Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay

Article abstract of DOI:10.1021/jacs.7b13710

We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C-C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity.

Full text of DOI:10.1021/jacs.7b13710

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Communication
Diastereo- and Enantioselective Formal [3+2] Cycloaddition of
Cyclopropyl Ketones and Alkenes via Ti-catalyzed Radical Redox Relay
Wei Hao, Johannes H. Harenberg, Xiangyu Wu, Samantha N. MacMillan, and Song Lin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 Feb 2018
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Diastereo- and Enantioselective Formal [3+2] Cycloaddition of
Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox
Relay
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Wei Hao1, Johannes H. Harenberg1,2, Xiangyu Wu1, Samantha N. MacMillan1, Song Lin1,3*
1Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853. 2Department Chemie,
Ludwig-Maximilians-Universität München, Munich, Germany 81377. 3Atkinson Center for a Sustainable Future,
Cornell University, Ithaca, NY 14853
Supporting Information Placeholder
which a TiIII catalyst triggers a series of tandem
ABSTRACT: We report a stereoselective formal [3+2]
radical redox processes leading to the [3+2]
cycloaddition of N-acylaziridines and alkenes to
furnish substituted pyrrolidine products (Scheme
1A).10 This approach exploits several unique
characteristics of Ti, including the oxophilicity of
TiIV, the capability of TiIII to induce bond
weakening,11 and the biradical character of TiIV
azaenolates.12
cycloaddition of cyclopropyl ketones and radical-
acceptor alkenes to form polysubstituted
cyclopentane derivatives. Catalyzed by a chiral
Ti(salen) complex, the cycloaddition occurs via a
radical redox-relay mechanism and constructs two
C–C bonds and two contiguous stereogenic centers
with
generally
excellent
diastereo-
and
enantioselectivity.
Although it resembles dual-catalytic photoredox
chemistry,13 our strategy is distinct in that it
integrates a redox mediator and a substrate-
activating cocatalyst into one molecular scaffold,14
thereby allowing us to control reactivity and
stereoselectivity by tuning the structure of a single
ligand. We hypothesized that this radical redox-relay
strategy could be applied to the [3+2] cycloaddition
of cyclopropyl ketones—structural analogues of N-
acylaziridines—and alkenes (Scheme 1C) to produce
highly substituted cyclopentanes. These carbocyclic
structures are ubiquitous in bioactive compounds
and frequently used as analogs to pyrrolidines in
medicinal chemistry studies.15
Owing to the high reactivity and unique selectivity
of organic radicals, the discovery of new reactions
mediated by these open-shell intermediates
continues to provide solutions to synthetic problems
challenging in traditional two-electron chemistry.1 In
this context, new catalyst-controlled stereoselective
reactions involving free radical intermediates remain
highly desirable.2 Since early reports of the use of
Lewis acids, transition metals, and organocatalysts,3
innovative catalytic strategies that regulate the
absolute stereochemistry of radical addition
reactions have provided powerful synthetic methods
and accelerated understanding of open-shell
reaction pathways.4
SCHEME 1. [3+2] Cycloaddition via Ti-catalyzed
radical redox relay and its related literature
precedents.
Because they can adopt multiple continuous
oxidation states, Ti complexes are highly versatile
catalysts for redox radical organic transformations.5
Although chiral Ti complexes can engage radical
pathways to catalyze enantioselective C–C
formation,6 such reactions have been primarily
limited to pinacol-type couplings,7 Barbier
reactions,8 and ring-opening functionalizations of
epoxides.9 Recently, we disclosed a new strategy in
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A. Titanium-catalyzed radical redox relay (ref. 10)
R4
R5
O
1
2
3
4
5
6
7
8
R3
O
R5
Cp*TiCl3 (cat.), Zn (cat.)
