Generation and application of Cu-bound alkyl nitrenes for the catalyst-controlled synthesis of cyclic β-amino acids

Article abstract of DOI:10.1039/d1sc01419f

The advent of saturated N-heterocycles as valuable building blocks in medicinal chemistry has led to the development of new methods to construct such nitrogen-containing cyclic frameworks. Despite the apparent strategic clarity, intramolecular C-H aminations with metallonitrenes have only sporadically been explored in this direction because of the intractability of the requisite alkyl nitrenes. Here, we report copper-catalysed intramolecular amination using an alkyl nitrene generated from substituted isoxazolidin-5-ones upon N-O bond cleavage. The copper catalysis exclusively aminates aromatic C(sp²)-H bonds among other potentially reactive groups, offering a solution to the chemoselectivity problem that has been troublesome with rhodium catalysis. A combined experimental and computational study suggested that the active species in the current cyclic β-amino acid synthesis is a dicopper alkyl nitrene, which follows a cyclisation pathway distinct from the analogous alkyl metallonitrene.

Full text of DOI:10.1039/d1sc01419f

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Generation and application of Cu-bound alkyl
nitrenes for the catalyst-controlled synthesis of
cyclic b-amino acids†
Cite this: DOI: 10.1039/d1sc01419f
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have been paid for by the Royal Society
of Chemistry
*
*
Raj K. Tak,‡ Fuyuki Amemiya,‡ Hidetoshi Noda
and Masakatsu Shibasaki
The advent of saturated N-heterocycles as valuable building blocks in medicinal chemistry has led to the
development of new methods to construct such nitrogen-containing cyclic frameworks. Despite the
apparent strategic clarity, intramolecular C–H aminations with metallonitrenes have only sporadically
been explored in this direction because of the intractability of the requisite alkyl nitrenes. Here, we
report copper-catalysed intramolecular amination using an alkyl nitrene generated from substituted
isoxazolidin-5-ones upon N–O bond cleavage. The copper catalysis exclusively aminates aromatic
C(sp2)–H bonds among other potentially reactive groups, offering a solution to the chemoselectivity
Received 11th March 2021
Accepted 24th April 2021
problem that has been troublesome with rhodium catalysis.
computational study suggested that the active species in the current cyclic b-amino acid synthesis is
dicopper alkyl nitrene, which follows cyclisation pathway distinct from the analogous alkyl
metallonitrene.
A combined experimental and
DOI: 10.1039/d1sc01419f
a
a
rsc.li/chemical-science
the Du Bois group, who used a rhodium dimer complex as
a catalyst and carbamates or sulfamates as nitrene precursors
under oxidative conditions for the synthesis of 1,2- and 1,3-
aminoalcohols, respectively.4 Although the rhodium conditions
favour aziridination over C(sp3)–H amination,5 the identica-
tion of new catalysts by the Du Bois6 and White7 groups has
enabled the selective allylic C(sp3)–H amination. Schomaker
has also reported a set of silver catalysts that allow for the
chemoselective synthesis using similar carbamate substrates
(Scheme 1a).8 Furthermore, Chang has recently documented
tunable Ir catalysts that are suitable for chemoselective nitrene
transfer towards C(sp3)–H or C(sp2)–H amination using 1,4,2-
dioxazol-5-ones as acyl nitrene precursors,9 affording a range of
lactam products (Scheme 1b).10,11
Saturated N-heterocycles have recently received signicant
attention in drug discovery programs.12 Despite the reported
means of constructing nitrogen-containing cyclic skeletons by
the intramolecular C–H amination of nitrenes, progress in this
direction has been sluggish. Although the above examples
represent the state-of-the-art in nitrene transfer chemistry, their
straightforward extension to the synthesis of pyrrolidines or
piperidines is not trivial; alkyl nitrenes bearing one or more
hydrogen atoms adjacent to the nitrogen are known to readily
isomerize to the corresponding imines,13 and are thus reluctant
to undergo productive cyclisations.14 As a part of our research
program exploiting substituted isoxazolidin-5-ones as b-amino
acid surrogates,15,16 we have identied that the cyclic hydroxyl-
amines can serve as alkyl nitrene precursors through the N–O
bond cleavage in the presence of a rhodium catalyst. The
generated rhodium alkyl nitrene undergoes intramolecular
Introduction
Catalyst-controlled transformations can streamline chemical
synthesis, as they channel reactions along a desired direction
among many possible pathways.1 Although syntheses oen
encounter various selectivity problems such as with enantio-,
diastereo-, or regioselectivity, controlling the chemoselectivity is
arguably the most difficult and has been the least developed. To
achieve such feats, catalysts must be able to differentiate
between multiple transition states that are energetically close
but structurally less similar. Challenges associated with the
development of chemoselective reactions have been docu-
mented in several review articles,2 and taming highly reactive
intermediates represents a formidable task due to the small
differences in activation energies (DDG‡).
