Direct Stereoselective Installation of Alkyl Fragments at the β-Carbon of Enals via Excited Iminium Ion Catalysis

Article abstract of DOI:10.1021/acscatal.7b03788

The direct introduction of sp³ carbon fragments at the β position of α,β-unsaturated aldehydes is greatly complicated by competing 1,2-addition manifolds. Previous catalytic enantioselective conjugate addition methods, based on the use of organometallic reagents or ground-state iminium ion activation, could not provide general and efficient solutions. We report herein that, by turning them into strong oxidants, visible light excitation of chiral iminium ions triggers a stereocontrolled radical pathway that exclusively affords highly enantioenriched β-substituted aldehydes bearing a variety of alkyl fragments.

Full text of DOI:10.1021/acscatal.7b03788

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Letter
Direct Stereoselective Installation of Alkyl Fragments at
the #-Carbon of Enals via Excited Iminium Ion Catalysis
Charlie Verrier, Nurtalya Alandini, Cristofer Pezzetta, Mauro Moliterno, Luca Buzzetti,
Hamish B. Hepburn, Alberto Vega-Peñaloza, Mattia Silvi, and Paolo Melchiorre
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03788 • Publication Date (Web): 05 Jan 2018
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Direct Stereoselective Installation of Alkyl Fragments at the
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β-Carbon of Enals via Excited Iminium Ion Catalysis
Charlie Verrier,† Nurtalya Alandini,† Cristofer Pezzetta,† Mauro Moliterno,† Luca Buzzetti,† Hamish B.
Hepburn,† Alberto Vega-Peñaloza,† Mattia Silvi,† and Paolo Melchiorre*,†,‡
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†ICIQ – Institute of Chemical Research of Catalonia, The Barcelona Institute of Science and Technology, Avinguda Països
Catalans 16, 43007 Tarragona, Spain
‡ICREA – Passeig Lluís Companys 23, 08010 Barcelona, Spain
ABSTRACT: The direct introduction of sp3 carbon fragments at the β position of α,β-unsaturated aldehydes is greatly complicated
by competing 1,2-addition manifolds. Previous catalytic enantioselective conjugate addition methods, based on the use of organome-
tallic reagents or ground-state iminium ion activation, could not provide general and efficient solutions. We report herein that, by
turning them into strong oxidants, visible light excitation of chiral iminium ions triggers a stereocontrolled radical pathway that
exclusively affords highly enantioenriched β-substituted aldehydes bearing a variety of alkyl fragments.
KEYWORDS: asymmetric catalysis, organocatalysis, iminium ion, photochemistry, radical reactivity.
The conjugate addition of hard carbon nucleophiles to electron-
deficient alkenes is a powerful synthetic method for creating new
C-C bonds in a catalytic enantioselective fashion.1 Over the last 20
years, asymmetric catalytic processes using organometallic rea-
gents have been extensively investigated, allowing the installation
of sp3 carbon fragments within Michael acceptors.2 Despite the ma-
jor progress achieved, applying this strategy to α,β-unsaturated al-
dehydes 1 has proven difficult. The main complication stems from
the high reactivity of the aldehyde moiety, which enables a com-
peting addition to the carbonyl, ultimately leading to a mixture of
1,2- and 1,4-addition adducts (Figure 1a). This regioselectivity is-
sue was highlighted by Bräse, who reported that the catalytic addi-
tion of diethyl zinc to enals could proceed with high enantioselec-
tivity but poor 1,4/1,2 selectivity (ranging from 4:1 to 1:1).3 Subse-
quent studies by Alexakis demonstrated that a chiral copper catalyst
could promote the addition of both dialkylzinc and Grignard rea-
gents to enals.4 While the former reacted with high 1,4 regioselec-
tivity but moderate stereocontrol,4a Grignard reagents afforded
highly enantioenriched β-substituted enals along with a large
amount of 1,2-addition adducts.4b
chiral β-enaminyl radical IV, generated from I* upon SET, led to
the direct β-benzylation of enals.
