Merging chiral organocatalysts: Enantio- and diastereoselective direct vinylogous Mannich reaction of alkylimines

Article abstract of DOI:10.1039/b917408g

An enantio- and diastereoselective direct vinylogous Mannich reaction of α,α-dicyanoolefins and N-sulfonyl alkylimines has been developed by the catalysis of a new family of bifunctional organocatalysts merging chiral BINOL and 9-amino-9-deoxyepi-cinchona

Full text of DOI:10.1039/b917408g

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Merging chiral organocatalysts: enantio- and diastereoselective direct
vinylogous Mannich reaction of alkyliminesw
Xiao-Feng Xiong,a Zhi-Jun Jia,a Wei Du,a Kun Jiang,a Tian-Yu Liua and Ying-Chun Chen*ab
Received (in Cambridge, UK) 24th August 2009, Accepted 17th September 2009
First published as an Advance Article on the web 8th October 2009
DOI: 10.1039/b917408g
An enantio- and diastereoselective direct vinylogous Mannich
reaction of a,a-dicyanoolefins and N-sulfonyl alkylimines has
been developed by the catalysis of a new family of bifunctional
organocatalysts merging chiral BINOL and 9-amino-9-deoxyepi-
cinchona alkaloid skeletons, from which chiral b-, d- or c-amino
compounds could be efficiently derived.
The development of reliable protocols to access both enantio-
mers of a target chiral compound is still a challenging
endeavour in asymmetric synthesis, especially for the chiral
ligands or organocatalysts are derived from the naturally
available sources in only one enantiomeric form.1 Although
many successful examples of the reversal of enantioselectivity
have been reported through careful manipulation of the
reaction components, such as Lewis acid, ligand, solvent, or
temperature, etc.,2 they are not always effective and are usually
unpredictable and time-consuming tasks. Moreover, the
problem would be further aggravated when the diastereo-
selectivity is involved and the synthesis of all the stereo isomers
must be considered.3 The design of catalysts which can be
available with resourceful chiral properties may be applicable
to stereo diversity synthesis. Herein we would like to present
an enantio- and diastereoselective asymmetric reaction by
means of merging chiral organocatalysts.
Fig. 1 The structures of bifunctional organocatalysts merging chiral
BINOL and 9-amino-9-deoxyepicinchona alkaloids.
Table 1 Screening studies of organocatalytic AVM reactiona
Entry
Cat.
3
Yieldb (%)
drc (4 : 5)
eec (4/5, %)
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
1a
1a
1a
1a
1a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
70
50
75
50
64
42
88
32
86
98
99
69 : 31
60 : 40
16 : 84
20 : 80
66 : 34
17 : 83
79 : 21
60 : 40
86 : 14
81 : 19
82 : 18
90/—
90/—
—/À45
—/À61
À90/—
—/53
93/—
89/—
96/—
97/—
97/—
Recently we have presented the first direct asymmetric
vinylogous Mannich (AVM) reaction4 of a,a-dicyanoolefins
and N-Boc arylimines catalysed by bifunctional thiourea-
tertiary amines.5 However, a mixture of a- and g-adducts
was afforded when N-Boc alkylimines6 were used and this
important problem remains unsolved to date.7,8 Nevertheless,
the g-selective product could be exclusively obtained by utilising
N-Tos alkylimines. Although disappointing results were
obtained in the extensive screenings with a variety of organo-
catalysts,9 it was pleasing that a chiral compound SBADQ10
1a (Fig. 1, 10 mol%), merging (S)-BINOL (SB) and 9-amino-
9-deoxyepiquinine (ADQ) scaffolds,11 exhibited promising
stereocontrol in the reaction of a,a-dicyanoolefin 2a and
N-Tos alkylimine 3a in toluene. The syn-adduct 4a was
obtained as the major isomer in a high ee value, while the
7
8d
9
10e,f
11e,f,g
a
Reactions were performed with 0.1 mmol of 2a, 0.12 mmol of imine
3, 0.01 mmol of catalyst 1, 15 mg 4 A MS in 0.4 mL of toluene
b
(entries 1–6) or mesitylene (entries 7–11) for 2–3 d. Combined
c
isolated yield of 4 and 5. By chiral HPLC analysis. For major
d
isomer (ee). Without 4 A MS. Adding 30 mg 4 A MS. For 1 d.
e
f
g
With 15 mol % of 1a.
diastereoselectivity was modest (Table 1, entry 1). The similar
results were attained in the presence of SBADCD 1b from SB
and 9-amino-9-deoxyepicinchonidine (ADCD) (entry 2).
