Iron-catalysed enantioselective carbometalation of azabicycloalkenes

Article abstract of DOI:10.1039/d1cc02387j

The first enantioselective carbometalation reaction of azabicycloalkenes has been achieved by iron catalysis toin situform optically active organozinc intermediates, which are amenable to further synthetic elaborations. The observed chiral induction, alon

Full text of DOI:10.1039/d1cc02387j

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Katsuhiro Isozaki, Masaharu Nakamura et al.
Iron-catalysed enantioselective carbometalation of
azabicycloalkenes

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Iron-catalysed enantioselective carbometalation
of azabicycloalkenes†
Cite this: Chem. Commun., 2021,
57, 6975
Laksmikanta Adak,‡abc Masayoshi Jin,
‡
Shota Saito,ab Tatsuya Kawabata,ab
abd
abe
ab
Takuma Itoh,ab Shingo Ito,
Akhilesh K. Sharma,
Nicholas J. Gower,ab
Received 5th May 2021,
Accepted 18th May 2021
Paul Cogswell,ab Jan Geldsetzer,
Hikaru Takaya,
Katsuhiro Isozaki
*
ab
ab
ab
ab
and Masaharu Nakamura
*
DOI: 10.1039/d1cc02387j
rsc.li/chemcomm
The first enantioselective carbometalation reaction of azabicy- stereocentres. Copper6 and iridium7 catalysts can also affect the
cloalkenes has been achieved by iron catalysis to in situ form asymmetric transformations of oxa- and azabicyclic alkenes
optically active organozinc intermediates, which are amenable to (Scheme 1a).
further synthetic elaborations. The observed chiral induction, along
The enantioselective carbometalation of azabicyclic alkenes
with the DFT and XAS analyses, reveals the direct coordination of without ring-opening is also of significant synthetic interest, as
the chiral phosphine ligand to the iron centre during the carbon– it can provide direct access to the azabicyclo[2.2.1]heptane
carbon and carbon–metal bond forming step. This new class of skeleton of alkaloid derivatives, such as epibatidine and epi-
iron-catalysed asymmetric reaction will contribute to the synthesis boxidine (Scheme 1b).8 Nevertheless, the catalytic asymmetric
and production of bioactive molecules.
addition of organometallic species (i.e., carbon nucleophiles) to
azabicyclic alkenes without the ring-opening remains virtually
Carbometalation reactions, the 1,2-addition of organometallic unexplored.9
species to alkenes or alkynes, are a powerful synthetic tool
Asymmetric iron catalyses have emerged rapidly in organic
for carbon–carbon (C–C) bond formation.1 In particular, the synthesis,10 while their use in enantioselective carbometala-
transition-metal-catalysed asymmetric carbometalation of oxa- tion remains limited to the highly strained cyclopropene
and azabicyclic alkenes is an effective strategy for the enantio- substrates.5b This can be attributed to the unstable coordina-
selective synthesis of chiral building blocks for various natural tion of chiral ligands with the iron centre, of which the
products.2 Lautens and co-workers have extensively studied the oxidation states often fluctuate during the catalytic cycle.
asymmetric transformations of bicyclic alkenes catalysed by Indeed, Bedford and coworkers discovered that phosphine
rhodium3 and palladium,2b,4 where the enantioselective carbome- ligands do not coordinate to the iron centre in the iron-
talation brings about desymmetrisation of the meso-substrates.5 catalysed Negishi coupling.11 On the other hand, we have
Subsequent ring-opening reactions of the carbometalation observed evident asymmetric induction in iron-bisphospine-
intermediates give optically active products bearing multiple catalysed enantioselective cross-coupling reactions,12 and an
a International Research Center for Elements Science,
Institute for Chemical Research (ICR), Kyoto University, Uji, Kyoto 611-0011,
Japan
b Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510,
Japan. E-mail: masaharu@scl.kyoto-u.ac.jp
c Department of Chemistry, Indian Institute of Engineering Science and Technology,
Shibpur, Botanic Garden, Howrah 711103, India
d Process Technology Research Laboratories, Pharmaceutical Technology Division,
Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014,
Japan
e Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University,
21Nanyang Link 637371, Singapore
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Transition-metal-catalysed asymmetric carbometalation reac-
d1cc02387j
tions (E = electrophile).
‡ These authors contributed equally to this work.
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Table
1
Scope of iron-catalysed enantioselective carbometalation
increased dramatically to give 3g in 93% yield with 99% ee. Other
sterically hindered arylzinc reagents such as o-methoxyphenyl-,
1-naphthyl-, and 9-phenanthrylzinc reagents also provided the
corresponding products (3h–3j) with high enantioselectivities
(93–97% ee). The heteroaromatic 4-chloro-3-pyridylzinc reagent
can also participate in the carbometalation to give 3k in 84% yield
with relatively low enantioselectivity (45% ee). The steric factor of
aryl nucleophiles had a substantial impact on the enantioselec-
tivity, suggesting that the spatial interaction of the aryl group
and the alkene substrate leads to mutual orientation of the
two reactants in the stereochemistry-determining carbometala-
tion step.
reactions.a
The electronic factors of alkene substrates seemed not
to affect this carbometalation reaction: substrates having
electron-withdrawing fluoro groups or electron-donating meth-
oxy groups provided the corresponding products 3l and 3m in
excellent yields (85% and 91%, respectively) and good enantios-
electivities (78% and 75% ee, respectively). On the other hand,
the reaction with an aliphatic azabicyclic alkene 1n became
sluggish and did not proceed at 0 1C: the expected product 3n
was obtained in 67% yield with 75% ee at an increased reaction
temperature. As this reaction’s enantioselectivity is comparable
to that of other substrates, the fused benzene ring has no
significant effect on the enantioselectivity.
Trapping of the carbometalation intermediate with various
electrophiles showed the stereospecific nature of the carbome-
talation/trapping sequence.5,9b The reaction of 1a with
o-tolylzinc reagent gave optically active organozinc intermedi-
ate 4, which underwent electrophilic trapping with CD3CO2D to
give deuterated product 5a in 96% yield with 99% ee and 499%
cis-selectivity (entry 1, Table 2). Similarly, when trapped with
iodine as the electrophile, product 5b was obtained in 84%
yield with 99% ee and a diastereomeric excess of 94% (entry 2,
Table 2).14
Preliminary mechanistic studies on the mixture of the iron
salt, (S,S)-chiraphos, and aryl zinc reagent by the combination
of X-ray absorption spectroscopy (XAS) and DFT-calculations
show that the diaryl iron(II) species is the most likely inter-
mediate responsible for this enantioselective carbometalation
reaction. The direct coordination between the chiral phosphine
a
Reactions were performed using 0.5–1.0 mmol of 1 and quenched
with degassed MeOH/AcOH (80/20, 1.0 mL) unless otherwise noted.
b
d
c
Reaction performed at À20 1C. Reaction performed at
0 1C.
Reaction performed at 30 1C. See the ESI for detailed reaction
conditions.
acceleration effect of a chelate phosphine in the diastereose- ligand and iron centre inferred by the fact of chiral induction is
lective carbometalation of oxa- and azabicyclic alkenes with also supported by the XAS analysis and the DFT calculations
arylzinc reagents.9b These conflicting observations have led us
to attempt an enantioselective carbometalation under iron
catalysis.
Table 2 Electrophilic trapping of a carbozincation intermediate
The study began with chiral phosphine ligand screening
based on our success in iron-catalysed enantioselective cross-
coupling reactions.12 We eventually found (S,S)-chiraphos as an
optimal ligand for the carbometalation of azabicycloalkene
with a phenylzinc reagent by using catalytic amounts of FeCl3
(details are shown in the ESI†).
Table 1 displays the scope of the reaction under the optimised
conditions: the reaction of 1a with para- and meta-substituted
