Asymmetric radical cyclopropanation of dehydroaminocarboxylates: Stereoselective synthesis of cyclopropyl α-amino acids

Article abstract of DOI:10.1016/j.chempr.2021.03.002

A catalytic radical process has been developed for asymmetric cyclopropanation of dehydroaminocarboxylates with in situ-generated α-aryldiazomethanes via Co(II)-based metalloradical catalysis (MRC). Through fine-tuning the environments of D₂-symmetric chiral amidoporphyrin platform as the supporting ligands, the Co(II)-metalloradical system can effectively activate various α-aryldiazomethanes to cyclopropanate different dehydroaminocarboxylates under mild conditions, enabling the stereoselective synthesis of chiral cyclopropyl α-amino acid derivatives. In addition to high yields and excellent enantioselectivities, the Co(II)-catalyzed asymmetric radical cyclopropanation exhibits (Z)-diastereoselectivity, which is the opposite of uncatalyzed thermal reaction. Combined computational and experimental studies support a stepwise radical mechanism for the Co(II)-catalyzed cyclopropanation reaction. The resulting enantioenriched (Z)-α-amino-β-arylcyclopropanecarboxylates, as showcased for the efficient synthesis of dipeptides, may serve as unique non-proteinogenic amino acid building blocks for the design and preparation of novel peptides with restricted conformations.

Full text of DOI:10.1016/j.chempr.2021.03.002

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Article
Asymmetric radical cyclopropanation of
dehydroaminocarboxylates: Stereoselective
synthesis of cyclopropyl a-amino acids
Wan-Chen Cindy Lee,
Duo-Sheng Wang, Congzhe
Zhang, Jingjing Xie, Bo Li, X.
Peter Zhang
peter.zhang@bc.edu
Highlights
Asymmetric catalytic system for
cyclopropanation of
dehydroaminocarboxylates
Asymmetric synthesis of chiral
cyclopropyl a-amino acids under
mild conditions
Detailed mechanistic studies on
elucidation of underlying stepwise
radical pathway
Importance of attractive
noncovalent interactions in
catalyst development
Cobalt(II)-based metalloradical catalysis (MRC) has been successfully applied for the
development of a new catalytic radical process that is highly effective for asymmetric
cyclopropanation of dehydroaminocarboxylates with in situ-generated
a-aryldiazomethanes. Supported by an optimal D2-symmetric chiral amidoporphyrin
ligand, the Co(II)-based catalytic system is applicable to broad combinations of
a-aryldiazomethanes and dehydroaminocarboxylates. In addition to high yields and
excellent enantioselectivities, the Co(II)-catalyzed asymmetric cyclopropanation
enables direct synthesis of a-amino-b-arylcyclopropanecarboxylates with (Z)-
diastereoselectivity, which is different from uncatalyzed thermal reaction.
Lee et al., Chem 7, 1588–1601
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Asymmetric radical cyclopropanation of
dehydroaminocarboxylates: Stereoselective
synthesis of cyclopropyl a-amino acids
Wan-Chen Cindy Lee,1 Duo-Sheng Wang,1 Congzhe Zhang,1 Jingjing Xie,1 Bo Li,1
and X. Peter Zhang1,2,
*
SUMMARY
The bigger picture
Chiral cyclopropyl a-amino acids
represent a unique class of non-
proteinogenic a-amino acids that
have found wide applications in
the design and synthesis of novel
peptides with restricted
A catalytic radical process has been developed for asymmetric
cyclopropanation of dehydroaminocarboxylates with in situ-generated
a-aryldiazomethanes via Co(II)-based metalloradical catalysis (MRC).
Through fine-tuning the environments of D2-symmetric chiral amido-
porphyrin platform as the supporting ligands, the Co(II)-metalloradical
system can effectively activate various a-aryldiazomethanes to cyclo-
propanate different dehydroaminocarboxylates under mild conditions,
enabling the stereoselective synthesis of chiral cyclopropyl a-amino
acid derivatives. In addition to high yields and excellent enantioselec-
tivities, the Co(II)-catalyzed asymmetric radical cyclopropanation
exhibits (Z)-diastereoselectivity, which is the opposite of uncatalyzed
thermal reaction. Combined computational and experimental studies
support a stepwise radical mechanism for the Co(II)-catalyzed cyclopro-
panation reaction. The resulting enantioenriched (Z)-a-amino-b-arylcy-
clopropanecarboxylates, as showcased for the efficient synthesis of
dipeptides, may serve as unique non-proteinogenic amino acid
building blocks for the design and preparation of novel peptides with
restricted conformations.