Interestingly, the anti-product 5a was dominantly attained in
moderate enantioselectivity catalysed by SBADQD 1c
(ADQD, 9-amino-9-deoxyepiquinidine) or SBADC 1d
(ADC, 9-amino-9-deoxyepicinchonine) (entries 3 and 4).
Subsequently, the catalytic efficacy of bifunctional RBADC
1e and RBADCD 1f derived from (R)-BINOL (RB) was
tested. As expected, the syn- or anti-Mannich adducts 4a or
5a with the opposite configuration were delivered, respectively
(entries 5 and 6). Then we screened more conditions with
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, China. E-mail: ycchenhuaxi@yahoo.com.cn;
Fax: +86 28 85502609
b State Key Laboratory of Biotherapy, West China Hospital, Sichuan
University, Chengdu, China
w Electronic supplementary information (ESI) available: Experimental
procedures, structural proofs and crystal data for 4m and 5m. CCDC
745436, 745437. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b917408g
ꢀc
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Fig. 2 The structures of a,a-dicyanoolefins.
1a to improve the stereoselectivity. Solvent had important
effects, and much better results were obtained in mesitylene
(entry 7).9 It should be noted that the reaction was quite
sluggish in the absence of 4 A molecular sieves, indicating that
the hydrogen bonding activation of hydroxyl groups of the
catalysts was crucial for the reaction (entry 8). Moreover,
better results were obtained for adduct 4b by using imine 3b
with a 2,4-dimethylbenzenesulfonyl group (entry 9).9 In addition,
the reaction could be greatly accelerated when more 4 A MS
was added (entry 10). Nevertheless, the similar data were
afforded when more catalyst 1a was added (entry 11).
With the optimal conditions in hand, we then explored a
variety of a,a-dicyanoolefins (Fig. 2) and N-sulfonyl alkyl-
imines to establish the reaction generality. The reaction was
firstly conducted with catalyst 1a to deliver the syn-Mannich
adducts 4. As summarised in Table 2, excellent enantio-
selectivities were obtained for a few a,a-dicyanoolefins derived
from cyclic aryl ketones (entries 1–4), and the diastereo-
selectivities were also acceptable except that of 2b (entry 2).12
A modest ee value was attained for a simple a,a-dicyanoolefin
2e (entry 5). It was noteworthy that a,a-dicyanoolefin 2f
from aliphatic ketone could be applied, and excellent enantio-
selectivity was gained (entry 6). Subsequently, an array of
aliphatic imines were tested, and remarkable ee values with
Table 2 syn-Stereoselective AVM reactiona
Fig. 3 X-Ray structures of enantiopure 4m and 5m. Thermal
ellipsoids are shown at 30% probability.
good dr ratios were generally obtained (entries 7–12), even for
two imines with side functional groups (entries 11 and 12).13
On the other hand, we also studied some reactions with
catalyst 1e for the synthesis of syn-4 with the opposite
configuration. Excellent ee values were fortunately afforded,
and the dr ratios were fair to good (entries 13–16).
Entry
2
R
t/d
4
Yieldb (%) drc
eed (%)
1
2
3
4
5
6
7
8
2a nPr
2b nPr
1
6
3
4
4
4
1
1
1
4b
4c
4d
4e
4f
4g
4h
4i
98
92
89
87
83
58e
95
92
97
84
89
86
86
95
77
71
81 : 19
97
89
95
90
63
96
97
86
97
96
97
51 : 49
86 : 14
87 : 13
—
85 : 15
82 : 18
91 : 9
84 : 16
82 : 18
90 : 10
We have also optimised the reaction conditions to prepare
the chiral anti-Mannich adducts catalysed by RBADCD 1f
(20 mol%). Better enantiocontrol could be delivered for imines
bearing a 2,4,5-trimethylbenzenesulfonyl group (Table 3, entry
1 vs. 2). Although only moderate stereoselectivities were
obtained, the enantiomerically pure anti-adducts 6a–6c
could be provided in fair yields after a single recrystallisation
(entries 2–4). In addition, the anti-adducts 6a–6c with the
opposite configuration were also similarly afforded catalysed
by SBADC 1d (entries 5–7).
