Catalytic Enantioselective [3 + 2] Cycloaddition of α-Keto Ester Enolates and Nitrile Oxides

Article abstract of DOI:10.1021/jacs.7b03782

An enantioselective [3 + 2] cycloaddition reaction between nitrile oxides and transiently generated enolates of α-keto esters has been developed. The catalyst system was found to be compatible with in situ nitrile oxide-generation conditions. A versatile array of nitrile oxides and α-keto esters could participate in the cycloaddition, providing novel 5-hydroxy-2-isoxazolines in high chemical yield with high levels of diastereo- and enantioselectivity. Notably, the optimal reaction conditions circumvented concurrent reactions via O-imidoylation and hetero-[3 + 2] pathways.

Full text of DOI:10.1021/jacs.7b03782

Article
pubs.acs.org/JACS
Catalytic Enantioselective [3 + 2] Cycloaddition of α‑Keto Ester
Enolates and Nitrile Oxides
Samuel L. Bartlett,† Yoshihiro Sohtome,* Daisuke Hashizume, Peter S. White, Miki Sawamura,
,‡,§
,†,‡
∥
§
†
,§
,†,‡
Jeffrey S. Johnson,* and Mikiko Sodeoka*
†
‡
∥
Synthetic Organic Chemistry Laboratory, RIKEN Center for Sustainable Resource Science, and RIKEN Center for Emergent
Matter Science, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
§
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S Supporting Information
*
ABSTRACT: An enantioselective [3 + 2] cycloaddition
reaction between nitrile oxides and transiently generated
enolates of α-keto esters has been developed. The catalyst
system was found to be compatible with in situ nitrile oxide-
generation conditions. A versatile array of nitrile oxides and α-
keto esters could participate in the cycloaddition, providing
novel 5-hydroxy-2-isoxazolines in high chemical yield with high
levels of diastereo- and enantioselectivity. Notably, the optimal
reaction conditions circumvented concurrent reactions via O-
imidoylation and hetero-[3 + 2] pathways.
INTRODUCTION
achieving catalytic asymmetric dipolar cycloadditions by way of
HOMO-raising activation exists. Yanagisawa and co-workers
reported the cycloaddition of nitrones and alkenyl acetates and
proposed the intermediacy of catalytically formed tin(IV)
■
Heterocycles are routinely encountered as structural units of
1
2
biologically active unnatural and natural organic compounds.
The contemporary chemist has at his or her disposal myriad
modern methods to synthesize heterocyclic structures, yet the
time-honored cycloaddition reaction between an olefin and
reactive 1,3-dipoles is central because of its chemical efficiency
and the breadth of structures accessible. The development of
new catalytic asymmetric 1,3-dipolar cycloaddition reactions
holds significant potential for the preparation of enantioen-
9
enolates. Additionally, enamine catalysis has been used to
facilitate asymmetric [3 + 2] cycloadditions of aldehydes and
10,11
azomethine imines.
Building on this concept, we recently
3
,4
developed a catalytic asymmetric [3 + 2] cycloaddition of α-
12
keto ester enolates and nitrones inspired by the structural
characterization of a Ni(II)−diamine catalyst that merges
1
3
5
Ni(II)−enolate and hydrogen-bonding activation modes.
riched five-membered heterocyclic scaffolds. In particular, new
However, the scope of the process was limited to isolable
E)-nitrones, specifically dihydroquinoline derivatives. The
activation modes allow the union of 1,3-dipoles with
unprecedented reaction partners. Herein we describe a catalytic
asymmetric [3 + 2] cycloaddition between in situ-generated
nitrile oxides and catalytically generated transition metal
enolates of α-keto esters.
(
generation of heretofore unknown isoxazolines via the reaction
of an ephemeral metalloenolate with a transient nitrile oxide
emerged as an attractive yet challenging next step (Scheme 1,
14
bottom).
