Asymmetric Synthesis of 2H-Azirines with a Tetrasubstituted Stereocenter by Enantioselective Ring Contraction of Isoxazoles

Article abstract of DOI:10.1002/anie.201710920

Highly strained 2H-azirines with a tetrasubstituted stereocenter were synthesized by the enantioselective isomerization of isoxazoles with a chiral diene–rhodium catalyst system. The effect of ligands and the coordination behavior support the proposed cat

Full text of DOI:10.1002/anie.201710920

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International Edition: DOI: 10.1002/anie.201710920
German Edition: DOI: 10.1002/ange.201710920
Asymmetric Catalysis Very Important Paper
Asymmetric Synthesis of 2H-Azirines with a Tetrasubstituted Stereo-
center by Enantioselective Ring Contraction of Isoxazoles
Kazuhiro Okamoto,* Atsushi Nanya, Akira Eguchi, and Kouichi Ohe*
Abstract: Highly strained 2H-azirines with a tetrasubstituted
stereocenter were synthesized by the enantioselective isomer-
ization of isoxazoles with a chiral diene–rhodium catalyst
system. The effect of ligands and the coordination behavior
support the proposed catalytic cycle in which the coordination
site is fixed in favor of efficient enantiodiscrimination by
a bulky substituent of the ligand. In silico studies also support
the existence of a rhodium–imido complex as a key intermedi-
ate for enantiodiscrimination.
although the starting azides are generally unstable and
potentially explosive (Scheme 1a).[5] For the enantioselective
synthesis of 2H-azirines, base-mediated elimination reactions
from aziridines with stoichiometric chiral auxiliaries, such as
sulfoxide moieties, have been reported (Scheme 1b).[6] Neber-
type reactions involving base-catalyzed elimination from
oxime or hydrazonium derivatives are also representative
methods for the synthesis of 2H-azirines (Scheme 1c).
Successful examples of the catalytic asymmetric synthesis of
2H-azirines are limited to only a few studies, in which
enantiomerically enriched 2H-azirines were generated by
Neber-type reactions of oxime sulfonates with chiral organo-
catalysts, such as a quinine, a chiral phase-transfer catalyst, or
a chiral thiourea catalyst.[7,8] The enantioselective synthesis of
2H-azirines with tetrasubstituted stereocenters has never
been achieved before.
N
itrogen-containing small-membered heterocyclic com-
pounds are recognized as an important class of compounds
often found in biologically active molecules, such as anti-
tumor aziridines and antibiotic b-lactams.[1] Of such com-
pounds, 2H-azirines, the most highly strained class of N-
=
heterocycles with C N bonds, are useful building blocks for
the construction of various nitrogen-containing molecules by
means of strain release.[2,3] Antibiotic natural products con-
taining chiral 2H-azirines are also known, such as azirinomy-
cin and dysidazirine.[4]
Synthetic methods for 2H-azirines are classified mainly
into three types (Scheme 1). The thermal or photochemical
denitrogenative cyclization of vinyl azides is the simplest way
to access achiral 2H-azirines without generating waste,
We have developed a series of transition-metal-catalyzed
decarboxylative reactions of isoxazol-5(4H)-ones that afford
various nitrogen-containing products depending on the tran-
sition metal.[9,10] Small N-heterocycles, such as bicyclic
aziridines[9a] and 2H-azirines,[9d,f] were synthesized selectively
(Scheme 2a). In our previous studies, catalytic asymmetric
reactions to afford three-membered molecules by using chiral
ligands were not successful, probably because the starting
compounds already had chirality on the isoxazolone ring.
Therefore, we decided to employ another strategy towards
the 2H-azirine ring: a [1,3] sigmatropic rearrangement of
isoxazoles.[11,12] We envisioned that an enantioselective trans-
formation would be possible by using a combination of
a chiral transition-metal catalyst and isoxazoles[13] with both
an achiral planar ring and a metal-coordination site. We
herein report a rhodium-catalyzed asymmetric ring contrac-
tion of isoxazoles as a novel enantioselective method for the
synthesis of 2H-azirines with tetrasubstituted stereocenters
(Scheme 2b).