Nitrene is a representative reactive intermediate in organic
chemistry. Among the multiple reactivities associated with
nitrenes, intramolecular C–H amination offers valuable means
for the reliable installation of a nitrogen atom at the preferred
position in a molecule. Since the pioneering work on a metal
porphyrin-catalysed cyclisation through C(sp3)–H amination,3
remarkable advances in metal nitrene chemistry have been
made. Notable contributions include a series of reports from
Institute of Microbial Chemistry (BIKAKEN), Tokyo3-14-23 Kamiosaki, Shinagawa-ku,
Tokyo 141-0021, Japan. E-mail: hnoda@bikaken.or.jp; mshibasa@bikaken.or.jp
† Electronic supplementary information (ESI) available. CCDC 2049408. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc01419f
‡ These authors equally contributed to this work.
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C(sp3)–H insertion to afford unprotected b-proline derivatives.17
Furthermore, the same reactive intermediate also participates
in aromatic C(sp2)–H amination if the substrate is suitably
decorated with an aromatic ring, providing benzo-fused cyclic b-
amino acids.18 The latter class of cyclic amino acids, tetrahy-
droquinoline-3-carboxylic acids, is an important building block
in medicinal chemistry, as exemplied by the structures of
myeloid cell leukemia-1 (Mcl-1) inhibitors,19 and our method
offers
a straightforward means to access functionalized
building blocks otherwise difficult to obtain (Scheme 2a).20
Given the difficulty of accessing compounds bearing a quater-
nary carbon at the a-position of the carboxylic acid by catalytic
hydrogenation, we attempted to expand the scope of the Rh-
catalysed reaction. The similar kinetics between the two
competitive C–H amination pathways, however, led to a mixture
of products, limiting the synthetic utility of the Rh-catalysed
protocol (Scheme 2b). In a related rhodium nitrene chemistry,
Falck reported a reagent-controlled approach to combat a che-
moselectivity issue between an olen and an aromatic C–H
bond, where the choice of aminating reagents governs the
reaction site.21,22 Herein, we report
a catalyst-controlled
approach employing copper23 instead of rhodium to overcome
the aforementioned chemoselectivity problem. This work, as far
as we are aware, represents the rst synthetic application of
a copper alkyl nitrene. The copper-catalysed conditions selec-
tively promote the desired C(sp2)–H amination even in the
presence of reactive functionalities toward nitrenes (Scheme
2c). Our mechanistic study reveals that a subtle difference in
reaction conditions toggles a distinctive cyclisation pathway of
an otherwise analogous transformation, highlighting
a nuanced reactivity of the underexplored reactive species.
Scheme
reactions.
1 Previously reported chemoselective nitrene transfer
Results and discussion
Screening of conditions
Inspired by the fact that different metals have oen brought
about notable reactivity differences in carbene and nitrene
chemistry, we sought to employ different metallonitrenes to
overcome the chemoselectivity problem. While our preliminary
attempts to use various metals, including Co, Ru, Pd, Ag, and Ir,
failed to exhibit any catalytic activity toward substrate 1a, the
addition of a copper salt converted 1a to the desired cyclic
compound, albeit in low yield. This promising result, together
with the generally less procient C(sp3)–H insertion of copper
carbenes,24 led us to further optimise the copper-catalysed
conditions. Table 1 summarizes our efforts using 1a as a model
substate. The choice of ligand on copper proved crucial in
promoting the desired cyclisation and suppressing decompo-
sition. Popular nitrogen-based ligands, such as bipyridine and
phenanthroline, did not deliver product 2a effectively (entries 1
and 2, Table 1. Also see the ESI† for further details). Salen ligand
L3 exhibited a higher reactivity, while L4, a hybrid ligand of
pyridine and benzoxazole, considerably improved the yield
(entries 3 and 4). Increasing the reaction temperature from 0 to
23 ꢀC signicantly accelerated the reaction (entry 5), whereas
modulating the electronic factors on the pyridine ring did not
provide benecial effects (entries 6–8). Of note, the use of HFIP
Scheme 2 Overview of chemoselectivity challenge and this work.
