Controlling Enantioselectivity and Diastereoselectivity in Radical Cascade Cyclization for Construction of Bicyclic Structures

Article abstract of DOI:10.1021/jacs.1c04719

Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, β-, γ-, and ?-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.

Full text of DOI:10.1021/jacs.1c04719

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Controlling Enantioselectivity and Diastereoselectivity in Radical
Cascade Cyclization for Construction of Bicyclic Structures
Congzhe Zhang, Duo-Sheng Wang, Wan-Chen Cindy Lee, Alexander M. McKillop, and X. Peter Zhang*
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ABSTRACT: Radical cascade cyclization reactions are highly
attractive synthetic tools for the construction of polycyclic molecules
in organic synthesis. While it has been successfully implemented in
diastereoselective synthesis of natural products and other complex
compounds, radical cascade cyclization faces a major challenge of
controlling enantioselectivity. As the first application of metal-
loradical catalysis (MRC) for controlling enantioselectivity as well as
diastereoselectivity in radical cascade cyclization, we herein report
the development of a Co(II)-based catalytic system for asymmetric
radical bicyclization of 1,6-enynes with diazo compounds. Through
the fine-tuning of D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process,
which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused
tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with
excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical
mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical
intermediates, including α-, β-, γ-, and ε-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans
that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful
intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-
MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically
attractive radical cascade reactions.
intermediates beyond the demonstrated radical substitution
for cyclopropene formation, we were attracted to the
possibility of applying Co(II)-based MRC for the development
of radical cascade processes by engaging the intermediates for
further radical addition to CC bonds and subsequent radical
reactions, with the potential to control enantioselectivity and
other stereoselectivities. Specifically, we were interested in
developing asymmetric radical bicyclization of 1,6-enynes 2
with diazo compounds 1 for stereoselective construction of
cyclopropane-fused tetrahydrofurans 3 (Scheme 1B). In
addition to the prerequisite for generation of α-Co(III)-alkyl
radicals I from metalloradical activation of diazo compounds 1,
it was unclear whether the intermediate I could undergo
effective radical addition to aliphatic alkynes like 2 to form the
corresponding γ-Co(III)-vinyl radicals II given that the
previous report mainly involved the use of aryl and conjugated
INTRODUCTION
■
Radical cascade represents a powerful synthetic strategy to
construct complex molecular structures bearing multiple
stereogenic centers in a single operation.1 Although they
have often been employed for total synthesis of natural
products in diastereoselective forms, control of enantioselec-
tivity remains a formidable challenge in free radical cascade
reactions.2 Among recent advances,3 metalloradical catalysis
(MRC) offers a new catalytic approach to controlling reactivity
as well as selectivity of radical reactions by generating metal-
supported organic radicals as key catalytic intermediates.1h,4−6
As stable 15e-metalloradicals, Co(II) complexes of D2-
symmetric chiral amidoporphyrins [Co(D2-Por*)] exhibit the
unusual ability to homolytically activate diazo compounds for
the generation of α-Co(III)-alkyl radicals, which can serve as
kinetically competent intermediates in various asymmetric
radical cyclization processes.7 Among transformations, [Co-
(D2-Por*)] was shown to catalyze enantioselective radical
cyclopropenation of alkynes with diazo compounds by a
stepwise radical mechanism that involves product-forming 3-
exo-tet radical cyclization of γ-Co(III)-vinyl radicals (Scheme
1A), which were formed by radical addition of initially
generated α-Co(III)-alkyl radicals to the CC bonds.8 To
explore new reactivities of the Co-bonded vinyl radical
Received: May 6, 2021
Published: July 14, 2021
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© 2021 American Chemical Society
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Scheme 1. Working Proposal for Radical Cascade
Cyclization of 1,6-Enynes with Diazo Compounds via
Co(II)-MRC
Figure 1. Selected examples of natural products and bioactive
compounds containing cyclopropane-fused tetrahydrofurans.
