Asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael-Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates

Article abstract of DOI:10.1016/j.tetlet.2011.12.114

We developed a novel method for the asymmetric synthesis of highly functionalized γ-lactams through an organocatalytic aza-Michael-Michael reaction cascade using fumaric acid amide esters as multi-reactive substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of γ-lactams with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2011.12.114

Tetrahedron Letters 53 (2012) 1245–1248
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of highly functionalized
c-lactams through an
organocatalytic aza-Michael–Michael reaction cascade using fumaric acid
amide esters as multi-reactive substrates
⇑
Takuya Yokosaka, Akinari Hamajima, Tetsuhiro Nemoto, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed a novel method for the asymmetric synthesis of highly functionalized c-lactams through an
organocatalytic aza-Michael–Michael reaction cascade using fumaric acid amide esters as multi-reactive
Received 5 December 2011
Revised 22 December 2011
Accepted 26 December 2011
Available online 10 January 2012
substrates. Using chiral primary or secondary amine organocatalysts, we obtained two types of -lactams
c
with three contiguous chiral centers in moderate to good yield with excellent enantioselectivity and
diastereoselectivity.
Ó 2012 Published by Elsevier Ltd.
Keywords:
Asymmetric synthesis
Cascade catalysis
Lactam
Organocatalyst
Michael reaction
Asymmetric cascade catalysis is an attractive method in modern
organic synthesis that allows for the rapid and efficient construc-
tion of complex chiral molecules from relatively simple starting
materials in a one-pot process, while minimizing cost and waste.1
Various asymmetric cascade reactions have been reported using
single-catalyst systems,2 as well as multi-catalyst systems.3 Among
the reactions reported to date, secondary amine-catalyzed asym-
metric C–C bond forming reaction cascades through sequential
iminium/enamine catalysis are most impressive examples in the
field. Using such cascade process, densely functionalized reaction
products bearing more than three contiguous stereocenters have
been produced in a highly enantioselective manner.4
pounds as their reaction partners would afford 3,4,5-trisubstituted
-lactams stereoselectively (Scheme 1). Herein we report an asym-
metric synthesis of highly functionalized -lactams through an
organocatalytic aza-Michael–Michael reaction cascade using fuma-
ric acid amide esters as multi-reactive substrates.
We first examined aza-Michael–Michael reaction cascade using
N-tosyl fumaric acid amide ester derivative 1 and trans-cinnamal-
dehyde 2 in the presence of (S)-diphenylprolinol trimethylsilyl
ether (S)-4 as a catalyst (Scheme 2(i)).6 Although the experiments
c
c
Functionalized
various natural products, biologically active compounds, and phar-
maceuticals. In addition, -lactams are useful synthetic precursors
c-lactams are ubiquitous structural motifs in
c
of pyrrolidine derivatives. These features have led to extensive ef-
forts focused on the development of an efficient method for the
stereoselective synthesis of functionalized
a novel method of synthesizing -lactams using asymmetric cas-
c
-lactams.5 To develop
c
cade catalysis, we envisioned that fumaric acid amide ester deriv-
atives bearing both nucleophilic and electrophilic sites in a single
molecule could be suitable building blocks. The application of such
compounds to a chiral amine-catalyzed asymmetric aza-Michael–
Michael reaction cascade using
a,b-unsaturated carbonyl com-
⇑
Corresponding author. Tel./fax: +81 43 226 2920.
E-mail address: hamada@p.chiba-u.ac.jp (Y. Hamada).
Scheme 1. Cascade reaction using fumaric acid amide esters as multi-reactive
substrates.
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.12.114