2c
nPr
2d nPr
2e
2f
nPr
nPr
2a Et
2a nHex
2a iBu
2a Ph(CH2)2
2a BnO(CH2)2
2a PhS(CH2)2
2a nPr
2a Et
2a PhS(CH2)2
2c
9
4j
10
11
12
13
14
15g
16g
1.5 4k
1
2
2
2
3
3
4l
4m
4b
4h
4m
4d
88 : 12 94f
75 : 25 À91
80 : 20 À94
70 : 30 À92
86 : 14 À94
Apart from the conversion of the AVM adducts to b- or d-
amino compounds 7 or 8, respectively, via known procedures,7
a diastereomerically pure g-lactam 9 could be smoothly
nPr
a
At 0.1 mmol scale, in 0.4 mL solvent. Entries 1–12: with 1a;
b
entries 13–16: with 1e. Yields of diastereomers. By HPLC or crude
c
prepared via
a tandem reduction–oxidative degradation
1H NMR analysis. By chiral HPLC analysis, for major isomer.
d
process (Scheme 1).15 Thus the malononitrile motif could
be regarded as a transient group for multiple functionalities
and would be quite useful for diversity oriented synthesis
(DOS).16
e
f
Yield of pure 4g. The absolute configuration of enantiopure 4m
was determined by X-ray analysis, see Fig. 3.14 The other products
g
were assigned by analogy. In 0.2 mL solvent.
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Table 3 anti-Stereoselective AVM reactiona
We are grateful for the financial support from Chinesisch-
Deutsches Zentrum fur Wissenschaftsforderung [GZ422 (362/6)]
and Sichuan University.
Notes and references
1 For reviews, see: (a) M. P. Sibi and M. Liu, Curr. Org. Chem.,
2001, 5, 719; (b) G. Zanoni, F. Castronovo, M. Franzini, G. Vidari
and M. Giannini, Chem. Soc. Rev., 2003, 32, 115.
Entry 2
R
t/d Product Yieldb (%) drc
eed (%)
2 For selected examples, see: (a) M. Murakami, K. Itami and Y. Ito,
J. Am. Chem. Soc., 1999, 121, 4130; (b) S. Arseniyadis, A. Valleix,
A. Wagner and C. Mioskowski, Angew. Chem., Int. Ed., 2004, 43,
3314; (c) B. M. Trost, A. Fettes and B. T. Shireman, J. Am. Chem.
Soc., 2004, 126, 2660; (d) W. Zeng, G.-Y. Chen, Y.-G. Zhou and
Y.-X. Li, J. Am. Chem. Soc., 2007, 129, 750; (e) W.-Q. Wu,
Q. Peng, D.-X. Dong, X.-L. Hou and Y.-D. Wu, J. Am. Chem.
Soc., 2008, 130, 9717 and references cited therein.
3 For selected diastereoselective asymmetric reactions, see:
(a) D. A. Evans, D. W. C. MacMillan and K. R. Campos,
J. Am. Chem. Soc., 1997, 119, 10859; (b) S. E. Denmark,
K.-T. Wong and R. A. Stavenger, J. Am. Chem. Soc., 1997, 119,
2333; (c) W.-W. Liao, K. Li and Y. Tang, J. Am. Chem. Soc., 2003,
125, 13030; (d) J. Barluenga, J. Alonso and F. J. Fananas, J. Am.
Chem. Soc., 2003, 125, 2610; (e) H. Zhang, M. Mifsud, F. Tanaka
and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 9630;
(f) X.-X. Yan, Q. Peng, Y. Zhang, K. Zhang, W. Hong,
X.-L. Hou and Y.-D. Wu, Angew. Chem., Int. Ed., 2006, 45,
1979; (g) X.-X. Yan, Q. Peng, Q. Li, K. Zhang, J. Yao,
X.-L. Hou and Y.-D. Wu, J. Am. Chem. Soc., 2008, 130, 14362
and references cited therein.
1
2
3
4
5
6
7
2a PhS(CH2)2
2a PhS(CH2)2
2a Et
2
3
3
5
3
3
5
5m
6a
6b
6c
6a
6b
6c
67 (27)
70 (44)
73 (39)
60 (36)
74 (46)
82 (45)
62 (37)
87 : 13 52 (97)e
84 : 16 83 (99)
84 : 16 73 (97)
2c nPr
85 : 15 77 (97)
2a PhS(CH2)2
2a Et
2c nPr
85 : 15 À81 (À93)
85 : 15 À70 (À99)
84 : 16 À74 (À97)
a
At 0.1 mmol scale, in 0.2 mL solvent. Entries 1–4: with 1f;
entries 5–7: with 1d. Data in parentheses were related to the pure 5
b
c
or 6 after one recrystallisation. Yields of two diastereomers. By
crude 1H NMR analysis. By chiral HPLC analysis. The absolute
configuration of enantiopure 5m was determined by X-ray analysis, see
Fig. 3.14 The other products were assigned by analogy.
d
e
4 S. F. Martin, Acc. Chem. Res., 2002, 35, 895.
5 T.-Y. Liu, H.-L. Cui, J. Long, B.-J. Li, Y. Wu, L.-S. Ding and
Y.-C. Chen, J. Am. Chem. Soc., 2007, 129, 1878.
