New Catalytic Radical Process Involving 1,4-Hydrogen Atom Abstraction: Asymmetric Construction of Cyclobutanones

Article abstract of DOI:10.1021/jacs.1c04968

While alkyl radicals have been well demonstrated to undergo both 1,5- and 1,6-hydrogen atom abstraction (HAA) reactions, 1,4-HAA is typically a challenging process both entropically and enthalpically. Consequently, chemical transformations based on 1,4-HAA have been scarcely developed. Guided by the general mechanistic principles of metalloradical catalysis (MRC), 1,4-HAA has been successfully incorporated as a key step, followed by 4-exo-tet radical substitution (RS), for the development of a new catalytic radical process that enables asymmetric 1,4-C-H alkylation of diazoketones for stereoselective construction of cyclobutanone structures. The key to success is the optimization of the Co(II)-based metalloradical catalyst through judicious modulation of D2-symmetric chiral amidoporphyrin ligand to adopt proper steric, electronic, and chiral environments that can utilize a network of noncovalent attractive interactions for effective activation of the substrate and subsequent radical intermediates. Supported by an optimal chiral ligand, the Co(II)-based metalloradical system, which operates under mild conditions, is capable of 1,4-C-H alkylation of α-aryldiazoketones with varied electronic and steric properties to construct chiral α,β-disubstituted cyclobutanones in good to high yields with high diastereoselectivities and enantioselectivities, generating dinitrogen as the only byproduct. Combined computational and experimental studies have shed light on the mechanistic details of the new catalytic radical process, including the revelation of facile 1,4-HAA and 4-exo-tet-RS steps. The resulting enantioenriched α,β-disubstituted cyclobutanones, as showcased with several enantiospecific transformations to other types of cyclic structures, may find useful applications in stereoselective organic synthesis.

Full text of DOI:10.1021/jacs.1c04968

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New Catalytic Radical Process Involving 1,4-Hydrogen Atom
Abstraction: Asymmetric Construction of Cyclobutanones
Jingjing Xie, Pan Xu, Yiling Zhu, Jingyi Wang, Wan-Chen Cindy Lee, and X. Peter Zhang*
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ABSTRACT: While alkyl radicals have been well demonstrated to
undergo both 1,5- and 1,6-hydrogen atom abstraction (HAA)
reactions, 1,4-HAA is typically a challenging process both
entropically and enthalpically. Consequently, chemical trans-
formations based on 1,4-HAA have been scarcely developed.
Guided by the general mechanistic principles of metalloradical
catalysis (MRC), 1,4-HAA has been successfully incorporated as a
key step, followed by 4-exo-tet radical substitution (RS), for the development of a new catalytic radical process that enables
asymmetric 1,4-C−H alkylation of diazoketones for stereoselective construction of cyclobutanone structures. The key to success is
the optimization of the Co(II)-based metalloradical catalyst through judicious modulation of D2-symmetric chiral amidoporphyrin
ligand to adopt proper steric, electronic, and chiral environments that can utilize a network of noncovalent attractive interactions for
effective activation of the substrate and subsequent radical intermediates. Supported by an optimal chiral ligand, the Co(II)-based
metalloradical system, which operates under mild conditions, is capable of 1,4-C−H alkylation of α-aryldiazoketones with varied
electronic and steric properties to construct chiral α,β-disubstituted cyclobutanones in good to high yields with high
diastereoselectivities and enantioselectivities, generating dinitrogen as the only byproduct. Combined computational and
experimental studies have shed light on the mechanistic details of the new catalytic radical process, including the revelation of facile
1,4-HAA and 4-exo-tet-RS steps. The resulting enantioenriched α,β-disubstituted cyclobutanones, as showcased with several
enantiospecific transformations to other types of cyclic structures, may find useful applications in stereoselective organic synthesis.