1246
T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248
through the retro-Michael reaction. In practice, the ratio of the ob-
tained mixture improved to 85:9:6 by treatment with K2CO3 in
ethanol (Reaction (B)). Because of the instability of the obtained
aldehydes, the overall yield of this reaction process was deter-
mined after converting into the corresponding alcohol, such as
8aa (Reaction (C)) (53% yield in 3 steps). Chiral HPLC analysis re-
vealed that the enantiomeric excess of 8aa was 99% ee. The relative
stereochemistry of 8aa was determined by NOE experiments, and
the absolute stereochemistry of 8aa (3S,4S,5S) was unambiguously
determined by transforming it into the known compound.8,9
The promising results of the feasibility study led us to optimize
the reaction conditions (Table 1). We first screened chiral amine
catalysts 4 and 9–11 (entries 1–4). Chiral amine catalyst 4 was
the best for chemical yield and enantiomeric excess. Less satisfac-
tory results were obtained using more acidic additives such as ben-
zoic acid (entry 5). There was a slight improvement in the yield and
diastereomeric ratio when the reaction was performed at 40 °C un-
der diluted reaction conditions (entries 6, 7). The best results were
obtained when the reaction was performed in the absence of acetic
acid (67% yield in 3 steps) (entry 8).
Having established the optimized conditions, we examined the
scope and limitations of the developed cascade reaction (Table 2).
When b-aryl
a,b-unsaturated aldehydes were utilized as sub-
strates, the aza-Michael–Michael reaction cascade proceeded at
40 °C in the presence of 20 mol % of (S)-4, providing a mixture of
chiral
diastereomeric mixtures, followed by the reduction of their alde-
hydes, afforded the corresponding -lactams in moderate to good
c-lactams. Base-promoted epimerization of the obtained
c
overall yield with high stereoselectivity. Substrates involving an
electron-donating group on the aromatic ring tended to result in
a higher yield (entries 2–4), compared with those bearing an elec-
tron-withdrawing group on the aromatic ring (entries 5–8), or a
Scheme 2. Feasibility study of organocatalytic aza-Michael–Michael reaction
cascade using trans-cinnamaldehyde 2a with fumaric acid amide esters 1 and 3a.
substrate with a hetero-aromatic ring (entry 9). b-Alkyl a,b-unsat-
urated aldehydes were also applicable to this cascade reaction pro-
cess. When crotonaldehyde 2j and 3-benzyloxycarbamoyl-acrylic
acid ethyl ester 3b were utilized as the substrates, the correspond-
were performed under several reaction conditions, all reactions
gave complex mixtures.7 To increase the nucleophilicity of the
amide nitrogen, hydroxylamine derivative 3a was selected as the
substrate (Scheme 2(ii)). Using 20 mol % of (S)-4 and 20 mol % of
acetic acid, the target reaction cascade proceeded at room temper-
ing c-lactams were obtained in a 49% overall yield with high dia-
stereoselectivity and enantioselectivity (entry 10). On the other
hand, there was a decreased reactivity and selectivity when
3-cyclohexyl-2-propenal 2k was used (entry 11).10
The satisfactory results of the asymmetric synthesis of function-
alized c-lactams using a,b-unsaturated aldehydes prompted us to
ature to give a diastereomeric mixture of
c-lactam derivatives
(Reaction (A)). Among the four possible diastereomers, compound
5aa was formed as the major isomer, and isomers 6aa and 7aa
were also detected in 1H NMR analysis (5aa:6aa:7aa = 68:16:16).
Based on the structure of the reaction products, the diastereomeric
ratio was expected to change under thermodynamic control
apply cyclohexenone 12 to the present sequential reaction process
(Table 3). We first tried an aza-Michael–Michael reaction cascade
Table 1
Optimization of the reaction conditions
Entry
Catalyst
Additive
Conc. (M)
Temp.
Time (h)
Yielda (%)
Ratio (6aa: sum of other isomers)b
Ee (% ee)c
1
2
3
4
5
6
7
8
(S)-4
(S)-9
(S)-10
(S)-11
(S)-4
(S)-4
(S)-4
(S)-4
AcOH
AcOH
AcOH
AcOH
PhCOOH
AcOH
AcOH
—
0.2
0.2
0.2
0.2
rt
rt
rt
rt
rt
rt
40 °C
40 °C
22
22
43
30
14
26
35
35
53
49
19
85:15
86:14
—
99
98
—
No reaction
—
—
0.2
28
50
57
67
73:27
92:8
92:8
91:9
98
98
99
99
0.05
0.05
0.05
a
b
c
Isolated yield of the mixture of diastereomers in 3 steps.
Determined by 1H NMR analysis.
Enantiomeric excess of the major isomer 8aa, which was determined by chiral HPLC analysis.

T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248
1247
Table 2
Scope and limitations
Entry
Substrate
Product
Time (h)
Yielda (%)
Ratiob
Ee (% ee)c
1
2
3
4
5
6
7
8
9
2a/3a
2b/3a
2c/3a
2d/3a
2e/3a
2f/3a
2g/3a
2h/3a
2i/3a
2j/3b
2k/3b
8aa
8ba
8ca
8da
8ea
8fa
8ga
8ha
8ia
35
31
39
47
34
67
17
67
82
17
82
67
86
70
80
48
55
48
46
55
49
49
91:9
90:10
91:9
99
99
98
98
99
98
98
96
94
98
91
94:6
86:14
90:10
91:9
91:9
89:11
92:8
10
11
8jb
8kb
80:20
a
Isolated yield of the mixture of diastereomers in 3 steps.
b
c
Ratio = major isomer:sum of other isomers. The ratios were determined by 1H NMR analysis.
Enantiomeric excess of the major isomers, which were determined by chiral HPLC analysis.
Table 3
Catalytic asymmetric aza-Michael–Michael reaction cascade using cyclohexenone 12 with 3b
Entry
Catalyst
Additive
Conc. (M)
Time (h)
Base
Yielda (%)
Ratio (13:14)b
Ee (% ee)c
1
2
3
4
5
6
7
8
(S)-4
15
15
15
15
15
16
16
—
—
0.1
0.1
0.1
0.1
35
64
19
54
30
40
47
47
—
No reaction
—
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DBU
55
56
37
74
71
70
86
95:5
97:3
94:6
97:3
96:4
96:4
96:4
84
86
51
87
89
91
91
PhCOOH
CF3COOH
AcOH
AcOH
AcOH
AcOH
0.1
0.05
0.05
0.05
a
b
c
Isolated yield of the mixture of diastereomers in 2 steps.
Ratio = major isomer:sum of other isomers. The ratios were determined by 1H NMR analysis.
Determined by chiral HPLC analysis.
using 3b and 12 in the presence of (S)-4 as the organocatalyst. The
desired bicyclic adducts, however, were not obtained at all. Catalyst
screening revealed that a primary amine organocatalyst 15 success-
fully promoted the target reaction cascade, affording a diastereo-
meric mixture of bicyclic lactams. Epimerization of the obtained
mixture was performed analogously by treating with potassium
reaction was preformed using chiral amine catalyst 16 under di-
luted reaction conditions (entry 7). The yield was improved up to
86%, when 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used to
replace potassium carbonate in the epimerization step (entry 8).
Other cyclic enones were also applied to this cascade process
(Scheme 3). When cyclic enone 17 with a methyl group on the b-po-
sition was used as the substrate, the corresponding bicyclic adducts
bearing a quaternary stereocenter were accessible with high diaste-
reoselectivity (18:19 = 92:8) and enantioselectivity (ee of 18: 90%
ee). Although the isolated yield was 32%, the product was obtained
in good conversion (74% yield based on the recovered starting
material). The same cascade process using cyclopentenone 20 was
carbonate in ethanol, affording bicyclic c-lactams 13 (84% ee) and
14 in a 55% yield (diastereomeric ratio 13:14 = 95:5) (entry 2).11
The relative stereochemistries of 13 and 14 were determined by
NOE experiments.8 Acetic acid was the most suitable acidic additive
in terms of chemical yield and stereoselectivity (entry 5). Further-
more, the enantiomeric excess increased to 91% ee when the