Catalytic bicyclization of 1,6-enynes with diazo compounds
represents an attractive method to construct 1-alkenyl-
bicyclo[3.1.0]hexane structures such as cyclopropane-fused
tetrahydrofurans with potential control of stereoselectivities.10
Among advances in the realm, Dixneuf and co-workers
reported the first Ru-based catalytic system for diastereose-
lective synthesis of 1-alkenylbicyclo[3.1.0]hexane derivatives
from bicyclization of 1,6-enynes with trimethylsilyl-
diazomethane and ethyl diazoacetate.10a,b,d−f Montgomery
and Ni also developed a Ni-catalyzed system for diaster-
eoselective synthesis of 1-alkenylbicyclo[3.1.0]hexanes, includ-
ing cyclopropane-fused tetrahydrofurans, from cycloaddition of
1,6-enynes with trimethylsilyldiazomethane.10c Liu and co-
workers subsequently developed Au-catalyzed system for
diastereoselective synthesis of cyclopropane-fused tetrahydro-
furan derivatives from reaction of 1,6-enynes with diazoketo-
nes.10g Zeng and co-workers later reported diastereoselective
synthesis of cyclopropane-fused pyrrolidine derivatives through
Rh-catalyzed cyclization of 1,6-enynes with α-diazocarbonyl
compounds.10h More recently, Chen and co-workers employed
Au-catalyzed diastereoselective bicyclization of 1,6-enynes with
α-aryl-α-diazoacetates to generate 1-alkenylbicyclo[3.1.0]-
hexanes.10i Despite these advances in diastereoselective
synthesis, asymmetric catalytic systems for stereoselective
construction of 1-alkenylbicyclo[3.1.0]hexanes such as cyclo-
propane-fused tetrahydrofurans with control of enantioselec-
tivity remain to be developed. As a new application of Co(II)-
based MRC, we herein report the development of the first
asymmetric catalytic system for radical cascade cyclization of
1,6-enynes with diazo compounds that enables stereoselective
construction of multisubstituted cyclopropane-fused tetrahy-
drofurans bearing three contiguous stereogenic centers,
including two all-carbon quaternary centers. In addition to
practical attributes such as operational simplicity and mild
conditions, we show that the Co(II)-catalyzed bicyclization
proceeds through a fundamentally different mechanism from
previous catalytic systems involving metallocarbene intermedi-
ates. Our combined experimental and computational studies
unveil a stepwise radical mechanism that involves α-Co(III)-
alkyl radicals as the key intermediate and its translocation
among several different Co-supported C-centered radicals,
alkynes.8 Furthermore, to avoid the production of the
undesired cyclopropenes 3′, the vinyl radical intermediate II
would be required to undergo competitive 5-exo-trig radical
cyclization for formation of ε-Co(III)-alkyl radicals III over the
previously demonstrated 3-exo-tet radical cyclization. More-
over, the subsequent 3-exo-trig radical cyclization of the alkyl
radical intermediate III for formation of β-Co(III)-alkyl
radicals IV might also face competitive radical processes,
such as potential 5-exo-tet and 4-endo-trig cyclization reactions
(Scheme S1 in the Supporting Information). Although radical
β-scission is typically facile, it was an unsettled question how
the α-substituents R1 and R2 in radical intermediate IV would
influence the last step of the catalytic process for production of
bicyclic compounds 3. Along with the breaking and forming of
the multiple bonds, the proposed radical cascade trans-
formation would create five stereogenic centers (three sp3-
carbons plus a pair of sp2-carbons) in the resulting 1-
alkenylbicyclo[3.1.0]hexane structures 3. Apart from the
aforementioned reactivity issues, how to control stereo-
selectivities in this radical cascade reaction, including
enantioselectivity and diastereoselectivity for the three chiral
centers as well as (E)/(Z) selectivity for the CC bond, is an
equally important question. We hoped to address these and
related issues by fine-tuning the D2-Por* ligand platform to
adopt proper steric, electronic, and chiral environments to
govern the course of the desired catalytic process. If achieved,
it would lead to the development of a new catalytic process for
asymmetric radical cascade cyclization to construct cyclo-
propane-fused tetrahydrofurans and other related 1-alkenyl-
bicyclo[3.1.0]hexanes, which have found wide-ranging appli-
cations (Figure 1 and Figure S1).9
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including β-, γ- and ε-Co(III)-alkyl radicals. We further show
that the resulting enantioenriched cyclopropane-fused tetrahy-
drofurans that contain a trisubstituted vinyl group at the
bridgehead are useful intermediates for stereoselective organic
synthesis.
