This is the peer reviewed version of the following article Nature 532, 218–222
which has been published in final form http://www.nature.com/nature/journal/v532/n7598/full/nature17438.html

LETTER
Enantioselective catalytic construction of quaternary carbons by
iminium ion trapping of photochemically-generated radicals
John J. Murphy1†, David Bastida1†, Suva Paria1, Maurizio Fagnoni2 & Paolo Melchiorre1,3*
A central goal of modern organic chemistry is to develop novel catalytic enantioselective carbon-carbon bond-forming
strategies for forging quaternary stereogenic centres. While considerable advances have been achieved in the realm of
polar reactivity1, radical transformations have found very limited application2. This is despite the fact that open-shell
intermediates are intrinsically primed for connecting structurally congested carbons, as their reactivity is only marginally affected by steric factors3. Herein we demonstrate how the combination of photoredox4 and asymmetric organic
catalysis5 enables enantioselective radical conjugate additions to β,β-disubstituted cyclic enones to set quaternary carbon stereocentres with high fidelity. Key to our success was the design of a chiral organic catalyst, purposely adorned
with a redox-active carbazole moiety, which drives the stereoselective interception of photochemically-generated carbon-centred radicals by means of an electron-relay mechanism. We demonstrate the generality of this organocatalytic
radical-trapping strategy with two sets of open-shell intermediates, formed through unrelated light-triggered pathways
from readily available substrates and photoredox catalysts. To the best of our knowledge, this method represents the
first application of iminium ion activation6 (a successful catalytic strategy for enantioselective polar chemistry) within
the realm of radical reactivity.
Organic chemists generally rely on polar reactivity to address the challenge of forging quaternary carbon stereocentres in a
catalytic enantioselective fashion1. Of the synthetic methods available, metal-catalysed conjugate additions of organometallic nucleophilic species to trisubstituted unsaturated carbonyl substrates have recently emerged as a powerful technology7-11 (Fig. 1a).
These are reliable and stereoselective processes, but they generally require controlled reaction conditions and preformed organometallic reagents7-10. In contrast, there has been limited success in developing analogous transformations with nucleophilic carbon-centred radicals. While a few examples of metal-catalysed enantioselective radical conjugate additions have been reported1215
, none of these approaches provide for the formation of sterically demanding quaternary carbons. Our herein-reported work was
prompted by the desire to address this gap in catalytic enantioselective methodology.
Our initial motivation stems from the notion that, due to the long incipient carbon-carbon bond in the early transition state16,
additions of radicals to electron-deficient olefins are rather insensitive to steric hindrance3. This makes radical reactivity particularly suited to connecting structurally complex carbon fragments while forging quaternary carbons, as testified to by literature
synthesis of a natural product facilitated by radical conjugate additions17.

1 – ICIQ, Institute of Chemical Research of Catalonia - the Barcelona Institute of Science and Technology, Av. Països Catalans 16 – 43007, Tarragona, Spain.
2 – Photogreen Lab, Department of Chemistry, University of Pavia, viale Taramelli 12, 27100 Pavia, Italy. 3 – ICREA, Catalan Institution for Research and Advanced
Studies, Passeig Lluís Companys 23 – 08010, Barcelona, Spain. †These authors contributed equally to this work. *email: pmelchiorre@iciq.es

1

Figure 1 | Conjugate addition technology for forging quaternary stereocentres. a, Established metal-catalysed enantioselective conjugate additions of organometallic reagents (R-M) via classical polar pathways. b, Design plan for dual photoredox and iminium ion catalysis of radical conjugate
additions; the grey circle represents the chiral organic catalyst scaffold. c, Challenges associated with implementing iminium ion-catalysed conjugate
addition of radicals (·R2). d, Our electron-relay strategy to rapidly pass over the short-lived α-iminyl radical cation B by intramolecular reduction,
and the role of tautomerisation to prevent back electron transfer. SET = single electron transfer. BET = back electron transfer. PC = photocatalyst;
PCred = reduced form of the photocatalyst. The blue circle represents an electron rich, reducing moiety, while the magenta circle represents a stable
oxidising species.