R2
R1
N
N
+
R2
R1
R4
TiIV
R3
TiIV
O
O
R5
+ TiIII
- TiIII
alkene
R4
R3
N
R3
N
R2
R1
R2 R1
9
B. Related literature on enantioselective cyclopentane synthesis via
10
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17
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[3+2] cycloadditions (ref. 15)
R2
R1O2C
R2
CO2R1
CO2R1
CO2R1
[Pd] or [Cu] or Ar–SH (cat.)
donor-acceptor
cyclopropanes
C. Radical [3+2] cycloaddition of cyclopropyl ketones and alkenes
R4
O
R3
Ar
O
R4
cat.
R1
R2
+
R1
R2
R3
Ar
Precedent (ref. 16): cat. = Ru(bpy)3(PF6)2 (2.5 mol%), Gd(OTf)3 (10–20 mol%),
PyBOX (20–30 mol%); demonstrated for electron-neutral and -rich alkenes
This work: cat. = Ti(salen) complex (2.5–10 mol%); demonstrated for electron-
neutral and -deficient alkenes
To date, the intermolecular cycloaddition strategy
for enantioenriched cyclopentanes has been largely
limited to the use of donor-acceptor-type
cyclopropanes. These substrates readily undergo ring
opening in the presence of a catalyst to form 1,3-
dipolar intermediates before alkene addition
(Scheme 1B).16 Yoon et al.17 reported an elegant
combination of photoredox chemistry and chiral
Lewis acid catalysis to expand the scope of the [3+2]
cycloaddition (see Scheme 1C). Despite its excellent
enantioselectivity, the reaction generally required
high loadings of the chiral Lewis acid and was
primarily demonstrated for electron-neutral and -
rich alkenes.
A survey of reaction parameters revealed that
salen-supported complex 3 bearing phenylene-1,2-
diamine and 3-adamantyl-5-methyl salicylaldehyde
was the optimal catalyst (Table 1, entry 1). With Mn
as the reductant and Et3N·HCl18 as an additive in
ethyl acetate at room temperature, the reaction
delivered a nearly quantitative yield of cycloadduct 2
in the trans configuration as effectively a single
stereoisomer (>19:1 dr, 97% ee). Altering the
salicylaldehyde (4) or the diamine backbone (5) on
the ligand substantially decreased both diastereo-
and enantioselectivity (entries 2, 3). Half-titanocene
CpTiCl3 (6), an effective catalyst in our previous
aziridine cycloaddition reactions, was also
competent. Notably, the cis isomer was the major
product in a 3:1 dr with acetonitrile as the solvent
(entry 4). As such, both diastereomeric products
could be obtained by changing the catalyst identity.
Similar results were obtained using catalyst 7 with
1,3-diaminopropane as the ligand backbone (entry
5). The cycloaddition was equally efficient and
marginally less enantioselective when Mn was
replaced with Zn (entry 6). The loading of Et3N·HCl
could be reduced to 50 mol% with marginal decrease
in yield (entry 7). In theory, the overall redox-neutral
transformation requires only a catalytic amount of
reductant to activate the catalyst. Decreasing the
loading of Mn to 20 mol%, however, led to
We studied radical [3+2] cycloaddition using 2,2-
dimethylcyclopropyl phenyl ketone (1) and styrene
as substrates. In principle, the coordination of TiIII to
the carbonyl group in 1 would trigger radical relay
from the metal center to the quaternary carbon,
leading to the homolytic cleavage of a C–C bond in
the cyclopropane to form a carbon-centered radical
tethered to a TiIV enolate. Similar to the mechanism
of our previous aziridine-alkene reaction,10 this
intermediate would engage styrene in a stepwise
radical cycloaddition to furnish cyclopentane 2,
during which TiIV would regain an electron from the
reactant assembly and return to TiIII, achieving
catalytic turnover.
TABLE 1. Reaction Optimization.
