Chiral DMAP-N-oxides as Acyl Transfer Catalysts: Design, Synthesis, and Application in Asymmetric Steglich Rearrangement

Article abstract of DOI:10.1002/anie.201812864

A DMAP-N-oxide, featuring an α-amino acid as the chiral source, was developed, synthesized and applied in asymmetric Steglich rearrangement. A series of O-acylated azlactones afforded C-acylated azlactones possessing a quaternary stereocenter in high yiel

Full text of DOI:10.1002/anie.201812864

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Accepted Article
Title: Chiral DMAP-N-oxides as Acyl Transfer Catalysts:
Design, Synthesis, and Application in Asymmetric Steglich
Rearrangement
Authors: Haiming Guo, Ming-Sheng Xie, Ye-Fei Zhang, Meng Shan,
Xiao-Xia Wu, and Gui-Rong Qu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812864
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10.1002/anie.201812864
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COMMUNICATION
Chiral DMAP-N-oxides as Acyl Transfer Catalysts: Design,
Synthesis, and Application in Asymmetric Steglich
Rearrangement
Ming-Sheng Xie,* Ye-Fei Zhang, Meng Shan, Xiao-Xia Wu, Gui-Rong Qu, and Hai-Ming Guo*
Abstract: A DMAP-N-oxide, featuring an α-amino acid as the chiral
source, was developed, synthesized and applied in asymmetric
Steglich rearrangement. A series of O-acylated azlactones afforded
C-acylated azlactones possessing a quaternary stereocenter in high
yields (up to 97% yield) and excellent enantioselectivities (up to 97%
ee). Compared to the widespread use of pyridine nitrogen, which
serves as the nucleophilic site in the asymmetric acyl transfer
reaction, we discovered that chiral DMAP-N-oxides, in which the
oxygen now acts as the nucleophilic site, are efficient acyl transfer
catalysts. Our finding might open a new door for the development of
chiral DMAP-N-oxides for asymmetric acyl transfer reactions.
3-10 in Figure 1) with central-chirality,[6] planar-chirality,[7] helical-
chirality,[8] and axial-chirality[9] have been developed and
demonstrated to be effective catalysts for enantioselective acyl-
transfer reactions. However, compared with the widespread use
of pyridine nitrogen which serves as the nucleophilic site in
asymmetric acyl transfer reactions, chiral DMAP-N-oxide, in
which the oxygen is the nucleophilic site, was only developed in
enantioselective sulfonylation and has yet to be reported in
asymmetric acyl transfer reactions.[10-12] Thus, the development
of a chiral DMAP-N-oxide and applying it in asymmetric acyl
transfer reaction would be highly significant.
Acyl transfer is one of the most common transformations utilized
in nature and organic synthesis.[1] Over the past two decades,
the development of chiral non-enzymatic acyl transfer catalysts
has become a vibrant area of research.[2] Among these acyl
transfer catalysts, chiral 4-(dimethylamino)pyridine (DMAP) and
closely related 4-pyrrolidinopyridine (PPY) have been
particularly attractive targets[3] since the pioneering studies of
Vedejs[4] and Fu.[5] In 1996, the Vedejs’s central-chiral DMAP
analogue 1[4a] and the Fu’s planar-chiral DMAP derivatives 2[5a]
were reported (Figure 1), which triggered the development of
various chiral DMAP analogues for asymmetric acyl transfer
reactions. Afterwards, various chiral DMAP analogues (such as
H
Me2N
N
N
N
H
OH
N
MeN
N
N
N
CPh3
OAc
Fe
R
H
R
R
tBu
OMe
N
R
R
Ar
Scheme 1. Catalyst design of chiral DMAP-N-oxides.
R = Me, Ph
1
3
5
4
2
(Vedejs 1996)
(Fuji & Kawabata 1997)
(Vedejs 2003)
(Spivey 1998)
(Fu 1996)
Ar
O
Ar
Et
Et
According to the nucleophilicity data[13] shown in Scheme 1,
PPY, bearing a pyrrolidinyl group is a more effective acylation
catalyst than DMAP.[3a] Triaminopyridine, with two amino groups
at the C3 and C5 positions, exhibits stronger nucleophilicity. As
for DMAP-N-oxide, the oxygen 2pπ electrons are conjugated
with the pyridine ring.[12a] In order to increase the electron
density of the oxygen atom, an electron donating pyrrolidinyl
group is embedded into the C3 position of DMAP-N-oxide, thus
3,4-diaminopyridine-N-oxide is formed, in which two amino
groups increase the electron density at the oxygen atom, thus
N
OH
N
MeN
N
N
N
OAc
HN
N
N
O
N
tBu
tBu
N
N
N
N
O
Bz
OH
Ar
HO
Ar Ar
Ar
7
6
8
9
10
(Mandai & Suga 2016)
(Vedejs 2009)
(Connon 2005)
(Sibi 2014)
(Carbery 2011)
Figure 1. Chiral DMAP and PPY based catalysts.
