Highly diastereo- and enantioselective Mannich reaction of lactones with N-Boc-aldimines catalyzed by bifunctional rosin-derived amine thiourea catalysts

Article abstract of DOI:10.1039/c000621a

A highly efficient diastereo- and enantioselective Mannich reaction of lactones with a variety of N-Boc-aldimines by using bifunctional rosin-derived amine thiourea catalysts was investigated for the first time, in general, affording the adducts bearing q

Full text of DOI:10.1039/c000621a

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Highly diastereo- and enantioselective Mannich reaction of lactones with
N-Boc-aldimines catalyzed by bifunctional rosin-derived amine thiourea
catalystswz
Xianxing Jiang,ab Dan Fu,a Gen Zhang,a Yiming Cao,a Luping Liu,a Jingjing Songa and
Rui Wang*ab
Received 11th January 2010, Accepted 29th April 2010
First published as an Advance Article on the web 17th May 2010
DOI: 10.1039/c000621a
A highly efficient diastereo- and enantioselective Mannich
reaction of lactones with a variety of N-Boc-aldimines by using
bifunctional rosin-derived amine thiourea catalysts was
investigated for the first time, in general, affording the adducts
bearing quaternary stereogenic centers with high levels of
enantio- and diastereoselectivity (up to 99% ee, and >20 : 1 dr).
during our recent efforts for expanding the synthetic utility of
this kind of rosin-derived amine thiourea,9 we wished that the
substrate scope could be extended to heterocyclic donors such
as lactones considering their potential versatility as chiral
building blocks.10 To the best of our knowledge, despite only
a few cases in the reported literature3g,11 when the Mannich
reaction of a-acetyl-g-butyrolactone to one or two aldimines
was achieved, a poor selectivity was observed without exception.
Furthermore, the use of lactones as nucleophiles in catalytic
asymmetric Mannich reaction have not yet been investigated
systematically, and we believe this represents a major challenge.
We postulated that the chiral tertiary amine-thiourea would
act in a bifunctional fashion (Scheme 2). The asymmetric
Mannich reaction of lactone 4a to N-Boc-aldimines might be
initiated, in the presence of a chiral tertiary amine, by activating
both N-Boc-aldimines and nucleophiles simultaneously to
generate ternary complex A, affording stereoselective products
by controlling the approach of nucleophiles to N-Boc-
aldimines. Herein, the catalytic asymmetric Mannich reaction
of several representative and useful lactones to a variety of
N-Boc-aldimines by using rosin-derived tertiary amine-thiourea
was investigated firstly, affording the products bearing
quaternary stereogenic centers with up to 99% ee, and
>20 : 1 dr. We present our preliminary results in this field.
During the initial elaboration of solvent and reaction
temperature, our investigation began by screening tertiary
amine-thiourea catalysts L1–L6 (Fig. 1) to evaluate their
ability to promote the Mannich reaction of a-acetyl-g-butyro-
lactone (4a) to N-Boc-aldimines (2a) in the presence of
15 mol% of ligand loading at ꢀ60 1C in toluene (Table 1).
These results indicated that a dramatic ligand effect on yield
and stereoselectivity was observed. Although thiourea L1
provided high overall yield and excellent diastereoselectivity, poor
enantioselectivity was obtained for the major diastereomer of
5a (Table 1, entry 1). Tertiary amine-thiourea L2, which
provided the best results in terms of yield and stereochemical
outcome, was found to be the most promising catalyst for the
The asymmetric construction of chiral quaternary stereocenters
on highly functionalized organic molecules represents a
considerable challenge in modern organic synthesis.1 The
direct asymmetric Mannich-type reaction2 of N-protected-
aldimines, to date, has become one of the most important
and versatile reactions for the construction of chiral amine-
containing synthons bearing quaternary carbon centers,3 and
the development of asymmetric catalytic protocols in this field
of research remains a highly desirable goal. In recent years,
considerable effort has been devoted to the development of
efficient chiral catalysts for enantioselective Mannich reactions
and catalytic asymmetric Mannich reactions of aldehydes,
ketones,4 enolates and enolizable b-dicarbonyl compounds5
have been presented by several groups. We recently reported a
new class of thiourea bifunctional catalysts6 based on rosin,
which have successfully been applied to the construction of
contiguous stereogenic centers containing an asymmetric
quaternary carbon by the Michael reaction of a-substituted
b-ketoesters to nitroalkenes.7 Encouraged by these elegant
advances, we found that this rosin-derived bifunctional thiourea
was also revealed to be highly efficient for the construction of
contiguous stereogenic centers containing an asymmetric
quaternary carbon under the Mannich-type reaction system,
and the excellent enantio- and diastereoselectivities were still
observed when the electrophiles were further extended to
N-Boc-aldimines (Scheme 1). In the context of our interest
in the construction of quaternary carbon stereocenters,7,8 and
a State Key Laboratory of Applied Organic Chemistry,
Institute of Biochemistry and Molecular Biology,
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, Lanzhou University, Lanzhou 730000, China.