Initially, we examined the effect of achiral and chiral
ligands by using the bis(ethylene)rhodium chloro-bridged
dimer [RhCl(C2H4)2]2 (5 mol% Rh) as the catalyst precursor
Scheme 1. Classification of synthetic methods for 2H-azirines. Ts =
p-toluenesulfonyl.
[*] Dr. K. Okamoto, A. Nanya, A. Eguchi, Prof. Dr. K. Ohe
Department of Energy and Hydrocarbon Chemistry
Graduate School of Engineering, Kyoto University
Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: kokamoto@scl.kyoto-u.ac.jp
ohe@scl.kyoto-u.ac.jp
Homepage: http://www.ehcc.kyoto-u.ac.jp/eh31/home/index-
e.html
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201710920.
Scheme 2. Transition-metal-catalyzed transformation of isoxazole deriv-
atives.
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in the isomerization of isoxazole 1a. The reaction proceeded
without any supporting ligand to afford racemic 2a (Table 1,
entry 1). Chiral bisphosphine and monophosphine ligands
drene.[15] The dialkyl-substituted diene L3 resulted in almost
the same ee value as observed with L2 (entry 10). The
hydroxyalkyl-substituted diene L4 and methoxycarbonyl-
resulted in poor conversion and enantioselectivity (entries 2– substituted diene L5 gave moderate enantioselectivity (58
6). The cyclooctadiene-coordinates complex [RhCl(cod)]2
effectively catalyzed the reaction to afford racemic 2a in
good yield (entry 7). Encouraged by this result, we then
utilized chiral diene ligands, which are known to as efficient
ligands for rhodium-catalyzed conjugate addition reactions.[14]
Simple C2-symmetric chiral diene ligands, such as Ph-bod (L1)
and Bn-bod (L2), afforded the products, but with low
enantioselectivity (3% ee with L1 and 30% ee with L2;
entries 8 and 9). To further vary the substituents on the
and 59% ee; entries 11 and 12). Use of the more hindered
tert-butoxycarbonyl-substituted diene ligand L6 improved the
enantioselectivity (67% ee; entry 13). 2-Naphthyl ester sub-
stituted L7 also provided moderate enantioselectivity
(69% ee; entry 14). Finally, with ligand L8, bearing a bulky
aromatic ester moiety, and DCE as the solvent, the catalyst
loading could be decreased to 5 mol% Rh, and the product
was obtained in 86% yield with 94% ee (Table 1, entry 18).
An iridium catalyst with ligand L8 exhibited higher catalytic
ligands, we then employed a series of chiral diene ligands L3– activity and comparable enantioselectivity (the reaction
L10 readily prepared from commercially available a-phellan-
reached completion even at 08C; 91% yield, 92% ee;
entry 19). The presence of two ester moieties on ligand L9
did not improve the ee value of the product further (84% ee;
entry 20),[16] and the use of amide-substituted ligand L10
resulted in lower enantioselectivity (53% ee; entry 21).
The present asymmetric isomerization method was
applied to the reaction of various 5-alkoxy isoxazoles 1 and
afforded the corresponding azirine-2-carboxylates 2 in good
yields with high enantioselectivity (Table 2). p-Methoxy- and
p-trifluoromethylphenyl groups were suitable as the R1
substituent (products 2b,c). 5-Ethoxy and 5-isopropoxy isox-
azoles also reacted to form ethyl ester 2d and isopropyl ester
2e with high ee values. n-Propyl and benzyl groups were
suitable as the R2 substituent (products 2 f,g). Azirine 2h, with
a phenyl group as the R2 substituent, was obtained with low
enantioselectivity (40% ee), probably owing to a steric effect
of the phenyl group. In this case, the use of the corresponding
iridium catalyst in the reaction at 08C improved the ee value
to 70%. 2H-Azirines with halogen substituents at the R2
position were obtained with high ee values (2i–k).