resulting in enhanced activity.[14] L-Proline,
a cheap and
[*] Dr. M.-S. Xie, Y.-F. Zhang, M. Shan, X.-X. Wu, Prof. G.-R. Qu, Prof.
Dr. H.-M. Guo
commercially available chiral source, also contains a pyrrolidinyl
moiety. Diverse L-prolinamides with tunable structures can be
generated through the coupling reactions of L-proline with
different amines.[12a] By superposing the pyrrolidinyl moiety
between 3,4-diaminopyridine-N-oxides and L-prolinamides, the
chiral DMAP-N-oxide analogue catalyst is obtained, in which a
hydrogen-binding site is located at the amide part (Scheme 1).
The catalysts were synthesized from L-prolinamides and 3-
bromo-4-nitropyridine N-oxide follow the synthetic route depicted
in Scheme 2.[15]
Henan Key Laboratory of Organic Functional Molecules and Drug
Innovation, Collaborative Innovation Center of Henan Province for
Green Manufacturing of Fine Chemicals, School of Chemistry and
Chemical Engineering, Henan Normal University
Xinxiang, Henan 453007 (China)
E-mail: xiemingsheng@htu.edu.cn; ghm@htu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://
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10.1002/anie.201812864
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COMMUNICATION
Table 2. Optimization of the reaction conditions.[a]
Scheme 2. Synthetic route for chiral DMAP-N-oxides.
Then, chiral DMAP-N-oxides 13 were applied in the
asymmetric Steglich rearrangement[16-17] of O-acylated
azlactones to their C-acylated isomers containing a quaternary
stereocenter, which served as a model system for evaluating the
efficiency of chiral acyl transfer catalysts (Table 1). When chiral
DMAP-N-oxide 13a bearing a bulky isopropyl group at the
aniline’s ortho positions was used, the C-carboxylated product
16a was generated in 55% yield with 77% ee. Comparatively,
when chiral DMAP 14a, the reduced derivative of DMAP-N-oxide
13a, was attempted, only 39% ee of product 16a was obtained.
As a result, chiral DMAP-N-oxide 13a exhibited better catalytic
effect than chiral DMAP 14a. The unexpected results indicated
that the introduction of an oxygen atom into chiral DMAP may
alter the catalytic effect.
Entry
1
Catalyst
13a
13b
13c
13d
13e
13e
13f
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
T (oC)
0
t (h)
6
Yield [%][b]
55
ee [%][c]
77
59
49
11
-
2
0
6
51
3
0
6
58
4
0
6
50
Table 1. Asymmetric Steglich rearrangement catalyzed by DMAP-N-oxide 13a
and DMAP 14a.
5
0
6
trace
45
6
rt
6
30
-7
7
0
6
46
8
13a
13a
13a
13a
13a
13a
13a
0
6
65
66
33
80
85
82
96
93
9
0
6
63
10
11
12
13[d]
14[d,e]
toluene
toluene
toluene
toluene
toluene
-20
-40
-60
-40
-40
24
36
60
16
16
60
73
45
96
89
[a] Unless otherwise noted, reaction conditions were as follows: 15a (0.05
mmol) and catalyst (5 mol%) in solvent (0.5 mL). [b] Isolated yield. [c]
Determined by chiral HPLC analysis. [d] 4Å MS (10 mg) was added. [e] 15a (3
mmol), 13a (5 mol%), 4Å MS (600 mg) in toluene (20 mL) for 56 h.
Optimization of reaction conditions were shown in Table 2.
DMAP-N-oxides containing different sterically hindered amide
groups were evaluated. In the case of DMAP-N-oxide 13a,
containing two bulky isopropyl groups at the ortho positions of
the aniline moiety, better results were obtained (entries 1 vs 2-3).
