Catalytic Enantioselective Protonation/Nucleophilic Addition of Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic Acids

Article abstract of DOI:10.1002/anie.201612655

A new chiral Br?nsted acid derived from carboxylic acid and a chiral oxazaborolidinium ion (COBI), as an activator, is introduced. This acid was successfully applied as a catalyst for the highly enantioselective protonation/nucleophilic addition of diazoesters with carboxylic acids.

Full text of DOI:10.1002/anie.201612655

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201612655
German Edition: DOI: 10.1002/ange.201612655
Asymmetric Catalysis
Catalytic Enantioselective Protonation/Nucleophilic Addition of
Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic
Acids
Ki-Tae Kang, Seung Tae Kim, Geum-Sook Hwang,* and Do Hyun Ryu*
Abstract: A new chiral Brønsted acid derived from carboxylic
acid and a chiral oxazaborolidinium ion (COBI), as an
activator, is introduced. This acid was successfully applied as
a catalyst for the highly enantioselective protonation/nucleo-
philic addition of diazoesters with carboxylic acids.
E
nantioselective protonation has become a fascinating
method for the construction of tertiary chiral carbon centers,
which are frequently found in valuable biologically active
natural products.[1] Various catalytic methods[1,2] have been
developed for efficient enantioselective protonation since the
first report by Pracejus.[3] Among these, catalytic tandem
reactions incorporating an enantioselective protonation step
have emerged recently, thus providing a powerful tool in the
construction of structurally complex chiral molecules.[1c,e,2]
Thus, the development of new types of catalytic tandem
reactions involving enantioselective protonation should con-
tinue to serve as important tools for synthetic organic
chemistry.
Scheme 1. Catalytic enantioselective protonation/nucleophilic addition
of diazoesters using LBA.
The formation of carboxylate esters by the reaction of
carboxylic acids with diazo compounds, most commonly
diazomethane (R2, R3 = H), is one of the most well-known
reactions of diazo compounds.[4] The reaction proceeds by
initial protonation of the diazo carbon atom to form
a diazonium cation[4a,5] (1), which can react directly with
a nucleophile or carboxylate [Scheme 1, Eq. (1), pathway a],
or can lose nitrogen to give a more stable phenonium ion[6] 3 if
the diazo compound has a neighboring phenyl group, for
example, R2 = CH2Ph. Nucleophilic addition to the pheno-
nium ion 3 occurs by two competing pathways to yield the
acyloxy-substituted products 4 [Scheme 1, Eq. (1), pathway b]
or 2 [Scheme 1, Eq. (1), pathway c]. In connection with our
work on rearrangement reactions of chiral diazonium inter-
mediates,[7] we speculated that enantioselective protonation
in the initial step might give either 1 or 3, and subsequent
nucleophilic addition could provide chiral a- or b-acyloxy-
substituted esters (2 or 4, R3 = COOR4), which are valuable
building blocks for the construction of natural products and
biologically active molecules.[8]
Coordination of a Brønsted acid to a Lewis acid increases
its acidity and reactivity. Yamamoto, Ishihara, and co-workers
have developed Lewis acid assisted Brønsted acids (LBAs) as
chiral proton reagents and have successfully applied these
LBAs to various enantioselective reactions.[9] We envisioned
that coordination of a carboxylic acid[10] to the chiral
oxazaborolidinium ion (COBI)[11] 5 would generate the new
chiral proton reagent 6 as an LBA [Scheme 1, Eq. (2)].[12] We
decided to investigate whether 6 could facilitate an enantio-
selective protonation of a diazoester with subsequent nucleo-
philic addition to afford enantioenriched a- or b-acyloxy
esters. Herein, we describe the first example of a catalytic
enantioselective protonation/nucleophilic addition of diazo-
esters to afford highly optically active a-aryl-b-acyloxy esters.