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Table 1 Screening of conditionsa
Entry
Substrate
Cu source
Ligand
Solvent
Temp (ꢀC)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
3a
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
CuOTf$0.5C6H6
[Cu(CH3CN)4]PF6
Cu(OTf)2
L1
L2
L3
L4
L4
L5
L6
L7
L4
L4
L4
L4
L4
L4
—
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
TFE
0
0
72
72
24 + 16
56
12
14
12
24
36
36
36
36
12
24
36
36
<5
<5
28
56
98
98
84
52
0
0
0
0
79
55
0
0 to 23
0
23
23
23
23
23
23
23
23
23
23
23
23
9
10
11
12
13
14
15
16
MeOH
THF
CH2Cl2
HFIP
HFIP
HFIP
HFIP
—
CuOTf$0.5C6H6
L4
0
a
b
1
1a (0.1 mmol), 0.1 M. Yields were determined by H NMR analysis of the unpuried reaction mixture.
is essential to attain the desired reactivity, while cyclisation did forming tetrahydroquinoline cores. For a substrate having
not occur even in the similarly utilised uorinated alcohol TFE, a propargyl moiety, further lactonization took place following
let alone in other non-uorinated solvents such as MeOH, THF, the aromatic amination, affording 5 in good yield. In this study,
and CH2Cl2 (entries 9–12). The result is in stark contrast to the we used 2 equiv. of the low-molecular-weight ligand with
previous Rh-catalysed reaction, where the preferred solvent was respect to the metal to ensure that sufficient amounts of L4 were
also HFIP but the reaction still proceeded in TFE at a slower available for the copper on a 0.1 mmol scale. A comparable
rate. Changing the counter anion of copper resulted in result was obtained with 1.2 equiv. of L4 on a larger scale,
a diminished yield, and employing Cu(II) instead of Cu(I) was suggesting that a 1 : 1 complex is likely responsible for the
similarly less effective (entries 13 and 14). No background cyclisation (2a). Regarding the substituent effect on the
reaction was observed in the absence of an added copper salt aromatic ring, the copper catalysis was found to be relatively
(entry 15). The use of an unprotected N–H substrate was sensitive to its electronic nature. While good yields were ob-
mandatory to achieve the desired reactivity (entry 16).
tained with methyl substituted substrates (entries 10 and 11),
the desired reactions were sluggish with substrates bearing
a halogen atom instead of a methyl group at the same position
(para or ortho), and unfavourable decomposition was again
observed for these electron-decient substrates (entries 12 and
13). This reactivity trend is consistent with the involvement of
electrophilic nitrogen species. All cyclisations appeared to occur
from the ortho carbon, and meta-substituted substrates formed
a mixture of regioisomers with varied ratios (80 : 20–40 : 60),
depending on the substituent structure (entries 14–16). For
methyl and uoro substituents, cyclisation proceeded in favour
of the sterically less demanding position. The reversed selec-
tivity of 3-MeO substrate 1o is not clear at the stage of this
investigation. Protected aldehyde or alkyne containing
Scope and limitations of Cu(I)-catalysed cyclic b-amino acid
synthesis
With ligand L4 identied as suitable for the desired C(sp2)–H
amination, the scope and limitations of the b-amino acid
synthesis were examined (Table 2). Cyclisation at the aromatic
ring proceeded smoothly in the presence of various a-substit-
uents (entries 1–9). It is noteworthy that no C–H insertion was
observed into the methylene (1b), benzylic (1c), or even methine
(1d) C–H bonds, which previously competed with the desired
aromatic amination. A range of potentially detrimental p-bonds
at the a-position such as an alkene (1g), a nitrile (1h), and an
alkyne (1i) did not interfere with the catalysis, selectively
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Table 2 Substrate scope for the synthesis of benzo-fused cyclic b-amino acidsa
a
1 (0.1 mmol), CuOTf$0.5C6H6 (5 mol%), L4 (10 mol%), HFIP (0.1 M), 23 ꢀC. b 1a(1.0 mmol), CuOTf$0.5C6H6 (5 mol%), L4 (6 mol%). c TFA (1 equiv.)
was added.
substrates also provided the corresponding products (entries 17 due to competitive undesired reactions, highlighting the benet
and 18). Although the main focus of the current work was to of the current copper catalysis.