Our groups have reported that late transition-metal
complexes act as catalysts for reactions that proceed via the
RESULTS AND DISCUSSION
6
■
soft enolization of carbonyl compounds. Transformations
6a
At the outset, we perceived a number of unique challenges to
our reaction plan. Foremost among these is the inherent
instability of nitrile oxides toward dimerization (Scheme 1, path
developed under this paradigm include Michael, halogen-
6
b,c
6d
6e
ation,
Mannich, and aldol reactions of β-keto esters as
6h,f
6g−i
well as Michael additions and halogenations
using α-keto
1
5,3b
7
A)
and the need to generate them in situ via base-mediated
esters as pronucleophiles. The integration of unconventional
electrophiles under this mechanistic construct carries with it the
possibility to create heretofore unknown compounds: 1,3-
dipolar synthons emerged as attractive targets. Sustmann
classified 1,3-dipolar cycloadditions based on the relevant
dehydrohalogenation of the corresponding hydroximoyl
16
chloride or by the dehydration of nitroalkanes. Additionally,
our laboratories have observed that α-keto esters 1 react via a
homoaldol reaction (path B) in the absence of other viable
pathways. The known hetero [3 + 2]-cycloaddition of nitrile
oxides with α-keto esters defines a third relative-rate concern
8
FMO interactions: type III cycloadditions are controlled by
the HOMO of the dipolarophile and the LUMO of the dipole
(
Scheme 1, top). Drawing a parallel with electron-rich
5
a−d
dipolarophiles,
we postulated that transition-metal enolates
Received: April 14, 2017
Published: June 5, 2017
could engage dipoles in [3 + 2] cycloadditions. Precedent for
©
2017 American Chemical Society
8661
DOI: 10.1021/jacs.7b03782
J. Am. Chem. Soc. 2017, 139, 8661−8666

Journal of the American Chemical Society
Article
Scheme 1. Dipolar Cycloaddition by Dual Reagent Activation
1
7
19
(
path C), especially since the latter will be present in great
dr), although the concurrence of the undesired hetero [3 +
2]-pathway was still observed. Diamine complexes of Ni(II)
excess relative to the derived metalloenolate. Finally, the
inherent competition of O- versus C-trapping of metal-
loenolates (path D vs E) must be effectively managed for a
successful outcome.
20
and Cu(II) exhibit distinct coordination geometries, thereby
leading to different coordination modes for the derived
enolates. We postulate that these differences are manifested
in opposite enantiofacial selectivity and preferential chiral
recognition of geometrically different nitrones and nitrile oxides
by the Ni(II) and Cu(II) complexes, respectively, via hydrogen
bonding with the H-bond-donating diamine ligand. A detailed
discussion of this effect can be found in the SI. Along these
lines, the inclination of Ni(II) enolates to undergo O-trapping
may, in part, result from a kinetic preference for this pathway
induced by the distinct geometry of Ni(II)-enolates.
Even though exchanging the cyclohexyl-substituted ligand B
with the benzyl-type ligand C did not lead to an improvement
in chemoselectivity, a noticeable enhancement in enantiose-
lectivity was observed (Table 1, entry 8: 74% ee). Further
solvent screening was performed. Whereas no improvement in
chemoselectivity occurred in DCM (Table 1, entry 9: 1:5 3a/
4a), 3a was favored slightly in PhMe (Table 1, entry 10: 1.6:1
3a/4a). Along with others, we have noted that reactions
involving transition-metal enolates display enhanced rates in
We hypothesized that the Ni(II) catalyst developed for the
12
cycloaddition of nitrones with α-keto ester 1 would display a
similar efficiency with nitrile oxides and that running the
reaction at −40 °C would preclude the undesired dioxazole
coproduct 4 (Table 1). Catalytic amounts of tertiary amine
bases have been shown to accelerate reactions involving
Ni(II)−enolates of α-keto esters, thus nitrile oxides were
generated in situ from hydroximoyl chlorides using triethyl-
amine. Hydroximoyl chloride 2a was chosen as a model
substrate. As shown in entries 1 and 2, when utilizing Ni(OAc)2
complexes of ligands A and B in the reactions, the conditions
did not favor the formation of the desired 5-hydroxy-2-
isoxazoline 3a. In addition to the anticipated dioxazole
coproduct 4a, the intervention of the O-imidoylation pathway
was concurrently observed (5a). However, we were
encouraged by the promising levels of stereoselectivity
observed for 3a (Table 1, entry 1: −82% ee, 11:1 dr and
entry 2: −53% ee, 11:1 dr) without interference by the
forecasted homodimerization (path A) and homoaldol (path B)
pathways. A solvent screen (entries 3−5) revealed that the
chemoselectivity could be dramatically improved (Table 1,
entry 5: 10:1 3a/5a) if N,N-dimethylformamide was employed
12
6h
1
8
6h,21
i
alcoholic solvent.
