A General Organocatalytic System for Enantioselective Radical Conjugate Additions to Enals

Article abstract of DOI:10.1002/anie.202014876

Herein, we report a general iminium ion-based catalytic method for the enantioselective conjugate addition of carbon-centered radicals to aliphatic and aromatic enals. The process uses an organic photoredox catalyst, which absorbs blue light to generate radicals from stable precursors, in combination with a chiral amine catalyst, which secures a consistently high level of stereoselectivity. The generality of this catalytic platform is demonstrated by the stereoselective interception of a wide variety of radicals, including non-stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium-ion-based radical trap with an enamine-mediated step, affording stereochemically dense chiral products in one-step.

Full text of DOI:10.1002/anie.202014876

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Accepted Article
Title: A General Organocatalytic System for Enantioselective Radical
Conjugate Additions to Enals
Authors: Emilien Le Saux, Dengke Ma, Pablo Bonilla, Catherine
Holden, Danilo Lustosa, and Paolo Melchiorre
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014876
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10.1002/anie.202014876
Angewandte Chemie International Edition
Asymmetric Radical Chemistry
A General Organocatalytic System for Enantioselective Radical
Conjugate Additions to Enals**
Emilien Le Saux,† Dengke Ma,† Pablo Bonilla, Catherine M. Holden, Danilo Lustosa, and Paolo
Melchiorre*
Abstract: Herein, we report a general iminium ion-based
catalytic method for the enantioselective conjugate addition of
carbon-centered radicals to aliphatic and aromatic enals. The
process uses an organic photoredox catalyst, which absorbs blue
light to generate radicals from stable precursors, in combination
with a chiral amine catalyst, which secures a consistently high
level of stereoselectivity. The generality of this catalytic platform
is demonstrated by the stereoselective interception of a wide
variety of radicals, including non-stabilized primary ones which
are generally difficult to engage in asymmetric processes. The
system also served to develop organocatalytic cascade reactions
that combine an iminium-ion-based radical trap with an enamine-
mediated step, affording stereochemically dense chiral products
in one-step.
activation of the substrate is essential for stereocontrol since it
facilitates the coordination of the chiral Lewis acid catalyst while
ensuring optimal geometry control over the activated intermediate. A
few methods can bypass the structural requirement of a binding
template, but they are limited to cyclic enones.[7]
Introduction
T
he conjugate addition of carbon-centered radicals to electron-
deficient olefins is a powerful strategy for C-C bond formation.[1]
Because of the high reactivity of radicals,[2] developing catalytic
stereocontrolled processes is greatly complicated by the presence of
a significant racemic background reaction. The seminal work by
Porter and Sibi[3] showcased the potential of chiral Lewis acid-
mediated catalysis to dictate the enantioselectivity of radical
conjugate additions to a variety of α,β-unsaturated carbonyl substrates
(Figure 1a, path i). [4] Further developments[5] have been spurred by
the combination of chiral Lewis acids with a visible-light-activated
photoredox catalyst,[6] which generates radicals from stable
precursors while avoiding the use of undesirable tin and BEt3 reagents
(Figure 1a, path ii). While effective, these enantioselective catalytic
Lewis acid-based approaches require the systematic use of substrates
bearing a preinstalled anchoring point. The two-point binding
Figure 1. (a) Lewis-acid-catalyzed asymmetric radical conjugate additions
generally require a purposely designed substrate bearing a binding template. (b)
Our previous study on the radical β functionalization of aromatic enals based on
the excitation of iminium ions I*; the stereo-defining step was a radical coupling
between II and III. (c) Design plan for the radical conjugate addition to aromatic
and aliphatic enals: the photoredox catalyst (PC) generates radicals II that are
stereoselectively intercepted by the ground-state chiral iminium ion I. SET: single-
electron transfer; RA: redox-auxiliary group.