broaden the a-substituent scope from the previous rhodium
system, a substrate lacking an a-substituent worked equally well
under the copper conditions (entry 19). We also found that the
addition of 1 equiv. of TFA tended to make the reaction cleaner
by reducing the rate of undesired decomposition (2l). Further-
more, 2p was obtained with similar regioisomer ratios with or
without added TFA, indicating that the structure of the elec-
trophilic nitrogen species in the C–N bond forming step is likely
Copper-catalysed asymmetric desymmetrization
comparable in both cases. TFA alone did not induce a detect-
able background reaction. The current conditions were also
suitable for the cyclisation of 3-substituted isoxazolidin-5-one to
afford 7 (eqn (1)). Several of the cyclic amino acids shown in
Table 2 were previously not accessible in an efficient manner
Another advantage of the copper catalysis over rhodium was
observed in the asymmetric desymmetrization of 8—another
class of catalyst-controlled synthesis. While well-established
chiral dirhodium catalysts provided only marginal enantiose-
lectivity for this transformation (see the ESI† for details),
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Scheme 3 Cu-catalysed asymmetric desymmetrization.
copper(I) salts ligated with a series of chiral ligands offered
signicantly higher enantioselectivities. Among those exam-
ined, tBu-BOX ligand exhibited the best selectivity, affording the
corresponding product in 93% ee in favour of the (R)-enan-
tiomer (Scheme 3).25 With respect to the nature of the active
copper species, a positive nonlinear effect was observed when
ees of the employed ligand were varied. In some reported
cases,26 the origin of nonlinear effects was ascribed to the
formation of a stable racemic complex, where the minor enan-
tiomer of the ligand is arrested in the stable, inactive hetero
complex and thus a smaller amount of enantiopure, active
complex is available for the catalysis. Given that similar reaction
rates were observed throughout the range of ligand ees, the
active catalyst concentration appeared to be constant for all
cases, and thus the current system seems not to follow this
scenario.
Scheme 4 Control experiments that disfavour the nitrogen-centred
radical pathway.
at all (Scheme 4a), (2) catalyst-controlled synthesis was possible
in catalytic asymmetric desymmetrization (vide supra), and (3)
N–Me substrate 10 exhibited no reactivity and remained
unchanged under otherwise identical conditions (Scheme 4b).
These results rule out, at least, the nitrogen-centred naked
radical pathway.
During the substrate scope study, we did not observe
detectable products derived from tentative nitrene decomposi-
tion, such as imines or hydrolysed ketones. To verify the
formation of a nitrene, we synthesized substrate 12 bearing
a phenyl group on the same carbon as the nitrogen atom. The
designed substrate was expected to facilitate the isomerization
to the imine if the corresponding nitrene was formed (Fig. 1a).
Role of the copper catalyst and nature of the active species
The results obtained through the substrate scope study indi-
cated the involvement of an electrophilic nitrogen intermediate.
We postulated three scenarios for the role of the copper catalyst.
The rst is a simple Lewis acid catalysis to enhance the elec-
trophilicity of the substrate through coordination to the
carbonyl oxygen or the nitrogen atom. The second mechanism
involves a nitrogen-centred radical upon the homolytic cleavage
of the N–O bond. In this scenario, copper acts as an electron
shuttle between Cu(I) and Cu(II) akin to the case involving Fe(II)/
Fe(III) found in the literature employing a hydroxylamine-
derived aminating reagent.27 The last mechanism is based on
a provisional copper-bound alkyl nitrene that undergoes
downstream transformations.
The results obtained through our optimization studies show
that noncoordinating solvents such as CH2Cl2 and toluene are
universally ineffective for the current system. The expected
enhanced Lewis acidity of copper by modulation of the ligand
structure did not lead to a higher reactivity. Furthermore, the
use of less coordinative anions, for example, PF6, did not
improve the reactivity. An N-Boc substrate, which is presumably
more electrophilic than the corresponding N–H substrate, did
not participate in the reaction (entry 16, Table 1). These
observations collectively disfavour the simple Lewis acid catal-
ysis mechanism for the current system.
Given the ample literature precedents, especially with regard
to enhanced reactivity in HFIP,28 the nitrogen-centred radical
pathway appears rather feasible. Nevertheless, this mechanism
is likely not operative in the current system because (1) the
Fig. 1 Mechanistic support for the nitrene formation. (a) Structure of
designed substrate 12 and its expected decomposition pathway to
acetophenone. (b) Stacked 13C NMR spectra. (c) A control experiment
to evaluate the reactivity of benzoylacetic acid under the influence of
addition of 1 equiv. of BHT did not affect the reaction outcome the copper catalyst. (d) Cyclic b-amino acid formation from 13.