In the case of 3,5-bis(trifluoromethyl)aniline derived catalyst 13d,
only 11% ee was obtained for 16a (entry 4). As for DMAP-N-
the ee of 16a reached 96% ee along with 96% yield (entry 13).
When the reaction was performed at 3 mmol scale, 1.11 g of the
desired 16a was obtained with 89% yield and 93% ee (entry 14).
Under the optimized reaction conditions (Table 2, entry 13),
the substrate scope of the Steglich rearrangement was explored
(Table 3). A series of C(4)-primary alkyl substituted benzyl
carbonates 15b-j
gave the corresponding C-carboxylated
o
oxide 13e, when the reaction was conducted at 0 C, only trace
products 16b-j in excellent yields and enantioselectivities
(entries 2-10). Rearrangement of the C(4)-iPr-substituted benzyl
carbonate 15k proceeded with 89% ee, although massive
amount (ca. 70%) of the parent azlactone was detected (entry
11). When C(4)-tBu-substituted benzyl carbonate 15l was
examined, the desired rearrangement product 16l was obtained
in 66% yield and 90% ee, in which small amount (ca. 15%) of
the parent azlactone was generated (entry 12). It should be
noted that it was the first asymmetric rearrangement of C4-tBu-
substituted oxazolyl carbonate. C(4)-phenyl substitution resulted
in poor enantioselectivity (entry 13). The migrating group had
been proven to play a pivotal role in different catalytic systems
(entries 1, 14-16). The -CO2Bn group could afford a better result
(entry 1), consistent with the work of Fu et al.[17a] The -CO2Ph
group only afforded a moderate result, in which excellent results
amounts of product 16a was detected, highlighting that the
benefit of the strong electron donating pyrrolidinyl group at the
C4 position (entries 5 vs 1); Comparatively, by increasing the
reaction temperature from 0 oC to rt, 30% ee of product 16a was
obtained, which demonstrated that the pyrrolidinyl group at the
C4 position also affected the orientation of the chiral amide
moiety (entries 6 vs 1). When the N-H proton in DMAP-N-oxide
was protected using the Me group, a dramatic decrease in the
ee of 16a was observed, indicating that the N-H proton on the
amide moiety was vital for the chiral induction (entries 7 vs 3).
Other solvents were explored, but the results were generally
lower than those obtained in toluene (entries 1 and 8-9).
Examination of the reaction temperature showed that -40 oC was
optimal (entries 1 and 10-12). Upon using 4Å MS as an additive,
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10.1002/anie.201812864
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COMMUNICATION
were obtained in the work of Smith et al.[17h] and Chen & Yu
group.[17r] Considering the sterically hindered -CO2C(Me)2CCl3 or
-CO2CH2CCl3 group has been achieved with excellent results by
Smith et al.[17h] and Ooi et al.,[17j] respectively, the rearrangement
of -CO2C(Me)2CCl3 derivatives 15o-p were examined, and the
C-carboxylated products 16o-p were given in excellent results
(entries 9-10). With regard to C(2) substituent, different aryl and
alkyl groups were also tolerated (entries 17-19).
15a with catalyst 13a was analyzed by ESI HRMS. The analysis
showed a peak at m/z 571.3260, which corresponded to
[13a+BnOCO+]+, and confirmed the generation of the O-acylated
13a (see Fig. S2 in SI). Besides, the analysis showed a peak at
m/z 280.0969, which corresponded to the enolate-anion II
(Figure 2), and proved the generation of the enolate-anion II
(see Fig. S3 in SI).
Table 3. Scope of asymmetric Steglich rearrangement.[a]
Yield
[%][b]
ee
Entry
R3/R4
R5
16
[%][c]
1
2
3[d]
Bn/Bn
Me/Bn
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-ClPh
16a
16b
16c
16d
16e
16f
96
92
88
94
94
93
91
89
94
90
23
66
52
82
92
97
83
87
92
96
96
95
93
94
92
90
93
94
92
89
90
31
76
95
97
93
91
94
Et/Bn
4
n-Pr/Bn
5
n-Bu/Bn
6
allyl/Bn
7
CH2CH2SMe/Bn
4-BnOC6H4CH2/Bn
4-BnO2COC6H4CH2/Bn
iBu/Bn
16g
16h
16i
8
Figure 2. Proposed reaction mechanism.