We also recognised that the emerging field of photoredox catalysis4 had recently provided an effective way of generating radical
intermediates from readily available, bench-stable precursors and under mild conditions. As a result, novel synthetic transformations have been invented that capitalise upon non-traditional open-shell mechanisms18. We sought to combine this effective
radical generation strategy, which does not require pre-functionalised reactant, with a suitable chiral catalyst that could drive the
stereoselective trapping of photogenerated carbon-centred radicals while setting quaternary stereocentres. If successful, this combination would provide direct access to chiral molecules that could not be synthesised using polar conjugate additions. In this
Letter, we report the realisation of this goal.
We used the iminium ion activation strategy6 to attack the problem of identifying a suitable chiral catalyst. This chemistry
exploits the electrophilic nature of the chiral iminium ion A (Fig. 1b), transiently generated upon condensation of chiral amine
catalysts and unmodified α,β-unsaturated ketones, to facilitate enantioselective conjugate additions of carbon nucleophiles19. This
catalytic platform has found many applications in the polar domain over the last 15 years5,6. However, to date, chiral iminium ions
A have never been used to trap nucleophilic radicals. This is most surprising, given the high tendency of open-shell species to react
with electron-deficient olefins3. We reasoned that this dearth of applications could stem from the nature of the radical intermediate B, generated upon the carbon-carbon bond forming event (Fig. 1c). Generally, olefinic radical traps are electrically neutral and,
as such, afford long-lived, neutral radical intermediates. In contrast, radical addition to the cationic iminium ion A generates a
short-lived and highly reactive α-iminyl radical cation B, which, in consonance with the classical behaviour of radical ions20, has a
high tendency to undergo radical elimination (β-scission)21 thus reforming the more stable conjugated iminium ion A.
Recognising the instability of B as the main obstacle to productive radical conjugate addition to iminium ions, we knew it would
be necessary to overcome this troublesome intermediate (Fig. 1d). As a mechanistic blueprint, we considered the possibility of
reducing the α-iminyl radical cation B in situ to generate the corresponding closed shell enamine C, which can be turned over in
a facile manner to release both the catalyst and the conjugate addition product. From the outset, we identified three design elements as key to realising this goal. First, the high reactivity of B requires a very rapid single electron transfer (SET) reduction. We
hypothesised that using a chiral amine catalyst adorned with a redox active, electron-rich moiety (electron pool unit in Fig. 1d)
would secure a fast, proximity-driven intramolecular reduction of B. This idea finds support in the mechanism of electron transfer
within biological systems, where even endergonic redox processes can be achieved via electron tunnelling if the redox centres are
in close proximity22. Second, we needed to identify a rapid process to interrupt a possible equilibrium between B and the nascent
enamine C established by an intramolecular back electron transfer (BET). Since secondary enamines are known to exist mainly as
tautomeric electron poor imines D23, the use of a chiral primary amine catalyst potentially offered an efficient mechanism to
preclude the BET by triggering a tautomeric equilibrium which converts C into D. Last, the oxidised centre (electron hole unit in
Fig. 1d), arising from the intramolecular SET event, had to be long-lived enough to undergo single electron reduction from the
photoredox catalysts (as detailed in both Fig. 1d & 2a), restoring the redox-active moiety while facilitating productive catalysis.
Achieving a high level of stereocontrol further complicated matters.