[]
Prof. Dr. P. Melchiorre
ICREA – Passeig Lluís Companys 23, 08010 Barcelona, Spain
E. Le Saux, Dr. D. Ma, P. Bonilla, Dr. C. M. Holden, Dr. D. Lustosa
and Prof. Dr. P. Melchiorre
Recently, our laboratories reported a method that could overcome
some of these substrate limitations. Specifically, we found that
iminium ions I, formed by condensation of a chiral amine catalyst
with aromatic enals 1, could be excited upon absorption of visible
light to become strong oxidants (Figure 1b).[8] Single-electron
transfer (SET) oxidation of substrates 2, adorned with a redox-
auxiliary (RA) group, afforded radicals II. A stereoselective radical
coupling of II, governed by the chiral β-enaminyl radical intermediate
III arising from I, finally set the β stereocenter. The net reaction was
an enantioselective radical β functionalization of enals. The main
limitation of this approach was the need for an aromatic substituent
at the β position of enals, since an aliphatic group shut down the
excited-state reactivity of the iminium ion.
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.
[] Financial support was provided by Agencia Estatal de Investigación
(PID2019-106278GB-I00 and CTQ2016-75520-P), the AGAUR
(Grant 2017 SGR 981), and the European Research Council (ERC-
2015-CoG 681840 - CATA-LUX). C.M. Holden and D. Ma thank the
EU for a Horizon 2020 Marie Skłodowska-Curie Fellowship (H2020-
MSCA-IF-2017 794211 and IF-2019 894795, respectively). C.M
Holden thanks Syngenta for material support, Dr Philip Sidebottom
at Syngenta for support with NMR studies, and Dr Kenneth Ling for
industrial supervision.
We surmised that a useful strategy to overcome this limitation
could rely on an external photoredox catalyst to independently
generate radicals II, which would then add onto a ground-state
iminium ion I (Figure 1c). Since the iminium ion would not need to
1
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10.1002/anie.202014876
Angewandte Chemie International Edition
reach an excited state, the presence of aliphatic substituents on enals
1 should be tolerated. Herein, we report the realization of this idea,
which led to a general iminium-ion-based system for radical
conjugate additions to aliphatic and aromatic enals. The chemistry
uses an organic photoredox catalyst, which selectively absorbs blue
light to generate radicals from stable radical precursors, in
combination with a chiral amine catalyst, which provides a
consistently high level of stereoselectivity. This catalytic system
offered a wide generality since a variety of radicals could be
effectively intercepted with high stereocontrol, including non-
stabilized primary radicals, which, due to their high reactivity, are
generally recalcitrant to asymmetric bond-forming processes. Overall,
the method expands the potential of enantioselective iminium-ion-
mediated catalysis from established polar conjugate additions[9] to
include the realm of radical chemistry.
Table 1. Optimization studies and control experiments.[a]
Results and Discussion
entry
1
amine
4
4a
[%] yield[b]
[%] ee[c]
A
B
30
99 (85)
99 (87)
34
33]
64
91
-
For initial explorations (Table 1), we selected 3,6-di-tert-butyl-9-
mesityl-10-phenylacridinium tetrafluoroborate 4a as the organic
photocatalyst (E* (4a*/4a·-) = +2.08 V vs SCE in CH3CN)[10] and α-
silylamine 2a, adorned with oxidizable trimethylsilyl group (Ep
(2a•+/2a) = +1.78 V vs Ag/AgCl in CH3CN), as the substrate. The
choice of 2a was informed by the tendency of the ensuing α-amino
radical to undergo addition to electron-deficient alkenes.[11]
Crotonaldehyde 1a was selected as the model acceptor because it was
unsuitable for the β-functionalization strategy based on the excitation
of chiral iminium ions.[8] In addition, the small size of the methyl
fragment poses an additional challenge for the chiral catalyst to infer
high stereoselectivity in the radical conjugate addition. The
2
4a
3
4[d]
C
4a
C
4b
4c
5
C
12
-
6[e]
7
C
4a
0
-
C
none
4a
0
-
8
none
35
0
[a]
Reactions performed on a 0.1 mmol scale for 16 h using 0.4 mL of CH3CN
under illumination by a single high-power (HP) LED (λmax = 460 nm, 60 mW/cm2)
and 2 equiv. of 1a. [b] Yield of 3a determined by 1H NMR analysis of the crude
mixture using trichloroethylene as the internal standard; yields of isolated 3a are
reported in brackets. [c] Enantiomeric excess of 3a. [d] λmax = 420 nm. [e] Reaction
in the dark. TFA: trifluoroacetic acid; TDS: thexyldimethylsilyl.
o
experiments were conducted at -10 C in CH3CN using a blue LED
(λmax = 460 nm) with an irradiance at 60 mW/cm2, as controlled by an
external power supply. This irradiation secured selective excitation of
the photocatalyst 4a against the transient iminium ion (aromatic
iminium ions absorb light below 430 nm, while the aliphatic
counterpart absorbs in the near UV region).