preference for the desired product 3a (Table 1, entry 11: 77%
yield, 70% ee, 11:1 dr). The protic solvent may promote
fragmentation of less-active catalyst oligomers, or catalyst
turnover from the Cu(II)-alkoxide intermediate proceeding [3
+ 2]-cycloaddition via protonolysis.
In fact, the use of PrOH gave a >20:1
2
2
i
as the solvent. In contrast, the use of PrOH as the solvent
induced a preference for 5a (Table 1, entry 6: 1:2 3a/5a).
Further screening of conditions with Ni(II) failed to yield
satisfactory results (See Supporting Information for details).
Switching to Cu(OAc) ·H O as the metal source in THF
completely eliminated the O-addition byproduct while favoring
the opposite enantiomer of 3a (Table 1, entry 7: 54% ee, 11:1
Having overcome the issue of low chemical yield, we shifted
our focus toward the influence of ligand structure on
enantioselectivity. The electronic features of the benzyl-type
ligands D and E have little influence on enantioselection (Table
1, entry 12: 66% ee and Table 1, entry 13: 64% ee). However,
the results with ligand F suggest that nonbonding interactions
2
2
8
662
DOI: 10.1021/jacs.7b03782
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Journal of the American Chemical Society
Article
Table 1. Reaction Optimization
c
d
d
e
entry
ligand
M(OAc)2
solvent
yield of 3a [%]
ratio 3:4:5
dr (3a)
ee major [%]
f
g
1
A
B
A
A
A
A
B
C
C
C
C
D
E
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
THF
THF
DCM
PhMe
DMF
34
20
22
25
65
24
<17
15
16
38
77
86
72
79
82
75
83
86
9
1:0.3:1
1:1:1
11:1
−82
−53
n.d.
n.d.
−58
−78
54
f
g
2
11:1
f
3
1:0.3:1
1:0.6:1
10:1:1
1:_:2
18:1
13:1
11:1
13:1
f
4
f
5
f
i
6
PrOH
h
g
7
THF
THF
DCM
PhMe
1:5:_
11:1
h
8
1:4:_
12:1
12:1
10:1
11:1
9:1
74
h
9
1:5:_
74
h
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
1.6:1:_
>20:1:_
8:1:_
70
h
h
h
h
h
I
i
PrOH
70
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
66
>20:1:_
>20:1:_
>20:1:_
>20:1:_
>20:1:_
>20:1:_
1:3:0.2
10:1
10:1
10:1
13:1
13:1
11:1
12:1
64
F
83
G
G
G
H
I
91
90
I
,
,
j
j
91
I
92
9,
j,k
8
a
b
c
Reactions were run on a 0.1 mmol scale; M(OAc) refers to hydrate. Used 20 mol % ligand and metal acetate unless otherwise noted. Isolated
2
d
1
e
yield. Determined by H NMR analysis of the crude reaction mixture, unless noted otherwise; _ = not observed HPLC analysis using a chiral
stationary phase, n.d. = not determined. Isolated complex used. Isolated dr. Catalyst complexed in situ. Used 5 mol % of isolated complex.
Consisted of 1.5 equiv 2, 2.5 equiv Et N. Scale of 0.2 mmol. Catalyst complexed in situ; 5 mol % loading.
f
g
h
I
j
k
3
are important (Table 1, entry 14: 83% ee). Ligand G provided
satisfactory levels of enantioselectivity (entry 15: 91% ee), and
we were pleased to find that the catalyst loading could be
reduced to 5 mol % without adversely influencing reactivity or
selectivity (entry 16). Additionally, the amounts of hydroximoyl
nitrile oxides also participated, and 4-PhC H -substituted 3d
6 4
and 4-MeC H -substituted 3e were obtained with similarly high
6
4
levels of diastereo- and enantioselectivity (Table 2, 3d: 58%
yield, 88% ee, 11:1 dr and 3e: 75% yield, 90% ee, 13:1 dr).