the development of enantioselective radical C−H alkylation of
diazo compounds involving 1,5-HAA as the key step for
stereoselective construction of 5-membered ring structures.8
To broaden the synthetic applications of Co(II)-MRC for
solving more challenging problems, we were intrigued by the
possibility of constructing strained 4-membered ring structures
such as cyclobutanones through radical 1,4-C−H alkylation of
α-aryldiazoketones (Scheme 1). However, this proposed
radical process presented several potential challenges. In view
of their unique electronic and steric properties compared with
other types of diazo compounds, it was uncertain whether
donor/acceptor-substituted diazo compounds 1 could be
effectively activated by [Co(D2-Por*)] to generate the
corresponding α-Co(III)-alkyl radicals I. Given that 1,4-HAA
is known to be an inherently challenging process due to both
unfavorable entropic and enthalpic factors,9 how could the
resulting tertiary radical intermediate I be promoted for the
desired intramolecular hydrogen atom abstraction to form δ-
INTRODUCTION
■
In the past decades, radical reactions have attracted the
growing attention of synthetic organic chemists in view of their
rich reactivities and attractive characteristics.1 Notably, hydro-
gen atom abstraction (HAA) by free radicals has long been
recognized as one of the most general pathways for C−H
activation,2 a fundamental radical reaction that can potentially
be utilized for direct functionalization of prevalent C−H bonds
in organic molecules. However, the realization of this immense
potential faces longstanding challenges that are associated with
governing reactivity as well as controlling selectivity of the
departing radicals from HAA for ensuing bond formation. To
address this and related challenges, metalloradical catalysis
(MRC) provides a conceptually new approach for achieving
controllable reactivity and selectivity in radical reactions
through catalytic generation as well as subsequent regulation
of metal-stabilized organic radical.3−5 As stable 15e-metal-
loradicals, Co(II) complexes of D2-symmetric chiral amido-
porphyrins [Co(D2-Por*)] enjoy the unique capability of
activating diazo compounds homolytically to generate α-
Co(III)-alkyl radicals.6 These Co-stabilized C-centered radical
intermediates can undergo common radical reactions, such as
radical addition and hydrogen atom abstraction as well as
following radical substitution, leading to new catalytic
processes for stereoselective radical transformations.7 In
particular, Co(II)-based MRC was successfully applied for
Received: May 13, 2021
Published: July 22, 2021
https://doi.org/10.1021/jacs.1c04968
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that are important moieties in natural products and
pharmaceuticals (Figure S1).10
Scheme 1. Working Proposal for Construction of
Cyclobutanones by Radical 1,4-C−H Alkylation via Co(II)-
Based Metalloradical Catalysis
Catalytic asymmetric intramolecular 1,4-C−H alkylation of
diazo compounds represents a potentially attractive strategy for
the stereoselective construction of four-membered cyclic
compounds.11 Due to the high strain associated with four-
membered ring structures, the catalytic process for 1,4-C−H
alkylation has been largely underdeveloped. While there have
been a few reports on the asymmetric synthesis of β-lactams12
and β-lactones13 from α-diazoamides and α-diazoesters,
respectively, by Ru, Rh, and Ir-based catalytic systems,
asymmetric synthesis of cyclobutanones via 1,4-C−H
alkylation from α-diazoketones has not been previously
realized.14 The absence of a catalytic system for cyclobutanone
synthesis is presumably attributed to the augmented challenge
of 1,4-C−H alkylation for α-diazoketones because of their
relatively higher conformational flexibility than α-diazoamides
and α-diazoesters. As an exciting new application of Co(II)-
based MRC for stereoselective organic synthesis, we herein
report the development of the first catalytic system that is
highly effective for asymmetric 1,4-C−H alkylation of α-
diazoketones to construct chiral cyclobutanones. Supported by
a new-generation D2-symmetric chiral amidoporphyrin ligand,
the Co(II)-based metalloradical system, which enjoys opera-
tional simplicity and mild conditions, can activate α-
aryldiazoketones with varied electronic and steric properties
for 1,4-alkylation of C(sp3)−H bonds, enabling stereoselective
construction of chiral α,β-disubstituted cyclobutanones. We
show the importance of catalyst development through the fine-
tuning of the ligand environments in achieving high reactivity
and stereoselectivity in this new radical process. Furthermore,
our combined experimental and computational studies on the
mechanism of the Co(II)-based metalloradical system have
shed light on the underlying stepwise radical pathway,
including the key steps of 1,4-HAA and 4-exo-tet-RS. A series
of further transformations of the resulting enantioenriched α,β-
disubstituted cyclobutanones are provided to showcase their
synthetic applications.