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substantially lower product yield (entry 8). The
interplay between 3, Mn, and Et3N·HCl in initiating
and maintaining the radical redox catalytic cycle is
intriguing,19 and mechanistic understanding of such
a process is currently underway. Finally, replacing
ethyl acetate with tetrahydrofuran or acetonitrile as
the solvent led to diminished stereoselectivity
(entries 9, 10).
1
2
3
4
5
6
7
8
9
We then explored the substrate scope of the radical
[3+2] cycloaddition under the trans selective
conditions using catalyst 3 (Scheme 2). A variety of
styrene derivatives proved excellent coupling
partners, yielding the corresponding products (2, 8–
15) in high dr and ee. Functional groups such as
pinacolborate (9) and N-heterocycles (14, 15) were
compatible. We noted that reactions using electron-
deficient styrenes (e.g., 9, 10) were less
enantioselective and required lower temperatures for
reaching high levels of ee. Cycloadduct 16 with N-
methylimidazol-2-yl group was isolated in high yield,
good dr, and excellent ee from the corresponding
heterocyclic substrate. 3-Vinyl-3-deoxyestrone was
converted to 17 as nearly a single stereoisomer. We
obtained crystal structures of 2 and 17 and
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determined
their
absolute
and
relative
stereochemistries. Stereochemical assignments for
structurally similar products were made by analogy.
1,1-Disubstituted alkenes were also suitable
substrates. Products 18–20, each with a quaternary
stereogenic centers, were isolated in high
stereochemical purity. Ethyl 2-phenylacrylate was
also converted to 21 in 9:1 dr and 80% ee. In all cases,
the aryl substituent from the alkene substrate
adopted a trans relationship with the benzoyl group
in the major diastereomeric product.20 Both isoprene
and
acrylamide
underwent
the
desired
transformation to furnish products 22 and 23,
respectively, in moderate to high dr and excellent ee.
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SCHEME 2. Substrate scope of Ti-catalyzed [3+2] cycloadditions.*
1
Cl
B(pin)
CN
F
OMe
O
2
Ph
3
O
4
5
6
7
O
O
O
O
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
2 (XRD)
98%, dr > 19:1, 97% ee
8a
9b
10b
11
12
75%, dr = 12:1, 96% ee
85%, dr = 12:1, 94% ee
89%, dr > 19:1, 96% ee
91%, dr > 19:1, 97% ee
53%, dr > 19:1, 89% ee
8
9
O
Me
N
Ph
O
NTs
O
H
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11
12
13
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16
17
18
19
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Me
H
H
O
Me
Me
Me
Me
O
N
N
Me
Ph
Me
Ph
Me
Ph
Me
O
Me
Me
15
Ph
13
14
16
17 (XRD)
92%, trans/cis > 19:1, 95% de
91%, dr > 19:1, 98% ee
92%, dr > 19:1, 94% ee
87%, dr > 19:1, 79% ee
92%, dr = 6:1, 88% ee
(83%, dr > 19:1, 92% ee)c
Me
Me
O
Me
Ph
Ph CO2Et
O
NMe2
O
O
O
O
O
Me
Ph
Me
Ph
Me
Me
Me
Me
Me
Ph
Ph
Ph
Me
Ph
Me
Me
Me
Me
18
19
20
21
22
23
96%, dr > 19:1, 96% ee
82%, dr > 19:1, 96% ee
81%, dr > 19:1, 90% ee
87%, dr = 9:1, 80% ee
90%, dr = 4:1, 96% ee
91%, dr = 11:1, 96% ee
CO2tBu
O
Me CO2tBu
O
SO2Ph
O
B(pin)
Ph
Ph
Ph
Ph
2
O
O
O
O
4
1
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Ph
Me
Ph
Ph
Ph
Me
Ph
Ph
Me
Me
Me
30e
24d
25
26b
27b
28b
90%, 45% ee
29
82%, dr = 5:1, 13% ee
93%, dr = 2:1, 79% ee
(major), 93% ee (minor)
91%, dr > 19:1, 73% ee 95%, dr > 19:1, 65% ee 81%, dr > 19:1, 51% ee 79%, dr > 19:1, 46% ee
*Reactions conducted on 0.1 mmol scale with 1 equiv cyclopropyl ketone, 1.2 equiv alkene, 10 mol% 3, 1.5 equiv
Mn, 1.5 equiv Et3N·HCl in EtOAc at 22 °C for 12 h. Isolated yields reported. aWith 5 mol% 3. bAt –25 °C for 48 h.
