Photo-Organocatalytic Enantioselective Radical Cascade Reactions of Unactivated Olefins

Article abstract of DOI:10.1002/anie.201808183

Radical cascade processes are invaluable for their ability to rapidly construct complex chiral molecules from simple substrates. However, implementing catalytic asymmetric variants is difficult. Reported herein is a visible-light-mediated organocatalytic strategy that exploits the excited-state reactivity of chiral iminium ions to trigger radical cascade reactions with high enantioselectivity. By combining two sequential radical-based bond-forming events, the method converts unactivated olefins and α,β-unsaturated aldehydes into chiral adducts in a single step. The implementation of an asymmetric three-component radical cascade further demonstrates the complexity-generating power of this photochemical strategy.

Full text of DOI:10.1002/anie.201808183

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Accepted Article
Title: Photo-Organocatalytic Enantioselective Radical Cascade
Reactions of Unactivated Olefins
Authors: Pablo Bonilla, Yannick Rey, Catherine Holden, and Paolo
Melchiorre
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808183
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10.1002/anie.201808183
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Enantioselective Photochemistry
Photo-Organocatalytic Enantioselective Radical Cascade Reactions of
Unactivated Olefins**
Pablo Bonilla,† Yannick P. Rey,† Catherine M. Holden, and Paolo Melchiorre*
Abstract: Radical cascade processes are invaluable for their
ability to rapidly construct complex chiral molecules from simple
substrates. However, implementing catalytic asymmetric variants
intermediate III can also govern the ensuing radical coupling step
with high stereoselectivity. We wondered if this new photochemical
activation mode could be used to expand the synthetic potential of
enantioselective radical cascades beyond the reactivity constraints of
formal cycloaddition chemistry.[8] In an initial attempt, we combined
the excited-state iminium ion chemistry with the ground-state
reactivity of enamines to access cyclopentanols from cyclopropanols
with high stereoselectivity (Figure 1b).[10] However, while the first
carbon-carbon bond-forming step in this cascade sequence is a radical
process, the subsequent carbon-carbon bond formation follows a two-
electron pathway. Herein, we detail how the photochemistry of
iminium ions has served to successfully implement an
enantioselective catalytic radical cascade reaction that combines two
sequential radical-based bond-forming processes without
mechanistically relying on a cycloaddition manifold (Figure 1c). This
organocatalytic photochemical process converts readily available
enals and unactivated olefins, bearing an oxygen-centered
nucleophilic handle, into complex chiral molecules containing
butyrolactone[11a] or tetrahydrofuran moieties.[11b] These two
structural elements are present in numerous biologically active and
naturally occurring molecules.
is difficult. Herein we report
a
visible-light-mediated
organocatalytic strategy that exploits the excited-state reactivity
of chiral iminium ions to trigger radical cascade reactions with
high enantioselectivity. By combining two sequential radical-
based bond-forming events, the method converts unactivated
olefins and α,β-unsaturated aldehydes into chiral adducts in a
single step. The implementation of an asymmetric three-
component radical cascade further demonstrates the complexity-
generating power of this photochemical strategy.
C
ascade processes are powerful strategies for rapidly increasing
structural and stereochemical complexity while delivering complex
chiral molecules in one step.[1] The high reactivity and selectivity of
open-shell intermediates[2] makes radical chemistry perfectly suited
for implementing cascades.[3] However, the intrinsic challenge of
carrying out reactions with radicals in a stereocontrolled fashion[4] has
greatly limited the development of enantioselective variants. The
majority of the reported strategies rely on chiral substrates or
stoichiometric ligands.[3c,4-5] Recently, photoredox catalysis[6] has
provided effective tools to enable single-electron transfer (SET)-
mediated radical cascade processes under mild conditions.[3a] The
combination with chiral Lewis acid catalysts has allowed the ensuing
radical cascade process to be channeled towards a stereocontrolled
pattern.[7] Although effective, these catalytic asymmetric methods are
generally limited to formal [2+2][7a] or [3+2][7b,c] photocycloaddition
reactions or cation radical Diels-Alder processes.[7d,8]
Recently, our laboratories identified a new photochemical
catalytic mode of substrate activation that exploits the excited-state
reactivity of chiral iminium ions I to generate radicals upon SET
oxidation of suitable substrates II (Figure 1a).[9] The resulting chiral
[]