ments in both yield (44%) and (E):(Z) selectivity (95:5) for
product cis-3a were observed. Encouraged by these initial
results, we decided to systematically investigate the ligand
effect on the reactivity as well as the enantioselectivity of the
Co(II)-catalyzed radical cascade cyclization. When first-
generation chiral metalloradical catalyst [Co(P3)] (P3 = 3,5-
DitBu-ChenPhyrin) was utilized,7a further increase in the yield
(53%) of cis-3a was attained while achieving a high level of
asymmetric induction (85% ee) without affecting the high (E):
(Z) selectivity (95:5). During the process of investigating the
ligand effect, it was discovered that the nonchiral substituents
at the meso-phenyl rings of ChenPhyrin ligand have a
significant influence on both reactivity and enantioselectivity
of the catalytic reaction. While the use of catalyst [Co(P4)]
(P4 = 2,6-DiMeO-ChenPhyrin) containing two methoxy
groups at the proximal 2,6-positions of the meso-phenyl units
resulted in dramatic diminishment in both yield (18%) and
enantioselectivity (4% ee), [Co(P5)] (P5 = 3,5-DiPh-
ChenPhyrin) bearing two phenyl groups at the 3,5-positions
further improved the yield (58%) without significantly
affecting the enantioselectivity (81% ee). This positive
outcome prompted us to fine-tune the substituents at 3,5-
positions of the ChenPhyrin ligand. Excitingly, when [Co(P6)]
(P6 = 3,5-DiMes-ChenPhyrin) bearing two mesityl groups at
3,5-positions was used as the catalyst, it afforded cyclopropane-
fused tetrahydrofuran 3a in high yield (86%) with excellent
enantioselectivity (91% ee) as well as with near-complete
configurational control of the newly formed trisubstituted
alkene ((E):(Z) ratio of 98:2) at the bridgehead of the allowed
cis-ring junction of the bicyclic structure. Considering that
[Co(P6)] differs from [Co(P5)] only by the distal methyl
groups at the 2′,4′,6′-positions of the 3,5-positions of the
phenyl group in the meso-phenyl units of the porphyrin core,
these remarkable results signify the immense power of
judicious tuning of ligand environment in controlling reactivity
and stereoselectivity of the Co(II)-based metalloradical system.
It is worth mentioning that ChenPhyrin ligands P3−P6 could
be modularly synthesized in three steps from readily available
starting materials by following the previously established
procedures.7a The absolute configurations of stereogenic
centers in 3a were confirmed by X-ray crystallography as
(S,S) and (E), respectively (Scheme 2). Among interesting
structural features, the trisubstituted (E)-olefin unit is almost
coplanar with the tetrahydrofuran ring, which is nearly
perpendicular to the pentasubstituted cyclopropane plane.