Mesityl ligand G displayed lower levels of enantioselection
when 2-substituted aryl nitrile oxides were used; however, the
2-CF3 analogue H promoted high selectivity with these
substrates. This effect was not as marked with smaller
substituents, as 2-FC H -subsituted 3f was obtained with high
chloride 2a and Et N could be reduced to 1.5 equiv and 2.5
3
equiv, respectively (entry 17). The 2-CF -substituted benzyl-
3
type ligand H also provided high selectivity for this substrate
(
entry 18: 92% ee) and was later found to be uniquely suited
6
4
for achieving high enantioselectivity with 2-substituted
benzenenitrile oxides. Finally, the reduced yield and stereo-
control obtained with N-Me ligand I suggest the secondary
diamine as a key design feature of the present catalyst system
levels of enantioselectivity using both catalysts (Table 2, ligand
G: 90% ee and ligand H: 92% ee). The difference in selectivity
increased upon moving from 2-OMe to the more sterically
demanding 2-Me substitution (Table 2, 3g: 80% ee vs 92% ee
and 3h: 76% ee vs 90% ee). The enantioselectivity difference
was accentuated in the case of 2-BrC H -substituted 3i, which
(
entry 19: 9% yield, 8% ee).
With suitable reaction conditions in hand, we sought to learn
6
4
how the steric and electronic parameters of the reaction
partners might affect the process (Table 2). Nitrile oxides
bearing electron-withdrawing groups in the 4-position were
tolerated under the optimized conditions. For instance, 4-
CF C H -substituted 3b and 4-FC H -substituted 3c were
obtained in good chemical yields with high levels of diastereo-
and enantioselectivity (Table 2, 3b: 91% yield, 90% ee, 10:1 dr
and 3c: 88% yield, 91% ee, 10:1 dr). Electron-rich aromatic
was obtained in 62% ee using the mesityl-substituted ligand G,
whereas the 2-CF C H -substituted ligand H provided 91% ee.
3
6
4
Heteroaromatic nitrile oxides were compatible with the
optimized reaction conditions; the 2-keto glutaric acid-derived
3-pyridyl-substituted 3j could be formed, albeit with lower
enantioselectivity (Table 2, 3j: 90% yield, 74% ee). Cyclo-
adduct 3k was obtained in good yield with excellent
diastereoselectivity, and with high levels of enantioselectivity
3
6
4
6
4
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Journal of the American Chemical Society
Article
a
Table 2. Scope of Reaction
a
The reactions were run on a 0.2 mmol scale, see SI for reaction times. Yields are for isolated products. Diastereomeric ratio (dr) values were
1
determined by H NMR analysis of the crude reaction mixture, isolated dr values were written in parentheses. The enantiomeric excess (ee) values
b
c
d
were determined by HPLC using a chiral stationary phase. Ligand G employed. Ligand H employed. 20 mol % Cu(OAc) −diamine employed.
2
e
3
.0 equiv of hydroximoyl chloride, 3.6 equiv of Et N.
3
i
(Table 2, 3k: 85% yield, 93% ee). The absolute stereochemistry
obtained for product 3s using the propyl-substituted analogue
of 3k was determined via X-ray crystallography, and the
configurations of the remaining products are assigned by
analogy. Other electronically diverse nitrile oxides reacted well
with this α-keto ester (3l−o). The homobenzyl-substituted α-
keto ester furnished the corresponding cycloadduct 3p in an
of our model α-keto ester 1a (Table 2, 88% ee). Finally, alkenyl
nitrile oxides are viable partners under the reaction conditions,
and the styryl isoxazoline 3t was obtained in good yield, as a
single diastereomer, with high levels of enantioselectivity
(Table 2, 65% yield, 20:1 dr, 90% ee). Unfortunately, aliphatic
nitrile oxides are not compatible at this stage of optimization
8
8% ee with high diastereoselection when the 2-FC H -
6 4
2
substituted hydroxyimidoyl chloride was employed. In contrast,
the n-propyl-substituted product 3q was formed with lower
levels of diastereoselectivity. A γ-branched α-keto ester could be
employed when the catalyst loading was increased to 20 mol %
(i.e. 3u). Aliphatic nitrile oxides are less stable than their sp -
15
carbon-substituted counterparts, and we believe that com-
petitive decomposition is to blame.
