Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by Photochemical Organocatalytic Acyl Radical Addition to Enals

Article abstract of DOI:10.1002/anie.201810798

We report a visible-light-mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4-dicarbonyl compounds. The process capitalizes upon the excited-state reactivity of 4-acyl-1,4-dihydropyridines that, upon visible-light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst-controlled bond-forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3-substituted 1,4-dicarbonyl products.

Full text of DOI:10.1002/anie.201810798

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Accepted Article
Title: Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by
Photochemical Organocatalytic Acyl Radical Addition to Enals
Authors: Giulio Goti, Bartosz Bieszczad, Alberto Vega-Peñaloza, and
Paolo Melchiorre
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810798
Angew. Chem. 10.1002/ange.201810798
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10.1002/anie.201810798
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Enantioselective Photochemistry
Stereocontrolled Synthesis of 1,4-Dicarbonyl Compounds by
Photochemical Organocatalytic Acyl Radical Addition to Enals**
Giulio Goti,† Bartosz Bieszczad,† Alberto Vega-Peñaloza, and Paolo Melchiorre*
Abstract: We report a visible-light-mediated organocatalytic
strategy for the enantioselective acyl radical conjugate addition
to enals, leading to valuable 1,4-dicarbonyl compounds. The
process capitalizes upon the excited-state reactivity of 4-acyl-1,4-
dihydropyridines that, upon visible-light absorption, can trigger
the generation of acyl radicals. By means of a chiral amine
catalyst, iminium ion activation of enals ensures a stereoselective
radical trap. We also demonstrate how the combination of this
acylation process with a second catalyst-controlled bond-forming
event allows to selectively access the full matrix of all possible
stereoisomers of the resulting 2,3-substituted 1,4-dicarbonyl
products.
enantioselective intermolecular catalytic Stetter reactions.[7] In a
strategically similar approach, acyl silanes served as acyl anion
precursors to develop a catalytic asymmetric acylation of α,β-
unsaturated amides.[8]
An alternative strategic disconnection to directly access 1,4-
dicarbonyls relies on radical manifolds (Figure 1a, path ii).
Specifically, the Giese-type addition of acyl radical intermediates[9]
to α,β-unsaturated carbonyl compounds offers a valuable alternative
to the use of acyl anion equivalents.[10] However, an enantioselective
catalytic version of this radical approach has not yet been achieved,
mainly because the high reactivity of acyl radicals hampers their
effective stereocontrolled trap. Herein, we report a photochemical
organocatalytic protocol[11] that addresses this deficit in
enantioselective synthesis (Figure 1b). We show that the activation of
enals 2 by means of iminium ion formation[12] triggers the
enantioselective interception of photochemically generated acyl
radicals to afford enantioenriched 1,4-dicarbonyls 3.
C
hiral 1,4-dicarbonyl compounds are versatile synthetic
intermediates[1] and important structural elements found in a wide
variety of natural products and pharmaceutical agents.[2] However,
their direct and stereocontrolled preparation is difficult. While
effective methods that rely on chiral auxiliaries were recently
reported,[3] catalytic asymmetric variants to access enantioenriched
1,4-dicarbonyl compounds are rare.[4] This is mainly because the
stereoselective union of two carbonyl units in a 1,4 relation generally
requires a polarity inversion of one of the carbonyl substrates (Figure
1a, path i). The Stetter reaction[5] is the prototypical example of such
umpolung[6] reactivity: an electrophilic aldehyde is converted into a
nucleophilic acyl anion equivalent (e.g. the Breslow intermediate)
that can attack α,β-unsaturated carbonyl compounds to afford the
target 1,4-dicarbonyl products. Despite the tremendous potential of
this approach, the literature contains only a few examples of
[]
Prof. Dr. P. Melchiorre
ICREA - Catalan Institution for Research and Advanced Studies,
Passeig Lluís Companys 23 – 08010, Barcelona, Spain
Figure 1. a) Intermolecular strategies to access 1,4-dicarbonyl compounds from
two carbonyl subunits: i) polar approach based on umpolung reactivity and ii)
acyl radical conjugate addition to α,β-unsaturated carbonyl compounds; FG:
functional group. b) Proposed photochemical stereocontrolled iminium ion-
mediated conjugate addition of acyl radicals, generated upon direct excitation of
4-acyl-1,4-dihydropyridines 1, to enals 2.
