Enantioselective Radical Cyclization for Construction of 5-Membered Ring Structures by Metalloradical C-H Alkylation

Article abstract of DOI:10.1021/jacs.8b01662

Radical cyclization represents a powerful strategy for construction of ring structures. Traditional radical cyclization, which is based on radical addition as the key step, necessitates the use of unsaturated substrates. Guided by the concept of metalloradical catalysis, a different mode of radical cyclization that can employ saturated C-H substrates is demonstrated through the development of a Co(II)-based system for catalytic activation of aliphatic diazo compounds for enantioselective radical alkylation of various C(sp³)-H bonds. It allows for efficient construction of chiral pyrrolidines and other valuable 5-membered cyclic compounds. This alternative strategy of radical cyclization provides a new retrosynthetic paradigm to prepare five-membered cyclic molecules from readily available open-chain aldehydes through the union of C-H and C=O elements for C-C bond formation.

Full text of DOI:10.1021/jacs.8b01662

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Enantioselective Radical Cyclization for Construction of 5-
Membered Ring Structures by Metalloradical C–H Alkylation
Yong Wang, Xin Wen, Xin Cui, and X. Peter Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b01662 • Publication Date (Web): 27 Mar 2018
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Enantioselective Radical Cyclization for Construction of 5-Mem-
bered Ring Structures by Metalloradical C–H Alkylation
Yong Wang,§ Xin Wen,§ Xin Cui,† and X. Peter Zhang*§†
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§Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
†Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States
Supporting Information Placeholder
Scheme 1. Radical Cyclization Pathways via C–C Bond For-
mation
ABSTRACT: Radical cyclization represents a powerful strategy
for construction of ring structures. Traditional radical cyclization,
which is based on radical addition as the key step, necessitates the
use of unsaturated substrates. Guided by the concept of metallorad-
ical catalysis, a different mode of radical cyclization that can em-
ploy saturated C–H substrates is demonstrated through the devel-
opment of Co(II)-based system for catalytic activation of aliphatic
diazo compounds for enantioselective radical alkylation of various
C(sp3)–H bonds. It allows for efficient construction of chiral pyr-
rolidines and other valuable 5-membered cyclic compounds. This
alternative strategy of radical cyclization provides a new retrosyn-
thetic paradigm to prepare five-membered cyclic molecules from
readily available open-chain aldehydes through the union of C–H
and C=O elements for C–C bond formation.
Alkyl radicals have been extensively explored as versatile inter-
mediates for chemical synthesis.1 Among applications, alkyl radi-
cals have been demonstrated to undergo radical cyclization for con-
struction of ring structures via C–C bond formation.1 While numer-
ous radical cyclization reactions have been implemented with alkyl
radicals,2 they are predominantly based on radical addition to mul-
tiple bonds as the key step, followed by further transformations
such as H-atom abstraction (RA-HAA) (Scheme 1a). Conse-
quently, traditional radical cyclization necessitates the use of un-
saturated substrates such as alkenes. Besides the established RA-
HAA cyclization, it is conceivable that the combination of H-atom
abstraction and radical substitution (HAA-RS) could give rise to an
alternative C–C bond forming pathway for radical cyclization that
could employ saturated C–H substrates (Scheme 1b). While HAA
is normally facile, RS at the carbon has been recognized as an in-
herently challenging pathway due to a highly organized transition
state involving three multi-substituted carbon centers.1a,3 There-
fore, this alternative radical cyclization, although seemingly tena-
ble, is largely undocumented for alkyl radicals. One potential solu-
tion would be the introduction of α-metalloalkyl radicals
R2(LnM)C•, where one of the substituents of common alkyl radicals
is replaced by a metal complex (MLn) (Scheme 1c). Since M–C
bonds are typically more polar and weaker than C–C bonds, the
radical substitution pathway would become both thermodynami-
cally and kinetically possible.4 Furthermore, this metalloradical-
based cyclization could be potentially rendered as a catalytic pro-
cess with possible control of enantioselectivity, allowing for stere-
oselective construction of cyclic compounds from C–H substrates.