conformations that are of
biological importance. As a
practical application of
metalloradical catalysis (MRC), we
have developed an asymmetric
catalytic system that is highly
effective for direct
cyclopropanation of
dehydroaminocarboxylates with
in situ-generated
a-aryldiazomethanes. The Co(II)-
based catalytic system, which
operates under mild conditions,
enables high-yielding preparation
of chiral cyclopropyl a-amino
acids with excellent
INTRODUCTION
Radical chemistry has been increasingly explored for the development of new syn-
thetic tools in construction of organic molecules due to its unique reactivity and
attractive characteristics, such as mild reaction condition and functional group
tolerance.1 However, controlling stereoselectivity, especially enantioselectivity, of
radical reactions has remained a paramount challenge.2 Among recent advances,3
metalloradical catalysis (MRC) has emerged as a new approach to use metal-
centered radicals to generate metal-stabilized organic radicals for achieving the
control of reactivity and stereoselectivity in radical processes.4–6 As stable 15e-met-
alloradicals, Co(II) complexes of D2-symmetric chiral amidoporphyrins [Co(D2-Por*)]
exhibit unusual capability of homolytically activating different classes of diazo com-
pounds to generate a-Co(III)-alkyl radicals.7 These Co-supported C-centered radical
intermediates are capable of radical addition to alkenes to deliver g-Co(III)-alkyl rad-
icals, which can undergo intramolecular radical substitution for catalytic formation of
chiral cyclopropanes with control of diastereoselectivity and enantioselectivity.8
Although monosubstituted alkenes, including styrene derivatives and a,b-unsatu-
rated carbonyls, as well as aliphatic olefins, have been demonstrated as suitable sub-
strates for Co(II)-based metalloradical system,8 asymmetric radical cyclopropanation
with 1,1-disubstituted alkenes remains rather underdeveloped. In particular, we
were interested in exploring the potential application of Co(II)-based MRC for
enantioselectivity and atypical (Z)-
diastereoselectivity.
Fundamentally, the underlying
stepwise radical mechanism of
Co(II)-catalyzed cyclopropanation
has been elucidated by combined
experimental and computational
studies, revealing the importance
of cooperative noncovalent
interactions, such as H-bonding
and p-stacking, in catalyst design
and development.
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Scheme 1. Proposed mechanism for radical cyclopropanation of dehydroaminocarboxylates via
Co(II)-based metalloradical catalysis
asymmetric cyclopropanation of dehydroaminocarboxylates (Scheme 1), a class of
1,1-disubstituted alkenes that have been widely employed in catalytic asymmetric
hydrogenation for synthesis of chiral a-amino acids.9 Considering the unique steric
and electronic properties of dehydroaminocarboxylates, their suitability as
substrates for Co(II)-based radical cyclopropanation was unsettled and presented
several potential challenges. In the specific case of using in situ-generated
a-aryldiazomethanes 10 as the radical precursor (also termed as ‘‘metalloradicophi-
le’’),8i it was unclear how the radical addition of the initially formed a-Co(III)-benzyl
radical intermediate I with the 1,1-disubstituted alkene could be impacted by the
steric hinderance associated with the two geminal substituents. Furthermore, during
this first C–C bond forming step, differentiation of the two prochiral faces of the
Co-bonded C-centered radical I for controlling enantioselectivity could be chal-
lenging in view of the similar sizes of the two geminal amino and ester groups in
alkene 2. For the same reasons, issues could also be encountered with the control
of both reactivity and diastereoselectivity in the subsequent 3-exo-tet radical cycli-
zation of the resulting g-Co(III)-aminoalkyl radicals II (Scheme 1). Besides the steric
concerns, the second C–C bond forming process might also experience an adverse
electronic effect in the light of higher stability of the tertiary radical intermediate II as
a result of captodative effect from the ester group and amino group.10 Additional
uncertainty might arise from potential H-bonding interactions between the amino/
ester groups and the amide units on the amidoporphyrin ligand. We hoped to
address these and related issues through the identification of a D2-symmetric chiral
amidoporphyrin ligand with proper electronic, steric, and chiral environments that
could govern the course of the Co(II)-based radical process as proposed. If success-
ful, it would lead to the development of the first asymmetric catalytic system that cat-
alyzes direct cyclopropanation of dehydroaminocarboxylates with diazo compounds
for stereoselective synthesis of chiral cyclopropyl a-amino acid derivatives 3. Chiral
cyclopropyl a-amino acid derivatives represent a unique class of non-proteinogenic
a-amino acids that have found interesting applications in the design and synthesis of
novel peptides with restricted conformations (Figures S1 and S2).11,12 Although
several synthetic methods have been previously reported,11,12 it is warranted to
develop new catalytic systems for asymmetric synthesis of chiral cyclopropyl
a-amino acid derivatives that are generally applicable and highly enantioselective.
1Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, MA 02467,
USA
2Lead contact
*Correspondence: peter.zhang@bc.edu
https://doi.org/10.1016/j.chempr.2021.03.002
Metal-catalyzed asymmetric cyclopropanation of dehydroaminocarboxylates with
diazo compounds offers a potentially attractive approach for stereoselective
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synthesis of valuable chiral cyclopropyl a-amino acid derivatives. However, there
have been only a few reports on metal-based catalytic systems for direct synthesis
of cyclopropyl a-amino acid derivatives from dehydroaminocarboxylates.13 It was
shown that control of diastereoselectivity in cyclopropanation reactions of 1,1-
disubstituted alkenes, such as dehydroaminocarboxylates, is typically more chal-
lenging than those of monosubstituted alkenes.13b,14 In addition to their moderate
diastereoselectivity and limited scopes, none of the reported systems involved the
control of enantioselectivity. The underdevelopment of this potentially useful
catalytic method is attributed to the electronic incompatibility of dehydroaminocar-
boxylates as electron-deficient alkenes with the existing catalytic systems involving
electrophilic metallocarbene intermediates.13a,13b,15 When donor-substituted diazo
compounds such as a-aryldiazomethanes are used as carbene sources, the develop-
ment of asymmetric catalytic system poses additional challenges due to competitive
uncatalyzed thermal process via [3+2] cycloaddition.13b,16a To circumvent the diffi-
culty, Aggarwal and co-workers reported an innovative solution that relied upon
the combined use of dirhodium tetracarboxylates and chiral sulfides as dual catalysts
to transfer the initially generated electrophilic Rh2-carbenes into nucleophilic chiral
sulfur ylides as demonstrated for asymmetric cyclopropanation of dehydroamino-
carboxylate substrates with in situ-generated a-phenyldiazomethane.17 Davies
and co-workers developed an alternative approach for stereoselective syntheses
of chiral cyclopropyl a-amino acid derivatives that was based on Rh2-catalyzed
asymmetric cyclopropanation of alkenes with vinyldiazomethanes, followed by
oxidation.18a As another alternative approach, Charette and co-workers synthesized
chiral cyclopropyl a-amino acid derivatives through reduction of enantioenriched
a-nitrocyclopropanecarboxylates that were formed by Rh2- and Cu-catalyzed
asymmetric olefin cyclopropanation.18b–18f Evidently, a new catalytic system that is
fundamentally different from the existing catalytic systems involving electrophilic
metallocarbene intermediates might be needed in order to achieve direct asym-
metric cyclopropanation of dehydroaminocarboxylates, a stereoselective transfor-
mation that has not been previously developed. We herein report the application
of Co(II)-based metalloradical catalysis (MRC) for the development of a new
catalytic radical process that is highly effective for asymmetric cyclopropanation
of dehydroaminocarboxylates with in situ-generated a-aryldiazomethanes.
Supported by an optimal D2-symmetric chiral amidoporphyrin ligand, the
Co(II)-based catalytic system is applicable to broad combinations of a-aryldiazome-
thanes and dehydroaminocarboxylates. In addition to high yields and excellent
enantioselectivities, the Co(II)-catalyzed asymmetric cyclopropanation enables
direct synthesis of a-amino-b-arylcyclopropanecarboxylates with (Z)-diastereoselec-
tivity, which is different from uncatalyzed thermal reaction.13b,16a
RESULTS AND DISCUSSION
Reaction development
Our effort started with the investigation of cyclopropanation reaction of dehydroa-
minocarboxylate 2a as the model substrate with in situ-generated a-phenyldiazome-
thane (1a’) from the combination of benzaldehyde trisylhydrazone 1a and Cs2CO3
using Co(II)-based metalloradical catalysts (Figure 1). In line with literature re-
ports,13b,16a the reaction occurred even at 4ꢀC in the absence of a catalyst, produc-
ing the corresponding cyclopropane 3a in 18% yield with 17/83 dr in favor of the (E)-
diastereomer (Figure 1; entry 1). When the simple metalloradical catalyst [Co(TPP)]
(TPP = 5,10,15,20-tetraphenylporphyrin) was used, the desired cyclopropane 3a
was generated in 65% yield with a 64/36 dr preference for the opposite (Z)-diaste-
reomer, implying the domination of catalyst-controlled process over the
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Figure 1. Ligand effect on Co(II)-based catalytic system for asymmetric cyclopropanation of dehydroaminocarboxylates with a-aryldiazomethanes
aConducted with 1 (0.12 mmol), 2 (0.10 mmol), and Cs2CO3 (0.24 mmol) using Co(II) catalyst (2 mol %) in chlorobenzene at 4ꢀC for 12 h.
bIsolated yields.
cDiastereomeric ratio (dr) determined by 1H NMR analysis of reaction mixture.
dEnantiomeric excess (ee) of major (Z)-isomer determined by chiral HPLC.
eDFT-optimized models showing H-bonding and p-stacking interactions; Substituents on the bottom side, as well as at the inside and outside meso
positions, omitted for clarity; see Scheme 2 and Supplemental information for details. Tris = 2,4,6-triisopropylbenzenesulfonyl.
competitive thermal reaction (Figure 1; entry 2). This initial result inspired us to
explore the possibility of achieving enantioselectivity in the Co(II)-catalyzed reaction
with the use of D2-symmetric chiral amidoporphyrins as the supporting ligands. To
our delight, when first-generation chiral metalloradical catalyst [Co(P1)] (P1 = 3,5-
DitBu-ChenPhyrin)8a was employed, cyclopropyl a-amino ester 3a was formed in a
similar yield with significant enantioselectivity despite diminished (Z)-diastereose-
lectivity (Figure 1; entry 3). Changing [Co(P1)] to second-generation chiral metallor-
adical catalyst [Co(P2)] (P2 = 3,5-DitBu-QingPhyrin)8g switched the asymmetric in-
duction in favor of the opposite enantiomer albeit with lower enantioselectivity
(from –36% ee to 16% ee) without significantly affecting the product yield and dia-
stereoselectivity (Figure 1; entry 4).