Prof. Dr. P. Melchiorre
ICREA - Catalan Institution for Research and Advanced Studies,
Passeig Lluís Companys 23 – 08010, Barcelona, Spain
P. Bonilla, Dr. Y. P. Rey, Dr. C. M. Holden, and Prof. Dr. P.
Melchiorre
Figure 1. a) Our previous study demonstrating that light excitation turns iminium
ions I into chiral oxidants, and the resulting SET-based mechanism for
generating radicals from precursors II bearing a redox auxiliary (RA). b) A
cascade reaction proceeding via an excited-iminium ion/ground-state enamine
sequence, where a stereocontrolled radical path is combined with polar
reactivity. c) Proposed enantioselective catalytic radical cascade proceeding via
two sequential radical steps: upon SET oxidation of an unactivated olefin, an
anti-Markovnikov addition to the radical cation IV is followed by a
ICIQ - Institute of Chemical Research of Catalonia
the Barcelona Institute of Science and Technology,
Avenida Països Catalans 16 – 43007, Tarragona, Spain
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research_group/prof-paolo-
melchiorre/
[†]
These authors contributed equally to this work.
stereocontrolled radical coupling. SET; single-electron transfer.
[]
Financial support was provided by MINECO (CTQ2016-75520-P),
and the European Research Council (ERC 681840 - CATA-LUX).
C.M.H. thanks the Marie Skłodowska-Curie Actions for a
postdoctoral fellowship (H2020-MSCA-IF-2017 794211).
Figure
2 details our proposed strategy to develop an
enantioselective SET-triggered radical cascade. We envisioned a
catalytic cycle wherein a chiral amine catalyst would form the colored
iminium ion intermediate I upon condensation with enal 1. Selective
1
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10.1002/anie.201808183
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excitation with a violet-light-emitting diode (LED) turns I into a
strong oxidant (I*), as implied by its reduction potential, which was
estimated as ≈+2.4 V (E*red (I*/I·–) vs Ag/Ag+ in CH3CN) using
electrochemical and spectroscopic methods.[9a] Therefore, the photo-
excited iminium ion can oxidize an alkene substrate 2[12] adorned with
a suitable oxygen-centred nucleophilic handle (alkenes 2 used in this
study have oxidation potentials ranging from +2.03 to +2.19 V vs
Ag/AgCl in MeCN, see section D in the Supplementary Information
for details). The SET activation of olefin 2 would concomitantly form
the chiral 5π-intermediate III and the alkene radical cation IV. The
nucleophilic moiety within IV would then trigger a polar-radical-
crossover cycloaddition,[13,14] capitalizing on the simultaneous polar
and radical nature of such radical cation species. This process would
proceed with an anti-Markovnikov selectivity to afford the more
stable tertiary radical intermediate V.[15] At this juncture, a stereo-
controlled radical coupling with III would afford the cascade product
3 with high enantioselectivity. This mechanistic plan finds support in
the high reactivity of the distonic intermediate IV, which has been
extensively investigated by Nicewicz to develop anti-Markovnikov
hydrofunctionalizations of olefins,[14-16] and its tendency to initiate
cycloaddition sequences leading to heterocyclic products.[14,16]
1:1 dr (entry 1). Increasing the amount of TFA to 60 mol% improved
the yield to 62% (entry 2). The chiral amine catalyst B, possessing
bulkier perfluoro-isopropyl groups on the arene scaffold, improved
the enantioselectivity (91% ee, entry 3), whereas the chiral
imidazolidinone catalyst
C afforded the product with low
stereocontrol (entry 4). Implementation of a two-phase solvent
system, using tetradecafluorohexane in a 1:1 ratio to CH3CN, further
increased the yield of the reaction (72% yield, entry 5).[17] Control
experiments indicated that both the light and the amine catalyst are
required for reactivity (entries 7 and 8), while the addition of a radical
trapping agent (TEMPO, 1 equiv.) completely inhibited the process.