To harness the potential of radical reactions for stereoselective
organic synthesis,5 metalloradical catalysis (MRC) has recently
been introduced as a conceptually new approach for addressing
some enduring challenges.6,7 MRC aims at the development of
metalloradical complexes as open-shell catalysts for generation of
metal-supported organic radicals and for control of their subse-
quent homolytic reactions. As stable metalloradicals, Co(II) com-
plexes of D2-symmetric chiral amidoporphyrins [Co(D2-Por*)] ex
hibit the unusual capability of activating diazo compounds to gen-
erate α-Co(III)-alkyl radicals.8 The α-metalloalkyl radicals can un-
dergo radical addition and H-atom abstraction as well as subse-
quent radical substitution, leading to invention of new catalytic sys-
tems for various stereoselective radical transformations.9 Among
them, we recently illustrated the aforementioned radical cyclization
strategy with stereoselective formation of sulfolanes from α-meth-
oxycarbonyl-α-diazosulfones.9b To demonstrate synthetic utility of
this new mode of radical cyclization via Co(II)-based MRC, we
were intrigued if linear aliphatic diazo compounds, which are typi-
cally generated in situ from sulfonyl hydrazones of the correspond-
ing carbonyl precursors due to their instability, could be employed
for the asymmetric synthesis of common ring structures, such as
pyrrolidines, tetrahydrofurans, and other important 5-membered
cyclic compounds (Scheme 2a). Mechanistically, it was unclear if
aliphatic diazo compounds could be activated by [Co(D2-Por*)] to
form the corresponding α-Co(III)-alkyl radicals I. If so, could the
rate of the metalloradical activation match with their in situ-gener-
ation? Could α-Co(III)-alkyl radicals I, which possess β-hydro-
gens, proceed 1,5-HAA to generate e-Co(III)-alkyl radicals II com-
petitively over the potential β-H-atom shift? Additional questions
arose from the flexible nature of the linear alkyl chain that could
pose extra challenges in achieving stereoselective construction of
the 5-membered structures. Without conformational rigidity, would
the intermediate II be capable of undergoing effective 5-exo-tet
radical cyclization? What determinant factors could be explored for
controlling the enantioselectivity of C–C bond forming process?
We reasoned that the key to address these and related challenges is
to develop suitable D2-symmetric chiral amidoporphyrin ligand
(D2-Por*) that directs the Co(II)-based catalysis for productive cy-
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clization. If realized, it would provide a general strategy for stere-
oselective radical synthesis of five-membered cyclic molecules
from aliphatic aldehyde-derived hydrazones. This mode of radical
cyclization based on metalloradical C–H alkylation would offer a
new retrosynthetic paradigm for construction of ring structures
where C–C bond can be disconnected as common C=O and C–H
units of open-chain aldehydes (Scheme 2b).
Page 2 of 6
more rigid conformation,9e was used. As expected, it could catalyze
the reaction in similarly high yield with substantially improved en-
antioselectivity (entry 4). Subsequent use of [Co(P5)] (P5 = 2,6-
DiMeO-ZhuPhyrin) resulted in further increase in both yield and
enantioselectivity (entry 5). These results prompted us to synthe-
size 2,4,6-TriMe-ZhuPhyrin ligand (P6), a new derivative of
ZhuPhyrin series, where even more sterically demanding mesityl
groups are attached at two achiral meso-positions. Remarkably,
[Co(P6)] could catalyze the enantioselective radical C–H alkyla-
tion, affording the cyclization product 2a in 93% yield with 92%
ee (entry 6; also see Table S1).
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Chiral pyrrolidines containing α-substituent are recurring core
structures in natural products and bioactive compounds (Fig. S1).
Considerable efforts have been devoted to devise strategies for their
asymmetric synthesis. While the existing catalytic systems mostly
involve functionalization of preformed pyrrolidine rings,10 there
has been no previous report on asymmetric construction of α-sub-
stituted chiral pyrrolidines via catalytic C–H alkylation with acy-
clic aliphatic diazo compounds.11 As a demonstration of HAA-RS
radical cyclization, we report the development of a new Co(II)-
based catalytic system that is highly efficient for stereoselective
synthesis of α-substituted pyrrolidines and other common 5-mem-
bered compounds from aliphatic diazo compounds by enantioselec-
tive intramolecular radical alkylation of various C(sp3)–H bonds.
In addition to chemoselectivity and regioselectivity, this new radi-
cal cyclization features functional group tolerance and heteroarene
compatibility.
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Table 1. Ligand Effect on Co(II)-Catalyzed Enantioselective
Radical Cyclization of Aliphatic Diazo Precursora
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Scheme 2. Proposed Radical Cyclization Mechanism via
Metalloradical C–H Alkylation: Construction of Five-Mem-
bered Ring Structures from Open-Chain Aldehydes
a
Carried out with 1a (0.1 mmol) in dioxane (0.6 mL); Isolated
yields; ee was determined by chiral HPLC analysis.