To further improve the enantioselectivity of the catalytic process, we then turned our
attention to another second-generation metalloradical catalyst [Co(P3)] (P3 = 3,5-
DitBu-Xu(20-Naph)Phyrin) containing naphthyl groups in the chiral amide units,19 which
could potentially enhance p-stacking interaction with the phenyl group in the corre-
sponding a-Co(III)-benzyl radical intermediate I[Co(P3)]/1a for achieving conformational
rigidity (Figure 1). As expected, the catalytic reaction by [Co(P3)] afforded (Z)-3a in a bet-
ter yield (80%) along with higher diastereoselectivity and enantioselectivity (68/32 dr;
43% ee) (Figure 1; entry 5). This positive outcome prompted us to install potential
H-bonding interaction as an additional rigidification element for the conformation of
intermediate I[Co(P3)]. Inspired by our previous report,8i we decided to explore the use
of o-methoxybenzaldehyde trisylhydrazone 1b to generate the corresponding radical
precursor for catalytic cyclopropanation of dehydroaminocarboxylate 2a by [Co(P3)].
As illustrated in the DFT-optimized structure models (Figure 1; see Scheme 2 and Sup-
plemental information for details), installation of –OMe group at the ortho-position of
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Scheme 2. Computational and experimental studies on reaction pathway of Co(II)-catalyzed cyclopropanation of dehydroaminocarboxylates
the a-Co(III)-benzyl radical intermediate I[Co(P3)]/1b gives rise to multiple H-bonding and
related interactions, in addition to the double p-stacking interactions, which together
rigidify the radical intermediate’s conformation. The DFT calculations also reveal multi-
ple H-bonding and p-stacking interactions in both the transition state for the generation
of intermediate I[Co(P3)]/1b (TS1[Co(P3)]/1b) and the transition state for its subsequent radical
addition with dehydroaminocarboxylate 2a (TS2[Co(P3)]/1b/2a). Furthermore, it shows the
existence of H-bonding and p-stacking interactions in the resulting g-Co(III)-aminoalkyl
radical II[Co(P3)]/1b/2a as well. According to the DFT models, it would lead to the preferred
formation of the corresponding cyclopropane product 3b as (Z)-diastereomer with
(1R,2R) configuration (Figure 1). In addition to the conformational rigidification of the
intermediates, these noncovalent attractive interactions can cooperatively lower the
activation barriers of the transition states (see Scheme 2), which may enhance catalytic
reactivity and improve stereoselectivities of the product. Excitingly, the cyclopropana-
tion reaction of dehydroaminocarboxylate 2a with o-methoxybenzaldehyde trisylhydra-
zone 1b by [Co(P3)] indeed delivered the desired chiral cyclopropyl a-amino ester 3b in
excellent yield (98%) with higher (Z)-diastereoselectivity (82/18 dr) and excellent enantio-
selectivity (93% ee) (Figure 1; entry 6). As suggested by the DFT model of g-Co(III)-ami-
noalkyl radical II[Co(P3)]/1b/2a, cyclopropane 3b was produced preferentially as (Z)-diaste-
reomer with (1R,2R) configuration (see Figure 2). In accordance with the postulation,
when o-methoxybenzaldehyde hydrazone 1b was replaced by sterically comparable
o-ethylbenzaldehyde hydrazone 1c, the observed enhancement in both reactivity
and selectivity vanished completely (Figure 1; entry 7), giving the corresponding chiral
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Figure 2. Substrate scope of asymmetric cyclopropanation of dehydroaminocarboxylates with
a-aryldiazomethanes catalyzed by [Co(P3)]
aConducted with 1 (0.12 mmol), 2 (0.10 mmol), and Cs2CO3 (0.24 mmol) using [Co(P3)] catalyst
(2 mol %) in chlorobenzene at 4ꢀC for 12 h; Isolated yields; Diastereomeric ratio (dr) determined by
1H NMR analysis of reaction mixture; Enantiomeric excess (ee) of major (Z)-isomer determined by
chiral HPLC.
bAbsolute configuration determined by X-ray crystallography.
cIn methanol at 23ꢀC.
cyclopropyl a-amino ester (Z)-3c in the same yield with similar stereoselectivities as those
obtained with non-substituted 1a (Figure 1; entry 5). To further examine the effect of
noncovalent interactions such as H-bonding interaction on reactivity and selectivity, a
new catalyst [Co(P4)] (P4 = 3,5-DitBu-Chen(N-Me)Phyrin) was prepared by methylation
of the four amide units in [Co(P1)] and then employed for comparative study on catalytic
cyclopropanation of dehydroaminocarboxylate 2a with o-methoxybenzaldehyde
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trisylhydrazone 1b (Figure 1; entries 8 and 9). It was found that both diastereoselectivity
and enantioselectivity as well as yield of the desired cyclopropane product 3b were
diminished when change the catalyst from [Co(P1)] to [Co(P4)], indicating the important
role of H-bonding interaction.