Recently, the synthetic potential of the asymmetric conjugate ad-
dition technology was greatly expanded by the ground-state reac-
tivity of electron-poor iminium ions I. Iminium ion-mediated catal-
ysis has found a myriad of applications in the direct stereo- and
regio-selective β-functionalization of enals 1 with soft nucleo-
philes.5 However, the installation of simple alkyl fragments at the
β position of enals through iminium ion activation6 largely remains
an unmet goal.7 We surmised that the excited-state reactivity of
iminium ions,8 which we recently disclosed, might provide an ef-
fective strategy to close this gap in synthetic methodology. Our pre-
vious study demonstrated that the photoexcitation of iminium ions
can switch on novel reaction pathways that are unavailable to
ground-state reactivity. Selective excitation with visible light, by
bringing the electron-poor intermediate I into an electronically ex-
cited state (I* in Figure 1b), turns a merely electrophilic species
into a strong oxidant, which could trigger the formation of the ben-
zylic radical III through single-electron transfer (SET) oxidative
cleavage of the silicon-carbon bond within benzyl trimethylsilane
II. The subsequent stereoselective coupling between III and the
Figure 1. (a) The regioselectivity issue plaguing the development of
the enantioselective catalytic conjugate addition of hard organometallic
nucleophiles to enals 1. (b) The previous study demonstrating that light
excitation turns iminium ions into chiral oxidants, and the resulting
SET-based radical generation mechanism for achieving the enantiose-
lective β-benzylation of enals. (c) The proposed radical-based strategy
for the direct and stereoselective installation of alkyl fragments at the
β-carbon of enals via excited iminium ion catalysis. SET: single-elec-
tron transfer; TMS: trimethylsilyl; filled grey circle represents a bulky
substituent on the chiral amine catalyst.
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Table 1. Optimization studies.a
We reasoned that, if the photochemistry of chiral iminium ions
could be used to generate C(sp3)-centered radicals upon SET oxi-
dation of suitable precursors 2, it might provide a solution for the
direct regioselective installation of alkyl fragments within enals
(Figure 1c). However, we found that the original methodology,8
based on the use of alkyl silanes, was limited to the generation of
either benzyl radicals or radicals stabilized by an adjacent heteroa-
tom.9 This required us to identify alternative precursors 2. Herein,
we detail the successful realization of this idea, which allowed us
to directly install alkyl fragments at the β-carbon of enals with per-
fect regioselectivity and high stereocontrol by using the excited-
state reactivity of iminium ions.10,11
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To test the feasibility of our idea, we selected cinnamaldehyde
1a as the model substrate while using the gem-difluorinated dia-
rylprolinol silylether catalyst A8 to promote the formation of the
chiral iminium ion Ia. Since the excited iminium ion has a reduc-
tion potential (E*red (Ia*/Ia·‾)) as high as +2.4 V (vs Ag/Ag+ in
CH3CN), as estimated on the basis of electrochemical and spectro-
scopic measurements, we surmised that a variety of different pre-
cursors 2 could productively undergo a SET oxidation to generate
alkyl radicals (Table 1). The experiments were conducted in
CH3CN at -10 ºC under irradiation by a single violet high-power
light-emitting diode (HP LED, λmax = 420 nm) with an irradiance
of 40 mW/cm2, as controlled by an external power supply (full de-
tails of the illumination set-up are reported in the Supporting Infor-
mation, Figure S1).
The use of potassium iso-propyl trifluoroborate 2a (Eox (2a·+/2a)
= +1.72V vs Ag/Ag+ in CH3CN) as the radical precursor12 led to the
formation of the desired β-alkylated product 3a in moderate yield
and stereoselectivity (entry 1). A cation exchange from potassium
(2a) to tetrabutylammonium (2b, Eox (2b·+/2b) = +1.65V vs Ag/Ag+
in CH3CN) greatly increased the reagent solubility. However, 2b
offered a similar reactivity in the enantioselective photochemical
β-alkylation of 1a (entry 2). We then focused on the use of iso-
propyl substituted dihydropyridine 2c (Eox (2c·+/2c) = +1.41V vs
Ag/Ag+ in CH3CN). This choice was motivated by the notion that
4-alkyl-1,4-dihydropyridines (alkyl-DHPs), which are readily pre-
pared from aldehydes in one step, easily undergo a homolytic
cleavage to form C(sp3)-centered radicals under oxidative condi-
tions.13 Pleasingly, the use of 2c resulted in a clean process, with
the β-alklyated aldehyde 3a formed in fairly good yield and a good
level of stereocontrol (entry 3). The reactivity was greatly im-
proved by increasing the amount of trifluoracetic acid (TFA,
needed to facilitate the formation of the iminium ion intermediate)
from 40 to 80 mol% (entry 4, the use of different acids offered re-
duced reactivity, see details in Table S1 of the Supporting Infor-
mation). The chiral amine catalyst B, possessing bulkier perfluoro-
isopropyl groups on the arene scaffold, was suitable for improving
enantiocontrol, but at the expense of reactivity (entry 5, reaction
performed in a CH3CN/perfluorohexane solvent mixture to im-
prove the catalyst’s solubility). A final cycle of optimization re-
vealed that a higher concentration of the reaction system and a
higher TFA loading (100 mol%) secured a better catalyst turnover
along with a satisfactory level of stereocontrol and a perfect 1,4
selectivity (entry 6 and 7).