2

To test the feasibility of this electron-relay strategy24, we explored the reaction between the commercially available β-methyl
cyclohexenone 1a and benzodioxole 2a (Table 1). We used the inorganic photocatalyst tetrabutylammonium decatungstate25
(TBADT, 5 mol%) because, upon light excitation, it can easily photogenerate a nucleophilic carbon-centred radical by homolytically cleaving the inactive methylene C-H bond in 2a26 via a hydrogen atom transfer (HAT) mechanism. The experiments were
conducted at 35 ̊C in acetonitrile (CH3CN) and under irradiation by a single black-light-emitting diode (black LED, λmax = 365
nm).
Table 1 | Exploratory studies on the feasibility of the electron-relay strategy.
amine catalyst (20 mol%)
TBADT (5 mol%)
black LED (365 nm)

O
O
+ H

benzoic acid (40 mol%)
TBABF4 (1 equiv)
CH3CN, 35 oC

O

Me
1a

2a

O
O
Me

O

3a

catalysts used in this study
4a: R = H

4e: R =

R

N

4b-d: R =

NH2

N

R1

4
R1

4b: R1 = H
4c: R1 = tBu
4d: R1 = CF3
Epox / Epred (4) vs Ag/AgCl‡

entry

catalyst

time

1

none

48 h

-

traces

-

2

4a

48 h

-

4

0

3

4b

48 h

33

82

4†

4a*

48 h

-

5

0

5

4c

48 h

+1.05 V / -1.28 V

35

84

6

4d

48 h

+1.49 V / -1.86 V

52

77

7

4e

48 h

+1.10 V / -1.38 V

46

93

8

4e

84 h

+1.10 V / -1.38 V

75

†

+1.15 V / -1.32 V

†

3a yield (%)

ee (%)

93
‡

ox

Using 40 mol% of trifluoroacetic acid (TFA) instead of benzoic acid. Ep and
Epred values describe the electrochemical properties of the redox active carbazole
moiety in 4. *In combination with 20 mol % of exogenous N-cyclohexyl-3,6-di-tertbutyl-carbazole.

We observed a negligible racemic background process in the absence of any amine catalyst, which is a necessary condition for
realising a stereoselective process (entry 1). We then focused on identifying a redox-active moiety that, when installed within the
chiral primary amine catalyst, could instigate a fast intramolecular reduction of the transient α-iminyl radical cation of type B and
thus trigger the entire radical conjugate addition. We identified carbazole as a suitable scaffold because of i) its excellent electrondonating capabilities, which would provide the electron pool unit, and ii) the high stability of the long-lived carbazole radical
cation27, which makes it a possible electron hole moiety. These properties form the basis of the wide application of carbazole
derivatives in hole-transport materials for light-emitting diodes and photovoltaic cells28. Gratifyingly, the chiral cyclohexylamine
scaffold 4b adorned with the carbazole moiety provided the desired product 3a with appreciable yield and stereoselectivity (33%
yield, 82% ee, entry 3). In consonance with the proposed electron-relay mechanism, the reaction could not be catalysed by cyclohexylamine 4a, which mimics the catalyst 4b’s scaffold while lacking the redox-active moiety (entry 2; for other primary amines
which failed to promote the radical process, see Figure S1 in the Supplementary Information, SI). An equimolar combination of 4a
and exogenous N-cyclohexyl-3,6-di-tert-butyl-carbazole (20 mol%) also proved unsuitable for catalysis, suggesting the importance
of a proximity-driven intramolecular SET process. We then modified the redox properties of the carbazole scaffold within the
amine catalysts by introducing substituents at the 3- and 6-positions. In addition, it is known that this substitution pattern can
further stabilise the carbazole radical cation27. Indeed, we could isolate and characterise a shelf-stable carbazoliumyl radical cation
salt from N-cyclohexyl-3,6-di-tert-butyl-carbazole upon treatment with SbCl5, as detailed in Section F3 within the SI. Concurrently,
the increased steric hindrance carried the additional benefit of inferring a higher stereocontrol. These considerations provide a
rationale for the high yield and enantioselectivity achieved when using the encumbered primary amine catalyst 4e (entry 8, product 3a formed in 75% yield and 93% ee). Notably, the presence of an electron-withdrawing group, which facilitates the reduction
of the carbazole radical cation, resulted in an improved reactivity, albeit with moderate stereocontrol (catalyst 4d, entry 6). This
result indicates how both redox steps of the electron-relay mechanism (reduction of B and regeneration of the carbazole unit, Fig.
1d) are essential for a productive radical conjugate addition. Finally, no product formation was detected in the absence of TBADT,
organic catalyst 4e, or light, demonstrating that all these components are needed for this catalytic protocol.