Co(III)-alkyl radicals II? Apart from the reactivity concerns,
could the 1,4-HAA of α-Co(III)-alkyl radicals I be rendered
enantioselective? Furthermore, the subsequent 4-exo-tet radical
cyclization of the alkyl radicals II via intramolecular radical
substitution was expected to be equally challenging in light of
the high strain associated with four-membered transition state.
What factors could be utilized to facilitate the ring closure for
product formation? Additionally, how could the C−C bond
formation be achieved with effective diastereoselective control
during radical cyclization? We reasoned that all these and
related questions could be potentially addressed through the
optimization of [Co(D2-Por*)] catalyst by the fine-tuning of
the D2-symmetric chiral amidoporphyrin ligand to adopt
suitable environments that govern the course of the catalytic
radical process (Scheme 1). If realized successfully, it would
give rise to the first catalytic radical process for asymmetric
intramolecular C−H alkylation involving 1,4-HAA as the key
step for stereoselective construction of highly strained
cyclobutanone structures, the four-membered carbocycles
a
Scheme 2. Ligand Effect on Co(II)-Based Catalytic System for Asymmetric 1,4-C−H Alkylation of α-Aryldiazoketone
a
b
Carried out with 1a (0.10 mmol) using [Co(Por)] (2 mol %) in tert-butyl methyl ether (TBME) (0.5 mL) at 40 °C for 12 h. Isolated yield.
c
d
Diastereomeric excess (de) determined by 1H NMR analysis of crude reaction mixture before purification. Isomerized to trans-enriched products
e
with 96% de after purification by silica gel column chromatography for all catalytic reactions. Enantiomeric excess (ee) of trans-diastereomer
determined by chiral HPLC after purification
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a b c d
, , ,
Table 1. Asymmetric Synthesis of Cyclobutanones by Co(II)-Catalyzed 1,4-C−H Alkylation of α-Diazoketones
a
b
c
Carried out with 1 (0.10 mmol) and [Co(P5)] (2 mol %) in TBME (0.5 mL) at 40 °C for 12 h. Isolated yield. Diastereomeric ratio (dr)
1
determined by H NMR analysis: trans-enriched products after purification by silica gel column chromatography due to isomerization; value in
parathesis determined from reaction mixture before purification. Enantiomeric excess (ee) of trans-diastereomer determined by chiral HPLC after
purification. Reaction performed in 1.0 mmol scale. Absolute configuration determined by X-ray crystallography. Relative configuration
d
e
f
g
determined by X-ray crystallography.
When switching to new-generation C6-bridged metalloradical
catalyst [Co(P4)] (P4 = 3,5-DitBu-Hu(C6)Phyrin) featuring
more rigid cavity-like environments,16 dramatic improvements
in both diastereoselectivity (94% de) and enantioselectivity
(78% ee) were observed even if in relatively lower product
yield (61%). Subsequent use of analogous catalyst [Co(P5)]
(P5 = 2,6-DiMeO-Hu(C6)Phyrin),17 which bears 2,6-dime-
thoxyphenyl instead of 3,5-di-tert-butylphenyl groups as the
5,15-diaryl substituents, further improvements in enantiose-
lectivity (96% ee) as well as yield (80%) were achieved without
significantly affecting the diastereoselectivity (82% de). These
results demonstrate that the rigidification of ligand environ-
ment of chiral metalloradical catalyst [Co(D2-Por*)] plays an
important role in achieving both high reactivity and stereo-
selectivity for the 1,4-C−H alkylation process. It should be
emphasized that the diastereomeric mixtures of the resulting
cyclobutanone 2a from all the catalytic reactions were
isomerized to trans-enriched 2a with 96% de after purification
by column chromatography on silica gel as a result of the
relative acidity of the tertiary α-C−H bond, regardless the
original diastereoselectivities before purification.
