result-
ing reaction mixture was stirred at 08C for three days (monitored by
TLC). The reaction mixture was purified by flash column chromatogra-
phy on silica gel (eluent: dichloromethane:ethyl acetate 50:1 to 30:1) to
yield pure products.
Acknowledgements
We are grateful for financial support from NSFC (20732006), MOST (973
program 2009CB25300), Ministry of Education, and CAS.
Keywords: aminolactams
·
asymmetric
catalysis
·
benzo[a]quinolizidine · cyclization · organocatalysis
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Received: March 30, 2009
Revised: May 17, 2009
Published online: June 16, 2009
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