IIT – Italian Institute of Technology
Laboratory of Asymmetric Catalysis and Photochemistry
via Morego 30 – 16163, Genoa, Italy
Dr. G. Goti, Dr. B. Bieszczad, Dr. A. Vega-Peñaloza, and Prof. Dr. P.
Melchiorre
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
The choice of a suitable acyl radical precursor was guided by our
recent findings that 4-alkyl-1,4-dihydropyridines, upon visible-light
excitation and at ambient temperature, directly afford C(sp3)-centered
radicals.[13] In analogy to this photochemical pattern, we surmised
that the excited-state reactivity of structurally related 4-acyl-1,4-
dihydropyridines (acyl-DHPs, 1) could generate the target acyl
radical under mild conditions (Figure 1b). To test our plan’s
feasibility, we used the benzoyl derivative 1a (Bz-DHP) as the model
substrate. 1a can be readily synthesized as a stable crystalline yellow
solid from commercially available phenylglyoxal. UV-vis
spectroscopic analysis established that 1a can absorb in the visible
frequency region (Figure 2a). The ability of 1a to trigger the
Homepage: http://www.iciq.org/research/research_group/prof-paolo-
melchiorre/
[†]
These authors contributed equally to this work.
[]
We thank MINECO (CTQ2016-75520-P) and the European
Research Council (ERC 681840 - CATA-LUX) for financial support.
AV-P thanks the CONACyT (Consejo Nacional de Ciencia y
Tecnología, Mexico—Ref. 237346) for a postdoctoral fellowship. We
thank Dr. Suva Paria for preliminary investigations and Professor
Maurizio Fagnoni (University of Pavia) for useful discussions.
1
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10.1002/anie.201810798
Angewandte Chemie International Edition
formation of benzoyl radicals upon simple photoexcitation at 460 nm
was corroborated by EPR studies, conducted at 77 K. The EPR
spectrum showed an isotropic X-band absorption with g factor =
2.0008 (Figure 2b), which is consistent with literature on the
characterization of benzoyl radicals.[14] In addition, irradiating a
CH3CN solution of 1a with a single high-power visible-light-emitting
diode (LED, λmax = 460 nm, irradiance of 30 mW/cm2) and in the
presence of the radical scavenger 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO, 1 equiv.) led to the formation of the
benzoyl-TEMPO adduct in 45% yield (details in Section H of the
Supporting Information). Overall, these experiments indicate that the
simple photoexcitation of 1a can trigger the formation of benzoyl
radicals.
Finally, the reactivity was completely inhibited in the absence of light,
demonstrating the photochemical nature of the process (entry 7).
Table 1. Optimization studies.[a]
entry
catalyst
T (°C)
λ
mW/cm2
[%] yield[b]
[%] ee[c]
1[d]
2
none
A
25
460
460
460
460
460
525
none
30
30
30
30
20
30
15
85
-
-15
-15
-15
-15
-15
-15
-14
27
74
76
76
0
3
B
43
4
C
84
5
C
96 (88)
74
Figure 2. a) Absorption spectrum of 1a in CH3CN (0.15 mM). b) EPR spectrum
of the benzoyl radical generated from 1a at 77 K after 170 min of light irradiation
at 460 nm (30 mW/cm2).