radical
precursor 2
TFA
(mol %)
entry
catalyst
yield (%)b
ee (%)
1
2
3
4
5
6
7
A
A
2a
2b
2c
2c
2c
2c
2c
40
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87
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A
40
70
A
80
91
Bc
Bc
Bd
80
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100
100
67
88 (83)e
TDS: thexyl-dimethylsilyl. a Reactions performed in CH3CN (0.5 mL) on a
0.1 mmol scale using 3 equiv of 1a and an irradiance of 40 mW/cm2. b NMR
yield of 3a determined using 1,3,5-trimethoxybenzene as the internal stand-
ard. c Performed in a 4:1 CH3CN/perfluorohexane (C6F14) solvent mixture
(0.5 mL). Performed in a 2:1 CH3CN/C6F14 solvent mixture (0.3 mL).
Number in parenthesis indicates the yield of the isolated 3a after chromato-
d
e
graphic purification on silica gel.
We then used the optimized conditions described in Table 1, en-
try 5 to demonstrate the generality of the β-alkylation process trig-
gered by the photoexcitation of iminium ions (Figure 2). First, we
evaluated the possibility of using 4-alkyl-1,4-dihydropyridines,
bearing alkyl fragments other than iso-propyl at the C4-position, as
radical precursors. Both linear and cyclic fragments could be suc-
cessfully introduced at the β carbon of cinnamaldehyde 1a, exclu-
sively leading to the 1,4-adducts with generally good yields and
stereocontrol (products 3a-m). An oxygen-containing heterocyclic
motif did not hamper the reaction (3f), while a piperidine moiety
could be installed at the β position of 1a with good stereocontrol
but a poor yield (adduct 3g). Sterically demanding fragments were
accommodated well, as demonstrated with the tert-butyl moiety
(product 3h, in this case the corresponding trifluoroborate salt was
used as the radical precursor since the corresponding 1,4-dihydro-
pyridine is not easily accessible). The use of alkyl-DHPs bearing a
chiral fragment afforded the formation of adducts 3i-m, that have
two vicinal stereogenic centres, with high enantiomeric purity, al-
beit with a poor diastereomeric ratio. Interestingly, alkyl fragments
adorned with both alkene and aromatic moieties could be installed,
leading to the corresponding products 3j-m. Also primary radicals
could successfully engage in this stereoselective coupling reaction
when adorned with a stabilizing α-oxygen atom, leading to adducts
3n and 3o with moderate yield and good stereoselectivity.
We also performed some control experiments, which indicated
that the process was completely inhibited in the absence of proto-
nated amine catalyst or light.14 Also the presence of TEMPO re-
sulted in no product formation, in consonance with a radical mech-
anism.
As for the scope of the α,β-unsaturated aldehydes 1, different
substituents at the β aromatic moiety could be accommodated well,
regardless of their electronic and steric properties and position on
the phenyl ring. The β-alkylation products 3p-v were formed with
exclusive 1,4 selectivity, in moderate to good chemical yields and
with good stereocontrol. As a limitation of the method, the presence
of a β-alkyl fragment in 1 completely inhibited the reaction.15
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Figure 2. Survey of the enals 1 and the 4-alkyl-1,4-dihydropyridines 2 that can participate in the photochemical catalytic strategy for the asymmetric
installation of alkyl fragments at the β position of enals. Reactions performed on a 0.1 mmol scale over 14 hours in a 4:1 CH3CN/perfluorohexane
(C6F14) solvent mixture (0.5 mL) using 3 equiv. of 1 and an irradiance of 40 mW/cm2. Yields and enantiomeric excesses of the isolated products are
indicated below each entry (average of two runs per substrate). a Performed using 100 mol% of TFA in a 2:1 CH3CN/C6F14 solvent mixture (0.3 mL).
b Performed using 40 mol% of TFA and the corresponding tetrabutylammonium trifluoroborate as the radical precursor. c Performed in dichloro-
methane using catalyst A and 100 mol% of TFA. d Performed in a 2:1 CH3CN/C6F14 solvent mixture (0.3 mL); TDS: thexyl-dimethylsilyl.