The substrate scope of [Co(P6)]-catalyzed radical cyclization
was evaluated by employing aliphatic aldehyde-derived tosylhy-
drazone substrates 1 containing different types of C–H bonds (Ta-
ble 2). As demonstrated with substrates 1a–1j, benzylic C–H bonds
with varied electronic and steric properties could be alkylated to
afford 2-arylpyrrolidines 2a–2j in high yields with excellent enan-
tioselectivities. The absolute configuration of the major enantiomer
of 2f was established as (S). In addition to CN, NO2, and halogen
functionalities, the alkylation could tolerate vinyl groups as exem-
plified with the formation of 2k from 1k. Similarly, the Co(II)-
based system could undergo allylic C–H alkylation with high
chemoselectivity, as demonstrated by the formation of 2-vinylpyr-
rolidine (2l) from 1l. Likewise, propargylic C–H substrate 1m also
underwent the alkylation, giving 2-(phenylethynyl)pyrrolidine
(2m) chemoselectively. Furthermore, with the stabilization of the
e-Co(III)-alkyl radical intermediate II by the adjacent heteroatom,
this system was applicable for even non-activated C–H bonds. For
example, [Co(P6)] could regioselectively alkylate the stronger ho-
mobenzylic over the weaker benzylic C–H bonds in substrate 1n,
forming the five-membered pyrrolidine 2n in 96% yield albeit
moderate enantioselectivity. This remarkable regioselectivity indi-
cated that the corresponding α-Co(III)-alkyl radicals I (Scheme 2a)
had a strong preference for 1,5- over 1,6-H abstraction. In a similar
fashion, the system underwent regioselective 1,5-alkylation of
stronger secondary C–H bonds in the presence of weaker tertiary
C–H bond as illustrated with formation of 2-cyclohexylpyrrolidine
(2o) from 1o. Notably, this radical cyclization was even suitable for
electron-deficient C–H bonds, as demonstrated by the formation of
naturally occurring L-proline ester 2p in 56% yield with 82% ee.
Aliphatic aldehyde-derived tosylhydrazone 1a was chosen as the
model substrate to test the proposed radical cyclization (Table 1).
The achiral metalloradical catalyst [Co(P1)] (P1 = 3,5-DitBu-Ibu-
Phyrin)12 could catalyze the reaction to afford 2-phenylpyrrolidine
(2a) in 81% yield, demonstrating the feasibility of the HAA-RS
pathway. The high yield indicated that the in situ-generated ali-
phatic diazo compound could be effectively incorporated into the
catalytic cycle. When chiral metalloradical catalyst [Co(P2)] (P2 =
3,5-DitBu-ChenPhyrin) was employed,9g the radical cyclization ex-
hibited almost no asymmetric induction despite the high yield (en-
try 2). Considering the flexible nature of the linear alkyl chain, this
negative result was not unexpected. To reduce the degree of con-
formational freedom of the Co(III)-alkyl radical intermediates, we
decided to crowd the steric environment of the ligand pocket. In-
deed, the employment of [Co(P3)] (P3 = 2,6-DiMeO-ChenPhyrin)
resulted in significant asymmetric induction without affecting the
reactivity (entry 3). To further this buttressing effect, [Co(P4)] (P4
= 3,5-DitBu-ZhuPhyrin), which was previously shown to have a
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The radical cyclization was also compatible with substrates con-
taining various heteroarenes, allowing for stereoselective construc-
tion of α-heteroarylpyrrolidines (Fig. S1).10 For example, 3-pyri-
dine-based precursor 1q could be effectively activated by [Co(P6)]
to construct the nicotine derivative 2q in 73% yield with 92% ee.
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Table 2. Enantioselective Radical Cyclization for α-Substituted Pyrrolidines via [Co(P6)]-Catalyzed C–H Alkylationa
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a See Table 1; b Absolute configuration was determined by X-ray as (S); c Performed on 2.0 mmol scale with 2 mol % of [Co(P6)]. d Achiral
catalyst [Co(P1)] (3 mol %) was used.