6[e]
7
C
C
0
[a]
Reactions performed on a 0.1 mmol scale for 40 h using 0.2 mL of solvent
With a suitable acyl radical precursor in hand, we then focused
on developing the photochemical asymmetric iminium ion-mediated
radical addition. We selected cinnamaldehyde 2a and Bz-DHP 1a as
model substrates (Table 1). The experiments were conducted in
CH3CN using a blue (HP) LED (λmax = 460 nm)[15] 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). A blank reaction conducted at ambient temperature in the
absence of any chiral amine catalyst delivered the 1,4-dicarbonyl
product 3a in 15% yield after only 4 hours (entry 1). This result
highlights the intrinsic challenge of developing an enantioselective
variant, which requires the chiral catalyst to override a fast racemic
background reaction. To mitigate the uncatalyzed path, we performed
further experiments under cryogenic conditions (-15 °C). We used
chiral secondary amine catalysts with an established profile in
promoting asymmetric iminium-ion-mediated processes. The
imidazolidinone catalyst A[16a] afforded product 3a in high yield but
low stereocontrol (entry 2), while the diarylprolinol silylether B[16b]
inferred a slightly higher enantiomeric excess, but at the expense of
reactivity (entry 3). Interestingly, the yield of product 3a correlated
positively with the electrophilicity of the iminium ions (catalyst A
forms a more reactive iminium ion than B upon condensation with
2a).[17] This observation prompted us to use the gem-difluorinated
diarylprolinol silylether catalyst C, which we previously designed for
the photo-activation of iminium ions.[15a] We reasoned that the
incorporation of electron-withdrawing fluorine atoms would facilitate
the stereoselective acyl radical trap by providing a chiral iminium ion
with an enhanced electrophilicity. Pleasingly, product 3a was formed
in high yield and good enantioselectivity under catalysis by C (74%
ee, entry 4). Lowering the irradiance to 20 mW/cm2, thus modulating
the amount of acyl radicals generated, further improved the system’s
efficiency, providing optimal conditions (entry 5, 3a formed in 86%
yield and 76% ee). Interestingly, the reaction maintained the same
efficiency under green light irradiation (LED with λmax = 525 nm),
but required an unpractically long time (92 vs 40 hours, entry 6).
under illumination by a single high-power (HP) LED. [b] Yield of 3a determined by
1H NMR analysis of the crude mixture using trichloroethylene as the internal
[c]
standard; yields of the isolated 3a are reported in brackets.
excess determined by UPC2 analysis on a chiral stationary phase.
Enantiomeric
[d]
Reaction
[e]
time: 4 h.
Reaction time: 92 h. TFA: trifluoroacetic acid; TMS: trimethylsilyl;
TDS: thexyl-dimethylsilyl.
Adopting the optimized conditions described in Table 1, entry
5, we then investigated the generality of the photo-organocatalytic
asymmetric acyl radical conjugate addition (Figure 3). We first
evaluated the reactivity of differently substituted acyl radicals,
photochemically generated from the precursor acyl-DHPs 1, towards
the addition to cinnamaldehyde. For aromatic moieties in 1, different
substitution patterns were tolerated well, regardless of their electronic
and steric properties, affording the corresponding 1,4-dicarbonyl
products 3a-h in high yields and moderate to good stereocontrol.
Heteroaryl frameworks can also be included in the product, as shown
for the furanyl- and thienyl-substituted adducts 3i and 3j, respectively.
Finally, alkyl substituents on the acyl group could be readily
introduced (products 3k-m), including the sterically demanding
adamantyl group (3k), which is used in medicinal chemistry to
improve ADME properties of lead compounds.[18] Interestingly, we
did not observe, under the reaction conditions, any byproducts arising
from competing decarbonylation (C=O loss) of the aliphatic acyl
radical.
Experiments to probe the scope of the cinnamaldehyde
component 2 revealed that a range of substituents are tolerated on the
aryl ring (products 3n-q). Importantly, aliphatic enals with short,
encumbered, or long fragments at the β position also reacted smoothly,
affording the corresponding 1,4-dicarbonyl products 3r-t. Finally, the
acyl radical conjugate addition to β,β'-disubstituted (E)-3-phenylbut-
2-enal enabled us to enantioselectively forge a quaternary carbon
stereocenter (3u).
Crystals from compound 3a were suitable for X-ray
crystallographic analysis,[19] which established the stereochemical
course of the radical process.
2
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10.1002/anie.201810798
Angewandte Chemie International Edition
Figure 3. Survey of the acyl DHPs 1 and enals 2 that can participate in the acyl radical conjugate addition. Reactions performed on a 0.1 mmol scale using 3 equiv.
of enal 2 in 0.2 mL of CH3CN under illumination at 460 nm with an irradiance at 20 mW/cm2. Yields and enantiomeric excesses of the isolated products 3 are indicated
below each entry (average of two runs per substrate). *Irradiance: 30 mW/cm2. Using 2 equiv. of enal 2.