Having established the scope of this transformation, we
sought to study the reactivity of the CN bond installed
during the cycloaddition reaction (Scheme 2). We found that
the 2-ketoglutaric acid-derived cycloadduct 3k could be
prepared on a gram scale (2.5 mol % catalyst). Under the
(
Table 2, 3r: 45% yield, 14:1 dr, 83% ee). A β-aryl-substituted
2
α-keto ester (R = 3-tolyl) provided low diastereo- and
enantiocontrol during the formation of the cycloadduct (59%
yield, 1.3:1 dr, 62% ee and 68% ee, see SI for details). Similarly,
lower levels of enantiocontrol were observed for a product
23
action of NaBH /NiCl , 3k (90% ee) was converted to γ-
4
2
2
derived from a Me-substituted α-keto ester (R = Me) and 2-
lactam 6k containing three vicinal stereocenters (2.5 mmol
scale). Lactam 6k was moderately enriched upon recrystalliza-
tion, and the structure of this product was obtained via X-ray
fluorobenzonitrile oxide, although satisfactory levels of
diastereocontrol were maintained (79% yield, 54% ee, 7:1 dr,
see SI for details). The isoxazoline, derived from tert-butyl
24
crystallography.
2
pyruvate (R = H), was furnished in racemic form (58% yield,
The isoxazoline products delivered by the title reaction are
hemiacetals that could in principle coexist with their ring-
opened acyclic γ-oximo-α-keto ester isomers (7, Scheme 3).
2
% ee, see SI for details). The identity of the ester influenced
the enantiocontrol, as lower levels of enantioselectivity were
8
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DOI: 10.1021/jacs.7b03782
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Journal of the American Chemical Society
Article
Scheme 2. Gram Scale Reaction and Isoxazoline Reduction
AUTHOR INFORMATION
Corresponding Authors
sodeoka@riken.jp
jsj@unc.edu
sohtome@riken.jp
■
*
*
*
ORCID
Jeffrey S. Johnson: 0000-0001-8882-9881
Mikiko Sodeoka: 0000-0002-1344-364X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The work described was supported by project funding from
RIKEN (Y.S. and M.S.), Grant-in-Aid for Scientific Research
■
Scheme 3. Isoxazoline Hemiacetals Do Not Racemize via
Tautomerization
(
B) 17H02213 (Y.S.), Award GM R35 GM118055 from the
National Institutes of General Medical Sciences (J.S.J.), and an
NSF EAPSI/JSPS Summer Program Fellowship (S.L.B.).
RIKEN Hokusai GreatWave (GW) provided the computer
resources for the DFT calculations.
REFERENCES
■
Such structures would appear to be quite vulnerable toward
racemization via facile keto−enol tautomerization because of
the high C−H acidity of the methine proton (7 ⇆ 8). The
obtention of isoxazoline adducts 3 and a downstream adduct
such as 6k with high enantiomeric enrichment allows us to
draw conclusions regarding the intervention of the equilibria
depicted in Scheme 3. We hypothesize that the lack of
racemization stems from the high stability of the isoxazoline
hemiacetal that disfavors ring opening. Circumstantial evidence
against the formation of the acyclic oxime 7 is the constant
product diastereomeric ratio as a function of time: ring
opening/ring closure would presumably change the diastereo-
meric composition. The kinetic reluctance to form the oxime 7
may stem from the system’s preference to avoid the creation of
a highly electrophilic α-keto ester in the presence of multiple
electronegative atoms/functional groups. The isoxazoline
hemiacetal thus insulates a potentially labile stereocenter from
undesired racemization.