E-mail: wangrui@lzu.edu.cn; Fax: (+86)-931-8911255
b Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Kowloon, Hong Kong.
E-mail: bcrwang@polyu.edu.h
w Dedicated to Professor Albert S. C. Chan on the occasion of his 60th
birthday.
z Electronic supplementary information (ESI) available: Experimental
details. CCDC 760713. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c000621a
Scheme 1 Catalytic asymmetric Mannich-type reaction of ethyl
cyclopentanone 2-carboxylate with N-Boc-aldimines.
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Table 1 Screening of tertiary amine-thiourea catalystsa
Entry
Catalyst
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7e
L1
L2
L3
L4
L5
L6
L2
88
86
65
Trace
55
72
>20 : 1
>20 : 1
>20 : 1
n.d.
3 : 1
4 : 1
46
91
73
n.d.
22
65
90
Scheme 2 Proposed mechanism for the asymmetric Mannich reaction
of lactones with N-Boc-aldimines catalyzed by a rosin-derived amine
thiourea catalyst.
58
>20 : 1
a
The reaction was conducted with a-acetyl-g-butyrolactone 4a
(0.12 mmol) and N-Boc-aldimines 2a (0.1 mmol) in toluene (1.0 mL) at
ꢀ60 1C for 12 h. Isolated yield. Determined by 1H NMR and
b
c
reaction (Table 1, entry 2). With the purpose of obtaining a
higher stereoselectivity, the reaction temperature was further
lowered. Notably, no enhancement in the enantioselectivity
was achieved with a significantly decrease in yield when the
reaction was carried out at ꢀ78 1C (Table 1, entry 7).
Next, we explored the scope of the asymmetric Mannich
reaction with respect to the lactones by using rosin-derived
tertiary amine-thiourea L2. As can be seen by the results
summarized in Table 2, the corresponding products 5a–8a
could be obtained with excellent diastereoselectivities. These
results indicated that the enantioselectivity was found to
depend significantly on the substituent R1 and the size of the
cycle of the starting lactone. The reactions of five cyclic
lactones bearing acetyl and propionyl groups as nucleophiles
furnished the desired product in high yields (86% and 82%,
respectively) with excellent enantioselectivities (91% and 90%,
respectively, entries 1 and 4). In contrast, the benzoyl-
substituted lactones gave low enantioselectivities (Table 2,
entries 2 and 3).
d
HPLC. The ee values were determined by HPLC, and the relative
and absolute configurations were determined by X-ray crystal data of
e
5g. The reaction was stirred at ꢀ78 1C.
Table 2 Variation of the lactonesa
Entry
4
Yield (%)b
drc
ee (%)d
1
4a
4b
4c
4d
(5a) 86
(6a) 72
(7a) 70
(8a) 82
>20 : 1
>20 : 1
>20 : 1
>20 : 1
91
57
30
90
2e
3f
4
We then investigated the generality of the protocol with
respect to N-Boc-protected aldimines under the optimized
reaction conditions. A range of substituted aromatic and hetero-
cyclic N-Boc-aldimines was first examined in the catalytic
a
The reaction was conducted with lactones (0.12 mmol) and
N-Boc-aldimines 2a (0.1 mmol) in toluene (1.0 mL) at ꢀ60 1C for
12 h. Isolated yield. Determined by 1H NMR and HPLC, the other
b
c
diastereomer was not observed by 1HNMR and HPLC. The ee
values were determined by HPLC, and the relative and absolute
d
e
configurations were determined by X-ray crystal data of 5g. The
f
reaction was stirred at 0 1C. The reaction was stirred at ꢀ15 1C.
