Amine-Urea-Mediated Asymmetric Cycloadditions between Nitrile Oxides and o-Hydroxystyrenes by Dual Activation

Article abstract of DOI:10.1002/anie.201705662

The first example of asymmetric 1,3-dipolar cycloadditions between nitrile oxides and o-hydroxystyrenes, mediated by cinchona-alkaloid-based amine-ureas is reported. The method is based on a dual activation involving both LUMO and HOMO activations. In addition to the stoichiometric asymmetric induction, a catalytic amount of amine-urea enables the cycloadditions to proceed in an enantioselective manner. Computational studies strongly support the HOMO activation of o-hydroxystyrenes and LUMO activation of nitrile oxides by hydrogen-bonding interactions with the Br?nsted acid/base bifunctional catalyst.

Full text of DOI:10.1002/anie.201705662

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Accepted Article
Title: Amine-urea Mediated Asymmetric Cycloadditions between Nitrile
Oxides and o-Hydroxystyrenes by Dual Activation, and Their
Computational Studies
Authors: Hiroyuki Suga, Yohei Hashimoto, Yasunori Toda, Kazuaki
Fukushima, Hiroyoshi Esaki, and Ayaka Kikuchi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705662
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Amine-urea Mediated Asymmetric Cycloadditions between Nitrile
Oxides and o-Hydroxystyrenes by Dual Activation, and Their
Computational Studies
Hiroyuki Suga,* Yohei Hashimoto, Yasunori Toda, Kazuaki Fukushima, Hiroyoshi Esaki, and Ayaka
Kikuchi
Abstract: The first example of cinchona alkaloid-based amine-urea-
mediated asymmetric 1,3-dipolar cycloadditions between nitrile
oxides and o-hydroxystyrenes, based on the dual activation
methodology involving both LUMO and HOMO activations, is
described. In addition to stoichiometric asymmetric induction, a
catalytic amount of amine-urea enables the cycloadditions in an
enantioselective manner. Computational studies strongly support the
HOMO activation of o-hydroxystyrenes and LUMO activation of
nitrile oxides via hydrogen-bonding interactions by a Brønsted
acid/base bifunctional catalyst.
1,3-Dipolar cycloadditions (1,3-DCs) between nitrile oxides and
olefins have served as a highly efficient methodology for the
synthesis of isoxazolines.[1] These isoxazolines can then be
converted to -aminoalcohols and -hydroxy ketones via
reductive cleavage of the N-O bond, while retaining
stereochemistry. Thus, the sequence of 1,3-DC followed by N-O
reductive cleavage has been utilized for the construction of
various natural products that possess continuous stereogenic
Figure 1. Working hypothesis based on dual activation by
bifunctional organocatalyst.
centers.[2] It is therefore necessary to develop enantioselective
1,3-DCs of nitrile oxides, as well as chiral substrate-based
diastereoselective 1,3-DCs.[3] For non-linear 1,3-dipoles, such as
achieve high enantioselectivity, we propose a novel dual-
activation strategy involving LUMO activation by a Brønsted acid
and HOMO activation by a Brønsted base in inverse electron-
nitrones and azomethine imines, a number of enantioselective
cycloadditions using chiral Lewis acids have been reported,[4]
and these types of transformations have also been reported
using several organocatalysts.[5] By contrast, there are only a
few examples of enantioselective 1,3-DCs of nitrile oxides (linear
1,3-dipoles) using chiral Lewis acids[6] or metal catalysts[7]. This
can be due to their linear structure, which lacks an enantioface
and higher reactivity, allowing non-catalytic reaction to proceed
easily in the background (Figure 1a and 1b). Furthermore, to the
best of our knowledge, enantioselective 1,3-DCs of nitrile oxides
that involve organocatalytic variants or even in the presence of
stoichiometric amounts of chiral organic media, have yet to be
demonstrated.[8] To overcome the intrinsic challenge and
demand 1,3-DCs between nitrile oxides
1
and o-
hydroxystyrenes 2 employing chiral amine-urea 3 (Figure 1c).[9]
Double hydrogen-bonding interactions between the urea moiety
of 3 and the oxygen atom of 1 would construct a plane to
distinguish the orientations of dipolarophile 2.[9m] Although
inverse electron-demand 1,3-DCs of azomethine imines with o-
hydroxystyrenes catalyzed by a chiral Brønsted acid have been
reported by Shi and co-workers,[5f] this approach can empower
bifunctional amine-urea catalysis as the premier organocatalytic
method for asymmetric transformation of linear 1,3-dipoles.