(
5
1) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
7, 10257−10274. (b) Bioactive Heterocyclic Compound Classes:
̈
Pharmaceuticals; Dinges, J., Jurgin, D., Eds.; Wiley-VCH: Weinheim,
Germany, 2012. (c) Berthet, M.; Cheviet, T.; Dujardin, G.; Parrot, I.;
Martinez, J. Chem. Rev. 2016, 116, 15235−15283.
(2) (a) Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinhem, Germany, 2011.
(
b) Bioactive Natural Products: Chemistry and Biology; Brahmachari, G.,
Ed.; Wiley-VCH: Weinheim, Germany, 2015.
3) (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John
Wiley and Sons: New York, 1984; Vols 1 and 2. (b) Nitrile Oxides,
Nitrones, and Nitronates in Organic Synthesis: Novel Strategies in
Synthesis, 2nd ed.; Feuer, H., Ed.; John Wiley and Sons: Hoboken, NJ,
(
2
(
008.
4) (a) Kanemasa, S.; Kobayashi, S.; Nishiuchi, M.; Yamamoto, H.;
Wada, E. Tetrahedron Lett. 1991, 32, 6367−6370. (b) Bode, J. W.;
Carreira, E. M. J. Org. Chem. 2001, 66, 6410−6424.
(5) Examples of asymmetric 1,3-dipolar cycloadditions: (a) Seerden,
J.-P. G.; Schotte op Reimer, A. W. A.; Scheeren, H. W. Tetrahedron
Lett. 1994, 35, 4419−4422. (b) Simonsen, K. B.; Bayon
G.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 1999, 121,
845−3853. (c) Ashizawa, T.; Ohtsuki, N.; Miura, T.; Ohya, M.;
Shinozaki, T.; Ikeno, T.; Yamada, T. Heterocycles 2006, 68, 1801−
810. (d) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int.
Ed. 2008, 47, 2411−2413. For reviews on asymmetric 1,3-dipolar
cycloadditions see (e) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015,
115, 5366−5412. (f) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998,
98, 863−909. (g) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108,
887−2902. (h) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun.
000, 1449−1458. (i) Adrio, J.; Carretero, J. C. Chem. Commun. 2014,
0, 12434−12446.
́
, P.; Hazell, R.
SUMMARY
■
3
We have developed an enantioselective [3 + 2] cycloaddition
reaction between nitrile oxides and transiently generated
enolates of α-keto esters catalyzed by a chiral copper(II)−
diamine complex. The catalyst system was found to be
compatible with in situ nitrile oxide generation. This constitutes
the first catalytic enantioselective preparation of this unique
class of heterocycles, which can be transformed into interesting
lactams. With this data in hand, we are currently assessing the
reactivity of the 5-hydroxy-2-isoxazolines in other downstream
transformations in addition to studying the mechanism of this
transformation in detail. These results will be reported in due
course.
1
2
2
5
(
6) β-Keto esters: (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am.
Chem. Soc. 2002, 124, 11240−11241. (b) Hamashima, Y.; Yagi, K.;
Takano, H.; Tamas, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
4530−14531. (c) Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura,
Y.; Sodeoka, M. J. Am. Chem. Soc. 2005, 127, 10164−10165.
d) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am.
́
1
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b03782.
(
■
*
S
Chem. Soc. 2006, 128, 14010−14011. (e) Umebayashi, N.;
Hamashima, Y.; Hashizume, D.; Sodeoka, M. Angew. Chem., Int. Ed.
008, 47, 4196−4199. α-Keto esters: (f) Nakamura, A.; Lectard, S.;
Hashizume, D.; Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc. 2010,
2
Experimental procedures and spectral, analytical, and
computational data(PDF)
Crystallographic data for 3k (CIF)
Crystallographic data for 6k (CIF)
1
32, 4036−4037. (g) Nakamura, A.; Lectard, S.; Shimizu, R.;
Hamashima, Y.; Sodeoka, M. Tetrahedron: Asymmetry 2010, 21,
1682−1687. (h) Suzuki, S.; Kitamura, Y.; Lectard, S.; Hamashima, Y.;
Sodeoka, M. Angew. Chem., Int. Ed. 2012, 51, 4581−4585. (i) Steward,
8
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Article
K. M.; Corbett, M. T.; Goodman, C. G.; Johnson, J. S. J. Am. Chem.
Soc. 2012, 134, 20197−20206.