Mannich-type reaction with lactone 4a (Table 3). It is seen that
a variety of aromatic N-Boc-aldimines bearing various types of
substituents underwent the reaction to afford the desired
products containing an asymmetric quaternary carbon in excellent
diastereoselectivities (>20 : 1) and high to excellent yields
(81%–92%, entries 1–9). Although a comparatively low
enantioselectivity was observed in para-Cl-substituted aromatic
aldimines (75% ee, entry 9), in general, the reactions afforded
high to excellent enantioselectivities (81%–99%). As expected,
the reactions of heterocyclic N-Boc-aldimines also proceeded in
>20 : 1 dr, high to excellent enantioselectivities (93% and 87%,
respectively) and high yields (80% and 81%, respectively, entries
10 and 11). The relative and absolute configurations of the
products were determined by X-ray crystal structure analysis of
5g (see the Supporting Informationz).
Fig. 1 Structure of thiourea catalysts.
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Table 3 Asymmetric Mannich reaction of lactone 4a with a variety of
N-Boc-aldiminesa
Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon,
New York, 1991, vol. 2, pp. 893–951.
3 Selected for recent examples, see: (a) X. Han, J. Kwiatkowski,
F. Xue, K.-W. Huang and Y. Lu, Angew. Chem., Int. Ed., 2009, 48,
7604; (b) Y. K. Kang and D. Y. Kim, J. Org. Chem., 2009, 74,
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J. Am. Chem. Soc., 2008, 130, 2170; (d) M. Hatano, T. Maki,
K. Moriyama, M. Arinobe and K. Ishihara, J. Am. Chem. Soc.,
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Y. Takemoto, Synthesis, 2007, 2571; (f) A. L. Tillman, J. Ye
and D. J. Dixon, Chem. Commun., 2006, 1191; (g) A. Ting, S. Lou
and S. E. Schaus, Org. Lett., 2006, 8, 2003; (h) Y. Hamashima,
N. Sasamoto, D. Hotta, H. Somei, N. Umebayashi and M. Sodeoka,
Angew. Chem., Int. Ed., 2005, 44, 1525.
4 Selected examples, see: (a) J. W. Yang, C. Chandler, M. Stadler,
D. Kampen and B. List, Nature, 2008, 452, 453; (b) H. Zhang,
S. Mitsumori, N. Utsumi, M. Imai, N. Garcia-Delgado,
M. Mifsud, K. Albertshofer, P. H. Y. Cheong, K. N. Houk,
F. Tanaka and C. F. III. Barbas, J. Am. Chem. Soc., 2008, 130,
875; (c) G. A. Cutting, N. E. Stainforth, M. P. John, G. Kociok-
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(d) H. Morimoto, G. Lu, N. Aoyama, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 9588; (e) J. Vesely,