3

We then undertook studies to better investigate the role of the active intermediates in the electron-relay mechanism (Fig. 2a).
We could synthesise stable tetrafluoroborate salts of the chiral iminium ion A-1, generated upon condensation of catalyst 4c and
substrate 1a, which were characterised by X-ray single-crystal analysis (Fig. 2b). Interestingly, the unusual stability of the secondary
iminium ion A-1 and the well-defined (Z)-configuration of the C=N double bond originate from a stabilising intramolecular charge
transfer π-π interaction between the electron-rich carbazole nucleus and the electron-deficient iminium ion. As a result, the measured interatomic separation in the solid state between the carbazole nitrogen and the sp2 α-carbon of the iminium ion (3.10 Å) is
significantly less than the van der Waals distance.

Figure 2 | Proposed mechanism and mechanistic investigations. a, Synergistic activities of the iminium ion and the photoredox catalytic cycles
to realise the enantioselective radical conjugate addition to enone 1a. Upon radical addition to the iminium ion A-1, the electron-relay mechanism
rapidly reduces the unstable radical cation B-1 producing a carbazoliumyl radical cation C-1, which is prevented from undergoing back-electron
transfer by tautomerisation of the secondary enamine to the corresponding imine D-1. Regeneration of the photocatalyst (PC) is achieved by reduction of the carbazoliumyl radical cation in D-1, while the aminocatalyst 4 is liberated upon hydrolysis of imine E-1. b, X-ray crystal structure of the
carbazole-based iminium ion A-1: the distance between the carbazole nitrogen and the sp2 α-carbon of the cyclohexene moiety is highlighted. c,
Cyclisation experiments indicating that the α-iminyl radical intermediate B-1 has been bypassed when using the carbazole-based catalyst 4e.

This highly organised topology of the iminium ion A-1, which NMR spectroscopic analyses confirmed to be also dominant in
solution, plays a critical dual role. On the one hand, it governs the stereocontrol in the radical conjugate addition, since the bulky
carbazole unit is positioned in such a way as to effectively shield the Si face of the iminium ion, leaving the Re face exposed for
enantioselective bond formation. Importantly, the sense of asymmetric induction observed in the model reaction is consistent
with this stereochemical model (Fig. 2b). On the other hand, the three-dimensional assembly of A-1 suggests that the α-iminyl
radical cation B-1, arising from the iminium ion trap of the radical, is generated in close proximity to the electron-rich carbazole
(electron pool), allowing for a fast, proximity-driven22 intramolecular reduction29. Once the carbazoliumyl radical cation (electron
hole) is generated, the fast tautomerisation of the secondary enamine C-1 to afford the electron-poor imines D-1 precludes the
back electron transfer. At this point, the long-lived carbazoliumyl radical cation in D-1 (Epred > -1.28 V vs Ag/Ag+ in CH3CN, see
Table 1) can be reduced by the photocatalyst (E1/2 [TBADT4-/TBADT5--H] = -0.96 V vs Ag/Ag+ in CH3CN)30, closing the photoredox
cycle (Fig. 2a, right panel). The iminium ion cycle terminates with the imine E-1 hydrolysis to regenerate the organic catalyst 4
while liberating the quaternary ketone product 3 (Fig. 2a, left panel).
To gain further evidence supporting the proposed electron-relay mechanism, we used the enone 1b, bearing a β-homoallyl
substituent, to trap the radical photogenerated from benzodioxole 2a (Fig. 2c). The reaction catalysed by cyclohexylamine 4a
provides preferentially the cyclised exo-adduct 5 (5:3b in a 2:1 ratio). This is because of the propensity of the electrophilic transient
α-iminyl radicals, emerging from the radical addition, to undergo cyclisation with unactivated olefins. In sharp contrast, the process catalysed by the amine 4e almost exclusively affords the conjugate addition product 3b (40% yield, 83% ee, 3b:5 in a >10:1
ratio). This result is consonant with a fast redox process, governed by the carbazole-based catalyst, which rapidly reduces the αiminyl radical cation B-1 intermediate preventing cyclisation.