(
7) 1,2-Dicarbonyls as pronucleophiles: Raimondi, W.; Bonne, D.;
Rodriguez, J. Chem. Commun. 2012, 48, 6763−6775.
8) (a) Sustmann, R. Tetrahedron Lett. 1971, 12, 2717−2720.
b) Sustmann, R. Pure Appl. Chem. 1974, 40, 569−593.
9) Yanagisawa, A.; Izumiseki, A.; Sugita, T.; Kushihara, N.; Yoshida,
K. Synlett 2012, 2012, 107−112.
10) Li, W.; Jia, Q.; Du, Z.; Zhang, K.; Wang, J. Chem. - Eur. J. 2014,
0, 4559−4562.
11) Li, W.; Wei, J.; Jia, Q.; Du, Z.; Zhang, K.; Wang, J. Chem. - Eur. J.
014, 20, 6592−6596.
12) An isomerizable aliphatic nitrone was also found to react.
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2
(
2
(
Sohtome, Y.; Nakamura, G.; Muranaka, A.; Hashizume, D.; Lectard, S.;
Tsuchimoto, T.; Uchiyama, M.; Sodeoka, M. Nat. Commun. 2017, 8,
1
(
4
(
4875.
13) Zhao, B.; Han, Z.; Ding, K. Angew. Chem., Int. Ed. 2013, 52,
744−4788.
14) Base-promoted cycloadditions to form triazoles have been
reported: (a) Ramachary, D. B.; Shashank, A. B.; Karthik, S. Angew.
Chem., Int. Ed. 2014, 53, 10420−10424. For a review on metal-free
click reactions leading to triazoles, see (b) Jalani, H. B.; Karagoz, A. Ç.;
̈
Tsogoeva, S. B. Synthesis 2017, 49, 29−41. Racemic isoxazolines have
employed stoichiometric lithium enolates: (c) Salomone, A.; Scilimati,
A.; Vitale, P. Synthesis 2015, 47, 807−816. Base-promoted
cycloadditions have been reported for isoxazole synthesis: (d) Mat-
suura, T.; Bode, J. W.; Hachisu, Y.; Suzuki, K. Synlett 2003, 11, 1746−
1748. (e) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Org. Lett.
2
003, 5, 391−394. (f) Zhou, X.; Xu, X.; Shi, Z.; Liu, K.; Gao, H.; Li,
W. Org. Biomol. Chem. 2016, 14, 5246.
(
15) Dimerization to furoxans: Yu, Z.−X.; Caramella, P.; Houk, K. N.
J. Am. Chem. Soc. 2003, 125, 15420−15425.
16) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339−
341.
(
5
(
(
(
17) Huisgen, R.; Mack, W. Tetrahedron Lett. 1961, 2, 583−586.
18) The precise geometry could not be determined.
19) (a) Escorihuela, J.; Burguete, M. I.; Luis, S. V. Chem. Soc. Rev.
2
(
013, 42, 5595−5617. (b) See Supporting Information.
20) The Ni(II) complex described in reference 12 exhibits a
distorted octahedral geometry, whereas a Cu(OAc) −diamine
2
complex exhibits distorted square-pyramidal geometry: CCDC
6
65454, CCDC 894524.
21) (a) Evans, D. A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1,
65−868. (b) Shi, D.; Xie, Y.; Zhou, H.; Xia, C.; Huang, H. Angew.
Chem., Int. Ed. 2012, 51, 1248−1251.
22) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 4925−4934.
23) Zhu, M.−K.; Zhao, J.−F.; Loh, T.−P. J. Am. Chem. Soc. 2010,
32, 6284−6285.
24) CCDC 1476444 (3k) and CCDC 1476445 (6) contain the
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1
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supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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DOI: 10.1021/jacs.7b03782
J. Am. Chem. Soc. 2017, 139, 8661−8666