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When 13C-labelled substrate 12 was treated with 1 equiv. of Cu/
L4 in HFIP, 12 was immediately consumed. The 13C NMR
spectrum of the solution in 1 : 1 THF-d8/HFIP displayed a major
peak at 198.6 ppm, which was shied from that of the substrate
at 63.2 ppm (Fig. 1b). The major product was isolated from the
crude sample and identied as 13C-labelled acetophenone. An
HRMS analysis of the unpuried solution also supported the
existence of acetophenone. A separate experiment revealed that
benzoylacetic acid did not undergo decarboxylation and
remained unchanged in the presence of Cu/L4 in HFIP (Fig. 1c).
Collectively, the formation of the labelled ketone likely reects
the generation of an alkyl nitrene, which isomerizes to the
imine, followed by decarboxylation and hydrolysis to form
acetophenone. Importantly, a productive 6-membered ring
formation was possible with the designed substrate once reac-
tive benzyl appendages were installed at the a-carbonyl carbon,
suggesting that the nitrene is a viable intermediate rather than
an irrelevant one (Fig. 1d). Given the comparison of the
conversions and product yields, the amination and decompo-
sition pathways likely occur at a similar rate. The observed high
diastereoselectivity also indicates that the cyclisation took place
from the opposite direction of the added aromatic ring.
Regioselectivity consideration: two possible cyclisation
pathways
Our previous study on the Rh-catalysed intramolecular C(sp2)–H
amination experimentally revealed that the cyclisation
comprises two steps: spirocycle formation from the ipso carbon
and subsequent C–N or C–C bond migration.29 The migration
aptitude is determined by the nature of the substituents: C–N
migration is the major pathway for 4-Me, whereas only C–C
migration is observed for 4-MeO (Scheme 5). In stark contrast,
the current catalytic system did not form any migrated
regioisomers, as shown in Table 2, and instead leaned toward
the direct 6-membered ring formation mechanism from the
ortho carbon rather than the two-step mechanism. In addition,
the lack of kinetic isotope effects with 8-d5 disfavoured an
archetypal C–H insertion-type transition state for direct cycli-
sation with the copper nitrene (Scheme 6a).30 Nevertheless, an
exclusive C–N bond migration following the ipso cyclisation was
not completely ruled out. To obtain further insights, we
Scheme 6 Mechanistic insights for the cyclisation event.
employed 4-OH substituted substrate 15, which would stabilize
and trap a spiro intermediate by isomerization to the corre-
sponding dienone if it were to form under these conditions.31
The outcome was rather unexpected and distinct from that of
the Rh catalysis (Scheme 6b). Both spirocycle 16 and 6-
membered ring 17 were formed in excellent combined yields. A
similar trend was observed with homologated substrate 18,
which presents three possible reaction sites. With 18, a distinct
chemoselectivity of the copper catalysis from the rhodium one
was again manifested (Scheme 6c). Whereas the rhodium
catalyst exclusively formed pyrrolidine 19 through a benzylic C–
H insertion, the copper catalyst selectively afforded spirocycle
20, presumably due to much slower kinetics for the 7-
membered ring formation. These data indicate that the two
cyclisation pathways from an aromatic ring are both energeti-
cally accessible under the copper-catalysed conditions in favour
of the formation of the spiro intermediate, given the assump-
tion that the reaction is kinetically controlled.
Scheme 5 Cyclisation pathway of previous Rh-catalysed reaction.
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suggested that more than one copper complexes were involved
in the catalytic cycle (see the ESI† for details). Based on the
structures of reported dinuclear copper nitrenes,35,36 we
computed an analogous pathway involving a tentative dicopper
nitrene (black line, Fig. 2). The energy landscape associated
with the dicopper complex qualitatively reproduces that of the
monocopper complex (blue line). Furthermore, the calculated
free energies of all intermediates and transition states are
universally lower for the dicopper nitrene, suggesting that
a dinuclear copper complex is possibly responsible for the C–N
bond formation. Close inspection of the nitrene and transition
states of the dicopper complex reveals that, in addition to the
delocalized spin density, they are stabilized by additional
interactions that are absent in the monocopper complex: they
include (1) an interaction between the carboxyl oxygen and
second copper atom and (2) attractive noncovalent interactions
between the copper complexes such as p-interaction of the
ligands. The latter factor also contributes to the lower activation
energies for cyclisations (3TS1_M vs. 3TS1_D, 3TS2_M vs.