Substrate scope
Under the optimized conditions, the scope of [Co(P3)]-catalyzed asymmetric
cyclopropanation of dehydroaminocarboxylates was then evaluated by employing
various aromatic aldehyde-derived sulfonylhydrazones (Figure 2). Like a-(o-methoxy)
phenyldiazomethane from hydrazone 1b, different a-aryldiazomethanes bearing
o-OMe group, which were in situ generated from the derivatives of o-methoxybenzalde-
hyde hydrazone, could also be effectively activated by [Co(P3)] for asymmetric cyclopro-
panation of dehydroaminocarboxylate 2a. For example, hydrazones derived from
o-methoxybenzaldehydes containing both electron-donating groups (–OMe and
–NMe2) and electron-withdrawing group (–CN) at the para-position could be employed
to cyclopropanate 2a in the presence of Cs2CO3, generating the desired cyclopropyl
a-amino ester 3d–3f in high yields with varied (Z)-diastereoselectivities and high
enantioselectivities (Figure 2; entries 2–4). As well, the Co(II)-based system could suc-
cessfully use o-methoxybenzaldehyde hydrazones with halogen substituents, such as
–Cl and –Br atoms at different positions for the cyclopropanation process, forming the
halogenated (Z)-cyclopropanes 3g–3j in similarly high yields with good diastereoselec-
tivities and high enantioselectivities (Figure 2; entries 5–8). Although the exact reason
is unclear, the significantly lower diastereoselectivity observed for 3e than 3g might
be attributed to potential role of p-NMe2 group as H-bonding acceptor, which could
interfere with desired H-bonding interaction of the o-OMe group. It was found that
benzodioxole aldehyde-derived hydrazone 1k was also suitable for the catalytic
process, producing the fused-arylcyclopropane 3k in high yield and stereoselectivities
(Figure 2; entry 9).
In addition to the observed positive effect of o-OMe group, a-aryldiazomethanes
bearing o-F atoms were also found to be effective metalloradicophiles for
[Co(P3)]-catalyzed asymmetric cyclopropanation of dehydroaminocarboxylate 2a.
For instance, hydrazones derived from both 2,6-difluorobenzaldehyde (1l) and
2,4,6-trifluorobenzaldehyde (1m) could be productively utilized to furnish fluori-
nated cyclopropane 3l and 3m (Figure 2; entries 10 and 11). Interestingly, placing
electron-donating –OMe group at the para-position further boosted both reactiv-
ities and stereoselectivities as shown with the formation of cyclopropane 3n and
3o in near quantitative yields with almost perfect control of enantioselectivities (Fig-
ure 2; entries 12 and 13). Surprisingly, with the presence of electron-donating –OMe
group at the para-position, even ortho-CN and ortho-Cl benzaldehyde hydrazones
were suitable for asymmetric cyclopropanation by [Co(P3)], generating products 3p
and 3q (Figure 2; entries 14 and 15) in good yields and stereoselectivities.
Furthermore, a-aryldiazomethanes containing other ortho-substituents that are
potentially removable, such as –Br and –SMe groups, could also be effectively
employed for asymmetric cyclopropanation of dehydroaminocarboxylate 2a,
delivering the desired cyclopropanes 3r–3t in similarly high yields with good
diastereoselectivities albeit lower enantioselectivities (Figure 2; entries 16–18).
To further challenge the catalytic system, we then explored the possibility of
employing a-heteroaryldiazomethanes as radical precursors for asymmetric
cyclopropanation of dehydroaminocarboxylates by [Co(P3)] in view of the potential
role of the heteroatoms as H-bonding acceptors. It was thrilling to find out that
furan-2-carbaldehyde-derived trisylhydrazone (1u) could be productively employed
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for the asymmetric cyclopropanation of 2a to form the desired cyclopropane (Z)-3u
with promising level of stereoselectivities (Figure 2; entry 19). Furthermore,
hydrazone 1v derived from thiophene-2-carbaldehyde could also be applied to
cyclopropanate 2a, furnishing cyclopropane (Z)-3v with better enantioselectivity
(Figure 2; entry 20). In addition to the O- and S-heteroaryldiazomethanes, N-heter-
oaryldiazomethanes generated in situ from the hydrazone precursors were found
to be also effective for [Co(P3)]-catalyzed asymmetric cyclopropanation of 2a
as demonstrated with the high-yielding formation of pyridine- and quinoline-
containing (Z)-cyclopropanes 3w and 3x with similarly promising stereoselectivities
(Figure 2; entries 21 and 22). It should be noted that a-heteroaryldiazomethanes
based on benzofuran and N-Boc-indole were found to be much less effective for
the catalytic process, presumably due to their reduced abilities as H-bonding
acceptors.