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T. Yokosaka et al. / Tetrahedron Letters 53 (2012) 1245–1248
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Scheme 3. Catalytic asymmetric aza-Michael–Michael reaction cascade using
cyclic enones 17 and 20 with 3b.
also examined under the optimized reaction conditions. The corre-
sponding products were obtained in a 62% yield (dr. 21:22 = 62:38)
with 71% ee.8
In summary, we successfully developed a catalytic asymmetric
aza-Michael–Michael reaction cascade using fumaric acid amide
ester derivatives and
which provided chiral
a
,b-unsaturated aldehydes as substrates,
c
-lactams with three contiguous chiral cen-
ters in up to 86% overall yield with up to 99% ee (dr = up to 94:6).
The developed reaction cascade was also applicable to the synthe-
sis of chiral bicyclic c-lactams using cyclic enones as the reaction
partners (up to 86% overall yield, up to 91% ee (dr = 96:4)). To
the best of our knowledge, this is the first example of an asymmet-
ric cascade catalysis using fumaric acid amide ester derivatives as
multi-reactive substrates. Further studies are in progress to inves-
tigate the applications of this cascade catalysis to the synthesis of
natural products.
5. For recent selected examples of asymmetric synthesis of functionalized
c-
Acknowledgment
lactams, see: (a) Zhao, X.; DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2011, 133,
12466–12469; (b) Satoh, N.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011, 13,
3028–3031; (c) Nguyen, H.; Ma, G.; Gladysheva, T.; Fremgen, T.; Romo, D. J. Org.
Chem. 2011, 76, 2–12; (d) Bisol, T. B.; Bortoluzzi, A. J.; Sá, M. M. J. Org. Chem.
2011, 76, 948–962; (e) Gu, W.; Silverman, R. B. J. Org. Chem. 2011, 76, 8287–
8293; (f) Shen, A.; Liu, M.; Jia, Z.-S.; Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12,
5154–5157; (g) Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008, 5263–5268; (h)
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N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki, M. J. Org. Chem. 2006, 71,
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Chem. Soc. 2005, 127, 8974–8976.
This work was supported in part by a Grant-in Aid for Encour-
agement of Young Scientist (B) from the Ministry of Education, Cul-
ture, Sports, Science, and Technology, Japan.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.114.
6. For reviews on the asymmetric synthesis using chiral secondary amine
derivatives as organocatalysts, see: (a) Nielsen, M.; Worgull, D.; Zweifel, T.;
Gschwend, B.; Bertelsen, S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632–649;
(b) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178–2189; (c)
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47, 6138–6171; (d) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922–948; (e)
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7. TLC analysis of the reaction mixture indicated that the decomposition of 1
occurred under the reaction conditions.
8. For the structural determination of the reaction adducts, see the
Supplementary data.
9. The relative stereochemistry of the second major diastereomer was determined
by NOE experiment of compound 6ea. See the Supplementary data for the
detail.
References and notes
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10. Reactions using b-aryl
withdrawing group on the aromatic ring, as well as b-alkyl
aldehydes, gave more complex mixtures in the stage of asymmetric aza-
Michael–Michael reaction cascade, compared with those using b-aryl ,b-
a
,b-unsaturated aldehydes with an electron-
a
,b-unsaturated
a
unsaturated aldehydes with an electron-donating group on the aromatic ring.
This would result in the lower isolated yield.
11. Among the four possible diastereomers, only 13 and 14 could be detected in
the 1H NMR analysis of the crude sample.