arylzinc reagents gave the corresponding products 3a–3f in
85–99% yield with good enantioselectivities (77–85% ee).13 When
an o-tolylzinc reagent was employed, the enantioselectivity
Entry Electrophile
E
Yield of 5a [%] ee [%] deb [%]
1
2
CD3OD/CD3CO2D = 80/20
I2
D
I
96 (5a)
84 (5b)
99
99
499
94
a
b
Isolated yield. Diastereomeric excess determined by 1H NMR
analysis.
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Researchers (NEXT Program)’, initiated by the Council for
Science and Technology Policy, Core Research for Evolutional
Science and Technology (CREST 1102545), ALCA from the
Japan Science and Technology Agency (JST), and the JSPS
Core-to-Core Program’ Elements Function for Transformative
Catalysis and Materials’. JSPS KAKENHI Grant Number
20H02740 also supported this work. L. A., J. G., and A. K. S.
are grateful for a research fellowship from JSPS and the MEXT
project ’Integrated Research Consortium on Chemical
Sciences’. L. A. also thanks SERB, DST, Govt. of India (Project:
SRG/2020/001350) and WBDST-BT for sanctioned Government
Order [Memo No: 1854 (Sanc.)/ST/P/S&T/15G-7/2019]. This work
was supported by the International Collaborative Research
Program of Institute for Chemical Research, Kyoto University
(grant #2019-20 and #2020-16). FAB-/ESI-MS and elemental
analyses were supported by the JURC at ICR, Kyoto University.
The synchrotron radiation experiments were performed at the
BL14B2 (2015A0121, 2015B0121, 2016A0121, and 2016B0121)
Fig. 1 Catalytic cycle based on the XAS and DFT analyses of the stoichio-
metric reactions.
(the experimental and computational details are described in and BL02B1 (2016A0114) of SPring-8 with the approval of the
the ESI†).15 Fig. 1 shows a plausible mechanism for the present Japan Synchrotron Radiation Research Institute (JASRI). The
carbometalation reaction. The catalytic cycle starts with diaryl computations were performed at the Research Center for
iron(II)–(S,S)-chiraphos complex A, which is generated by Computational Science, Okazaki, Japan.
the reduction of FeCl3 with an excess organozinc reagent
(43.0 equivalents) in the presence of (S,S)-chiraphos. The
XAS and DFT analyses reveal that the geometry of A is tetra-
hedral. An azabicyclic alkene coordinates to the intermediate
Conflicts of interest
The authors declare no conflict of interest.
likely in an exo-fashion to give intermediate B. Enantioselective
olefin insertion proceeds to form carboferration intermediate
C. Subsequent transmetalation with the organozinc reagent
leads to optically active organozinc intermediate D and regen-
erates iron(II) species A. Upon the sequential addition of
electrophiles to the reaction mixture, intermediate D undergoes
trapping to provide final product E. The sharp contrast between
Bedford’s and our observations can be attributed to the differ-
ence of the redox behaviours of the iron centre in cross-
coupling and carbometalation; the latter reaction maintains
iron(II) oxidation states during the catalytic cycle and the
bisphosphine ligand predominantly coordinated to the iron
centre, rather than to the zinc centre.16,17
In summary, we have developed the first enantioselective
carbometalation reactions between various azabicycloalkenes
and arylzinc reagents, which proceed under mild conditions by
using a readily available FeCl3 and (S,S)-chiraphos catalytic
system. Trapping experiments reveal the formation of a densely-
functionalised optically active organozinc intermediate. XAS and
DFT studies provided evidence for the direct coordination of the
chiral phosphine ligand to the iron(II) centre, even in the presence
of an excess zinc species that can undergo competitive coordina-
tion of the phosphine ligands. The present findings demonstrate
the potential of iron-catalysed stereoselective C–C bond forma-
tions for synthesising complex chiral molecules of biological
relevance. Further mechanistic studies on the detailed multi-
spin reaction pathway and the origin of the asymmetric induction
are currently underway.
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