Initially, cycloadditions between isolable nitrile oxide 1a
and o-hydroxystyrene (2a) were carried out in toluene in the
presence of various chiral amine-ureas (See Supporting
Information (SI) for details). After screening numerous variations
of the reaction, the optimal enantioselectivity was achieved at
0 °C using amine-urea 3a (R3 = vinyl) at a concentration of 0.2 M
(Scheme 1, 89% ee for 4aa). To assess the influence of the
hydroxy group on the enantioselectivity, we examined the
relationship between the position of the hydroxy group and the
corresponding hydrogen-bond donors. In contrast to 2a,
attempts using m- and p-hydroxystyrene (2b and 2c), and o-
methoxystyrene (2d) resulted in little or no asymmetric induction
in the presence of 3a. Likewise, the reaction involving
homoallylic alcohol (2e) did not exhibit any significant
[*]
Prof. Dr. H. Suga, Y. Hashimoto, Dr. Y. Toda, A. Kikuchi
Department of Chemistry and Material Engineering, Faculty of
Engineering, Shinshu University
Wakasato, Nagano 380-8553 (Japan)
E-mail: sugahio@shinshu-u.ac.jp (H.S.)
Homepage: http://www.shinshu-
u.ac.jp/faculty/engineering/chair/chem002/e_index.html
Prof. Dr. K. Fukushima, Dr. H. Esaki
Department of Chemistry, Hyogo College of Medicine
Mukogawa-cho, Nishinomiya, Hyogo 663-8501 (Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705662
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the reaction afforded the 4-methyl regioisomer 4am with high
regioselectivity (4am/4am’ = 91:9, 93% combined yield) and
enantioselectivity (94% ee, 4am). Notably, no cis-cycloadducts
were observed from trans-alkene 2m, implying that this reaction
proceeded through a concerted pathway.
Scheme 1. Initial studies
To gain insight into the mechanism of asymmetric
induction, the 1,3-DC between 1a and 2i was studied using
density functional theory (DFT). Recently, Houk et al. reported
on computational studies of an asymmetric conjugate addition
reaction catalyzed by
a cinchona alkaloid-derived amine-
urea.[9c,11] For protonated 3c (Figure 1, R3 = Me), the anti-open
and syn-open conformers were proved to be favored over other
conformers.[12] On the basis of Houk’s system, four possible
transition states (TSs) [(a) anti-open TS (S), (b) syn-open TS (S),
(c) anti-open TS (R), (d) syn-open TS (R)] were generated
(Figure 3, see SI for full computational details). We ruled out the
TS models in which the phenoxide generated from 2 coordinates
with the urea moiety of protonated 3, while this activation mode
has often been used to explain (thio)urea-tertiary amine
organocatalysis.[13] This is because no proton transfer between 1
and 2 is required during the course of the 1,3-DC.
asymmetric induction. These results suggest that the acidity and
the position of the hydroxy group are crucial for obtaining high
levels of enantioselection.
Table 1 summarizes the scope of asymmetric 1,3-DCs. For
isolable nitrile oxides, the reactions proceeded smoothly to
afford the corresponding cycloadducts in high yields with 78 –
95% ee (Table 1a). X-ray crystal structure analysis was
employed to determine the absolute configuration of
enantiomerically pure 4da, in which the methine carbon at the 5-
position was determined to possess an (S)-configuration (see
SI). Next, the scope of the o-hydroxystyrenes was examined
(Table 1b). Although the inclusion of substituents such as 5-Br,
5-OMe, 4-OMe, or 3-OEt led to comparable enantioselectivities,
the inclusion of a 3-OMe substituent produced a dramatic
increase in enantioselectivity (96% ee for 4ai). Conversely,
decreased enantioselectivies were observed for 4ak and 4al.