Substrate Scope. Under the optimized conditions, the
scope of the [Co(P6)]-catalyzed radical bicyclization with tert-
butyl α-cyanodiazoacetate (1a) was then evaluated by
employing different 1,6-enynes 2 (Table 1). Like 1,1-
diphenyl-1,6-enyne 2a (entry 1), 1,1-diaryl-1,6-enynes con-
taining various aryl groups with substituents at different
positions, such as p-OMe (2b), p-F (2c), and m-F (2d), could
be bicyclized with 1a by [Co(P6)], affording the correspond-
ing cyclopropane-fused tetrahydrofurans (+)-3b, (+)-3c, and
(+)-3d as the allowed cis-ring junction in good to high yields
with excellent (E):(Z) selectivities and enantioselectivities
(entries 1−4). It is worth mentioning that the catalytic radical
cascade process could be readily scaled up as demonstrated
with the bicyclization reaction of 2a with 1a on a 2.0 mmol
scale, delivering optically active compound (+)-cis-3a in 86%
yield with 98:2 (E):(Z) and 91% ee (entry 1). Both (E)- and
(Z)-1,1-diaryl-1,6-enynes containing the p-OMe substituted
aryl group ((E)-2e and (Z)-2f) underwent radical cascade
RESULTS AND DISCUSSION
■
Catalyst Development. At the outset of this project, 1,1-
diphenyl-1,6-enyne 2a was chosen as the model substrate for
investigation of the proposed radical cascade process by
Co(II)-based metalloradical catalysts with tert-butyl α-
cyanodiazoacetate (1a) as the radical precursor (Scheme 2
Scheme 2. Ligand Effect on Co(II)-Catalyzed Radical
Cascade Cyclization of 1,6-Enyne with α-
a
Cyanodiazoacetate
a
Carried out with 1a (0.12 mmol) and 2a (0.10 mmol) by [Co(Por)]
(5 mol %) in CH3CN (0.25 mL) at 40 °C for 16 h; isolated yields;
only cis-ring junction product formed; (E):(Z) of olefin configuration
1
determined by H NMR; enantiomeric excess (ee) determined by
chiral HPLC.
and Table S1). It was found that the simple achiral catalyst
[Co(P1)] (P1 = tetraphenylporphyrin) could catalyze the
formation of the desired cyclopropane-fused tetrahydrofuran
3a but in low reactivity (19% yield) with moderate control of
the olefin configuration ((E):(Z) ratio of 80:20) as the allowed
cis-ring junction. With the use of achiral catalyst [Co(P2)] (P2
= 3,5-DitBu-IbuPhyrin),11 which contains amide units in the
supporting ligand for potential H-bonding stabilization of the
corresponding α-Co(III)-alkyl radical intermediate, improve-
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a
Table 1. Asymmetric Radical Bicyclization of 1,6-Enynes with tert-Butyl α-Cyanodiazoacetate Catalyzed by [Co(P6)]
a
Carried out with 1a (0.12 mmol) and 2 (0.10 mmol) by [Co(P6)] (5 mol %) in CH3CN (0.25 mL) at 40 °C for 16 h; isolated yields; only cis-ring
junction product formed; (E):(Z) of olefin configuration determined by 1H NMR; enantiomeric excess (ee) determined by chiral HPLC.
b
c
d
Absolute configurations determined by X-ray crystallography. Performed on a 2.0 mmol scale. Diastereomeric ratio (dr) between endo- and exo-
e
f
1
isomers determined by H NMR. From (E)-enyne. From (Z)-enyne.
process stereospecifically to afford the corresponding (+)-3e
and (+)-3f as exo- and endo-isomers, respectively (entries 5 and
6). The same stereospecific transformations were observed for
(E)- and (Z)-1,1-diaryl-1,6-enynes containing p-Cl-substituted
aryl group ((E)-2g and (Z)-2h), offering the relevant (+)-3g
and (+)-3h as exo- and endo-isomers, respectively (entries 7
and 8). The absolute configurations of (+)-3g and (+)-3h were
established as (S,S,S) and (R,S,S), respectively, by X-ray
crystallography, confirming the stereospecificity of the trans-
formations. Likewise, 1,1-diaryl-1,6-enynes substituted with
different aryl groups ((E)-2i, (E)-2j, (Z)-2k, (E)-2l, and (E)-
2m) could be stereospecifically bicyclized to generate the
desired products ((+)-3i, (+)-3j, (+)-3k, (+)-3l, and (+)-3m)
in moderate to high yields with high levels of diastereose-
lectivities and enantioselectivities as well as (E):(Z)-
selectivities (entries 9−13). Furthermore, enyne substrates
containing extended aromatic and heteroaromatic groups,
including naphthalene ((E)-2n), furan ((Z)-2o), and pyrrole
((Z)-2p), were also compatible with the radical cascade
cyclization, bringing about stereospecific production of the
corresponding (+)-3n, (+)-3o, and (+)-3p (entries 14−16).