Substrate Scope. Under the optimized conditions, the
substrate scope of the [Co(P5)]-catalyzed intramolecular 1,4-
C−H alkylation was evaluated with α-aryldiazoketones 1
containing different types of C−H bonds (Table 1). Like the
parent 1a, 1,4-diaryl-α-diazoketone derivatives containing 4-
aryl substituents with various steric and electronic properties at
different positions, including 4-OMe (1b), 3-OMe (1c), 2-
OMe (1d), 3,4-di-OMe (1e), 1′,3′-dioxolane-3,4-fused (1f), 4-
Ph (1g), 4-F (1h), 3,4-di-F (1i), and 4-CN (1j), could be
efficiently alkylated by [Co(P5)] at the benzylic C−H bonds,
RESULTS AND DISCUSSION
■
Catalyst Development. At the outset of this research
project, 1-diazo-1,4-diphenylbutan-2-one (1a) was used as the
model substrate to examine the feasibility of the proposed
catalytic process for 1,4-C−H alkylation (Scheme 2). Simple
achiral metalloradical catalyst [Co(TPP)] (TPP = 5,10,15,20-
tetraphenylporphyrin) was shown to be incapable of activating
1a for the intramolecular C−H alkylation reaction, failing to
generate any cyclobutanone product. Instead, diazoketone 1a
was thermally decomposed to the carboxylic acid derivative via
Wolff rearrangement, followed by nucleophilic reaction of the
corresponding ketene intermediate with water. Excitingly,
when the achiral amidoporphyrin catalyst [Co(P1)] (P1 =
3,5-DitBu-IbuPhyrin)15 was used, it could productively catalyze
the C−H alkylation reaction to deliver the desired product 2,3-
diphenylcyclobutan-1-one (2a) in 54% yield with 40% de. The
dramatic difference in reactivity between [Co(P1)] and
[Co(TPP)] might be attributed to rate acceleration through
the potential hydrogen bonding interaction between amide
units of the porphyrin and the carbonyl group of the α-
diazoketone. Employment of first-generation chiral metal-
loradical catalyst [Co(P2)] (P2 = 3,5-DitBu-ChenPhyrin)7a
enabled asymmetric induction in the 1,4-C−H alkylation
reaction, affording cyclobutanone 2a with moderate enantio-
selectivity (46% ee) without significantly affecting the product
yield (50%) and diastereoselectivity (52% de). When second-
generation chiral metalloradical catalyst [Co(P3)] (P3 = 3,5-
DitBu-TaoPhyrin) bearing chiral amide units with ester
moieties was used for the catalytic reaction,16 it led to the
increase in both product yield (71%) and diastereoselectivity
(86% de) but the decrease in enantioselectivity (15% ee).
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Scheme 3. Mechanistic Studies on Co(II)-Catalyzed 1,4-C−H Alkylation of α-Aryldiazoketones
a
Free energy profile of the [Co(P5)]-catalyzed 1,4-C−H alkylation. Density functional theory calculations were performed at
SMD(diisopropylether)-BP86-D3(BJ)/def2TZVPP//BP86-D3(BJ)/def2SVP level of theory.
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delivering the corresponding cyclobutanones 2b−2j in good
yields with high enantioselectivities (Table 1; entries 2−10).