To further expand the synthetic utility of the methodology, the
optimized conditions were applied for the stereocontrolled prepa-
ration of saccharide-containing aldehydes 5. The 1,4-dihydro-
pyridine 4, which contains a galactosyl moiety,16 was used as rad-
ical precursor to access the target adducts 5 in fairly good yields
and high stereocontrol (Figure 3). The reactions were performed
with both enantiomers of the chiral amine catalyst A, which pro-
vided access to different diastereomers of the galactose derivatives
(adducts 5a and 5b). These results indicate that the chiral organic
catalyst governs the stereoselectivity of the process, and can over-
write the inherent stereochemical information encoded within the
chiral substrate 4. The stereochemistry of product 5a was estab-
lished by single crystal X-ray crystallographic analysis.17
our laboratories to fully explore the excited-state reactivity of chiral
iminium ions and its potential in chiral molecule synthesis.
In summary, we have reported a method for the direct regio- and
stereo-selective installation of alkyl fragments at the β position of
α,β-unsaturated aldehydes. The chemistry relies on the visible light
excitation of chiral iminium ions, which turns them into strong ox-
idants able to generate C(sp3)-centered radicals from readily avail-
able 4-alkyl-1,4-dihydropyridines. Further studies are ongoing in
Figure 3. Stereoselective photochemical synthesis of galactose-con-
taining aldehydes 5 under catalyst control; the configuration of the
stereocenter highlighted in pink is dictated by the chiral aminocatalyst
A.
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(3) (a) Bräse, S.; Höfener, S. Angew. Chem., Int. Ed. 2005, 44,
7879–7881. (b) Ay, S.; Nieger, M.; Bräse, S. Chem. Eur. J.
2008, 14, 11539–11556.
(4) (a) Palais, L.; Babel, L.; Quintard, A.; Belot, S.; Alexakis, A.
Org. Lett. 2010, 12, 1988–1991. (b) Goncalves-Contal, S.;
Gremaud, L.; Palais, L.; Babel, L.; Alexakis, A. Synthesis, 2016,
48, 3301–3308.
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
Corresponding Author
*pmelchiorre@iciq.es
ORCID
Nurtalya Alandini: 0000-0001-6841-2501
Cristofer Pezzetta: 0000-0003-1647-0368
Mauro Moliterno: 0000-0001-5275-1138
Luca Buzzetti: 0000-0002-1096-8272
Hamish B. Hepburn: 0000-0002-9609-3672
Alberto Vega-Peñaloza: 0000-0003-0374-8033
Paolo Melchiorre: 0000-0001-8722-4602
(5) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006, 39, 79–
87.
(6) We recently reported that the ground-state reactivity of iminium
ions can catalyze the stereoselective conjugate addition of alkyl
radicals to β-substituted cyclic enones to forge quaternary car-
bon stereocenters. However, any attempt to expand this strategy
to enals 1 met with failure. (a) Murphy, J. J.; Bastida, D.; Paria,
S.; Fagnoni, M.; Melchiorre, P. Nature 2016, 532, 218–222. (b)
Bahamonde, A.; Murphy, J. J.; Savarese, M.; Bremond, E.;
Cavalli, A.; Melchiorre, P. J. Am. Chem. Soc. 2017, 139, 4559–
4567.
(7) A combination of copper and iminium ion catalysis was recently
used for the enantioselective β-alkylation of enals 1. However,
the conjugate addition process was limited to the use of methyl
and ethyl zinc reagents and suffered from poor 1,2/1,4-regiose-
lectivity, see: Afewerki, S.; Breistein, P.; Pirttilä, K.; Deiana, L.;
Dziedzic, P.; Ibrahem, I.; Córdova, A. Chem. Eur. J. 2011, 17,
8784–8788.