cOn 1.0 mmol scale with 2.5 mol% 3 and 1.05 equiv alkene for 60 h. dAt –35 °C for 50 h. eAt 0 °C for 48 h.
Electron-deficient alkenes were also investigated as
radical acceptors in the [3+2] cycloaddition.
Acrylates (24, 25), phenyl vinyl sulfone (26), and
vinyl pinacolborane (27) underwent the radical
cascade to yield the corresponding products in
nearly complete diastereoselectivity favoring the
configuration in which the electron-withdrawing
substituent is placed trans to the benzoyl group.
Achieving high enantioselectivity was challenging
with these alkene under the standard conditions.
Lowering the temperature, however, improved
selectivity with the expense of longer reaction times.
1-Phenylstyrene was also converted to the desired
product (28) in moderate ee. We hypothesize that in
these cases, the greater stability of the carbon-
centered radicals resulting from the first C–C bond
formation might alter the position of the selectivity-
determining transition state on the reaction
coordinate, thus influencing enantioinduction by
the chiral catalyst. Mechanistic studies of the origin
of enantioselectivity and its dependence on the
electronic properties of the alkene are underway.
dr, albeit with low ee. 2-Phenylcyclopropyl phenyl
ketone reacted to furnish 30 in 2:1 dr with respect to
the stereochemistry at position 4; both
diastereomers were formed in high ee.
We also demonstrated the scalability of the
reaction. On a 1 mmol scale with only 2.5 mol%
catalyst 3, product 15 was obtained in 83% yield,
complete trans selectivity, and 92% ee.21
The Lewis acid catalyzed 1,3-dipolar cycloaddition
of donor−acceptor cyclopropanes with 2π coupling
partners has been reported.22 Compared with our
system, this canonical two-electron mode of
activation is usually applied to different
cyclopropane derivatives and dipolarophiles, giving
rise to different product structures. To further
support the radical intermediacy in our Ti-catalyzed
cycloaddition, we conducted a spin trapping
experiment using 5,5-dimethyl-pyrroline N-oxide
(DMPO) and observed the formation of persistent
nitroxide radical adduct 31 with ESR spectrometry
and mass spectrometry (see Scheme 3 and SI).
SCHEME 3. Spin trapping experiment.
Methyl 2,2-dimethylcyclopropyl ketone was
converted to cycloadduct 29 in synthetically useful
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Tetrahedron Lett. 1996, 37, 9123-9126. (g) Hamachi, K.; Irie, R.;
Katsuki, T. Tetrahedron Lett. 1996, 37, 4979-4982.
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Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; MacMillan, D. W. C.
Nat. Chem. 2017, 9, 1073-1077. (b) Miller, Z. D.; Lee, B. J.; Yoon, T.
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J.-L.; Riant, O. Org. Lett. 2001, 3, 3863-3865. (b) Chatterjee, A.;
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2
3
4
5
6
7
8
9
In sum, we developed a stereoselective formal [3+2]
cycloaddition of cyclopropyl ketones and alkenes
using our previous reported radical redox relay
strategy. With a Ti catalyst supported by a salen
ligand, the reaction yielded highly substituted
cyclopentanes in generally excellent diastereo- and
enantioselectivity from readily accessible starting
materials. We expect this radical redox catalysis to
provide solutions to other challenging synthetic
problems.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures
and characterization data (PDF). Crystallographic data
were deposited in the Cambridge Structural Database
(compound
2:
CCDC1589640;
compound
17:
CCDC1589641). The Supporting Information is available
free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
Tetrahedron: Asymmetry 2004, 15, 1707–1710. For
a
mechanistically related carbonyl-nitrile reductive coupling, see:
(d) Streuff, J.; Feurer, M.; Bichovski, P.; Frey, G.; Gellrich, U.