The Co(II)-catalyzed 1,4-C−H alkylation was shown to be
compatible with substrates containing heteroarenes, such as
furan (1k), thiophene (1l) and indole (1m), allowing for
stereoselective construction of β-heteroarylcyclobutanones
2k−2m in similarly good yields with the same high
enantioselectivities (Table 1; entries 11−13). Furthermore,
the Co(II)-based catalytic system could chemoselectively
alkylate allylic C−H bonds without affecting the typically
more reactive CC π bonds as demonstrated by the
productive formation of β-alkenylcyclobutanone 2n from the
reaction of 4-alkenyl-substituted diazoketone (Z)-1n in good
yield albeit with lower enantioselectivity (Table 1; entry 14). It
was noted that the olefin configuration was completely
isomerized from (Z) to (E) during the catalytic process (see
Scheme 3D for detailed discussion). Likewise, propargylic C−
H bonds could also be chemoselectively alkylated by [Co(P5)]
without reacting with the CC π bonds, as exemplified by the
reaction of 4-alkynyl-substituted diazoketone 1o to generate β-
alkynylcyclobutanone 2o in good yield with better enantiose-
lectivity (Table 1; entry 15). In addition to the substrates with
different 4-aryl substituents, the Co(II)-based metalloradical
system was shown to be applicable to α-diazoketones
containing 1-aryl substituents with various steric and electronic
properties at different positions. For example, catalytic 1,4-C−
H alkylation reactions of 1-aryl-4-phenyl-α-diazoketones, such
as those bearing 3-OMe (1p), 4-CF3 (1q), and 4-Br (1r)
phenyl groups as well as 2-naphthyl group (1s), proceeded
smoothly to afford the corresponding cyclobutanones 2p−2s
in good to high yields with excellent enantioselectivities (Table
1; entries 16−19). 1,4-Diaryl-α-diazoketones containing both
1- and 4-aryl substituents were found to work equally well as
shown with the successful reaction of α-diazoketone 1t for
formation of the desired α,β-bisarylcyclobutanone 2t with
excellent level of enantioselectivity despite in moderate yield
(Table 1; entry 20). Furthermore, the Co(II)-based catalytic
system could be also applicable to cyclic substrates such as 2-
indane-derived α-diazoketone 1u, resulting in asymmetric
desymmetrization of the two benzylic C−H sites in the indane
ring to deliver cyclobutanone 2u (Table 1; entry 21). It is
remarkable that the strained tricyclic structure with fused 4-/5-
membered rings could be constructed through catalytic 1,4-C−
H alkylation in good yield despite with low enantioselectivity.
A new Co(II)-metalloradical catalyst supported by a different
type of D2-symmetric chiral amidoporphyrin ligand would
likely be needed in order to achieve high enantioselectivity for
the asymmetric desymmetrization 1,4-C−H alkylation process.
Finally, [Co(P5)] was found to be ineffective for 1,4-alkylation
of nonbenzylic C−H bonds due to the competition from
predominant 1,5-C−H alkylation. However, preliminary results
from the catalytic reaction of 1-diazo-1,7-diphenylheptane-2-
one with C−H bonds at different positions indicated that site-
selective 1,4- over 1,5-C−H alkylation could be potentially
achieved through fine-tuning of the D2-symmetric chiral
amidoporphyrin as the supporting ligand for Co(II)-metal-
loradical catalyst (see Scheme S1 in Supporting Information
for the details). As aforementioned, the diastereomeric
mixtures of the resulting cyclobutanones 2, regardless the
original diastereoselectivities from the catalytic reactions, were
all further enriched to give trans-dominant products with
excellent diastereoselectivities after purification by column
chromatography on silica gel (Table 1), which was realized by
isomerization as a result of the relative acidity of the tertiary α-
C−H bonds. The only exception was observed for product 2o,
the diastereoselectivity of which was decreased after the
purification (Table 1; entry 15), which is presumably a result
of the less steric hindrance of the alkyne group. It is worth
mentioning that the Co(II)-based catalytic process for the
synthesis of cyclobutanone derivatives could be readily scaled
up under the same condition as exemplified by the stereo-
selective syntheses of optically active cyclobutanones 2a, 2j
and 2q on 1.0 mmol scale in similarly good yields with the
same level of high enantioselectivities (Table 1; entries 1, 10
and 17).