Besides 1,1-diaryl-1,6-enynes, 1-aryl-1-alkyl-1,6-enynes such as
(E)-2q and (E)-2r were also suitable substrates for the catalytic
system, leading to stereospecific formation of cyclopropane-
fused tetrahydrofurans (+)-3q and (+)-3r in good yields with
excellent diastereoselectivities and good enantioselectivities
(entries 17 and 18). Tricyclic structure (+)-3s that contains
both spiro and fused rings could be constructed by the catalytic
system from 1,1-dialkyl-1,6-enyne 2s containing exocyclic
alkene unit (entry 19). Notably, this cascade process was
also applicable to 1,2-disubstituted 1,6-enynes such as 1-
phenyl-2-methyl-1,6-enyne (E)-2t, resulting in stereospecific
construction of cyclopropane-fused tetrahydrofuran (−)-3t
bearing two all-carbon quaternary centers at both bridgeheads
in moderate yield with good diastereoselectivity and
enantioselectivity (entry 20). Additionally, 1,6-enynes bearing
α,β-unsaturated esters as the alkene unit such as (E)-2u and
(E)-2v could also be applied in the radical cascade process,
affording the corresponding cyclopropane-fused tetrahydrofur-
ans (+)-3u and (+)-3v in moderate yields with low to good
enantioselectivities and high diastereoselectivities (entries 21
and 22).
Mechanistic Studies. Combined experimental and
computational studies were performed to comprehend the
underlying mechanism of the Co(II)-based catalytic system for
cascade cyclization. To experimentally detect the first α-
Co(III)-alkyl radical intermediate, the reaction solution of
[Co(P2)] with α-cyanodiazoacetate 1a in the absence of enyne
substrate was monitored by electron paramagnetic resonance
(EPR) spectroscopy at room temperature (Scheme 3A). The
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Scheme 3. Mechanistic Studies on Co(II)-Catalyzed System for Bicyclization of 1,6-Enynes with Diazo Compounds
isotropic EPR spectrum exhibits a strong signal at a g-value of
∼2.00 as a well-resolved octet, which is diagnostic of the
corresponding α-Co(III)-alkyl radical I[Co(P2)] generated from
metalloradical activation of 1a by [Co(P2)]. The observed
spectrum (in black) could be near perfectly simulated (in red)
by involving two resonance forms of radical I[Co(P2)] on the
[C83H97CoN9O6]+ (m/z = 1374.6888). The experimental
detection of the α-Co(III)-alkyl radical I[Co(P2)] by EPR and
HRMS has provided strong evidence to support the first step
of metalloradical activation in the proposed mechanism
(Scheme 1).