We then evaluated the synthetic potential of this strategy adopting
the optimized conditions described in Table 1, entry 3. We first
examined the enals that could intercept the α-amino radical generated
from substrate 2a. A wide range of aliphatic substituents at the β
position of enals were tolerated well (Figure 2a), with the
corresponding adducts being formed with consistently high
stereoselectivity (products 3a-e, ees higher than 90%). The presence
of a terminal olefin did not lead to undesired side reactions, smoothly
affording product 3f. An ether functionality was also tolerated
(product 3g). The reaction of (E)-3-cyclopropylacrylaldehyde led to
the exclusive formation of the β-alkylated product 3h, with the
cyclopropyl fragment left untouched. This result is mechanistically
relevant, since it excludes the formation of the β-enaminyl radical of
type III (Figure 1b) during the process. The α-silyl amine radical
precursors 2 could be modified without affecting the efficiency of the
radical conjugate addition (products 3i-3k). Performing the model
reaction on a 1 mmol scale only slightly affected the efficiency of the
process (3a formed in 74% yield and 86% ee), showing that the
method is amenable to synthetically useful purposes.
Aromatic enals[16] were equally suitable substrates for the
protocol (Figure 2b, products 3l-s). Different substitution patterns at
the aromatic moiety of enals 1 were well-tolerated, regardless of their
electronic and steric properties and position on the phenyl ring. The
reaction of a heteroaromatic enal was more sluggish but still delivered
the β-alkylated product 3r in high enantioselectivity. We also tested
the ability of our protocol to stereoselectively forge quaternary carbon
stereocenters. The reaction of β,β’-disubstituted (E)-3-phenylbut-2-
enal led to the formation of the product 3s with moderate yield and
enantioselectivity.
We first used amine catalysts with an established profile in
promoting asymmetric iminium-ion-mediated processes. The
diarylprolinol silylether A[12] afforded product 3a with poor yield and
stereocontrol (entry 1), while better results were obtained using the
imidazolidinone catalyst B[9b] (entry 2, 85% yield and 64% ee). Both
catalysts were largely outperformed by the gem-difluorinated
diarylprolinol silylether catalyst C (entry 3, 87% yield and 91%
ee),[13] which we previously designed for the photoactivation of
iminium ions.[8] The high catalytic activity of C is ascribable to the
enhanced electrophilicity imparted to the iminium ion by the electron-
withdrawing fluorine atoms, which facilitates a stereoselective radical
trap (see Section F4 in the Supporting Information for further
discussion). Other photoredox catalysts (4b-c) were not suitable to
efficiently promote the model reaction (entries 4-5).[14] Control
experiments indicated that the photocatalyst and light were both
essential for the reaction (entries 6-7). The reactivity observed in the
absence of amine C (entry 8) implied that the rate acceleration offered
by iminium ion activation is large enough to overcome the racemic
background process.[15]
2
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10.1002/anie.202014876
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Figure 2. Substrate scope for the radical conjugate additions to enals. Survey of the (a) aliphatic and (b) aromatic enals, and of (c) the silyl radical precursors that can
participate in the reaction. Reactions performed on a 0.1 mmol scale using 2 equiv. of enal 1 in 0.4 mL of CH3CN under illumination at 460 nm. Yields and enantiomeric
excesses of the isolated products 3 are reported below each entry (average of two runs per substrate). [a] Results between brackets refer to a 1 mmol scale reaction.
[b]Reaction time: 48 h. [c] Performed in a CH3CN/H2O mixture (3:1) as solvent. Ts: toluenesulfonyl; Bn: benzyl; PMB: p-methoxybenzyl; Piv: pivaloyl; Boc: tert-
butyloxycarbonyl.
We then evaluated other silyl radical precursors suitable for this
method (Figure 2c). The protocol enabled the stereoselective
installation of N-heterocyclic fragments of pharmaceutical interest
within products 3, such as a carbazole and an indole moiety (adducts
3t and 3u, respectively). Benzyl silanes, bearing both electron-
releasing and electron-withdrawing substituents on the aryl ring, were
successfully used (Figure 2c, products 3v-3z). We found that also α-
silyl thioethers and ethers could be used in the radical conjugate
addition (products 3aa and 3ab). As a limitation of the system, the
use of allyl silane led to the β-allylation product with low efficiency,
while α-silyl cyclic amines remained unreacted (see Figure S1 in the
Supporting Information, which includes a list of moderately
successful and unsuccessful substrates).