Mechanistic Studies. To gain insights into this metal-
loradical process, combined computational and experimental
studies were conducted to explore the proposed stepwise
radical mechanism for the Co(II)-catalyzed 1,4-C−H
alkylation (Scheme 1). First, density functional theory
(DFT) calculations were performed to elucidate the catalytic
pathway for 1,4-C−H alkylation reaction of α-aryldiazoketone
1a with the use of the actual catalyst [Co(P5)] (Scheme 3A;
see Supporting Information for details). The computational
study reveals the initial formation of intermediate B between
diazo 1a and catalyst [Co(P5)] through a network of
noncovalent attractions, including multiple H-bonds and π-
interactions. This complexation process, which is exergonic by
6.9 kcal/mol, places the substrate underneath the bridge of the
catalyst and positions the α-carbon atom of diazo 1a in a close
proximity to the Co center of [Co(P5)] (C---Co: ∼ 2.70 Å)
for further interaction. Upon metalloradical activation (MRA)
by [Co(P5)], the bound 1a undergoes the extrusion of
dinitrogen to generate α-Co(III)-alkyl radical C. The metal-
loradical activation step, which is exergonic by 11.5 kcal/mol,
is found to be associated with a relatively high but accessible
activation barrier (TS1: ΔG‡ = 18.1 kcal/mol). Subsequent
1,4-HAA of intermediate C, which is exergonic by 14.3 kcal/
mol, gives rise to the corresponding δ-Co(III)-alkyl radical
intermediate D with a relatively low activation barrier (TS2:
ΔG‡ = 6.5 kcal/mol). Such a low barrier for 1,4-HAA revealed
by the DFT computation, which is uncommon for free radical
processes,18 may be attributed to the presence of the multiple
noncovalent interactions that stabilize transition state TS2. As
illustrated by the computed model of TS2 (Scheme 3A), these
cooperative noncovalent attractive interactions orient the
reacting substrate within the catalyst cavity in proximity with
proper conformation to facilitate the 1,4-HAA. According to
the DFT calculations, the final step of 4-exo-tet cyclization of
alkyl radical D via intramolecular radical substitution also has a
relatively low activation barrier (TS3: ΔG‡ = 8.4 kcal/mol),
leading to the formation of cyclobutanone 2a while
regenerating catalyst [Co(P5)].
To experimentally detect α-Co(III)-alkyl radical I and δ-
Co(III)-alkyl radical II, the reaction mixture of α-aryldiazoke-
tone 1a with catalyst [Co(P1)] was analyzed by high-
resolution mass spectrometry (HRMS) with electrospray
ionization (ESI) in the absence of any additives as electron
carriers (Scheme 3B). The obtained spectrum clearly reveals a
signal corresponding to [(P1)Co−C(C6H5)(C(O)-
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CH2CH2C6H5)]+ (m/z = 1457.7266), which resulted from
neutral α-Co(III)-alkyl radical intermediate I[Co(P1)]/1a or δ-
Co(III)-alkyl radical intermediate II[Co(P1)]/1a by the loss of
one electron. Both the exact mass and the pattern of isotope
distribution determined by ESI-HRMS matches almost
perfectly with those calculated from the formula
[C92H102CoN8O5]+ (see Supporting Information for details).
In addition to the HRMS detection, we made multiple
attempts to observe I[Co(P1)]/1a and II[Co(P1)]/1a by electron
paramagnetic resonance (EPR) without success. This negative
outcome of EPR observation was attributed to the fleeting
nature of the alkyl radical intermediates as a result of facile 1,4-
HAA and RS steps, as revealed from DFT calculations.
Accordingly, the common spin trap phenyl N-tert-butyl-α-
phenylnitrone (PBN) was employed to trap I[Co(P1)]/1a or
II[Co(P1)]/1a, which resulted in the generation of radicals
III[Co(P1)]/1a or IV[Co(P1)]/1a that could be successfully observed
by EPR at room temperature (Scheme 3B; see Supporting
Information for details). The observed triplet of doublet signals
in the isotropic EPR spectrum could be fittingly simulated on
the basis of hyperfine couplings by 14N (I = 1) and 1H (I = 1/
2): g = 2.00581; A(N) = 43.9 MHz; A(H) = 5.7 MHz.
evidence for formation of ring-opening product in both
reactions, it was concluded that the C−C and related bond
formation were faster than the ring-opening of the cyclo-
propylcarbinyl radical within the cavity-like ligand environment
of the catalyst (see Supporting Information for details).
