A chiral bis(betaine) catalyst for the mannich reaction of azlactones and aliphatic imines

Article abstract of DOI:10.1002/anie.201107741

By design: New chiral bis(betaine)s, for example 1, containing two catalytically active centers have been designed. They have proven to be promising organocatalysts for the direct Mannich-type reaction of azlactones with a broad spectrum of aliphatic imines, thus affording α- tetrasubstituted α,β-diamino acid surrogates with excellent enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201107741

Angewandte
Chemie
DOI: 10.1002/anie.201107741
Organocatalysis
A Chiral Bis(betaine) Catalyst for the Mannich Reaction of Azlactones
and Aliphatic Imines**
Wen-Quan Zhang, Ling-Feng Cheng, Jie Yu, and Liu-Zhu Gong*
The design of novel and efficient chiral catalysts capable of
inducing substantial stereochemical outcomes has been
a longstanding frontier in organic synthesis.[1,2] In recent
decades, the design of highly efficient chiral catalysts has
encompassed the incorporation of two catalytically active
centers into a single chiral molecule with the assumption that
cooperative catalysis might occur between the two catalytic
Scheme 1. The general consideration for the design of bis(betaine)
organocatalysts.
sites. Numerous chiral catalysts of this type have been
discovered and have enabled a wide range of enantioselective
transformations.[3–13] In particular, great advances have been
made with the dinuclear metal complexes which have enabled
bimetallic cooperative catalysis and have been exploited to
accelerate numerous asymmetric transformations.[3–7] How-
ever, those dinuclear organocatalysts having multiple cata-
lytic centers, wherein each catalytically active site is bifunc-
tional, have been investigated to a lesser extent for asym-
metric protocols.[8–13]
Recently, Ooi and co-workers demonstrated that artificial
chiral betaines were promising chiral organocatalysts in base-
catalyzed asymmetric protocols.[14] In particular, the mono-
betaines, having a binaphthyl backbone, stereoselectively
activated nucleophiles having acidic protons, thus allowing
the discovery of highly enantioselective transformations.
These betaines contain a basic aryl oxide moiety and an
ammonium cation. We and others have demonstrated that the
introduction of a binol backbone as an extra chiral element
into Schiff base ligands for bimetallic catalysts is beneficial to
the stereocontrol.[6,7] On the other hand, binol and its
derivatives have been employed as Brønsted acids in asym-
metric catalysis, wherein an intramolecular hydrogen bond
between the two hydroxy groups exists to assist in the single
hydrogen-bonding activation.[15–18] Inspired by these achieve-
ments, we designed chiral bis(betaine) organocatalysts of type
1 (Schemes 1 and 2), which contain two chiral ammonium
Scheme 2. Organobases evaluated in this study.
moieties, two basic naphthoxides, as well as axial chirality.
Upon encountering nucleophiles (H-Nu), the bis(betaine)
might participate in a deprotonation and in turn be trans-
formed into the chiral Brønsted acidic nucleophilic species A
or B which have Brønsted-acid-assisted Brønsted acid func-
tionalities. Both A and B are principally capable of activating
the incoming electrophiles (E) through a hydrogen-bonding
interaction. As such, these compounds would be potentially
ideal chiral catalysts for promoting stereoselective nucleo-
philic addition reactions involving nucleophiles having acidic
protons. We describe herein a highly enantioselective Man-
nich reaction of azlactones and imines (up to 99% ee)
catalyzed by the newly designed bis(betaine)s 1 (Scheme 2),
thus demonstrating the potential of 1 in asymmetric catalysis.
The designed bis(betaine)s 1 and monobetaines 2 were
easily accessed by using classical transformations starting
from binol and naturally occurring cinchona alkaloids (for
[*] W.-Q. Zhang, L.-F. Cheng, J. Yu, 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)
E-mail: gonglz@ustc.edu.cn
Homepage: http://staff.ustc.edu.cn/~gonglz/index.htm
[**] We are grateful for financial support from the Chinese Academy of
Sciences, MOST (973 project 2010CB833300), the Ministry of
Education, and BASF (GLZ).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107741.