Its major enantiomer was confirmed to have the same (S) absolute
configuration as naturally occurring nicotine.10c Use of 2- and 4-
pyridine-based hydrazones 1r and 1s permitted the synthesis of
α- and γ-nicotine derivatives 2r and 2s, respectively. Likewise,
this alkylation could be applied for both quinoline- and indole-
based substrates 1t and 1u to form the corresponding α-het-
eroarylpyrrolidines. Furthermore, chiral pyrrolidines containing
α-thiophene (2v) and α-benzothiophene (2w) were efficiently
constructed. Notably, the reaction could be scaled up as demon-
strated with the high-yielding synthesis of 2w on 2.0 mmol scale
without affecting the enantioselectivity. Interestingly, the C–H
bond adjacent to the cyclopentadienyl ring of ferrocene-based
substrate 1x could be selectively alkylated to form the chiral α-
ferrocenylpyrrolidine 2x in 53% yield with 92% ee, which has
potential applications as a chiral ligand.13
respectively, in good yields with high enantioselectivities. Fur-
thermore, the cyclization even allowed for direct formation of cy-
cloalkanes from diazo precursors with flexible all-methylene
linkers, as exemplified by the high-yielding synthesis of phenyl-
cyclopentane (2aa) from 5-phenylpentanal tosylhydrazone (1aa).
Actually, 5-membered cyclic compounds with varied substitution
patterns could be accessed in a similar fashion from diazo precur-
sors derived from aliphatic aldehydes with different linkers, as
demonstrated by formation of β-substituted pyrrolidine 2ab from
substrate 1ab.
Several experiments were performed to shed light on the un-
derlying mechanism of the Co(II)-catalyzed process (Scheme 3).
First, mono-deuterated 1a-D was synthesized to measure the in-
tramolecular kinetic isotope effect (KIE) (Scheme 3a). 1H-NMR
analysis of the product mixture revealed kH/kD = 9.2/1 (Fig. S2).
This high level of primary KIE conforms with the proposed C–H
activation via HAA by α-Co(III)-alkyl radical intermediate I
(Scheme 2a). Second, the effect of TEMPO on the C–H alkyla-
tion was examined for the reaction of 1t by [Co(P1)] (Scheme
3b). While no alkylation product 2t was observed, it produced the
TEMPO-trapped compound 3t. The observation of 3t supports
Preliminary results showed this radical cyclization strategy
could also be applied for construction of other common five-
membered ring structures. For example, [Co(P6)] could catalyze
intramolecular C–H alkylation of both ether- and thioether-linked
diazo precursors 1y and 1z for radical cyclization, forming α-phe-
nyltetrahydrofuran (2y) and α-phenyltetrahydrothiophene (2z),
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VCH: Weinheim, 2008; (c) Zard, S. Z. Radical Reactions in Organic Syn-
the existence of e-Co(III)-alkyl radical intermediate II, which
was apparently trapped by two molecules of TEMPO at the α-
and ε-carbon centers (Fig. S3). Third, the enantiopure (R)-4a was
prepared to evaluate the stereochemistry of the catalytic alkyla-
tion by the achiral catalyst [Co(P1)] (Scheme 3c). The tertiary C–
H bond was alkylated to form α,α-disubstituted pyrrolidine 5a as
a mixture of enantiomers. Chiral HPLC analysis showed that (S)-
5a was the major enantiomer with 81% ee. The results indicate
that the resulting radical intermediate II from HAA of (R)-4a un-
derwent radical substitution with retention of stereochemistry at
a much faster rate than racemization (Fig. S4). Last, the Co(III)-
supported alkyl radical intermediates from the reaction of 1a by
[Co(P1)] could be directly detected by HRMS (Fig. S5) and
trapped by phenyl N-tert-butylnitrone (PBN) to give the charac-
teristic EPR signal (Fig. S6). Together, these results support the
stepwise radical mechanism for Co(II)-based cyclization through
metalloradical C–H alkylation (Scheme 2a).
thesis; Oxford University Press: Oxford, 2003; (d) Shaw, M. H.; Twilton,
J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898; (e) Yan, M.; Lo,
J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692.
(2) For select recent examples, see: (a) Kern, N.; Plesniak, M. P.;
McDouall, J. J. W.; Procter, D. J. Nat. Chem. 2017, 9, 1198; (b) Adams,
K.; Ball, A. K.; Birkett, J.; Brown, L.; Chappell, B.; Gill, D. M.; Lo, P. K.
T.; Patmore, N. J.; Rice, C. R.; Ryan, J.; Raubo, P.; Sweeney, J. B. Nat.
Chem. 2017, 9, 396; (c) Brill, Z. G.; Grover, H. K.; Maimone, T. J.
Science 2016, 352, 1078; (d) Logan, M. M.; Toma, T.; Thomas-Tran, R.;
Du Bois, J. Science 2016, 354, 865; (e) Hashimoto, T.; Kawamata, Y.;
Maruoka, K. Nat. Chem. 2014, 6, 702.