To test this hypothesis, our exploration was initially
carried out with achiral LBAs which were generated in situ
from benzoic acid and various Lewis acids. While the reaction
of a-benzyl diazoester and benzoic acid did not proceed
without a Lewis acid activator, all achiral LBAs increased the
acidity of benzoic acid and provided a mixture of a- and b-
acyloxy ester compounds (Table 1, entries 1–5). Among the
Lewis acids, only BF3·OEt2-activated benzoic acid showed
catalytic activity, thus giving the best yield and selectivity
(entry 5). When the reaction was carried out at À788C in
dichloromethane, the b-acyloxy ester 4 was obtained as the
major product in 81% yield by addition to the sterically less
[*] K.-T. Kang, S. T. Kim, Prof. Dr. D. H. Ryu
Department of Chemistry, Sungkyunkwan University
300, Cheoncheon, Jangan, Suwon, 16419 (Korea)
E-mail: dhryu@skku.edu
K.-T. Kang, Prof. Dr. G.-S. Hwang
Western Seoul Center, Korea Basic Science Institute
150, Bugahyeon-ro, Seodaemun-gu, Seoul, 03759 (Korea)
E-mail: gshwang@kbsi.re.kr
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201612655.
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Table 1: Optimization of the enantioselective protonation/nucleophilic
addition.[a]
Table 2: Substrate scope with respect to the carboxylic acid.[a]
Entry
4
R1
t [h]
4/2[b]
Yield [%][c]
ee [%][d]
1
2
3
4
4a
4d
4e
4 f
4g
4h
4i
Ph
0.5
0.5
0.5
1
1
4
4
3
1
90:10
80:20
83:17
75:25
80:20
83:17
80:20
67:33
80:20
86
75
81
70
75
83
73
66
77
98
93
92
92
99
86
85
85
90
4-MeC6H4
4-MeOC6H4
4-BrC6H4
2,5-F2C6H3
4-CF3C6H4
4-NO2C6H4
2,4,6-Me3C6H2
2-Np
Entry
4
Cat.
R4
4/2[b]
Yield [%][c]
ee [%][d]
5
6[e]
7[e]
8[e]
9
1
2
3
4
5
6
7
8
–
none
TiCl4
Sc(OTf)3
SnCl4
BF3·OEt2
5a
5b
5c
5c
5c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
–
–
–
–
–
–
–
83
98
98
93
98
63
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
67:33
75:25
67:33
88:12
83:17
86:14
90:10
50:50
86:14
75:25
13
32
21
81
77
81
86
41
82
72
4j
4k
[a] The reaction of diazoester (0.22 mmol) with carboxylic acid
(0.2 mmol) was performed in the presence of 5c (20 mol%) in 1.4 mL of
dichloromethane at À788C. [b] Determined by 1H NMR analysis of the
crude reaction mixture. [c] Yield of isolated 4. [d] The ee value of 4 was
determined by chiral-phase HPLC. [e] The reaction was performed at
08C. Np=naphthyl.
9[e]
10
11
5c
tBu
[a] The reaction of diazoester (0.22 mmol) with benzoic acid (0.2 mmol)
was performed in the presence of catalyst (20 mol%) in 1.4 mL of
dichloromethane at À788C for 0.5 h. [b] Determined by 1H NMR analysis
of the crude reaction mixture. [c] Yield of isolated 4. [d] The ee value of 4
was determined by chiral-phase HPLC. [e] The reaction was performed in
toluene. Tf=trifluoromethanesulfonyl.
the reaction rate to afford the desired product in lower yield
and enantioselectivity (entry 8), presumably because the
bulky 2,4,6-trimethyl benzoic acid significantly reduces the
degree of complexation with 5 in the formation of 6
[Scheme 1, Eq. (2)]. 2-Naphthoic acid was a suitable substrate
for the reaction, thus affording the corresponding product 4k
in 77% yield and 90% ee (entry 9).
hindered site of 3 (Scheme 1, pathway b). A minor product,
the a-acyloxy ester 2, was also isolated in 17% yield
(Scheme 1, pathway a or c). Next, the enantioselective
protonation/nucleophilic addition reaction was examined in
the presence of 20 mol% COBI 5a (Table 1, entry 6). When
the reaction was carried out at À788C in dichloromethane, the
b-acyloxy ester 4 was obtained as the major product in 77%
yield and 83% ee. We then screened the catalyst structure and
found that the catalyst system with Ar= 3,5-dimethylphenyl
and R = phenyl gave the best result. The yield and ee value of
4 improved to 86 and 98%, respectively, with a 4/2 ratio of
90:10 (entry 8). Use of the nonpolar solvent toluene led to
a decreased ratio of 4 (entries 8 and 9). Replacement of the
methyl group of the diazoester to a more sterically hindered
ethyl or tert-butyl group diminished the ratio of 4/2 as well as
the enantioselectivities (entries 8, 10, and 11). For the
successful implementation of the diazoester, methyl diazo-
ester was selected for the enantioselective protonation/
nucleophilic addition (entries 6–8).