Table 1. Optimization studies.[a]
entry
catalyst
conditions
[%] yield[b]
[%] ee[c]
1
2
3
4
5
7
8
A
A
B
C
B
A
-
40% TFA
60% TFA
55
62
88
88
91
33
91
-
60% TFA
63
60% TFA
60
CH3CN/HexF (1:1)
no light
72 (58)
0
no catalyst
0
-
[a]
Reactions performed on a 0.1 mmol scale at 30 °C for 16 h using 0.2 mL of
solvent under illumination by a single high-power (HP) LED (λmax = 420 nm) with
an irradiance of 30 mW/cm2. [b] Yield of 3a determined by 1H NMR analysis of the
crude mixture using trichloroethylene as the internal standard; yields of the
isolated 3a are reported in brackets. [c] Enantiomeric excess determined by HPLC
analysis on a chiral stationary phase. TFA: trifluoroacetic acid; TDS: thexyl-
dimethylsilyl; HexF: tetradecafluorohexane.
Using the optimized conditions described in Table 1, entry 5,
we then turned our attention to the scope of the photocatalytic
asymmetric radical cascade process (Figure 3). We first evaluated the
possibility of using differently substituted olefins. The presence of
geminal methyl groups at the alpha position of the alkenoic acid
substrate 2 significantly improved the yield and enantioselectivity
(adduct 3b, 75% yield and 94% ee). An ethyl fragment could also be
installed (3c), while the inclusion of a cyclohexyl group afforded the
spirocyclic adduct 3d in moderate yield and high enantioselectivity.
The absence of α-substituents in substrate 2 did not significantly
affect the overall efficiency (product 3e). This indicates that the
Thorpe-Ingold effect is not critical to the cascade process. Concerning
the substitution of the double bond, introducing a cyclohexyl in place
of the dimethyl moiety slightly increased the diastereoselectivity to
Figure 2. Mechanistic proposal for a SET-triggered asymmetric photocatalytic
radical cascade process.
To test the feasibility of our photochemical plan, we selected
cinnamaldehyde 1a and the gem-difluorinated diarylprolinol
silylether catalyst A[9a] for the formation of the chiral iminium ion
(Table 1). The experiments were conducted in CH3CN using a single
high-power (HP) LED (λmax = 420 nm) with an irradiance at 30
mW/cm2, as controlled by an external power supply (full details of
the illumination set-up are reported in the Supporting Information,
Figure S1). The alkenoic acid 2a was selected as the model substrate
based on the oxidation potential (Epox (2a•+/2a) = +2.09 V vs Ag/AgCl
in MeCN) and its tendency to undergo SET oxidation-mediated anti-
Markovnikov lactonization.[16a] Using 40% of trifluoroacetic acid
(TFA) to assist the formation of the iminium ion I, the desired product
3a was obtained at ambient temperature in 55% yield, 88% ee, and
1.3:1 (3f) while maintaining
a high chemical yield and
enantioselectivity. Importantly, tetrahydrofuran derivatives 4a and 4b
could also be synthesized when decorating the alkene substrate with
an alcohol acting as the nucleophilic moiety.
Crystals from compound 3a were suitable for X-ray
crystallographic analysis,[18] which established the stereochemical
course of the radical cascade process.
2
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10.1002/anie.201808183
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Figure 3. Survey of the alkenoic acids and alkenols 2 that can participate in the
radical cascade process with cinnamaldehyde 1a. Reactions performed on 0.1
mmol scale using 1:1 mixture of acetonitrile and tetradecafluorohexane. Yields
and enantiomeric excesses of the isolated products 3 are indicated below each
entry (average of two runs per substrate). Enantiomeric excesses measured on
the enoate derivatives of adducts 3 obtained upon olefination of the aldehyde with
PPh3CHCO2Et. Dr was inferred by 1H NMR analysis of the crude mixture.