Table 1: Rhodium-catalyzed enantioselective isomerization of isoxazole
1a to give 2H-azirine 2a.[a]
Entry
Ligand
Conv. [%][b]
Yield [%][c]
ee [%][d]
1
2
none
(R)-binap
86
22
75
9
–
8
3
4
5
6
(R)-segphos
(R)-phanephos
(R)-mop
(R)-monophos
10
33
31
0
100
71
94
98
100
76
83
89
99
100
98
100
100
100
93
(9)
(14)
(21)
(0)
68
50
79
77
85
38
64
51
89
82
84
86
91
91
83
nd
nd
nd
nd
–
3
30
31
58
59
67
69
88
53
85
94
92
84
53
Table 2: Scope of the enantioselective synthesis of 2H-azirines 2.[a]
7[e]
8
cod
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L9
L10
9
10
11
12
13
14
15
16[f]
17[g]
18[g,h]
19[i]
20
21
[a] The reaction was carried out with isoxazole 1a (0.20 mmol), [RhCl-
(C2H4)2]2 (5 mol%), and a ligand (10 mol%) in toluene (1.5 mL).
[b] Conversion was determined by 1H NMR spectroscopy of the crude
product. [c] Yield of the isolated product. Yields in parentheses were
1
determined by H NMR spectroscopy. [d] The ee value was determined
by HPLC analysis on a chiral stationary phase. [e] [RhCl(cod)]2 (5 mol%)
was used as the catalyst. [f] The reaction was carried out at 808C. [g] The
reaction was carried out with 2.5 mol% of [RhCl(C2H4)2]2 and 5.5 mol%
of the ligand. [h] 1,2-Dichloroethane (DCE) was used instead of toluene.
[i] [IrCl(C2H4)2]2 was used at 08C instead of [RhCl(C2H4)2]2. Ar*=2,6-
diisopropylphenyl, cod=1,5-cyclooctadiene.
[a] The reaction was performed with isoxazoles 1 (0.10 mmol), [RhCl-
(C2H4)2]2 (2.5 mol%), and L8 (5.5 mol%) in DCE (1.0 mL) at 408C for
17 h. Yields are for the isolated product. HPLC analysis on a chiral
stationary phase was used to determine ee values. [b] [IrCl(C2H4)2]2 was
used instead of [RhCl(C2H4)2]2. The reaction temperature was 08C.
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À
To gain insight into the reaction mechanism and the origin
of enantioselectivity, we carried out some stoichiometric
experiments with chiral diene–rhodium complexes. First,
a mixture of [RhCl(C2H4)2]2 and chiral diene ligand L6 was
stirred in DCE at room temperature for 12 h, and then N,N-
dimethylaminopyridine (DMAP) was added to the mixture
(Scheme 3).[17] Characterization of the resulting DMAP
intermediate. Complex C causes the C N bond-forming
ring reconstruction to form azirine complex D. Finally, azirine
2 is released in exchange for the coordination of isoxazole 1,
which regenerates complex B.
In silico studies were performed with a simplified model
for the rhodium-catalyzed 2H-azirine formation (Figure 2).
The starting isoxazole complex B undergoes the N O bond
À
cleavage to give imido complex C as an intermediate via
transition state TS1 (DG° = 17.6 kcalmolÀ1). In imido com-
Scheme 3. Coordination experiments with the rhodium-L6 complex.
Figure 2. Reaction coordinate calculated with density functional meth-
ods (DFT) at the B3LYP/6–311+G(d,p) level. Free-energy differences
[kcalmolÀ1] from isoxazole complex B are shown.
complex 4 by 1H NMR spectroscopy including NOE analysis
revealed the site selectivity of DMAP coordination. The
DMAP ligand in complex 4 coordinates at the site cis to the
alkene substituted with the tert-butoxycarbonyl group, which
indicates that the coordination site of heteroaromatic mole-
cules containing a coordinating nitrogen atom is definitive
owing to the non-C2-symmetric coordination sphere.[18] The
plex C, the substrate moiety has an planar structure and is
almost in the plane of the coordination square plane. The
ester moiety on the substrate then moves to avoid the steric
repulsion from the ester moiety on the chiral diene ligand.
actual substrate 1a similarly coordinated to the chiral diene– Transition state TS2 lies at the highest free energy level
rhodium complex to form isoxazole complex 5 as a single
isomer, which also exhibited a similar spectral change (see the
Supporting Information). Isoxazole 1a is also considered to
occupy the site cis to the electron-deficient alkene.