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a detailed procedure see the Supporting Information). a,b-
Diamino acids are prevalent in many biologically active
compounds,[19] and a direct Mannich reaction is one of the
most straightforward approaches for accessing these mole-
cules.[19d,20] Recently, the Mannich reactions of 4-substituted
azlactones and a-substituted nitroacetates for synthesizing
a-tetrasubstituted diamino acids have attracted much atten-
tion.[3,14a,c,21–26] However, very few reports have described
access to the highly enantioselective variants of aliphatic
imines.[14a,21,22] Thus, we focused our initial study on the
catalytic Mannich reaction of N-tosyl imine 3a and 4-butyl-2-
phenyloxazol-5(4H)-one (4a) in THF at À408C in the
presence of 5 mol% 1a, which was derived from quinidine
(Table 1). As anticipated, the reaction worked well to give the
desired product 5aa in 78% yield with an anti/syn ratio of
2.5:1. We were encouraged by the isolation of anti-5aa in
81% ee (Table 1, entry 1). Additional investigation into the
effect of the 4-aryl substituent of the azlactones 4 indicated
that the introduction of an alkyl substituent to the phenyl
group of the azlactones enhanced both the yield and
enantioselectivity (entries 1–3 and 5), whereas 4-chloro-
phenyl and 3,5-dimethylphenyl azlactones gave comparable
enantioselectivities (entry 1 versus 4 and 6). Among the
azlactones examined, 4g, bearing a 2-naphthyl substituent,
provided the highest level of enantioselectivity for the major
product anti-5ag (entry 7). Further optimization showed that
the use of 10 mol% of the catalyst 1a provided 96% ee for
anti-5ag (entry 8).[27] Under these optimized reaction con-
ditions, other betaines derived from cinchona alkaloids were
evaluated (entries 9–14). Interestingly, the quinine-derived
base 1b offered the enantiomer of anti-5ag with a high level
of enantioselectivity, but with poor diastereoselectivity
(entry 9), thus suggesting that the stereochemistry was
governed by the chirality of the alkaloid moiety. A similar
outcome was observed in the reactions catalyzed by cincho-
nine- and cinchonidine-derived bis(betaine)s 1c and 1d, both
of which provided moderate enantioselectivities (entries 10
and 11). The monobetaines 2a and 2b showed excellent
catalytic activity, but afforded a much lower ee value than the
bis(betaine) 1a (entries 12 and 13), thus indicating that the
stereochemical control benefits greatly from the axial chir-
ality of the binol moiety. The catalyst 1a’, which was derived
from (S)-binol and quinidine, delivered a lower enantiose-
lectivity than 1a, further demonstrating that the axial chirality
has an impact on the stereoselectivity (entry 14 versus 8). A
further enhancement in the enantioselectivity was achieved
when 4-isopropylphenylsulfonyl imine 3b was employed as
a substrate (97% ee, entry 15).
Moreover, we investigated the effect of the stoichiometry
of trifluoroacetic acid (TFA) and 1a on the reaction. The
enantioselectivity fell when the amount of TFA increased
(Table 2). The addition of 10 mol% TFA, principally gener-
ating a monoanion of type A (Scheme 1), also showed
Table 1: Evaluation of chiral catalysts and optimization of conditions.[a]
Table 2: The effect of the stoichiometry of TFA and the catalyst 1a.[a]
Entry
x (mol%)
Yield [%][b]
d.r.[c]
ee [%][d]
Entry
3
4
Cat. [%]
5
Yield [%][c]
d.r.[d]
ee [%][e]
1
2
3
4
0
5
10
15
86
92
66
–
2.7:1
3.5:1
1.7:1
–
96
82
72
–
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
4a
4b
4c
4d
4e
4 f
4g
4g
4g
4g
4g
4g
4g
4g
4g
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a(10)
1b(10)
1c(10)
1d(10)
2a(10)
2b(10)
1a’(10)
1a(10)
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ag
5ag
5ag
5ag
5ag
5ag
5ag
5bg
78
93
98
95
99
99
97
86
95
82
99
94
94
88
91
2.5:1
3:1
3.8:1
2:1
3:1
2.5:1
3:1
2.7:1
1:1
1.3:1
2:1
1.5:1
1:1.4
1:1
81
83
84
81
88
81
90
96
[a] Reactions were carried out with 3a (0.1 mmol), 4g (0.12 mmol), 1a
(10 mol%) and TFA (x mol%) in THF (0.5 mL) at À408C for 24 h.
[b] Yield of isolated product. [c] Determined by 1H NMR analysis of the
crude reaction mixture. [d] Enantiomeric excess of anti isomer was
determined by HPLC analysis.
8[b]
9[b]
10[b]
11[b]
12[b]
13[b]
14[b]
15[b]
87(9)[f]
76(10)
68(70)[f]
76(26)
77(29)
63(7)
97
catalytic activity despite the erosion in the stereoselectivity
and yield (entry 3), thus indicating the feasibility of forming
intermediate B (Scheme 1). However, the reaction was
almost inhibited upon addition of 15 mol% TFA (entry 4).
The substrate scope with respect to aliphatic imines and
azlactones was then investigated under the optimized reaction
conditions (Table 3).[28] A variety of 4-substituted azlactones
participated in the Mannich reaction with high yields and
excellent levels of enantioselectivity (entries 1–7). More
interestingly, the azlactone 4m containing a thioether, which
may add more synthetic utility,[29] cleanly underwent the
2.6:1
[a] Unless otherwise noted, reactions were carried out with 3 (0.1 mmol),
4 (0.15 mmol), and 1a (5 mol%) in THF (0.5 mL) at À408C for 24 h.