Using the optimized reaction conditions for the new
catalytic enantioselective protonation/nucleophilic addition,
we evaluated this methodology with a range of substituted
benzoic acids (Table 2).[13] As summarized in Table 2, regard-
less of the electronic properties of the R1 group, the reactions
proceeded with good regioselectivities, and the corresponding
b-acyloxy esters 4 were obtained in good yields with high
enantioselectivities (entries 1–9). Electron-withdrawing sub-
stituents such as either p-CF3 or p-NO2 significantly retarded
the reaction in comparison with electron-donating substitu-
ents such as p-methyl or p-methoxy (entries 2, 3 and 6, 7). The
sterically more hindered 2,4,6-trimethyl substituent reduced
To further investigate the substrate scope of the present
catalytic system, we performed the catalytic enantioselective
protonation/nucleophilic addition with a range of diazoesters.
As summarized in Table 3, the electronic properties of the
aryl group (R5) in the diazoester obviously affected the yield
and enantioselectivity of the product (entries 1–13). In cases
Table 3: Substrate scope with respect to the a-diazoester.[a]
Entry Product R5
t [h]
4/2[b] Yield [%][c] ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4l
Ph
0.5
2
2
0.5
2
2
90:10
94:6
75:25
94:6
98:2
67:33
98:2
86
91
73
93
97
60
96
90
81
55
57
92
95
47
98
90
85
95
91
99
96
92
95
98
96
98
64
76
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
1,3-benzodioxole
2-Np
4-BrC6H4
4-FC6H4
4-CF3C6H4
4-NO2C6H4
Me
4m
4n
4o
4p
4q
4r
4s
4t
4u
2v
2w
2x
0.5
2
91:9
0.5
0.5
0.5
0.5
0.2
86:14
67:33
67:33
6:94
3:97
0.5 <5:95
[a] The reaction of diazoester (0.22 mmol) with benzoic acid (0.2 mmol)
was performed in the presence of 5c (20 mol%), in 1.4 mL of
dichloromethane at À788C. [b] Determined by 1H NMR analysis of the
crude reaction mixture. [c] Yield of isolated major product. [d] The
ee value of the major product was determined by chiral-phase HPLC.
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of electron-rich substituted benzyl diazoester substrates, the
b-acyloxy esters 4 were obtained as the major products with
consistently high enantioselectivities (entries 2–8). Methyl- or
methoxy-substituted benzyl diazoesters at the meta position
significantly reduced the regioselectivity in comparison with
ortho- or para-substituted diazoesters (entries 2, 4, 5, 7 and 3,
6). It is notable that the large 2-naphthyl-substituted a-methyl
diazoester effectively reacted with benzoic acid to give good
results (entry 9). While a weak electron-withdrawing group,
such as p-halogen-substituted benzyl diazoesters, provided
the corresponding b-acyloxy esters 4 in good yields and high
enantioselectivities (entries 10 and 11), a strong electron-
withdrawing group, for example, p-CF3- or p-NO2-substituted
substrates, provided the a-acyloxy ester[8c] 2 as the major
product instead of 4 (entries 12 and 13). We expect that this
result reflects a more favorable pathway a [Scheme 1, Eq. (1)]
because of the instability of 3.[6e] As expected, reactions of a-
diazobutanoate ester provided only the a-acyloxy ester 2 by
pathway a in 47% yield with moderate enantioselectivity
(Table 3, entry 14).
Scheme 3. Evidence of the enantioselective protonation/nucleophilic
addition pathway.
a mixture of deuterated and nondeuterated benzoic acid, and
the kH/kD was found to be 3.23 (Scheme 4), which suggests
that protonation of the diazoester is under the influence of
a primary kinetic isotope effect (PKIE),[5a] and that enantio-
selective protonation rather than nucleophilic addition is the
rate-determining step.
The feasibility of reducing the catalyst loading and
increasing the reaction scale to gram scale was examined
(Scheme 2). The loading of 5c could be reduced to 4 mol%
Scheme 4. Kinetic isotope effect experiment.