1
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(3) Walton, J. C. Acc. Chem. Res. 1998, 31, 99.
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(4) Bougeard, P.; Bury, A.; Cooksey, C. J.; Johnson, M. D.;
Hungerford, J. M.; Lampman, G. M. J. Am. Chem. Soc. 1982, 104, 5230.
(5) For reviews and select examples, see: (a) Sibi, M. P.; Manyem, S.;
Zimmerman, J. Chem. Rev. 2003, 103, 3263; (b) Brimioulle, R.; Lenhart,
D.; Maturi, M. M.; Bach, T. Angew. Chem., Int. Ed. 2015, 54, 3872; (c)
Blum, T. R.; Miller, Z. D.; Bates, D. M.; Guzei, I. A.; Yoon, T. P. Science
2016, 354, 1391; (d) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.;
Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681; (e) Lin,
J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.; Tan, B.; Liu, X.-Y. J. Am.
Chem. Soc. 2016, 138, 9357; (f) Huo, H.; Shen, X.; Wang, C.; Zhang, L.;
Rose, P.; Chen, L.-A.; Harms, K.; Marsch, M.; Hilt, G.; Meggers, E.
Nature 2014, 515, 100; (g) Nicewicz, D. A.; MacMillan, D. W. C. Science
2008, 322, 77.
Scheme 3. Mechanistic Studies for Co(II)-Catalyzed Stepwise
Radical Cyclization
(6) For reviews and highlights on Co(II)-based MRC, see: (a) Miyabe,
H.; Kawashima, A.; Yoshioka, E.; Kohtani, S. Chem. Eur. J. 2017, 23,
6225; (b) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58;
(c) Pellissier, H.; Clavier, H. Chem. Rev. 2014, 114, 2775; (d) Lu, H. J.;
Zhang, X. P. Chem. Soc. Rev. 2011, 40, 1899; (e) Doyle, M. P. Angew.
Chem., Int. Ed. 2009, 48, 850.
(7) For select examples on Ti(III)-based MRC, see: (a) Zhang, Y.-Q.;
Vogelsang, E.; Qu, Z.-W.; Grimme, S.; Gansäuer, A. Angew. Chem., Int.
Ed. 2017, 56, 12654; (b) Hao, W.; Wu, X.; Sun, J. Z.; Siu, J. C.;
MacMillan, S. N.; Lin, S. J. Am. Chem. Soc. 2017, 139, 12141; (c) Gan-
säuer, A.; Hildebrandt, S.; Vogelsang, E.; Flowers II, R. A. Dalton Trans.
2016, 45, 448; (d) Gansäuer, A.; Fleckhaus, A.; Lafont, M. A.; Okkel, A.;
Kotsis, K.; Anoop, A.; Neese, F. J. Am. Chem. Soc. 2009, 131, 16989.
(8) For detailed experimental and theoretical studies on the radical
mechanism involving α-Co(III)-alkyl radical (also known as Co(III)-
carbene radical) intermediates for olefin cyclopropanation, see: (a) Lu, H.
J.; Dzik, W. I.; Xu, X.; Wojtas, L.; de Bruin, B.; Zhang, X. P. J. Am.
Chem. Soc. 2011, 133, 8518; (b) Belof, J. L.; Cioce, C. R.; Xu, X.; Zhang,
X. P.; Space, B.; Woodcock, H. L. Organometallics 2011, 30, 2739; (c)
Dzik, W. I.; Xu, X.; Zhang, X. P.; Reek, J. N. H.; de Bruin, B. J. Am.
Chem. Soc. 2010, 132, 10891.
(9) For select examples on asymmetric Co(II)-MRC, see: (a) Wang, Y.;
Wen, X.; Cui, X.; Wojtas, L.; Zhang, X. P. J. Am. Chem. Soc. 2017, 139,
1049; (b) Cui, X.; Xu, X.; Jin, L.-M.; Wojtas, L.; Zhang, X. P. Chem. Sci.
2015, 6, 1219 (c) Xu, X.; Lu, H. J.; Ruppel, J. V.; Cui, X.; de Mesa, S. L.;
Wojtas, L.; Zhang, X. P. J. Am. Chem. Soc. 2011, 133, 15292; (d) Cui,
X.; Xu, X.; Lu, H. J.; Zhu, S. F.; Wojtas, L.; Zhang, X. P. J. Am. Chem.