[b] Reactions were carried out with 3 (0.1 mmol), 4 (0.12 mmol), and the
catalyst (10 mol%) in THF (0.5 mL) at À408C for 24 h. [c] Yield of
isolated product. [d] Determined by 1H NMR analysis of the crude
reaction mixture. [e] Enantiomeric excess was determined by HPLC
analysis and the ee value within parentheses is for the minor diastereo-
mer. [f] An opposite enantiomer was obtained. THF=tetrahydrofuran.
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Table 3: Substrate scope for imines.[a]
Scheme 3. The application of the protocol in the synthesis of highly
functionalized chiral caprolactone.
Entry
3
4
5
Yield [%][c]
d.r.[d]
ee [%][e]
1
2
3b
3b
3b
3c
3c
3c
3c
3d
3e
3 f
3g
3h
3i
4h
4i
4j
4h
4k
4l
4m
4h
4h
4h
4h
4h
4h
4h
5bh
5bi
5bj
86
93
86
90
98
92
96
89
95
93
99
89
89
76
3.5:1
3:1
2:1
96
96
99
97
96
98
98
96
97
96
96
98
96
98
3[b]
4
excellent enantioselectivity of 97% ee.[33] The flexibility and
synthetic significance of caprolactone with multiple function-
alities of type 7 implies the potential usefulness of the current
protocol.
5ch
5ck
5cl
5cm
5dh
5eh
5 fh
5gh
5hh
5ih
7:1
5
6
7
8
2.7:1
3.4:1
2.9:1
4.6:1
5.9:1
4:1
In addition, the resulting products 5 can be easily
deprotected under acidic conditions. For example, the com-
pound 5bj was first hydrolyzed into the acid 8. Subsequently,
the treatment of 8 with concentrated hydrochloric acid at
1008C smoothly generated the corresponding a,b-diamino
acid dihydrochloride 9 in a high yield without the loss of the
enantioselectivity (Scheme 4).
9
10
11
12[f]
13
14
4:1
5.2:1
4.2:1
3.4:1
3j
5jh
[a] Unless otherwise noted, reactions were carried out with 3 (0.1 mmol),
4 (0.12 mmol), and 1a (10 mol%) in THF (0.5 mL) at À40 oC for 24 h.
[b] The reaction was carried out at À50 oC. [c] Yield of isolated product.
[d] Determined by 1H NMR analysis of the crude reaction mixture.
[e] Enantiomeric excess of anti isomer was determined by HPLC analysis.
[f] Absolute configuration of 5hh was determined to be (2S,3S) by X-ray
diffraction analysis.
reaction to furnish the major diastereomer in 98% ee
(entry 7). The protocol was also applicable to different
aliphatic imines (entries 8–14). Linear aliphatic imines
reacted with the azlactone 4h to give the desired products
with high levels of enantioselectivity (entries 8–11). More
Scheme 4. Deprotection of anti-5bj to prepare a,b-diamino acid dihy-
drochloride.
=
significantly, the introduction of a C C bond to 3 was well
tolerated with excellent enantioselectivities (entries 12 and
13). Moreover, the branched aliphatic imine 3j afforded
a product with 98% ee (entry 14). It is worth noting that the
syn products were always obtained from the catalysts
reported by Ooi and co-workers.[21] Therefore, the current
protocol represents an important complement to the known
highly enantioselective Mannich-type reactions.[3,14a,c,21–26]
The caprolactone structural motif has been found in many
biologically active natural products.[30] Moreover, they are
important monomers in the preparation of biologically
compatible materials.[31] The chiral caprolactones can be
accessed in high optical purity starting from the current
Mannich reaction (Scheme 3). The treatment of anti-5hh with
aqueous hydrochloride furnished an a,b-diamino acid deriv-
ative 6 in quantitative yield, which then underwent an
iodocyclization[32] to afford the highly functionalized chiral
caprolactone 7 in 90% yield with a diastereomeric ratio of
3.5:1. The major diastereomer of 7 was obtained with an
In summary, we have developed a new type of chiral
bis(betaine) base for the Mannich reaction of azlactones and
aldimines. The synergism among the multiple functionalities
within these organobases provided high levels of enantiose-
lectivity (94–99% ee) for a variety of aliphatic imines and
azlactones. Importantly, the catalyst can be easily modified
for different reactions through changes to both the binaphthyl
and cinchona motifs. Moreover, the strategy presented in this
work has led to a versatile platform for the design of chiral
organobase catalysts. Further studies will be focused on the
reaction mechanism and the development of other base-
catalyzed asymmetric reactions by using the chiral bis-
(betaine) bases.
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Keywords: Brønsted base · heterocycles · imines ·
organocatalysis · synthetic methods
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