The observed stereochemistry for the enantioselective
protonation/nucleophilic addition using 6, derived from (S)-
COBI catalyst 5c, can be rationalized using the transition
state model shown in Figure 1. In the pre-transition state
Scheme 2. Gram-scale experiment and enantioselective synthesis of
(S)-tropic acid methyl ester.
while maintaining excellent yields and enantioselectivities.
The synthetic utility of the present reaction was further
demonstrated by synthesis of (S)-tropic acid methyl ester (7).
(S)-Tropic acid is an important building block for biologically
active tropane alkaloids, such as atropine and scopolamine.[14]
Comparison of the optical rotation data of 7 confirmed the
absolute (S) stereochemistry of 4.[15]
Our attention next turned to elucidating the mechanism of
this novel transformation. On treatment of methyl a-benzyl
diazoester with [D]benzoic acid (> 95% D) under BF3·OEt2
catalysis, the protonation/nucleophilic addition proceeded to
give the corresponding deuterated product 8 (Scheme 3,
conditions a). The NMR spectrum revealed greater than 98%
deuterium incorporation at the a-position of the diazoester.
In addition, we performed a deuterium-labeling experiment
with the COBI catalyst, and it yielded 8 with 82% deuterium
incorporation at the chiral center (Scheme 3, conditions b).
Considering about a 20% exchange of deuterium with the
ammonium proton of COBI 5c, this result indicates that the
hydrogen atom on the chiral center was derived exclusively
from the [D]benzoic acid. For further mechanistic insight,
a kinetic isotope effect (KIE) experiment was conducted with
Figure 1. Transition-state model for the enantioselective protonation/
nucleophilic addition of an a-benzyl diazoester with benzoic acid,
catalyzed by 5c.
assembly 9, the carboxylic acid group is situated above the
3,5-dimethylphenyl group, which effectively shields the back
face from attack by the diazoester. Because of the dipole–
dipole interaction between the two carbonyl groups, the
diazoester approaches the carboxylic acid for protonation
with the ester group situated away from the carboxylic acid
group. Meanwhile, an apparent p–p interaction between the
aryl ring of the benzoic acid and the diazoester aryl group
holds the two aryl rings together.[16] Thus, protonation of the
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protonation/nucleophilic addition of diazoesters using the
new chiral LBA catalyst 6, prepared from COBI as a Lewis
acid, and a carboxylic acid as a Brønsted acid. In the presence
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absolute configuration of the product was the same as
predicted by the transition state model in Figure 1. We
believe that there are many potential uses for 6 in catalytic
enantioselective syntheses beyond those outlined here. Other
applications of 6 and further mechanistic studies are under-
way.
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Acknowledgments
This research was supported by the National Research
Foundation of Korea(NRF) grant funded by the Korea
government (MSIP; No. NRF-2016R1A2B3007119, No.
2016R1A4A1011451, No. NRF-2015H1A2A1034266), the
National Research Council of Science and Technology
(CAP-2012-2-KBSI), and Korea Basic Science Institute
(C37705).
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · boron · Brønsted acid ·
diazo compounds · reaction mechanisms
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4908 – 4944. For a selected paper on p-p interaction, see:
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5525 – 5534.
[12] For NMR analysis of LBA 6, see the Supporting Information.
[13] Enantioselective protonation-nucleophilic addition between
acetic acid and methyl a-benzyl diazoester provided the
a-acyloxy ester as a major product in about 40% yield and
40% ee with a 4/2 ratio of 1:3.
[14] a) E. Leete, J. Am. Chem. Soc. 1960, 82, 612 – 614; b) N.
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Manuscript received: December 31, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
K.-T. Kang, S. T. Kim, G.-S. Hwang,*
D. H. Ryu*
&&&& — &&&&
Catalytic Enantioselective Protonation/
Nucleophilic Addition of Diazoesters with
Chiral Oxazaborolidinium Ion Activated
Carboxylic Acids
COBI-Wan: A new chiral Brønsted acid
derived from a carboxylic acid and a chiral
oxazaborolidinium ion (COBI), as an
activator, is introduced. This acid was
successfully applied as a catalyst for the
highly enantioselective protonation/
nucleophilic addition of diazoesters and
carboxylic acids. Tf=trifluoromethane-
sulfonyl.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!