3TS2_D). For instance, the angle of Cu–N–Cu changes from
Computational investigations
The experimental results discussed above supported the
involvement of a copper alkyl nitrene in the catalytic cycle, but
did not reach a conclusion regarding the subsequent reaction
pathway from the reactive intermediate. Hence, a computa-
tional investigation was performed at the DFT level32 to gain
further insight into the energetic landscape of the current
system. In accordance with previous computational studies on
nitrene chemistry, a triplet nitrene is more stable than the
singlet at the DFT level, and thus only the triplet potential
energy surface was extensively explored in this study.33
Fig. 2 displays a free energy prole for spirocycle formation
and direct 6-membered ring formation from triplet nitrenes
3NTR. The general trend is in line with the experimental
observations and shows that both pathways are energetically
accessible (3TS1 vs. 3TS2). Furthermore, the computations
revealed that the activation energy for the subsequent C–N bond
3
migration from spiro intermediate INT1 is signicantly high
(3TS3), and thus the spiro intermediate must return to the
nitrene unless it has another low-energy lying pathway to follow,
such as isomerization to the dienone. Therefore, the Curtin–
Hammett scenario is consistent with the observed regioisomer
formation. With respect to the structure of the interim copper
nitrene,34 the observed positive non-linear effect in the asym-
metric desymmetrization (vide supra) may suggest the involve-
ment of two copper complexes in the C–N bond forming step.
Our kinetics study under synthetically relevant conditions also
3
107.5ꢀ in NTR_D to 83.8ꢀ in 3TS2_D, resulting in a closer
contact between the copper complexes and leading to a stronger
attractive interaction (Fig. 3). Counterpoise corrected energy
using the truncated structures corroborated the higher inter-
action energy. The existence of a minimum energy crossing
point (MECP) between the singlet and the triplet energy
surfaces37 allows for the formation of singlet copper-bound 6-
Fig. 2 Calculated free energies for spiro formation and direct 6-membered ring formation at the DFT level. The numbers next to the structures in
black and red denote bond lengths (A˚) and Mulliken spin densities, respectively.
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Research Fellow. H. N. thanks The Research Foundation for
Pharmaceutical Sciences, and The Uehara Memorial Founda-
tion, for the nancial support. We are grateful to Dr Ryuichi
Sawa, Yumiko Kubota, Dr Kiyoko Iijima, and Yuko Takahashi at
the Institute of Microbial Chemistry for technical assistance in
NMR and MS analyses, and Dr Tomoyuki Kimura at the Insti-
tute of Microbial Chemistry for X-ray crystallographic analysis
of 9. Part of the computational resources in this work was
provided by the Research Center for Computational Science,
Okazaki, Japan.
Fig. 3 Calculated structures of 3NTR_D and 3TS2_D.
membered ring product 1PRO via 1TS4_D. The interaction
energy of the substrate with Cu/L4 is higher than that of the
product, preventing product inhibition and thus facilitating the
closing of the catalytic cycle. Therefore, in contrast to the re-
ported example involving an isolated dicopper nitrene, where
a dissociated monocopper complex is responsible for intermo-
lecular C(sp3)–H amination,35c a dicopper nitrene seems likely
to be responsible for the intramolecular C(sp2)–H amination in
the current system.
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Conclusions
We have developed copper-catalysed conditions for the che-
moselective synthesis of cyclic b-amino acids from substituted
isoxazolidin-5-ones. This work represents the rst synthetic
application of a copper-bound alkyl nitrene. The proposed
copper catalysis allows for the selective amination of aromatic
C(sp2)–H bonds, even in the presence of potentially detrimental
functionalities including double and triple bonds. The advan-
tage of copper catalysis was also evidenced by catalytic asym-
metric desymmetrization.
A combined experimental and
computational investigation suggested that a dicopper nitrene
seems likely to be responsible for the key C–N bond forming
step. Our mechanistic study also reveals that switching the
metal from rhodium to copper triggers a distinctive pathway in
the 6-membered ring forming amination, showcasing
a nuanced nature of the underexplored reactive intermediate.
The development of other catalyst-controlled reactions
involving alkyl nitrenes is currently underway in our laboratory.
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Author contributions
H. N. and M. S. conceived the project. R. K. T., F. A., and H. N.
conducted experiments and analysed data. H. N. performed the
density functional theory calculations. H. N. and M. S. wrote the
manuscript with help from all authors.
Conflicts of interest
There are no conicts to declare.
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Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
18K14878 and 20K06957. R. K. T. is a JSPS International
Chem. Sci.
© 2021 The Author(s). Published by the Royal Society of Chemistry

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Chem. Sci.