Besides the acyl group in 2a, dehydroaminocarboxylates bearing various other
amino protecting groups, such as –Piv, –Bz, –Boc, and –Cbz, were all suitable sub-
strates for the Co(II)-based system, affording the corresponding (Z)-a-aminocyclo-
propanecarboxylates 3y–3ab in similarly high yields with the same high level of
enantioselectivities (Figure 2; entries 23–26). Besides methyl esters, the catalytic
cyclopropanation could be applied for other esters of dehydroaminocarboxylates
as demonstrated with stereoselective production of ethyl ester 3ac (Figure 2; entry
27) and benzyl ester 3ad (Figure 2; entry 28) of cyclopropyl a-amino acids in high
yields. However, dehydroaminocarboxylates with N-Ts protecting group were found
to be ineffective substrates, likely due to the increased steric hinderance. It is noted
that changing the steric hindrance of the amino protecting group and the ester
group in dehydroaminocarboxylates had different effects on diastereoselectivity
of the resulting a-aminocyclopropanecarboxylate products. While changing the
ester group of dehydroaminocarboxylates seemed have almost no effect (Figure 2;
entry 12: 82:18 dr for Me ester; entry 27: 80:20 dr for Et ester; entry 28: 81:19 dr for
Bn ester), more pronounced effect was observed with different N-protecting groups.
Although changing of the N-protecting groups from N-Ac (Figure 2; entry 12: 82:18
dr) to N-Piv (Figure 2; entry 23: 82:18 dr) to N-Bz (Figure 2; entry 24: 80:20 dr) had
little effect on diastereoselectivity, significant decrease in diastereoselectivity was
observed with both N-Boc group (Figure 2; entry 25: 65:35 dr) and N-Cbz group (Fig-
ure 2; entry 26: 75:25 dr). In general, the level of diastereoselectivity seems depend
on the difference in the relative overall size between the amino protecting group and
the ester group.
In addition to dehydroaminocarboxylates with protected secondary amines, the
[Co(P3)]-catalyzed asymmetric cyclopropanation could even be applicable to dehy-
droaminocarboxylate substrates bearing cyclic tertiary amine functionalities at the
vinyl position. For examples, cyclopropyl a-amino acids 3ae and 3af could be
formed in high yields with high enantioselectivities and good diastereoselectivities
from the reactions of dehydroaminocarboxylates containing pyrrole and indole het-
eroaryl functionalities, respectively (Figure 2; entries 29 and 30). Interestingly, when
N-vinylcarbazole, which contains cyclic tertiary carbazole functionality at the vinyl
position without the geminal ester group, was used as a substrate for the catalytic
system, it could also form the corresponding cyclopropane 3ag in good yield with
similarly high diastereoselectivity and enantioselectivity (Figure 2; entry 31). Howev-
er, when dehydroaminocarboxylate bearing azide group at the vinyl position was
used as the substrate, the catalytic reaction gave a mixture of unidentifiable prod-
ucts without observation of the corresponding cyclopropane, presumably due to
the involvement of the azide unit in the catalytic reaction.
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It is worth noting that the catalytic process could be readily scaled up under the same
conditions as exemplified by the synthesis of cyclopropyl a-amino ester (Z)-3d in
high yield and stereoselectivities on 2.0 mmol scale (Figure 2; entry 2). The absolute
configurations of cyclopropyl a-amino esters 3i and 3o were both determined as
(1R,2R) by X-ray crystallography (Figure 2; entries 7 and 13), which is consistent
with the DFT models (Figure 1).
Mechanistic studies
In addition to the optimized structure models of a-Co(III)-benzyl radical intermediate
I[Co(P3)]/1b and g-Co(III)-aminoalkyl radical II[Co(P3)]/1b/2a, as well as associated transi-
tional states TS1[Co(P3)]/1b and TS2[Co(P3)]/1b/2a (Figure 1), we carried out further
DFT calculations on the energetics associated with the catalytic pathway for the
cyclopropanation reaction of dehydroaminocarboxylate 2a with o-methoxyphenyl-
diazomethane 1b’ by [Co(P3)] (Scheme 2A; see Supplemental information for
details). The DFT calculations indicate that the formation of a-Co(III)-benzyl radical
intermediate B (I[Co(P3)]/1b) upon activation of diazo 1b0 by [Co(P3)] is exergonic by
–8.3 kcal/mol, with the elimination of dinitrogen as the byproduct. The metallorad-
ical activation has a relatively low activation barrier (TS1: DGz = 11.7 kcal/mol) and
represents the rate-determining step. The subsequent radical addition of radical
intermediate B to alkene 2a, which is highly exergonic by –19.4 kcal/mol, has an
even lower activation barrier (TS2: DGz = 9.4 kcal/mol), leading to the formation
of g-Co(III)-aminoalkyl radical intermediate C (Scheme 2A). According to the DFT
calculations, the final step of 3-exo-tet cyclization through radical substitution, which
is exergonic by –14.3 kcal/mol, is found to be an almost barrierless process, leading
to the formation of the corresponding cyclopropane 3b and the regeneration of the
catalyst [Co(P3)]. The overall low activation barrier is consistent with the fact that the
catalytic reaction could proceed effectively even at 4ꢀC.