We then tested the possibility of activating radical precursors with
a redox auxiliary group other than trimethylsilane (Figure 3). The use
of a trifluoroborate salt 5a enabled the incorporation of a cyclopentyl
fragment at the β position of octenal (product 6a, Figure 3a).
Dihydropyridines proved useful to stereoselectively functionalize
cinnamaldehyde with an isopropyl moiety, a derivative of the
insecticide carbaryl, and a 3,4-dihydroquinolone, leading to products
6b-d, respectively (Figure 3b). One limitation is that dihydropyridine
derivatives provided poor yields in the radical conjugate addition to
aliphatic enals (e.g. the cyclopentyl group could be installed within
octenal with 92% ee but with 20% yield, see Figure S1 for further
details). The alkylsilicate[17] 5e accounted for the stereoselective
incorporation of a cyclohexyl moiety in both aromatic and aliphatic
enals (Figure 3c, products 6e and 6f). Importantly, we could also use
the cyclopropanol 5g as a suitable radical precursor (Figure 3d).[18]
Upon SET oxidation-mediated ring-opening, the resulting non-
stabilized primary radical could be effectively intercepted with high
stereocontrol to afford products 6g and 6h. This result is particularly
relevant since the stereocontrolled interception of highly reactive
primary alkyl radicals is a difficult goal, for which few asymmetric
catalytic strategies are available.[19] Finally, the alkenoic acid 5i,
which generates a tertiary radical upon SET oxidation-mediated anti-
Markovnikov lactonization,[20] afforded product 6i (Figure 3e). This
example shows the potential of the system to promote an asymmetric
radical cascade reaction which combines two sequential radical-based
bond-forming events. The overall cascade converts an unactivated
3
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10.1002/anie.202014876
Angewandte Chemie International Edition
olefin and α,β-unsaturated aldehyde into chiral adducts in a single
step.
Figure 4. Proposed mechanism.
The mechanism of this strategy requires the formation of the
enamine intermediate V to close the aminocatalytic cycle. We
therefore sought to capitalize on the nucleophilic nature of this chiral
intermediate V to design cascade processes initiated by an iminium-
ion-triggered radical conjugate addition. In a first approach, we used
radical precursor 7 adorned with an electrophilic keto-functionality,
which provided a suitable handle for an intramolecular aldol step
catalyzed by the chiral enamine (Figure 5a). This cascade, which
performed better in the presence of biphenyl as an electron mediator,
led to the one-step preparation of biologically relevant and
stereochemically dense piperidines (8a-8c).[24] The stereochemistry
of the major diastereoisomer of product 8c was established by single
crystal X-ray crystallographic analysis.[25]
Figure 3. Further applications and use of different radial precursors. [a]Using 1.1
equiv. of octenal.
A
plausible mechanism for the enantioselective radical
conjugate addition is depicted in Figure 4. Blue light irradiation
brings the organic photocatalyst 4a into the excited state 4a*, from
where it can activate substrate 2 via SET oxidation. The TMS redox-
auxiliary group in 2, by facilitating oxidation and undergoing solvent-
assisted fragmentation,[21] leads to radical II, which is
stereoselectively intercepted by the ground-state electrophilic
iminium ion I, generated upon condensation of catalyst C with the
enal 1. The radical conjugate addition delivers the unstable α-iminyl
radical cation IV, which is reduced via SET by the reduced form of
the photoredox catalyst (E1/2 (4a/4a•-) = -0.59 V vs SCE in
CH3CN).[10] The last step delivers the enamine V, which, upon
hydrolysis, forms the β-functionalized product 3, while turning over
both the aminocatalyst C and the photocatalyst 4a.
In consonance with this proposal, a series of Stern–Volmer
studies, detailed in section F of the Supporting Information, revealed
that silane 2a effectively quenched the excited state of photocatalyst
4a, thus supporting an initial reductive quenching of 4a. We also
measured the quantum yield of the model reaction between 1a and
substrate 2a, which was found to be as low as Φ = 0.02.[22] This
fractional value is congruent with the closed photoredox cycle
depicted in Figure 4.[23] Finally, the exclusive formation of product
3h (Figure 2a) and the absence of any cyclopropyl ring-opening
adduct excludes a path (analogous to the mechanism in Figure 1b)
proceeding though SET reduction of the iminium ion and formation
of radical III.