Entry
R
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
Ph
(5a) 86
(5b) 82
(5c) 83
(5d) 89
(5e) 83
(5f) 92
(5g) 85
(5h) 85
(5i) 81
(5j) 80
(5k) 81
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
91
99
93
88
99
82
98
81
75
93
87
4-MePh
2-MePh
2-MeOPh
3-MeOPh
3-MePh
2-BrPh
2-FPh
4-ClPh
2-Thienyl
3-Furyl
9
10
11
R. Rios, I. Ibrahem and A. Cordova, Tetrahedron Lett., 2007, 48,
´
a
421; (f) T. Hashimoto and K. Maruoka, J. Am. Chem. Soc., 2007,
129, 10054; (g) B. M. Trost, J. Jaratjaroonphong and V. Reutrakul,
J. Am. Chem. Soc., 2006, 128, 2778; (h) S. Harada, S. Handa,
S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2005, 44,
4365; (i) A. Okada, T. Shibuguchi, T. Ohshima, H. Masu,
K. Yamaguchi and M. Shibasaki, Angew. Chem., Int. Ed., 2005,
44, 4564; (j) T. Kano, Y. Yamaguchi, O. Tokuda and K. Maruoka,
J. Am. Chem. Soc., 2005, 127, 16408; (k) D. Enders, C. Grondal,
M. Vrettou and G. Raabe, Angew. Chem., Int. Ed., 2005, 44, 4079.
5 Selected examples, see: (a) M. Sickert and C. Schneider, Angew.
Chem., Int. Ed., 2008, 47, 3631; (b) J. Itoh, K. Fuchibe and
T. Akiyama, Synthesis, 2008, 1319; (c) Y. Hamashima,
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Tetrahedron, 2007, 63, 8425; (e) K. Saruhashi and S. Kobayashi,
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Y. Mizuki, H. Ishitani and Y. Yamashita, Proc. Natl. Acad. Sci.
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K. Fuchibe, Angew. Chem., Int. Ed., 2004, 43, 1566.
The reaction was conducted with lactone 4a (0.12 mmol) and
N-Boc-aldimines (0.1 mmol) in toluene (1.0 mL) at ꢀ60 1C for
12 h. Isolated yield. Determined by 1H NMR and HPLC, the other
b
c
diastereomer was not observed by 1HNMR and HPLC. The ee
values were determined by HPLC, and the relative and absolute
configurations were determined by X-ray crystal data of 5g.
d
In summary, we have disclosed a highly efficient diastereo-
and enantioselective Mannich reaction of lactones with a
variety of N-Boc-aldimines catalyzed by bifunctional rosin-
derived amine thiourea catalysts, affording the adducts bearing
quaternary stereogenic centers with high levels of enantio- and
diastereoselectivity (up to 99% ee, and >20 : 1 dr). These
organocatalysts based on rosin have been proved to be very
effective promoters for this kind of catalytic asymmetric
process. Further investigation and synthetic utility of the
products are ongoing in our laboratories.
6 For reviews concerning amine-thiourea catalysis, see:
(a) A. G. Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107,
5713; (b) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418;
(c) M. S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed.,
2006, 45, 1520; (d) Y. Takemoto, Org. Biomol. Chem., 2005, 3,
4299.
We are grateful for the grants from the National Natural
Science Foundation of China (nos. 20932003, and 90813012)
and the National
(2009ZX09503-017).
S & T Major Project of China
7 X. X. Jiang, Y. F. Zhang, X. Liu, G. Zhang, L. H. Lai, L. P. Wu,
J. N. Zhang and R. Wang, J. Org. Chem., 2009, 74, 5562.
8 F. X. Chen, C. Shao, Q. Liu, P. Gong, C. L. Liu and R. Wang,
Chirality, 2009, 21, 600.
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G. Zhang, X. Liu, H. L. Zhang, D. Fu and R. Wang, Adv. Synth.
Catal., 2009, 351, 2096.
10 For examples concerning catalytic asymmetric synthesis of
a-quaternary keto lactones, see: (a) T. Ooi, T. Miki,
K. Fukumoto and K. Maruoka, Adv. Synth. Catal., 2006, 348,
1539; (b) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo,
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5604.
Notes and references
1 Selected for the examples of recent reviews, see: (a) M. Bella and
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L. E. Overman, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5363.
2 For reviews concerning Mannich-type reaction, see: (a) J. M.
M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg and
F. P. J. T. Rutjes, Chem. Soc. Rev., 2008, 37, 29; (b) A. Ting and
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B. Marques, Angew. Chem., Int. Ed., 2006, 45, 348;
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´
(f) M. Arend, B. Westermann and N. Risch, Angew. Chem., Int.
Ed., 1998, 37, 1044; (g) E. F. Kleinmann, in: Comprehensive
11 M. Hatano, T. Horibe and K. Ishihara, J. Am. Chem. Soc., 2010,
132, 56.
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This journal is The Royal Society of Chemistry 2010
4296 | Chem. Commun., 2010, 46, 4294–4296