To demonstrate the synthetic utility of the method, we prepared
the acylated product 3a on a synthetically useful scale (1 mmol scale,
74% yield and 70% ee). 3a served as an intermediate for the
steps of the process could enable selective access to any product
enantiomer or diastereomer of 5 by judicious catalyst selection.[21] In
implementing this stereodivergent plan, we capitalized on the
electron-poor nature of the difluorinated catalyst C, which makes it
very suitable for iminium ion activation. In contrast, these electronic
properties greatly hamper the condensation of C with the adduct 3 to
generate the enamine intermediate. We hypothesized that the addition
of the more electron-rich amine catalyst B would therefore
exclusively assume the control of the enamine-mediated step.
Switching the enantiomer of the specific enamine catalyst B would
therefore ensure a selective access to both diastereoisomeric 2,3-
difunctionalized products 5 with high enantioselectivity.
preparation of
the
biologically
active
(S)-(+)-4-(4-(2-
methoxyphenyl)piperazin-1-yl)-1,2-diphenylbutan-1-one (4),
a
serotonin 5HT1A receptor antagonist.[20] 4 was synthesized in a single
step by reductive amination of 3a without eroding the stereochemical
integrity of the progenitor (Scheme 1).
Scheme 1. Synthesis of serotonin 5HT1A receptor antagonist 4; STAB = sodium
triacetoxyborohydride.
We recognized that the structure of the β-acylated products 3
could provide the opportunity to stereoselectively access 2,3-
disubstituted 1,4-dicarbonyls, which are valuable chiral motifs in
natural products and drug scaffolds.[2] Since the aldehyde-containing
product 3 bears the chemical handle required for enamine activation,
we envisioned the possibility of combining the iminium-ion-mediated
acyl radical addition process with a second bond-forming event
controlled by
a
different organic catalyst (aldehyde α-
functionalization). This sequential iminium ion-enamine activation
approach would lead to the target 2,3-disubstituted 1,4-dicarbonyl
adduct 5 (Scheme 2). Ideally, the identification of two distinct chiral
catalysts that specifically trigger the two mechanistically orthogonal
Scheme 2. One-pot stereodivergent synthesis of 2,3-difunctionalized 1,4-
dicarbonyl compounds via cycle-specific iminium ion/enamine catalysis;
cyclopentyl methyl ether (CPME) .
3
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10.1002/anie.201810798
Angewandte Chemie International Edition
This plan was tested by performing the photochemical β-
acylation of cinnamaldehyde 2a and Bz-DHP 1a catalyzed by the
fluorinated catalyst (S)-C. After completion of the radical addition
step, the aminocatalyst (S)-B (20 mol%) was added along with 1,1-
bis(phenylsulfonyl)ethylene 6 as a reactive Michael acceptor[22] and
cyclopentylmethylether (CPME) as the solvent (Scheme 2). This one-
pot procedure granted access to the 2,3-disubsitituted product 5 with
high enantioselectivity (95% ee) and good anti diastereoselectivity
(4.8:1 anti/syn). In consonance with our design plan, using the other
enantiomer of the enamine catalyst B while retaining the iminium
J. Am. Chem. Soc. 2008, 130, 14066; d) D. A. DiRocco, T. Rovis, J.
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[9] For acyl radical properties, reactivity, and classical methodologies for
their generation, see: C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu,
Chem. Rev. 1999, 99, 1991.
[10] For examples of non-stereocontrolled acyl radical addition to electron-
poor olefins, see: a) R. Scheffold, R. Orlinski, J. Am. Chem. Soc.,
1983, 105, 7200; b) S. Esposti, D. Dondi, M. Fagnoni, A. Albini,
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Wang, R. Shang, W.-M. Cheng, Y. Fu, Org. Lett. 2015, 17, 4830; e)
L. Capaldo, R. Riccardi, D. Ravelli, M. Fagnoni, ACS Catal. 2018, 8,
304.
specific catalyst
C isomer resulted in complete reversal of
diastereocontrol to provide the syn adduct 5 without loss in reaction
efficiency or enantioselectivity (51 yield, 97% ee, 3:1 syn/anti).