4

With a clearer mechanistic picture in mind and adopting the optimised conditions described in Table 1, entry 8, we demonstrated the generality of the radical conjugate addition by evaluating a variety of cyclic enones 1 and benzodioxoles 2 (Figure 3).
The presence of a methyl substituent at the methylene position of the radical precursor 2 provides the corresponding product 3c,
bearing two adjacent tetrasubstituted carbons, with nearly perfect enantioselectivity. This experiment further illustrates the propensity of radical reactivity for connecting structurally congested carbons. Experiments to probe the scope of the cyclic enone
component revealed that a wide range of carbocycles and β-olefin substituents are well tolerated. For example, high levels of
stereocontrol are achieved with ring systems that incorporate different β-alkyl groups (products 3d,e), while the radical conjugate
addition performs well for a diverse range of ring sizes, including cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl
architecture (adducts 3a, 3f-h). One limitation of the system is that the presence of an aromatic β-substituent completely inhibits
the reaction. As for the benzodioxole substrates 2, different substituents can be installed at the aromatic ring without compromising the efficiency of the reaction (adducts 3i-k). Crystals from compound 3i were suitable for X-ray analysis, which secured the
absolute configuration of the products.

Figure 3 | Substrate scope for the enantioselective trap of benzodioxole-derived radicals via the dual photoredox organocatalytic strategy.
Survey of the cyclic enones 1 and substituted benzodioxoles 2 that can participate in the organocatalytic asymmetric radical conjugate addition to
forge quaternary stereocentres. Yields and enantiomeric excesses of the isolated products are indicated below each entry. Details of the TBADTmediated photoredox cycle to produce carbon-centred radicals from 2 via a HAT mechanism are reported in Figure 2a. TBS: tert-butyldimethylsilyl;
TBABF4: tetrabutylammonium tetrafluoroborate.

The general applicability of a chemical strategy is crucial for evaluating its usefulness. We wondered if the synthetic utility of
the chiral amine carbazole catalyst 4e could be expanded to successfully trap other carbon-centred radicals, formed through an
unrelated light-triggered mechanism, while forging quaternary stereocentres. Specifically, we used the commercially available
photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8) which, upon absorption of visible light, can generate α-amino radicals directly from
simple tertiary amines 6 via single electron oxidation18 (SET mechanism in Fig. 2a). Gratifyingly, the conjugate addition adducts 7
were provided with high stereoselectivity by using the combination of catalysts (R,R)-4e and 8 while conducting the reactions
with enones 1 at 15 ̊C in toluene and under irradiation by a white LED (λemiss > 400 nm) (Fig. 4a). We next sought to explore the
scope of both substrates in this dual photoredox organocatalytic strategy. As highlighted in Fig. 4b, cyclic enones of different ring
sizes (7a, c-e) and bearing alkyl β-substituents (products 7a,b) are suitable substrates. We found that both mixed N-alkyl-N-aryl
(adducts 7a, 7f-g) and N,N-diaryl tertiary amines (7h-j) efficiently participated in the radical conjugate addition. Substituents of
different electronic nature were easily accommodated at the aryl para (7f-g, i) or ortho position (7j), without affecting the efficiency
of the process, while the use of a cyclic amine afforded compound 7k, bearing two vicinal stereogenic centres, with high enantiomeric purity, albeit with a 3:2 diastereomeric ratio. For this enantioselective trap of α-amino radicals, we have determined a quantum yield (Φ) of 0.4 (λ = 400 nm), while Stern–Volmer fluorescence quenching experiments have demonstrated that the excited
state of the iridium photocatalyst 8 is quenched by the amine 6. Both experiments are consistent with the electron-relay mechanism depicted in Fig. 2a. Notably, the radical conjugate addition can be performed without any metal when replacing the photocatalyst 8 with the benzophenone derivative 9, which can generate the radical acting as an organic photosensitiser (Fig. 4c).