Synthetic Applications. Considering that the resulting
enantioenriched cyclobutanones contain both versatile carbon-
yl group and strained four-membered structure, they may serve
as useful intermediates for stereoselective organic synthesis
(Scheme 4). To demonstrate the synthetic utility of this
Scheme 4. Synthetic Transformations of Resulting Chiral
Cyclobutanones from Co(II)-Catalyzed 1,4-C−H
a
Alkylation
To further study the 1,4-HAA step in the catalytic process,
monodeuterated diazo 1aD was prepared as the substrate for
the study of kinetic isotopic effect (KIE) using both achiral
catalyst [Co(P1)] and chiral catalyst [Co(P5)] (Scheme 3C).
The KIE values for the catalytic reaction of diazo 1aD by
[Co(P1)] and [Co(P5)] were determined to be 11.5 and 7.3,
respectively. These large values of primary KIE are in good
agreement with the proposed step of homolytic C−H bond
cleavage via intramolecular H-atom abstraction by α-Co(III)-
alkyl radical intermediate I. To further probe the existence of
δ-Co(III)-alkyl radical intermediate II, (Z)-1n was employed
as the substrate for 1,4-C−H alkylation reaction using
[Co(P1)] as the catalyst (Scheme 3D). Like the catalytic
reaction by [Co(P5)] (Table 1; entry 14), it was found that
(E)-2n was generated as the only product, indicating
isomerization of the olefin configuration during the catalytic
process. The formation of (E)-2n from (Z)-1n implies the
involvement of δ-Co(III)-allylic radical II(E)‑1n, which could be
generated through isomerization of δ-Co(III)-allylic radical
II(Z)‑1n. To directly trap the alkyl radical intermediate, the
catalytic reaction of 1a using [Co(P1)] as the catalyst was
conducted in the presence of TEMPO (Scheme 3E).
Interestingly, TEMPO-trapping product 3a was isolated in
32% yield, the structure of which was confirmed by X-ray
crystallography. Formation of 3a further implies the initial
generation of α-Co(III)-alkyl radical I1a by MRA, followed by
1,4-HAA to deliver δ-Co(III)-alkyl radical II1a in the catalytic
reaction. Instead of radical recombination with TEMPO, it is
presumed to be more favorable for intermediate II1a to
undergo HAA by TEMPO, furnishing Co(III)-alkyl inter-
mediate V1a with the extended conjugation. Subsequent radical
substitution with another molecule of TEMPO delivered the
TEMPO-trapping product 3a. In a similar pathway, the
catalytic reaction of allyl diazoketone 1v by [Co(P1)] in the
presence of TEMPO could give TEMPO trapping product 3v,
indicating the involvement of the corresponding radical
intermediates I1v, II1v and V1v. Furthermore, catalytic reactions
of allyl diazoketone bearing a cyclopropyl ring as radical-clock
substrate were performed with [Co(P5)] in both absence and
presence of TEMPO to probe the lifetime of the correspond-
ing δ-Co(III)-alkyl radical intermediate. Since there was no
a
(a) Triethyl Phosphonoacetate (1.5 equiv); Sodium Hydride (1.2
equiv); THF; RT; 12 h. (b) Hydroxylamine Hydrochloride (2.0
equiv); Pyridine; RT; 2 h. (c) Benzoyl Chloride (1.5 equiv);
Triethylamine (2.0 equiv); DCM; 0 °C; 6 h. (d) Sodium Borohydride
(1.0 equiv); MeOH; −78 °C; 10 h. (e) Benzylamine (1.1 equiv);
Sodium Triacetoxyborohydride (2.0 equiv); DCM; RT; 12 h. (f)
Benzylmagnesium Chloride (1.5 equiv); THF; 0 °C; 1 h. (g)
Vinylmagnesium Bromide (1.5 equiv); THF; 0 °C; 1 h. (h)
Ethynylmagnesium Bromide (1.5 equiv); THF; 0 °C; 1 h. (i) m-
CPBA; DCM; 0 °C; 2 h. (j) o-Aminobenzylamine (1.1 equiv);
CHCl3; 60 °C; 9 h. (k) NCS (1.5 equiv); DCM; 0 °C; 2 h.