To experimentally probe the existence of the γ-Co(III)-vinyl
radical intermediate II and ε-Co(III)-benzyl radical inter-
mediate III, both (Z)- and (E)-isomers of 1-phenyl-1,6-enyne
2w were synthesized and subjected to the radical cascade
cyclization by [Co(P2)] (Scheme 3B). While the reaction of
(E)-2w afforded exo-3w as the only diastereomer, the radical
cascade cyclization of (Z)-2w generated a diastereomeric
mixture of endo-3w and exo-3w in a ratio of 62 to 38. The
observation of both endo-3w and exo-3w from the reaction of
(Z)-2w implies the existence of ε-Co(III)-benzyl radical
III[Co(P2)]/(Z)‑2w, which was generated from the 5-exo-trig
cyclization of γ-Co(III)-alkyl radical intermediate
basis of hyperfine couplings by 59Co (I = 7/2): 96% of C-
C
centered radical at α-position I[Co(P2)] (g = 2.00637; A(Co)
=
84.7 MHz) and 4% of O-centered radical at γ-position
OI[Co(P2)] (g = 2.00554; A(Co) = 69.4 MHz). Moreover, the
α-Co(III)-alkyl radical I[Co(P2)] from the reaction solution
could be detected by high-resolution mass spectrometry
(HRMS) with electrospray ionization (ESI). The observed
mass of 1374.6850 evidently resulted from α-Co(III)-alkyl
radical I[Co(P2)] by the loss of one electron. Both the exact mass
and the pattern of isotope distribution determined by ESI-
HRMS match nicely with those calculated from the formula
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a
Scheme 4. Synthetic Applications of Resulting Bicyclo[3.1.0]hexanes from Co(II)-Based Asymmetric Radical Bicyclization
a
Enantiospecificity (es) determined by chiral HPLC.
II[Co(P2)]/(Z)‑2w and its conformational isomer III[Co(P2)]/(E)‑2w
that resulted from σ-bond rotation (Scheme 3B). Furthermore,
1,6-enyne 2x bearing a cyclopropyl ring was synthesized to
probe the existence of the ε-Co(III)-alkyl radical intermediate
through cyclopropylcarbinyl radical ring-opening (Scheme
3C). When the catalytic reaction of 2x was conducted at
elevated temperature by using [Co(P6)] as the catalyst, the
formation of conjugated triene 3x could be observed in 10%
yield. Compound 3x likely originated from homoallylic alkyl
radical V[Co(P6)]/2x that was generated from the ring-opening of
the corresponding ε-Co(III)-cyclopropylcarbinyl radical inter-
mediate III[Co(P6)]/2x. Presumably, radical intermediate
structure of TS1, there exist multiple H-bonding interactions
between the chiral amide units in [Co(P6)] and the cyano/
ester groups of diazo 1a. The subsequent radical addition of
intermediate B to enyne 2a, which is exergonic by 2.4 kcal/
mol, has a lower activation barrier (TS2: ΔG‡ = 15.6 kcal/
mol), leading to the formation of the γ-Co(III)-vinyl radical
intermediate C as the indicated (Z)-configuration. The
presence of double-hydrogen-bonding interactions between
the two amide units of the catalyst and the α-cyano/ester
groups was evident in both steps of metalloradical activation
and radical addition (see Scheme S6), which rigidifies the
conformations of the intermediates and lowers the activation
barrier of the transition states. According to the DFT
calculations, intermediate C undergoes facile 5-exo-trig radical
cyclization with an exceedingly low activation barrier (TS3:
ΔG‡ = 1.5 kcal/mol), which is also highly exergonic by 28.4
kcal/mol, delivering the ε-Co(III)-alkyl radical intermediate D.
The low barrier is attributed to the multiple H-bonding
interactions between the cyclopropyl amide units in the
catalyst and the cyano/ester functionalities as illustrated in the
optimized structure of TS3. In contrast, the potential
cyclopropenation of the γ-Co(III)-vinyl radical C is found to
have a significantly higher activation barrier (TS3′: ΔG‡ = 13.9
kcal/mol). The large difference in activation barriers between
the two competitive pathways of intermediate C explains the
experimental absence of the cyclopropenation product. As the
initial stereogenic center generated from radical addition of
intermediate B to enyne 2a is nonconsequential, the
subsequent 5-exo-trig radical cyclization of intermediate C is
considered as the enantio-determining step. To shed light on
the asymmetric induction, the energy barrier for the transition
state that leads to the formation of the minor enantiomer was
V
[Co(P6)]/2x first proceeded via intramolecular 1,5-HAA (hydro-
gen atom abstraction) to deliver the δ-Co(III)-allylic radical
aVI[Co(P6)]/2x. And then its resonance form β-Co(III)-allylic
b
radical intermediate VI[Co(P6)]/2x underwent radical β-scission
to give the observed product 3x. Collectively, these
experimental results (Schemes 3A−C) provided convincing
evidence for the proposed stepwise radical mechanism of the
Co(II)-based catalytic system for cascade cyclization.