Soc. 2011, 133, 3304; (e) Zhu, S. F.; Ruppel, J. V.; Lu, H. J.; Wojtas, L.;
Zhang, X. P. J. Am. Chem. Soc. 2008, 130, 5042; (f) Fantauzzi, S.; Gallo,
E.; Rose, E.; Raoul, N.; Caselli, A.; Issa, S.; Ragaini, F.; Cenini, S.
Organometallics 2008, 27, 6143; (g) Chen, Y.; Fields, K. B.; Zhang, X.
P. J. Am. Chem. Soc. 2004, 126, 14718; For select examples on
nonasymmetric Co(II)-MRC, see:(h) Roy, S.; Das, S. K.; Chattopadhyay,
B. Angew. Chem., Int. Ed. 2018, 57, 2238; (i) te Grotenhuis, C.; van den
Heuvel, N.; van der Vlugt, J. I.; de Bruin, B. Angew. Chem., Int. Ed. 2018,
57, 140; (j) Reddy, A. R.; Hao, F.; Wu, K.; Zhou, C.-Y.; Che, C. M.
Angew. Chem., Int. Ed. 2016, 55, 1810; (k) Zhang, J.; Jiang, J.; Xu, D.;
Luo, Q.; Wang, H.; Chen, J.; Li, H.; Wang, Y.; Wan, X. Angew. Chem.,
Int. Ed. 2015, 54, 1231.
In summary, we have broadened the applicability of the newly
emerged radical cyclization mode via metalloradical catalysis
(MRC), which involves sequential radical H-atom abstraction
and radical substitution (HAA-RS), as a catalytic C–C bond
forming strategy for stereoselective construction of pyrrolidines
and other common 5-membered cyclic compounds from C–H
substrates. This alternative radical cyclization, which is funda-
mentally different from the traditional radical cyclization of un-
saturated substrates involving sequential radical addition and H-
atom abstraction (RA-HAA), provides a new retrosynthetic para-
digm to synthesize five-membered chiral cyclic molecules from
readily available open-chain aldehydes via enantioselective C–C
bond formation through the union of C–H and C=O units.
ASSOCIATED CONTENT
Supporting Information
Experimental details and analytical data for all new compounds.
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AUTHOR INFORMATION
Corresponding Author
peter.zhang@bc.edu
(10) For select examples on asymmetric synthesis of α-substituted
pyrrolidine derivatives, see: (a) Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Nat.
Chem. 2017, 9, 140; (b) Cordier, C. J.; Lundgren, R. J.; Fu, G. C. J. Am.
Chem. Soc. 2013, 135, 10946; (c) Campos, K. R.; Klapars, A.; Waldman,
J. H.; Dormer, P. G.; Chen, C.-Y. J. Am. Chem. Soc. 2006, 128, 3538; (d)
Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.;
MacMillan, D. W. C. Science 2016, 352, 1304.
(11) For select examples on C–H insertion with in situ-generated
unstable diazo compounds, see: (a) Reddy, A. R.; Zhou, C. Y.; Guo, Z.;
Wei, J.; Che, C. M. Angew. Chem., Int. Ed. 2014, 53, 14175; (b) Soldi,
ACKNOWLEDGMENT
We are grateful for financial support by NSF (CHE-1624216) and
NIH (R01-GM102554).
REFERENCES
(1) (a) Chatgilialoglu, C.; Studer, A. Encyclopedia of Radicals in
Chemistry, Biology and Materials; John Wiley & Sons: Chichester, U.K.,
2012; (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Rad-
ical Reactions: Concepts, Guidelines, and Synthetic Applications; Wiley-
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C.; Lamb, K. N.; Squitieri, R. A.; Gonzalez-Lopez, M.; Di Maso, M. J.;
(12) Ruppel, J. V.; Jones, J. E.; Huff, C. A.; Kamble, R. M.; Chen, Y.;
Zhang, X. P. Org. Lett. 2008, 10, 1995.
(13) Dai, L.-X.; Hou, X.-L. In Chiral Ferrocenes in Asymmetric Catal-
ysis: Synthesis and Applications; Wiley-VCH: Weinheim, 2010.
Shaw, J. T. J. Am. Chem. Soc. 2014, 136, 15142; (c) Lindsay, V. N. G.;
Viart, H. M. F.; Sarpong, R. J. Am. Chem. Soc. 2015, 137, 8368; (d) Su,
N.; Deng, T.; Wink, D. J.; Driver, T. G. Org. Lett. 2017, 19, 3990.
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