6 (a) J. Song, Y. Wang and L. Deng, J. Am. Chem. Soc., 2006, 128,
6048; (b) J. Song, H.-W. Shih and L. Deng, Org. Lett., 2007, 9, 603.
7 (a) B. Niess and K. A. Jørgensen, Chem. Commun., 2007, 1620;
(b) H.-L. Cui and Y.-C. Chen, Chem. Commun., 2009, 4479.
8 For recent examples on AVM reaction, see: (a) M. Sickert and
C. Schneider, Angew. Chem., Int. Ed., 2008, 47, 3631;
(b) D. S. Giera, M. Sickert and C. Schneider, Org. Lett., 2008,
10, 4259; (c) H. Mandai, K. Mandai, M. L. Snapper and
A. H. Hoveyda, J. Am. Chem. Soc., 2008, 130, 17961;
(d) A. S. Gonzalez, R. G. Arrayas, M. R. Rivero and
J. C. Carretero, Org. Lett., 2008, 10, 4335; (e) A. Yamaguchi,
S. Matsunaga and M. Shibasaki, Org. Lett., 2008, 10, 2319;
(f) T. Akiyama, Y. Honma, J. Itoh and K. Fuchibe, Adv. Synth.
Catal., 2008, 350, 399; (g) E. L. Carswell, M. L. Snapper and
A. H. Hoveyda, Angew. Chem., Int. Ed., 2006, 45, 7230;
(h) Z.-L. Yuan, J.-J. Jiang and M. Shi, Tetrahedron, 2009, 65, 6001.
9 See the Supplementary Information for more details.
Scheme 1 Synthetic transformations of AVM adducts.
10 H.-L. Cui, J. Peng, X. Feng, W. Du, K. Jiang and Y.-C. Chen,
Chem.–Eur. J., 2009, 15, 1574.
In conclusion, we have designed
a new family of
11 (a) J.-R. Chen, X.-L. An, X.-Y. Zhu, X.-F. Wang and W.-J. Xiao,
J. Org. Chem., 2008, 73, 6006; (b) K. Matsui, S. Takizawa and
H. Sasai, J. Am. Chem. Soc., 2005, 127, 3680; (c) Z. Hou, J. Wang,
X. Liu and X. Feng, Chem.–Eur. J., 2008, 14, 4484.
12 The ether structure of 2b might affect the hydrogen bonding
activation of the catalyst.
13 However, poor results were obtained for N-sulfonyl arylimines.
14 For crystal data of enantiopure 4m and 5m, see ESIw.
15 S. Forster, O. Tverskoy and G. Helmchen, Synlett, 2008, 2803.
16 For reviews on DOS, see: (a) M. D. Burke and S. L. Schreiber,
Angew. Chem., Int. Ed., 2004, 43, 46; (b) T. E. Nielsen and
S. L. Schreiber, Angew. Chem., Int. Ed., 2008, 47, 48;
(c) W. R. J. D. Galloway, M. Diaz-Gavilan, A. Isidro-Llobet
and D. R. Spring, Angew. Chem., Int. Ed., 2009, 48, 1194.
bifunctional organocatalysts merging chiral BINOL and
9-amino-9-deoxyepi-cinchona alkaloid skeletons. They have
been successfully applied in an enantio- and diastereoselective
direct vinylogous Mannich reaction of a,a-dicyanoolefins and
N-sulfonyl alkylimines, from which four stereo isomers could
be attainable in a highly enantioenriched form catalysed by a
proper combination. Moreover, the chiral b-, g- or d-amino
compounds could be efficiently derived from the AVM
adducts. Currently, further applications of these bifunctional
organocatalysts in other stereoselective reactions are underway
in our laboratory.
ꢀc
This journal is The Royal Society of Chemistry 2009
6996 | Chem. Commun., 2009, 6994–6996