DFT calculations were also performed to examine the details
of the catalytic pathway and associated energetics for the
bicyclization reaction of 1,6-enyne 2a with α-cyano-
diazoacetate 1a with the use of the actual catalyst [Co(P6)]
(Scheme 3D; see the Supporting Information for details). The
DFT calculations indicate the formation of α-Co(III)-alkyl
radical intermediate B (I[Co(P6)]) upon activation of diazo 1a
by [Co(P6)], with the generation of dinitrogen as the
byproduct. The metalloradical activation, which is exergonic
by 17.5 kcal/mol, has a relatively high but accessible activation
barrier (TS1: ΔG‡ = 23.4 kcal/mol) and is found to be the
rate-determining step. As illustrated with the optimized
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also calculated and shown to be much higher than that for the
major enantiomer (see Scheme S5 for details), which is
consistent with the observed high enantioselectivity. The DFT
calculations indicate that intermediate D, once generated,
proceeds with a near barrierless 3-exo-trig cyclization,
presumably through the potential β-Co(III)-alkyl radical
intermediate E, to deliver the desired cyclopropane-fused
tetrahydrofuran 3a while regenerating catalyst [Co(P6)].
Despite considerable efforts, intermediate E could not be
located by DFT computation, indicating that the last step of
radical β-scission is exceedingly facile. The calculated catalytic
pathway and associated energetics seem in good agreement
with the experimental observations for the Co(II)-based
catalytic system for cascade cyclization.
crystallography as (S,S,S,R), revealing remarkable syn-addition
of the aryl and allyl groups to the CC bond. This result
demonstrates the effectiveness of the cyclopropane-fused
tetrahydrofuran assembly as a chiral auxiliary for controlling
the stereochemistry of the alkene vicinal difunctionalization
process. To further showcase the synthetic application, (+)-3a
was shown to proceed a sequential vinylation and allylation
process by reacting first with vinylmagnesium bromide as the
nucleophile and then with allyl bromide as the electrophile,
giving rise to compound (−)-11a bearing four contiguous
stereogenic centers in good yield with excellent diastereose-
lectivity and full preservation of the original enantiopurity
(Scheme 4, eq 6). Subsequent ring-closing metathesis of the
two terminal olefin units in (−)-11a with second-generation
Grubbs catalyst led to effective construction of tricyclic
compound (−)-12a with the cyclopentene linked directly at
the bridgehead in good yield with high retention of
enantiopurity.
Synthetic Applications. Given that the bicyclo[3.1.0]-
hexane structure represents a key motif in natural products and
bioactive molecules, it would be synthetically useful if the
dangling trisubstituted alkene unit at the bridgehead of the
resulting enantioenriched cyclopropane-fused tetrahydrofurans
3 from the Co(II)-catalyzed radical cascade cyclization could
be stereoselectively transformed to other functionalities. As an
initial exploration of the synthetic applications, enantioen-
riched cyclopropane-fused tetrahydrofuran (+)-3a was chosen
as the model substrate for various transformations (Scheme 4).