5

Figure 4 | Substrate scope for the enantioselective trap of α-amino radicals via the dual photoredox organocatalytic strategy. a, The photochemical organocatalytic radical conjugate addition developed to forge quaternary stereocentres. b, Survey of the cyclic enones 1 and tertiary amines
6 that can participate in the reaction. Yields and enantiomeric excesses of the isolated products are indicated below each entry. Details of the iridiummediated photoredox cycle to produce carbon-centred radicals via a SET mechanism are reported in Figure 2a. c, Fully organocatalytic enantioselective radical conjugate addition using the benzophenone photocatalyst 9.

In summary, we have developed the first catalytic strategy that allows quaternary carbon stereocentres to be set with high
fidelity using an enantioselective radical conjugate addition manifold. The approach, which relies on the mechanistic merger of
photoredox and organic catalysis, requires mild conditions and readily available unfunctionalised substrates. This effectively complements established polar conjugate addition technologies based on preformed organometallic reagents. Our studies also established the possibility of expanding the versatility of iminium ion activation, a powerful catalytic strategy for enantioselective polar
chemistry, within the realm of radical reactivity.
Supplementary Information is linked to the online version of the paper at www.nature.com/nature.
Acknowledgements Financial support was provided by the ICIQ Foundation, MINECO (project CTQ2013-45938-P and Severo Ochoa Excellence
Accreditation 2014-2018, SEV-2013-0319), the AGAUR (2014 SGR 1059), and the European Research Council (ERC 278541 - ORGA-NAUT). J.J.M. and
S.P. thank the Marie Curie COFUND action (291787-ICIQ-IPMP) and the CELLEX Foundation, respectively, for postdoctoral fellowships. The
authors thank Dr Manuel Nappi and Dr Eva Raluy for preliminary investigations, Dr Daniele Merli and Dr Daniele Dondi for assistance with EPR
experiments and Dr Davide Ravelli for insightful discussions.
Author contributions J.J.M., D.B., and S.P. performed the experiments and analysed the data. J.J.M., D.B., S.P., M.F., and P.M. designed the
experiments. M.F. and P.M. conceived the project. P.M directed the project and P.M and J.J.M. wrote the manuscript with contributions from all
the authors.
Author information Crystallographic data for the iminium ion A-1 and for compounds 3i and 7h have been deposited with the Cambridge Crystallographic Data Centre, accession numbers CCDC 1437991, 1437992, and 1437993, respectively. Reprints and permissions information is available
at www.nature.com/reprints. The authors declare no competing financial interests. Correspondence and requests for materials should be addressed to P.M. (pmelchiorre@iciq.es).
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secondary enamines generated upon catalyst condensation with cyclohexanone, because of the unfavourable imine/enamine tautomeric equilibrium. Given that tertiary enamines have ionization potentials in the range of 0.7-0.8 V, a slightly endergonic intramolecular redox process,
facilitated by the close proximity of the redox centres in B-1, is likely taking place during the electron-relay mechanism.
30. Yamase, T., Takabayashi, N. & Kaji, M. Solution photochemistry of tetrakis(tetrabutylammonium) decatungstate(VI) and catalytic hydrogen evolution from alcohols, J. Chem. Soc. Dalton Trans. 793–799 (1984).

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