The 1,3-DC of 1a with trans--substituted o-hydroxystyrene 2m
exhibited intriguing results in terms of not only enantioselectivity
but also regioselectivity. In the absence of 3b (Figure 1, R3 = Et),
the reaction favored the 5-methyl regioisomer 4am’ (4am/4am’ =
27:73, 83% combined yield).[10] In the presence of 3b, however,
All calculations were performed using the M06-2X/def2-
TZVPP-IEFPCM (toluene)//M06-2X/6-31G(d)-IEFPCM (toluene)
level of theory with Gaussian09 D.01.[14,15] The intrinsic reaction
coordinate (IRC) approach was used to search for pre-reaction
complexes (PCs) and products. First, TSs providing (S)-products
were considered since (S)-4 was experimentally obtained as a
major enantiomer (4da in Table 1). Although anti-open TS (S)
was favored over syn-open TS (S) by only Gǂ = 0.7 kcal mol-1,
anti-open PC (S) was favored over syn-open PC (S) by G = 2.3
kcal mol-1 (Figure 2a vs. 2b, and Figure 3). Hydrogen-bonding
interactions between the amine N and the phenol H (1.74 – 1.76
Å) and between the nitrile oxide O and the urea H (1.87 – 2.20
Å) were apparent in the TSs. From these results and the energy
profiles, it is highly likely that the reaction involving anti-open TS
(S) is the preferred pathway for the 1,3-DC between 1a and 2i.
Regarding the TSs, the 1,3-DC proceeds through a concerted
but asynchronous pathway, where the C-O bond lengths (2.41 –
2.45 Å) are longer than C-C bonds (2.14 – 2.15 Å). To further
explore the mechanism behind the high enantioselectivities of
asymmetric 1,3-DCs, energies were calculated for anti-open TS
(R), which corresponds to the (R)-isomer of the cycloadduct.
The Gǂ energy for the anti-open TS (R)-conformation was
higher than that of the (S)-conformation by 6.2 kcal mol-1 (Figure
2a vs. 2c). The energy profiles also indicate that the anti-open
(S) arrangement is favored over the anti-open (R) in terms of
their pre-reaction complexes as well as their TSs. Moreover,
even in comparison with the syn-open TS (R), it was confirmed
that the anti-open TS (S) is the lowest energy TS (Figure 2a vs.
2d). On the other hand, in order to validate our working
hypothesis, i.e. the dual-activation strategy, we calculated the
HOMO–LUMO gap between 1a and 2i (see SI for details). The
gap is smaller for LUMO_1a–HOMO_2i than for LUMO_2i–
HOMO_1a (155.5 vs. 174.3 kcal mol-1), which suggests that the
1,3-DCs proceed in an inverse electron-demand fashion.
Importantly, both the LUMO_1a and HOMO_2i can be activated
by 3a engaging the two reactants (overall 11.2 kcal mol-1
preferred).
Table 1. Scope of asymmetric 1,3-DCs[a]
[a]All reactions were carried out using 0.1 mmol of 1. Isolated yields are shown.
[b]0.1 M. [c]-20 oC. [d]Amine-urea 3b was used (at 26 oC).
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Figure 2. TSs corresponding to the anti-open and syn-open conformers of protonated 3a. M06-2X/def2-TZVPP-IEFPCM
(toluene)//M06-2X/6-31G(d)-IEFPCM (toluene). Noncritical hydrogen atoms omitted for clarity. Energy in kcal mol-1.