First, the alkene unit in (+)-3a could be converted to the
formyl functionality by ozonolysis, resulting in the formation of
bicyclic aldehyde (−)-4a in high yield with complete retention
of the stereochemistry. Considering the versatility of the
formyl functionality, (−)-4a may serve as a valuable
intermediate for further transformations. For instance, treat-
ment of (−)-4a with Bestmann reagent under basic conditions
led to high-yielding production of bicyclic compound (−)-5a
bearing a terminal alkyne, which is a popular motif in click
chemistry for bioconjugation applications (Scheme 4, eq 1).12
As another example, the aldehyde functionality in (−)-4a
could undergo reductive amination with different amines by
using sodium triacetoxyborohydride,13 as shown by its
productive reaction with secondary amine morpholine to
generate bicyclic compound (−)-6a in good yield (Scheme 4,
eq 2).12 Furthermore, the trisubstituted alkene in (+)-3a could
be productively reduced with dihydrogen on Pd/C to give α-
cyanoacetate-containing compound 7a, which could undergo
decarboxylation to afford bicyclic compound (−)-8a bearing
propanenitrile in good yield with almost full preservation of the
original optical purity (Scheme 4, eq 3). In addition to the
reduction, the electron-deficient olefin in (+)-3a could even
undergo epoxidation with sodium hypochlorite in the presence
of neutral alumina, furnishing tricyclic compound (−)-9a with
the three-membered cyclic ether linked directly at the
bridgehead in excellent yield with good diastereoselectivity
and complete enantiospecificity (Scheme 4, eq 4).14 Moreover,
the highly electron-deficient trisubstituted conjugated alkene in
(+)-3a could serve as an effective Michael acceptor for
nucleophilic addition and subsequent alkylation, a sequential
double C−C bond-forming process that would allow for the
generation of two additional vicinal stereocenters. For example,
the reaction of (+)-3a with Grignard reagent phenyl-
magnesium bromide, followed by addition of allyl bromide,
resulted in arylation and allylation of the CC bond, affording
compound (−)-10a in high yield with excellent diastereose-
lectivity and high retention of the original enantiopurity
(Scheme 4, eq 5). The configurations of the four contiguous
stereogenic centers in (−)-10a were established by X-ray
CONCLUSIONS
■
In summary, we have demonstrated the application of
metalloradical catalysis (MRC) for controlling enantioselectiv-
ity as well as diastereoselectivity in radical cascade cyclization.
Applying Co(II)-based metalloradical catalysis, the first
asymmetric catalytic system has been successfully developed
for radical bicyclization of 1,6-enynes with diazo compounds.
With the D2-symmetric chiral amidoporphyrin 3,5-DiMes-
ChenPhyrin as the optimal supporting ligand, the Co(II)-
catalyzed radical cascade process enables activation of tert-
butyl α-cyanodiazoacetate under mild conditions to react with
different 1,6-enynes for asymmetric construction of multi-
substituted cyclopropane-fused tetrahydrofurans bearing three
contiguous stereogenic centers, including two all-carbon
quaternary centers, in high yields with excellent enantiose-
lectivities and diastereoselectivities. Combined computational
and experimental studies have shed light on the underlying
stepwise radical mechanism involving several Co-supported C-
centered radical intermediates for the Co(II)-based cascade
bicyclization. The resulting enantioenriched cyclopropane-
fused tetrahydrofurans that contain a trisubstituted vinyl
group at the bridgehead, as showcased in several stereospecific
transformations, may serve as useful intermediates for
stereoselective organic synthesis. More broadly, we hope that
the successful demonstration of this Co(II)-catalyzed asym-
metric radical cascade cyclization will inspire further
applications of metalloradical catalysis (MRC) as a potentially
general approach to controlling enantioselectivity as well as
diastereoselectivity in synthetically attractive radical cascade
reactions.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c04719.
Experimental details and analytical data for all new
compounds (PDF)
Accession Codes
CCDC 2083358−2083361 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
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Article
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Enantioselective C−H Bond Functionalization Triggered by Radical
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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
Congzhe Zhang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0001-8139-474X
Duo-Sheng Wang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0002-3519-2386
Wan-Chen Cindy Lee − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0002-2433-7404
Alexander M. McKillop − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
0001-5085-5419
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c04719
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support by the NSF (CHE-
1900375) and in part by the NIH (R01-GM102554).
■
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