9
10
11[e]
12[e]
13
14
15[d]
16[d]
17
18
19
16j
iPr/Bn
16k
16l
On the basis of previous reports[17a,h,j,r] on the asymmetric
Steglich rearrangement and our control experiments, a possible
mechanism was proposed in Figure 2. Initially, chiral DMAP-N-
oxide 13a reacted with O-acylated azlactone 15a through a
reversible nucleophilic acyl substitution, generating the ion-pair
intermediate, O-acylated pyridinium-cation I and enolate-anion II.
In the transition state (TS), the amide moiety was located at the
upper right of the pyridine ring. The enolate-anion II was
activated by the H-bonding interaction between the N-H moiety
present in the catalyst and the oxygen atom of enolate-anion II.
The activated enolate-anion II attacked the carbonyl group from
the top of the pyridine ring, generating the corresponding (R)-
configured C-carboxylated product 16a[18] along with the release
of catalyst DMAP-N-oxide 13a.
tBu/Bn
Ph/Bn
16m
16n
16o
16p
16q
16r
Bn/Ph
Bn/C(Me)2CCl3
Me/C(Me)2CCl3
Bn/Bn
Bn/Bn
Ph
Bn/Bn
tBu
16s
[a] Reaction conditions: 15 (0.1 mmol), 13a (5 mol%), and 4Å MS (20 mg) in
toluene (1.0 mL) at -40 oC for 16 h. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] 40 h. [e] 20 oC, N2.
In summary, we have designed and synthesized a chiral
DMAP-N-oxide, featuring an α-amino acid as the chiral source,
as an acyl transfer catalyst and applied it in an asymmetric
Steglich rearrangement. A series of O-acylated azlactones were
suitable reactants, giving the C-acylated azlactones possessing
a quaternary stereocenter in high yields (up to 97% yield) and
excellent enantioselectivities (up to 97% ee). Compared the
commonly used pyridine nitrogen, we discovered that chiral
DMAP-N-oxides, in which oxygen is now the nucleophilic site, is
an efficient acyl transfer catalysts. This might open the door to
new and exciting possibilities in the development of chiral
DMAP-N-oxides for asymmetric acyl transfer reactions.
Scheme 3. Crossover experiment of O-acylated azlactones 15a and 15p.
To probe the mechanism of the reaction catalyzed by chiral
DMAP-N-oxide, a crossover experiment was conducted using a
50:50 mixture of O-acylated azlactones 15a and 15p in the
presence of catalyst 13a (Scheme 3). A 42:28:16:14 mixture of
four C-acylated products 16a, 16p, 16o, and 16b was detected,
showing that the reaction catalyzed by DMAP-N-oxide 13a was
an intermolecular process. Afterwards, the reaction mixture of
Acknowledgements
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COMMUNICATION
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We are grateful for financial support from the NSFC (Nos.
U1604283 and 21778014), the Program for Science
&
Technology Innovation Talents in Universities of Henan Province
(19HASTIT036), and the 111 Project (No. D17007).
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The authors declare no conflict of interest.
Keywords: asymmetric catalysis • acyl transfer • nucleophilic
catalysis • organocatalysis • rearrangement
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10.1002/anie.201812864
Angewandte Chemie International Edition
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Tsai, P.-K. Tsou, G.-T. Huang, C.-H. Yu, Chem. Sci. 2017, 8, 524; s) T.
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[18] The absolute configuration of (R)-16a was determined by comparison
with optical rotation in the literature; for details please see SI.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812864
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Dr. Ming-Sheng Xie,* Ye-Fei Zhang,
Meng Shan, Xiao-Xia Wu, Prof. Gui-
Rong Qu, and Prof. Dr. Hai-Ming Guo*
Page No. – Page No.
Chiral DMAP-N-oxides as Acyl
Transfer Catalysts: Design,
Synthesis, and Application in
Asymmetric Steglich Rearrangement
A DMAP-N-oxide, featuring an α-amino acid as the chiral source, was developed,
synthesized and applied in asymmetric Steglich rearrangement. A series of O-
acylated azlactones afforded C-acylated azlactones possessing a quaternary
stereocenter in high yields (up to 97% yield) and excellent enantioselectivities (up to
97% ee). Compared to the widespread use of pyridine nitrogen, which serves as
the nucleophilic site in the asymmetric acyl transfer reaction, we discovered that
chiral DMAP-N-oxides, in which the oxygen now acts as the nucleophilic site, are
efficient acyl transfer catalysts. Our finding might open a new door for the
development of chiral DMAP-N-oxides for asymmetric acyl transfer reactions.
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