Scheme 2. Enantioselective 1,3-DCs of nitrile oxides
(a)
R1
3a
Amine-urea
(30 mol %)
OH
N
R1
O
OMe
C
N O
OH
OMe
Toluene (0.1 M)
–20 ºC
1
2i
(2 equiv)
4
R1:
OMe
OMe
Cl
9-anthracenyl-
[b]
4ei
(24 h)
MeO
OMe MeO
OMe
Cl
Cl
93%, 93% ee
tBu-
[a,b]
4bi
4ci
4di
(16 h)
(192 h)
(16 h)
4ai
(36 h)
4fi
(24 h)
91%, 92% ee
95%, 85% ee 90%, 91% ee
96%, 94% ee
90%, 96% ee
[a]0.2 M. [b]0 °C.
(b)
3a
Amine-urea
(30 or 100 mol %)
Cs2CO3
or Et3N
O
N
C
OH
N
O
R1
Figure 3. Energy profiles of the 1,3-DC. Energy in kcal mol-1.
N
2
+
OH
R1
nitrile oxide
generation[c]
Cl
Toluene
–20 or 0 ºC
R1
5
Encouraged by the results of the DFT calculations, we
finally attempted the catalytic enantioselective reactions shown
in Scheme 2a. It is noteworthy that the use of a catalytic amount
(30 mol %) of 3a enhanced the asymmetric 1,3-DCs between 2i
and isolable nitrile oxides resulting in high yields and
enantioselectivities (85 – 96% ee).[16,17] The catalysis was also
applicable to the reactions between o-hydroxystyrenes and
unstable nitrile oxides that are generated from hydroxymoyl
chlorides 5 with a base, providing cycloadducts 4 in high yields
with good to high enantioselectivities (Scheme 2b).
In conclusion, we have developed the first example of
highly enantioselective cinchona alkaloid-based amine-urea-
mediated 1,3-DCs between nitrile oxides and o-hydroxystyrenes
involving the dual activation methodology. The high levels of
asymmetric induction are strongly supported by DFT
calculations of the energy differences between the anti-open TS
(S) and anti-open TS (R). Asymmetric 1,3-DCs of other dipoles
based on the methodology described herein are currently under
investigation in our laboratory.
1
4
G
N
Cy
N
N
N
O
F
tBu
Ph
Cy
O
O
O
OH
OH
OH
OH
F
4fa
4ga
4hn
4ho
(100 mol %)
90%, 82% ee
(100 mol %)
90%, 91% ee
(100 mol %)
92%, 83% ee
(100 mol %)
87%, 73% ee
N
N
N
tBu
Ph
Cy
O
O
O
OH
OMe
OH
OMe
OH
OMe
4fi
4gi
4hi
(30 mol %)
86%, 90% ee
(30 mol %)
93%, 80% ee
(30 mol %)
94%, 75% ee
[c]See supporting information for details of the reaction conditions.
Keywords: nitrile oxide • 1,3-dipolar cycloaddition • isooxazoline
• organocatalyst • bifunctional catalyst
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This work was supported in part by the Japan Society for the
Promotion of Science (JSPS) through
a Grant-in-Aid for
Scientific Research (C) (Grant No. JP15K05497).
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Entry for the Table of Contents (Please choose one layout)
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Hiroyuki Suga,* Yohei Hashimoto,
Yasunori Toda, Kazuaki Fukushima,
Hiroyoshi Esaki, and Ayaka Kikuchi
Page No. – Page No.
Amine-urea Mediated Asymmetric
Cycloadditions between Nitrile
Oxides and o-Hydroxystyrenes by
Dual Activation, and Their
The first example of cinchona alkaloid-based amine-urea-mediated asymmetric 1,3-
dipolar cycloadditions between nitrile oxides and o-hydroxystyrenes, based on the
dual activation methodology involving both LUMO and HOMO activations, is
described. Computational studies strongly support the HOMO activation of o-
hydroxystyrenes and LUMO activation of nitrile oxides via hydrogen-bonding
interactions by a Brønsted acid/base bifunctional catalyst.
Computational Studies
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