methodology, we carried out a series of synthetic trans-
formations using enantioenriched cyclobutanone 2a (96% ee)
as the model reactant. For example, cyclobutanone 2a could
undergo efficient Horner-Wadsworth-Emmons reaction to
provide the corresponding chiral methylenecyclobutane 4a in
high yield without the loss of either diastereopurity or
enantiopurity. Cyclobutanone 2a could also be stereospecifi-
cally converted to the corresponding O-benzoyl oxime 5a,
which is known to undergo various ring-opening trans-
formations.19 In addition, 2a could undergo both efficient
reduction and reductive amination, allowing for the production
of chiral cyclobutanol 6a and cyclobutanamine 7a, respectively,
with excellent diastereoselectivities. Moreover, the ketone
functionality in cyclobutanone 2a could undergo nucleophilic
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addition with Grignard reagents such as benzylmagnesium
chloride, vinylmagnesium bromide, and ethynylmagnesium
bromide to provide corresponding cyclobutanols 8a, 9a, and
10a bearing a newly-formed quaternary stereogenic center in
excellent yields with effective control of diastereoselectivities. It
is worth mentioning that tertiary cyclobutanols such as 8a, 9a,
and 10a can be potentially employed for downstream
functionalization via C−C bond cleavage.20 In view of the
wide applications of the chiral γ-lactone scaffold,21 it was
shown that γ-lactone 11a could be efficiently generated from
cyclobutanone 2a through Baeyer-Villiger oxidation with the
retention of the original stereochemical purity. Gratifyingly,
chiral dihydroquinazoline 12a, as a family of heterocycles with
interesting biological activities,22 could be synthesized from the
reaction of 2a with o-aminobenzylamine through simple two-
step transformation.23
AUTHOR INFORMATION
Corresponding Author
■
X. Peter Zhang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0001-7574-8409; Email: peter.zhang@bc.edu
Authors
Jingjing Xie − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States; orcid.org/0000-0002-1063-5558
Pan Xu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States; orcid.org/0000-0002-3433-3378
Yiling Zhu − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Jingyi Wang − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Wan-Chen Cindy Lee − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0002-2433-7404
CONCLUSIONS
■
In summary, we have demonstrated the first catalytic system
for asymmetric radical 1,4-C−H alkylation via Co(II)-based
MRC that involves the typically challenging 1,4-hydrogen atom
abstraction. The key to the successful development is the
judicious modulation of D2-symmetric chiral amidoporphyrin
ligand to adopt desired steric, electronic and chiral environ-
ments around the Co(II)-metalloradical center that maximize a
network of noncovalent attractive interactions in catalytic
intermediates. With the bridged D2-symmetric chiral amido-
porphyrin 2,6-DiMeO-Hu(C6)Phyrin as the optimal support-
ing ligand, the Co(II)-based metalloradical system, which
operates under mild conditions, can catalyze asymmetric 1,4-
C−H alkylation of α-aryldiazoketones with varied electronic
and steric properties to construct chiral α,β-disubstituted
cyclobutanones in good yields with high diastereoselectivities
and enantioselectivities. The combined computational and
experimental studies have shed light on the working details of
this new catalytic process that proceeds through a stepwise
radical mechanism, which is fundamentally different from the
concerted C−H insertion by the existing catalytic systems
involving metallocarbenes. As showcased with several
enantiospecific transformations to other types of cyclic
structures from the resulting enantioenriched α,β-disubstituted
cyclobutanones, this Co(II)-based metalloradical system for
asymmetric 1,4-C−H alkylation should find broad applications
in organic synthesis. We envision that catalytic radical
processes incorporating 1,4-H-atom abstraction as the key
step may offer a general strategy for asymmetric construction
of highly strained four-membered cyclic structures.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04968
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support by NIH (R01-
GM132471) and in part by NSF (CHE-1900375).
■
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ASSOCIATED CONTENT
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sı
* Supporting Information
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Experimental details and analytical data for all new
compounds (PDF)
Accession Codes
CCDC 2083314−2083317 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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