In summary, we have demonstrated that easily accessible 4-acyl-
1,4-dihydropyridines can generate acyl radicals upon irradiation with
visible light. The mild reaction conditions of this photochemical
radical-generating strategy were used to develop the first reported
example of enantioselective catalytic acyl radical conjugate addition.
This iminium-ion-mediated process affords valuable enantioenriched
acyclic 1,4-dicarbonyl compounds and can be used for the
stereoselective synthesis of a biologically relevant molecule. We also
demonstrated that, by combining this acylation process with a second
catalyst-controlled bond-forming event, it is possible to selectively
access 2,3-substituted 1,4-dicarbonyl products using a one-pot
procedure, and that both stereoisomers can become available by
judicious catalyst selection. Efforts are ongoing to expand the
synthetic potential of this asymmetric acyl radical addition strategy
and fully elucidate the reaction mechanism.[15]
[11] M. Silvi, P. Melchiorre, Nature 2018, 554, 4.
[12] D. W. C. MacMillan, Nature, 2008, 455, 304.
[13] L. Buzzetti, A. Prieto, S. Raha Roy, P. Melchiorre, Angew. Chem. Int.
Ed. 2017, 56, 15039; Angew. Chem. 2017, 129, 15235.
[14] P. J. Krusic, T. A. Rettig, J. Am. Chem. Soc. 1970, 92, 722.
[15] Irradiance at 460 nm secured the selective excitation of the acyl-DHP
substrate 1. The resulting acyl radical is then stereoselectively
intercepted by the ground-state electrophilic chiral iminium ion. The
excitation of the transiently generated chiral iminium ion cannot be
operative under these conditions, since this intermediate cannot absorb
wavelengths longer than 430 nm, see: a) M. Silvi, C. Verrier, Y. P.
Rey, L. Buzzetti, P. Melchiorre, Nat. Chem. 2017 9, 868; b) C.
Verrier, N. Alandini, C. Pezzetta, M. Moliterno, L. Buzzetti, H. B.
Hepburn, A. Vega-Peñaloza, M. Silvi, P. Melchiorre, ACS Catal.
2018, 8, 1062; c) D. Mazzarella, G. E. M. Crisenza, P. Melchiorre, J.
Am. Chem. Soc. 2018, 140, 8439.
[16] a) G. Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79; b)
K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht, K. A. Jørgensen,
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[17] a) S. Lakhdar, A. R. Ofial, H. Mayr, J. Phys. Org. Chem. 2010, 23,
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[18] G. Lamoureux, G. Artavia, Curr. Med. Chem. 2010, 17, 2967.
[19] Crystallographic data for compound 3a has been deposited with the
Cambridge Crystallographic Data Centre, accession number CCDC
1867805.
[20] T. D. Kohlman, Y.-C Xu, A. G. Godfrey, J. C. O'Toole, T. Y. Zhang,
1999, EP 924205-A1-19990623.
[21] For the use of cyclic specific catalysts in organocatalytic cascade
processes, see: a) B. Simmons, A. M. Walji, D. W. C. MacMillan,
Angew. Chem. Int. Ed. 2009, 48, 4349; Angew. Chem. 2009, 121,
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J. Am. Chem. Soc. 2005, 127, 15051.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: organocatalysis • Stetter reaction • acyl radicals •
photochemistry • stereodivergence
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4
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10.1002/anie.201810798
Angewandte Chemie International Edition
Enantioselective Photochemistry
Giulio Goti, Bartosz Bieszczad, Alberto Vega-
Peñaloza, and Paolo Melchiorre* __________
Page – Page
Stereocontrolled Synthesis of 1,4-Dicarbonyl
Compounds by Photochemical
Organocatalytic Acyl Radical Addition to Enals
A 1,4 relation problem. Chiral 1,4-dicarbonyls are important motifs, but
their stereocontrolled synthesis is difficult.
A
photochemical
asymmetric acyl radical addition to enals 2 is presented as one solution
to this problem. This enantioselective catalytic strategy is triggered by
iminium ion activation. It exploits the visible-light excitation of 4-acyl-
1,4-dihydropyridines 1 to generate acyl radicals under mild conditions.
5
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