On the basis of the above results and discussion, we
propose the following catalytic cycle (Figure 1):[19] First,
chiral-diene–rhodium dinuclear species A, which is not
predominant in the whole reaction,[20] undergoes coordination
with isoxazole 1 to form isoxazole complex B. The coordina-
tion site of isoxazole 1 in complex B is fixed by analogy with
(DG° = 19.0 kcalmolÀ1), but such a low activation barrier can
be overcome at the reaction temperature of 408C. Although
further calculation studies are required to reveal the origin of
the high enantioselectivity, the present insight supports the
existence of the rhodium–imido complex as the key inter-
mediate.[21]
The product azirine-2-carboxylic esters could readily be
transformed into various nitrogen-containing chiral mole-
cules by simple reactions. Azirine 2a was hydrolyzed by
treatment with dilute aqueous HCl to give ketoamino acid
ester 6 without any loss of optical purity [Eq. (1)]. Treatment
with Zn(BH4)2 caused diastereoselective hydride reduction
À
the observed complex 5. Complex B then undergoes N O
bond cleavage to form imido complex C as a possible
À
by chelation control to afford N H aziridine 7 with 15:1 dr
[Eq. (2)].[22] The ee value of the major diastereomer was
maintained from that of the starting azirine.[23]
Figure 1. Proposed catalytic cycle for the rhodium-catalyzed asymmet-
ric isomerization of isoxazoles.
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In conclusion, we have developed a novel asymmetric
synthesis of 2H-azirines with a tetrasubstituted stereocenter
based on rhodium-catalyzed asymmetric ring contraction of
isoxazoles. 2-Alkoxycarbonyl 2H-azirines with various sub-
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Acknowledgements
This research was supported by JSPS KAKENHI, Grants-in-
Aid for Scientific Research (C) (No. 17K05861). We are also
grateful for financial support from Nissan Chemical Indus-
tries, Ltd. Chiral diene ligand L2 was kindly provided by Prof.
Takahiro Nishimura (Osaka City University).
Conflict of interest
The authors declare no conflict of interest.
Keywords: 2H-azirines ·chiral diene ligands ·isoxazoles ·
nitrogen heterocycles ·rhodium catalysis
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[16] The absolute configuration of azirine-2-carboxylate 2a was
determined as a the R form by X-ray crystallographic analysis of
palladium bis(azirine) complex 3. CCDC 1581115 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre. See the Supporting Information
for details.
have also been studied; see: a) T. Nishimura, Y. Maeda, T.
Hayashi, Angew. Chem. Int. Ed. 2010, 49, 7234; Angew. Chem.
2010, 122, 7392; b) D. Chen, X. Zhang, W.-Y. Qi, B. Xu, M.-H.
Xu, J. Am. Chem. Soc. 2015, 137, 5268; c) D. Chen, D.-X. Zhu,
M.-H. Xu, J. Am. Chem. Soc. 2016, 138, 1498.
[20] We have observed the almost linear correlation between the ee
of the reaction product and that of the ligand (see Supporting
Information). This result indicates that the chiral diene-rhodium
catalyst remains a mononuclear species due to the coordination
of substrate or product and that an equilibrium with the
dinuclear chloro-bridged species is not involved in the rate-
determining step.
[21] We tried to calculate the mechanism of concerted [1,3]
sigmatropic rearrangement from isoxazole complex B directly
to azirine complex D, but failed to find transition states with
a sufficiently low activation barrier.
[22] J. L. Jat, M. P. Paudyal, H. Gao, Q.-L. Xu, M. Yousufuddin, D.
Ess, D. H. Devarajan, L. Kürti, J. R. Falck, Science 2014, 343, 61;
and references therein.
[23] Other transformations of chiral azirine 2a are known: The
addition of MeMgBr to give the corresponding aziridine and
ring-opening hydrogenation to give the corresponding a-amino
acid ester were reported in Ref. [6c].
[17] A similar type of achiral rhodium –dmap complex ([RhCl(nbd)-
(dmap)]) has been reported: Y. Takenaka, K. Osakada, Bull.
Chem. Soc. Jpn. 2000, 73, 129.
[18] This site selectivity may arise from the difference in the trans
influence of the olefinic ligands. A similar effect on rhodium-
catalyzed 1,4-addition is discussed in Ref. [15b].
Manuscript received: October 24, 2017
Accepted manuscript online: November 27, 2017
Version of record online: December 12, 2017
Angew. Chem. Int. Ed. 2018, 57, 1039 –1043
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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