Angew. Chem., Int. Ed. 2012, 51, 8661–8664.
(8) For an examples, see: Estévez, R. E.; Justicia, J.; Bazdi, B.;
Fuentes, N.; Paradas, M.; Choquesillo-Lazarte, D.; García-Ruiz, J.
M.; Robles, R.; Gansäuer, A.; Cuerva, J. M.; Oltra, J. E. Chem. Eur.
J. 2009, 15, 2774–2791.
(9) For representative examples, see: (a) Gansäuer, A.; Bluhm,
H.; Lauterbach, T. Adv. Synth. Catal. 2001, 343, 785–787. (b)
Gansäuer, A.; Shi, L.; Otte, M. J. Am. Chem. Soc. 2010, 132, 11858–
11859. (c) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 3237-
3240.
(10) Hao, W.; Wu, X.; Sun, J. Z.; Siu, J. C.; MacMillan, S. N.;
Lin, S. J. Am. Chem. Soc. 2017, 139, 12141-12144. For a review on a
similar strategy for epoxide cycloaddition reactions, see ref. 5d.
(11) Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R. R.
J. Am. Chem. Soc. 2015, 137, 6440-6443.
(12) Studies describing the biradical character of structurally
analogous TiIV enolates: (a) Beaumont, S.; Ilardi, E. A.; Monroe,
L. R.; Zakarian, A. J. Am. Chem. Soc. 2010, 132, 1482-1483. (b) Cież,
D.; Pałasz, A.; Trzewik, B. Eur. J. Org. Chem. 2016, 1476-1493. (c)
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Twilton, J., Le, C., Zhang, P., Shaw, M. H., Evans, R. W. &
MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 1-18.
(14) Chiral catalysts integrating both the photoredox and
enantioselective catalysts in the same molecular scaffold have
recently developed. For a review, see: Zhang, L.; Meggers, E. Acc.
Chem. Res. 2017, 50, 320−330.
(15) For examples, see: (a) Defauw, J. M.; Murphy, M. M.;
Jagdmann Jr., E.; Hu, H.; Lampe, J. W.; Hollinshead, S. P.;
songlin@cornell.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This study made use of the Cornell Center for Materials
Research Shared Facilities (DMR-1120296), the NMR
facility (CHE-1531632) supported by the NSF, and the
ESR facility supported by the NIGMS (P41GM103521).
We thank Juno Siu for experimental assistance, Dr.
Geoffrey Coates for kindly sharing salen ligands, Dr.
Ivan Keresztes for help with NMR spectral analysis, and
Dr. Boris Dzikovski for assistance with ESR data
acquisition and analysis.
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(1) (a) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis;
Wiley-VCH: Weinhein, 2001. (b) Yan, M.; Lo, J. C.; Edwards, J. T.;
Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692-12714. (c) Studer,
A.; Curran, D. P. Angew. Chem., Int. Ed. 2015, 55, 58-102. (d)
Ischay, M. A.; Yoon, T. P. Eur. J. Org. Chem. 2012, 3359-3372.
(2) (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev.
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Stereochemistry of Radical Reactions; Wiley-VCH: Weinheim,
1996.
(3) For early examples, see: (a) Kameyama, M.; Kamigata, N.;
Kobayashi, M. J. Org. Chem. 1986, 52, 3312-3316. (b) Groves, J. T.;
Viski, P. J. Am. Chem. Soc. 1989, 111, 8537-8538. (c) Mok, P. L. H.;
Roberts, B. P. J. Chem. Soc., Chem. Commun. 1991, 150-152. (d)
Larrow, J. F.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 12129-
12130. (e) Sibi, M.; Ji, J.; Wu, J. H.; Gürtler, S.; Porter, N. A. J. Am.