[a]Reaction performed using catalyst A in acetonitrile.
Figure 4. Survey of the enals 1 that can participate in the radical cascade process
with alkenoic acid 2b. Reactions performed on 0.1 mmol scale using 1:1 mixture
of acetonitrile and tetradecafluorohexane. Yields of the isolated products are
indicated below each entry (average of two runs per substrate). Enantiomeric
excesses measured on the enoate derivatives of adducts 3 obtained upon
olefination of the aldehyde with PPh3CHCO2Et. Dr was inferred by 1H NMR
analysis of the crude mixture.
The use of α,α-difluorinated acids 6 enabled the successful
realization of this enantioselective three-component cascade. The
aldehydes 7 were converted into enoates 8a-c, which could be
isolated in moderate yields and enantioselectivities. The acids play a
dual role in this transformation, since they assist the iminium ion
formation while acting as nucleophilic substrates in the three-
component cascade.
Regarding the scope of the α,β-unsaturated aldehydes 1,
moderately electron-withdrawing and electron-donating groups on
the aromatic ring are tolerated without diminishing the yield or
enantioselectivity (Figure 4). The substituent can also be moved
around the ring without impeding reactivity (3g-l). Notably,
synthetically useful groups, which can undergo further
functionalization, were tolerated. These included halogens (3g-j),
trimethylsilyl (3m), and pinacolborane (3n). One limitation of this
reaction is that aliphatic enals, including tert-butylacroleine and (E)-
2-octenal, remained unreacted under the reaction conditions.
We then focused on the design of a three-component radical
cascade process to assemble complex chiral molecules from simple
substrates in a single step. Specifically, we surmised that the excited
iminium ion I* could oxidize amylene 5, an unfunctionalized alkene
hydrocarbon (Epox (5·+/5) = + 2.03 V vs Ag/AgCl in MeCN).[19] The
anti-Markovnikov intermolecular addition of a carboxylic acid[20] to
the less substituted position of the resulting cation radical VI would
then provide the key radical intermediate VII (Figure 5). VII would
eventually engage in a stereoselective radical coupling governed by
the chiral 5π-intermediate III (structure shown in Figure 2). This
catalytic asymmetric cascade process, which combines two
intermolecular radical steps, would provide a one-step access to
complex aldehydes 7.
Figure 5. Catalytic enantioselective three-component radical cascade process
that combines two intermolecular radical steps. Reactions performed on 0.1
mmol scale in CH3CN. Yields and enantiomeric excess given on the isolated
enoate derivatives 8 obtained upon olefination of the aldehyde precursor
(average of two experiments). Dr was inferred by 1H NMR analysis of the crude
mixture. [a]Yield of the isolated intermediate aldehyde 7b.
3
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10.1002/anie.201808183
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Moliterno, L. Buzzetti, H. B. Hepburn, A. Vega-Peñaloza, M. Silvi, P.
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For a review, see: d) M. Silvi, P. Melchiorre, Nature 2018, 554, 41–
49.
In summary, the photochemical activity of chiral iminium ions
has been exploited to activate unfunctionalized olefins and trigger an
enantioselective radical cascade process. We expect that this
photochemical organocatalytic activation mode could be useful for
designing other radical cascade processes and for stereoselectively
synthesizing more complex chiral scaffolds.
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Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: organocatalysis • cascade reactions • radicals •
photochemistry • asymmetric catalysis
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4
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10.1002/anie.201808183
Angewandte Chemie International Edition
Enantioselective Photochemistry
Pablo Bonilla, Yannick P. Rey, Catherine M.
Holden, and Paolo Melchiorre* __________ Page
– Page
Photo-Organocatalytic Enantioselective
Radical Cascade Reactions of Unactivated
Olefins
A radical approach. A photochemical asymmetric radical cascade
process that converts unactivated olefins and α,β-unsaturated
aldehydes into chiral adducts in a single step is reported. This
enantioselective strategy, which is triggered by the excited-state
reactivity of chiral iminium ion intermediates, combines two sequential
radical-based bond-forming events.
5
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