Figure 5. Iminium ion-enamine cascade processes: (a) Radical conjugate
addition/intramolecular aldol sequence and (b) one-pot radical conjugate
addition/intermolecular Michael addition. aThe process afforded a 2:1 dr, but the
pure major diastereoisomer 8c could be isolated. CPME: cyclopentyl methyl ether.
We also implemented a different cascade (Figure 5b), where the
Michael acceptor 9 was intercepted intermolecularly by the transient
enamine. After completion of the conjugate radical addition, we
added 9 along with aminocatalyst (S)-A (20 mol%), which assisted
the enamine step of the cascade. This one-pot procedure granted
access to the 2,3-disubsitituted product 10 with high
enantioselectivity and good anti diastereoselectivity.
4
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10.1002/anie.202014876
Angewandte Chemie International Edition
[12] K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht, K. A. Jørgensen, Acc.
Chem. Res. 2012, 45, 248−264.
Conclusion
[13] We recently used the gem-difluorinated catalyst C to catalyze the
addition of acyl radicals to enals with moderate enantioselectivity, see:
a) G. Goti, B. Bieszczad, A. Vega-Peñaloza, P. Melchiorre, Angew.
Chem. Int. Ed. 2019, 58, 1213–1217; Angew. Chem. 2019, 131, 1226–
1230. For a related study, see: b) J.-J. Zhao, H.-H. Zhang, X. Shen, S.
Yu, Org. Lett. 2019, 21, 913–916.
[14] The excited 4b is a strong oxidant that leads to the degradation of
catalyst C while 4c did not afford any conversion of the radical
precursor.
In summary, we have developed a general catalytic strategy to
stereoselectively intercept photochemically generated carbon-
centered radicals with chiral iminium ions. The chemistry requires a
readily available organic photocatalyst and a chiral amine catalyst and
uses blue light irradiation to stereoselectively functionalize simple
aliphatic and aromatic enals with a variety of stable radical precursors.
Importantly, the system is flexible and effective enough to allow for
the interception of highly reactive primary radicals and for designing
asymmetric radical cascade processes. Overall, this study expands the
established potential of iminium-ion-mediated catalysis to promote
highly stereoselective asymmetric conjugate additions of
nucleophiles to include radicals.
[15] Competition experiments established that the iminium ion activation
greatly increases the radical addition rate by at least a factor of 9 × 103,
see section F5 of the Supporting Information for details.
[16] Control experiments established that the reactions with aromatic enals
can proceed to a minor extent also in the absence of the acridinium
photocatalyst 4a, e.g. the process between cinnamaldehyde and radical
precursor 2a affords the corresponding product 3l in 8% yield and 94%
ee (vs 79% yield and 96% ee in the presence of 4a). In analogy to our
previous studies in Ref. [8], this reactivity is ascribed to the direct
excitation of aromatic iminium ions, which can partially absorb light
under illumination of the high-power blue LEDs used in our
experiments. Further control experiments, performed using a 300 W
xenon lamp equipped with a band-pass filter at 450 nm (± 5 nm),
revealed that the reaction of cinnamaldehyde with 2a was completely
inhibited in the absence of photocatalyst 4a, while it performed
normally under standard conditions. See section F1 of the Supporting
Information for further details.
Keywords: asymmetric catalysis • cascade reactions •
organocatalysis • photoredox catalysis • radical chemistry
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5
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10.1002/anie.202014876
Angewandte Chemie International Edition
Asymmetric Radical Chemistry
Emilien Le Saux, Dengke Ma, Pablo Bonilla,
Catherine M. Holden, Danilo Lustosa, and Paolo
Melchiorre* __________ Page – Page
A General Organocatalytic System for
Enantioselective Radical Conjugate Additions
to Enals
Lights on radicals. An organocatalytic method for the enantioselective
conjugate addition of carbon radicals to aliphatic and aromatic enals is
reported. The system imparts consistently high stereoselectivity for the
interception of a wide variety of radicals, including highly reactive primary
radicals. The protocol also serves to develop radical cascade processes
leading to stereochemically dense chiral products in one-step.
6
This article is protected by copyright. All rights reserved.