While the initially formed key a-Co(III)-alkyl radical intermediates were previously
observed spectroscopically,7,8 we were interested in the possibility of directly trap-
ping the Co-supported benzyl radicals with different methods. To trap the a-Co(III)-
benzyl radical intermediate I for detection, we first added spin trapping reagent PBN
(N-tert-butyl-a-phenylnitrone) into a reaction mixture of [Co(TPP)] with hydrazone 1a
in benzene in the absence of alkene substrate and then recorded the X-band
electron paramagnetic resonance (EPR) spectrum at room temperature
(Scheme 2B). The isotropic EPR spectrum displays the characteristic triplet of
doublet signals at g value of ꢁ2.00, which was taken as the evidence for the forma-
tion of radical III[Co(TPP)]/1a from PBN trapping of the initially generated a-Co(III)-
benzyl radical I[Co(TPP)]/1a. The observed spectrum could be fittingly simulated on
the basis of the hyperfine couplings by 14N (I = 1) and 1H (I = 1/2) at g value of
2.00619 with A(N) = 40.6 MHz and A(H) = 6.8 MHz. Subsequently, a-(o-methoxy)phe-
nyldiazomethane from hydrazone 1b was allowed to react with [Co(TPP)] without
olefin substrates but in the presence of tert-butylthiol as H-atom source (Scheme
2C). After the reaction, compound 4 was isolated in 71% yield and characterized
as tert-butyl(2-methoxybezyl)sulfane. The formation of thioether 4 can be conceived
to proceed through a sequence of radical H-atom abstraction from tert-butylthiol by
a-Co(III)-benzyl radical intermediate I[Co(TPP)]/1b and subsequent radical substitution
of the resulting Co(III)-benzyl complex IV[Co(TPP)]/1b by tert-butyl thiyl radical (Scheme
2C). In addition to H-atom abstraction from H-atom sources such as tert-butylthiol,
efforts were made to directly trap the metal-supported benzyl radical intermediates
by stable 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) radical (Scheme 2D). After
a-(p-cyano)phenyldiazomethane from hydrazone 1y was reacted with [Co(TPP)] in
the presence of TEMPO, we were thrilled to isolate a new product 5 in high yield
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(82%), whose structure contains two geminal TEMPO units at the a-position of
p-cyanotoluene as confirmed by X-ray crystallography. The formation of
bis(TEMPO)methane derivative 5 indicated the existence of the initial a-Co(III)-
benzyl radical intermediate I[Co(TPP)]/1y from metalloradical activation of the a-aryl-
diazomethane by [Co(TPP)]. Evidently, radical intermediate I[Co(TPP)]/1y was trapped
by TEMPO to form Co(III)-benzyl complex V[Co(TPP)]/1y, which further underwent
radical substitution by another molecule of TEMPO to deliver the final product 5
(Scheme 2D). It is worth noting that compound 5 represents the first isolated
example of such compounds that contain two geminal TEMPO substituents.
Furthermore, N-vinylacetamide 2k bearing
a geminal cyclopropyl ring was
employed as a radical-clock substrate to probe the lifetime of the corresponding
g-Co(III)-aminoalkyl radical intermediate II[Co(P3)]/1b/2k in the catalytic cyclopropana-
tion reaction with hydrazone 1b by [Co(P3)] (Scheme 2E). It was found that the
cyclopropanation reaction of 2k with 1b generated the corresponding 1,10-linked
bicyclopropane 6 in 55% yield with no formation of N-cyclohexenylacetamide prod-
uct 7, a potential product that would be expected from ring opening of cyclopropyl-
carbinyl radical intermediate. Conceivably, g-Co(III)-aminoalkyl radical intermediate
II[Co(P3)]/1b/2k, which was formed from radical addition of the initially generated
a-Co(III)-benzyl radical intermediate I[Co(P3)]/1b with 2k, underwent facile 3-exo-tet
radical cyclization via radical substitution to form product 6 at a reaction rate that
was even faster than the ring opening of tertiary cyclopropylcarbinyl radicals for
generation of z-Co(III)-alkyl radical intermediate VI[Co(P3)]/1b/2k. This experimental
observation seems in good agreement with the result of DFT calculations that
suggests a barrierless step of radical substitution (Scheme 2A).
Synthetic applications
Among potential applications, the resulting enantioenriched (Z)-a-aminocyclopro-
panecarboxylates from the Co(II)-based catalytic process may serve as non-protei-
nogenic a-amino acid building blocks for the synthesis of peptides with restricted
conformations. It would be practically important for this application that N-pro-
tected cyclopropyl a-amino esters 3 could be selectively or fully deprotected
through controlled hydrolysis to provide N-protected cyclopropyl a-amino acids,
N-unprotected cyclopropyl a-amino esters or fully unprotected cyclopropyl a-amino
acids without affecting the original stereoisomeric purities. To this end, we showed
that methyl ester in 3d could be selectively hydrolyzed under mild basic conditions,
affording N-protected cyclopropyl a-amino acid 8 in 92% yield with 100% es and
100% ds (Scheme 3A). The free acid functionality in compound 8 was further
confirmed by X-ray crystallography. On the other hand, when the hydrolysis was
conducted under mild acidic conditions, the N-Boc-group in 3aa could be selec-
tively removed to furnish cyclopropyl a-amino ester 9 in 93% yield with 100% es
and 100% ds, which could be further enriched by recrystallization to provide 9
with 92:8 dr and 99% ee (Scheme 3B). The free amino group in compound 9 was
further confirmed by X-ray crystallography. Full hydrolysis of both amide and ester
groups could be achieved under acidic conditions at an elevated temperature as
demonstrated for the production of cyclopropyl a-amino acid 10 in 86% yield with
100% es and 100% ds, enantiopurity of which could be increased to 99% ee upon
recrystallization (Scheme 3C).