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Notes
The authors declare no competing financial interest.
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manu-
script
(8) Silvi, M.; Verrier, C.; Rey, Y.; Buzzetti, L.; Melchiorre, P. Nat.
Chem. 2017, 9, 868–873.
(9) Our attempts to extend the methodology to the use of trimethyl-
tert-butyl silane were unsuccessful and no appreciable product
formation was observed.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data. The Supporting Infor-
mation is available free of charge on the ACS Publications website.
(10) The literature contains a few examples of metal-catalyzed enan-
tioselective conjugate addition of alkyl radicals to opportunely
modified Michael acceptors. Addition to α,β-unsaturated acyl-
oxazolidinone: (a) Sibi, M. P.; Ji, J. J. Am. Chem. Soc. 1996,
118, 9200–9201. (b) Sibi, M. P.; Ji, J. J. Org. Chem. 1997, 62,
3800–3801. (c) Ruiz Espelt, L.; McPherson, I. S.; Wiesnsch, E.
M.; Yoon, T. P. J. Am. Chem. Soc. 2015, 137, 2452−2455. Ad-
dition to α,β-acyl-imidazoles: (d) Huo, H.; Harms, K.; Meggers,
E. J. Am. Chem. Soc. 2016, 138, 6936–6939. See also (e) Sibi,
M.P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263–
3295. f) Sibi, M.P.; Ji, J.; Sausker, J.B.; Jasperse, C.P. J. Am.
Chem. Soc. 1999, 121, 7517–7526
(11) For the rhodium-catalyzed stereocontrolled installation of aryl
moieties at the β-carbon of enals, see: Hayashi, T.; Tokunaga,
N.; Okamoto, K.; Shintani, R. Chem. Lett. 2005, 34, 1480–1481.
(12) (a) Sorin, G.; Mallorquin, R. M.; Contie, Y.; Baralle, A.; Malac-
ria, M.; Goddard, J.-P.; Fensterbank, L. Angew. Chem., Int. Ed.
2010, 49, 8721–8723. (b) Yasu, Y.; Koike, T.; Akita, M. Adv.
Synth. Catal. 2012, 354, 3414–3420. (c) Tellis, J. C.; Primer, D.
N.; Molander, G. A. Science 2014, 345, 433–436; see also Ref.
10d.
ACKNOWLEDGMENT
Financial support was provided by the Generalitat de Catalunya
(CERCA Program), Agencia Estatal de Investigación (AEI)
(CTQ2016-75520-P and Severo Ochoa Excellence Accreditation
2014-2018, SEV-2013-0319), and the European Research Council
(ERC-2015-CoG 681840 - CATA-LUX). C.V. thanks the Marie
Skłodowska-Curie Actions for a postdoctoral fellowship (H2020-
MSCA-IF-2014 658980). L.B. thanks MINECO for a predoctoral
fellowship (CTQ2013-45938-P). N. A. and C. P. thank H2020-
MSCA-ITN-2016 (722591 – PHOTOTRAIN) for predoctoral fel-
lowships. The authors thank Dr. Giulio Goti for useful discussions.
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(14) We recently reported that 4-alkyl-1,4-dihydropyridines, upon
light excitation, become strong reducing agents that can activate
reagents via SET manifolds while undergoing a homolytic
cleavage to generate alkyl radicals, see: L. Buzzetti, A. Prieto,
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15039–15043. However, the isopropyl derivative 2c cannot ab-
sorb light at 420 nm and it is stable upon illumination (see details
in Table S2 and Figure S7 of the Supporting Information), which
leaves the photoexcitation of iminium ions as the only reaction
pathway that can be operative in this system.
(15) Irradiation at 365 nm of a non-enolizable aliphatic enal, bearing
a tert-butyl group at the β-position, in the presence of substrate
2b and catalyst A afforded trace amounts of the β-alkylation
product (about 10% yield after 60 hours, as inferred by NMR
analysis). Other aliphatic enals (i.e. pentenal and octenal) re-
mained completely unreacted under the same conditions.
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(16) Tewari, N.; Dwivedi, N.; Tripathi, R. Tetrahedron Lett. 2004,
45, 9011−9014.
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(17) Crystallographic data for compound 5a has been deposited with
the Cambridge Crystallographic Data Centre, accession number
CCDC 1581199.
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