Chem. Soc. 1996, 118, 9200-9201. (f) Haque, M. B.; Roberts, B. P.
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Mitchell, T. J.; Crane, H. M.; Heerding, J. N.; Mendoza, J. S.;
Sure, R.; Grimme, S.; Fianu, G. D.; Sadasivam, D. V.; Flowers II,
R. A. J. Am. Chem. Soc. 2014, 136, 1633–1671. (c) Gansäuer, A.; von
Laufenberg, D.; Kube, C.; Dahmen, T.; Michelmann, A.;
Behlendorf, M.; Sure, R.; Seddiqzai, M.; Grimme, S.; Sadasivam,
D. V.; Fiana, G. D.; Flowers II, R. A. Chem. Eur. J. 2015, 21, 280–
289.
Davis, J. E.; Darges, J. W.; Hubbard, F. R.; Hall, S. E. J. Med.
Chem. 1996, 39, 5215–5227. (b) Hanessian, S.; Yun, H.; Hou, Y.;
Yang, G.; Bayrakdarian, M.; Therrien, E.; Moitessier, N.; Roggo,
S.; Veenstra, S.; Tintelnot-Blomley, M.; Rondeau, J.-M.;
Ostermeier, C.; Strauss, A.; Ramage, P.; Paganetti, P.; Neumann,
U.; Betschart, C. J. Med. Chem. 2005, 48, 5175–5190.
(16) (a) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011,
50, 6167–6170. (b) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J.
Am. Chem. Soc. 2013, 135, 7851–7854. (c) Hashimoto, T.;
Kawamata, Y.; Maruoka, K. Nat. Chem. 2014, 6, 702–705.
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(19) For mechanistic studies of related TiIII-catalyzed epoxide
ring opening reactions, see ref. 18.
(20) The relative stereochemistry of products 18–22 was
determined using 2D NMR. See SI.
(21) The lower enantioselectivity likely arose from the
decreased catalyst loading. Under the standard conditions in
Table 1, using 2.5 mol% 3 instead of 10 mol% gave the product in
91% ee. This concentration dependence of reaction ee is
currently under investigation.
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(17) (a) Amador, A. G.; Sherbrook, E. M.; Yoon, T. P. J. Am.
Chem. Soc. 2016, 138, 4722–4725. For a closely related, racemic
intramolecular [3+2] cycloaddition, see: (b) Lu, Z.; Shen, M.;
Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 1162-1164.
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(18) ESR data suggested that Et3N·HCl promotes the reduction
of TiIV to TiIII. See SI. Analogous pyridinium salts have been
shown to stabilize TiIII catalysts in epoxide ring opening: (a)
Gansäuer, A.; Behlendorf, M.; von Laufenberg, D.; Fleckhaus, A.;
Kube, C.; Sadasivam, D. V.; Flowers II, R. A. Angew. Chem. Int.
Ed. 2012, 51, 4739−4742. (b) Gausäuer, A.; Kube, C.; Daasbjerg, K.;
(22) (a) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009,
131, 3122−3123. (b) Parsons, A. T.; Smith, A. G.; Neel, A. J.;
Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688−9692. Also see
ref. 15.
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Insert Table of Contents artwork here
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R4
*
O
R3
*
R2
O
R4
TiIII catalyst
R1
R1
+
R1
R1
R3
O
R2
TiIV
TiIV
O
R3
+ TiIII
- TiIII
alkene
R4
R2
R2
R1
R1
R1 R1
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13
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17
18
19
20
21
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32
33
34
35
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38
39
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24 examples, 53–98% yield, 2:1 to >19:1 dr, 13–98% ee
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