Furthermore, N-protected cyclopropyl a-amino acid 8 was readily cyclized in the
presence of N,N0-dicyclohexylcarbodiimide (DCC) to deliver spirocyclopropyl
oxazolone 11 in 84% yield with 100% es and 100% ds (Scheme 3D). In addition to
their known bioactivities such as anti-HIV and anti-herpes protease activities,20a,20b
Chem 7, 1588–1601, June 10, 2021 1597

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Scheme 3. Synthetic applications of enantioenriched (Z)-a-aminocyclopropanecarboxylates
spirocyclopropyl oxazolones like 11 were also demonstrated as building blocks for
the synthesis of peptides.20c To demonstrate the potential applications for
conformationally rigid peptides, we showcased the synthesis of two dipeptides
from enantioenriched N-protected cyclopropyl a-amino acid 8 (Scheme 3E). When
8 was coupled with glycine methyl ester hydrochloride (12) and L-phenylalanine
ethyl ester hydrochloride (13) using the combination of hydroxybenzotriazole
(HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride
under basic conditions, it afforded dipeptides 14 and 15, respectively, in high
yields with full retention of the original stereochemistry. As revealed by X-ray
crystallography, dipeptide 15 has constrained f- and c-torsion angles of 77 and
17 degrees, respectively. This constrained structural property, together with relative
and absolute stereochemistry, may result in profound changes in conformation,
stability, and bioactivity of peptidomimetics incorporated with cyclopropyl a-amino
acid units.11d,11e,12e,12f
Conclusions
In summary, we have developed the first asymmetric catalytic system for direct
cyclopropanation of dehydroaminocarboxylates with in situ-generated a-aryldiazo-
methanes via Co(II)-based metalloradical catalysis (MRC). With D2-symmetric chiral
amidoporphyrin 3,5-DitBu-Xu(2’-Naph)Phyrin as the optimal supporting ligand,
the Co(II)-based metalloradical system enables stereoselective synthesis of (Z)-
a-aminocyclopropanecarboxylates directly from dehydroaminocarboxylates in
high yields with high enantioselectivities under mild conditions. Mechanistically,
the detailed pathway of the underlying stepwise radical mechanism of Co(II)-based
metalloradical cyclopropanation has been elucidated by DFT study, revealing the
importance of cooperative noncovalent interactions such as multiple H-bonding
and p-stacking offered by the ligand environment of 3,5-DitBu-Xu(20-Naph)Phyrin.
In addition to computational elucidation, the key intermediate a-Co(III)-benzyl
radicals have, for the first time, been directly trapped by thiol and TEMPO and
experimentally characterized. As showcased for the efficient synthesis of dipeptides,
it is our hope that the resulting enantioenriched (Z)-a-amino-b-arylcyclopropanecar-
boxylates from this newly developed asymmetric process will find applications as a
unique class of non-proteinogenic a-amino acid building blocks for the design and
1598 Chem 7, 1588–1601, June 10, 2021

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synthesis of novel peptides with restricted conformations that may have interesting
biological properties.
EXPERIMENTAL PROCEDURES
Resource availability
Lead contact
Further information and requests for resources should be directed to and will be ful-
filled by the Lead Contact, X. Peter Zhang (peter.zhang@bc.edu).
Materials availability
Unique and stable reagents generated in this study will be made available on
request, but we might require a payment and/or a completed materials transfer
agreement if there is potential for commercial application.
Data and code availability
The crystal structure data of compounds (1R,2R)-3i, (1R,2R)-3o, 5, (1R,2R)-8, (1R,2R)-
9, and (1R,2R,S)-15 have been deposited in the Cambridge structural database un-
der reference numbers CCDC: 2043163, 2043164, 2043165, 2043166, 2043167,
and 20431638, respectively.
Full experimental procedures are provided in the Supplemental information.
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.chempr.
2021.03.002.
ACKNOWLEDGMENTS
This paper is dedicated to the memory of late Professor Chia-Kuang (Frank) Tsung,
our friend, teacher, and colleague in the Department of Chemistry at Boston Col-
lege. We are grateful for financial support by NSF (CHE-1900375) and, in part, by
NIH (R01-GM102554).
AUTHOR CONTRIBUTIONS
W.-C.C.L. conducted the experiments. D.-S.W. performed the DFT calculations. C.Z.
and J.X. assisted the experiments. B.L. carried out the X-ray crystallography. X.P.Z.
conceived the work and directed the project. W.-C.C.L. and X.P.Z. designed the ex-
periments and wrote the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: November 9, 2020
Revised: January 30, 2021
Accepted: February 28, 2021
Published: March 29, 2021
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