Enantioselective conjugate additions of α-amino radicals via cooperative photoredox and Lewis acid catalysis

Article abstract of DOI:10.1021/ja512746q

We report the highly enantioselective addition of photogenerated α-amino radicals to Michael acceptors. This method features a dual-catalyst protocol that combines transition metal photoredox catalysis with chiral Lewis acid catalysis. The combination of these two powerful modes of catalysis provides an effective, general strategy to generate and control the reactivity of photogenerated reactive intermediates.

Full text of DOI:10.1021/ja512746q

Communication
pubs.acs.org/JACS
Enantioselective Conjugate Additions of α‑Amino Radicals via
Cooperative Photoredox and Lewis Acid Catalysis
Laura Ruiz Espelt, Iain S. McPherson, Eric M. Wiensch, and Tehshik P. Yoon*
Department of Chemistry, University of Wisconsin−Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
functionalized radical intermediates. More recently, several
ABSTRACT: We report the highly enantioselective
addition of photogenerated α-amino radicals to Michael
acceptors. This method features a dual-catalyst protocol
that combines transition metal photoredox catalysis with
chiral Lewis acid catalysis. The combination of these two
powerful modes of catalysis provides an effective, general
strategy to generate and control the reactivity of
photogenerated reactive intermediates.
groups have shown that transition metal photoredox sensitizers
can be used to produce α-amino radicals under visible light
irradiation.11 Although the utility of these amine-functionalized
radical species in the synthesis of complex alkaloids has long been
appreciated,12 methods to control the enantioselectivity of their
addition reactions are extremely rare. To the best of our
knowledge, the only prior example of an asymmetric reaction in
this class is a single, elegant addition reaction reported by Bach in
which a chiral hydrogen-bonding photosensitizer catalyzes the
intramolecular conjugate addition of a photogenerated α-amino
radical to a quinolone scaffold.13 A more general method to
control the stereochemistry of such additions, particularly in an
intermolecular context, is an unrealized goal with great synthetic
potential.
We recently reported the photocatalytic functionalization of
N-aryl tetrahydroisoquinolines via an α-amino radical inter-
mediate.8 This study provided two important observations that
informed the design of our exploratory investigations. First, we
found that the conjugate addition of the α-amino radicals to
Michael acceptors was catalyzed by Brønsted acids. If chiral
Lewis acids could have a similar effect, they might also control the
stereochemistry of these additions.14 Indeed, Sibi, Porter, and
others have established that chiral Lewis acids can dictate the
enantioselectivity of radical conjugate additions,15 although these
investigations have been limited to simple, unfunctionalized alkyl
radicals. Second, we found that the rate-limiting step was a chain-
propagating H atom abstraction process that was only efficient
with N-aryl tetrahydroisoquinoline substrates with especially
activated α-amino C−H bonds. We wondered if this narrow
restriction on viable substrates could be overcome by an
alternative method for generating the α-amino radical. In
particular, we were inspired by Mariano’s insight that α-silyl
amines undergo facile oxidative fragmentation and generate α-
amino radicals several orders of magnitude more efficiently than
their nonsilylated analogues.9e
hile photochemistry has long been appreciated as a
1
Wpowerful tool in organic synthesis,
stereocontrol in
photochemical reactions remains a significant challenge with few
general solutions.2 A number of novel dual catalytic systems have
recently been developed to address this long-standing problem.
The combination of transition metal photoredox catalysts with
chiral amine,3 carbene,4 and Brønsted acid organocatalysts5 has
enabled a number of highly enantioselective photoinduced
reactions. We recently reported the first method combining
photoredox and chiral Lewis acid catalysis in the context of an
asymmetric [2 + 2] photocycloaddition.6 Compared to organo-
catalysts, chiral Lewis acids possess a greater diversity of
structures known to provide effective enantiodifferentiating
environments for a wide range of mechanistically distinct organic
reactions.7 We wondered if the ability to combine organic
chemists’ detailed understanding of asymmetric Lewis acid
catalysis with the emerging versatility of photoredox activation
might provide a robust approach to controlling stereochemistry
in photocatalytic reactions. Herein, we report our application of
the principle of cooperative Lewis acid−photoredox catalysis to
highly enantioselective reactions of α-amino radicals (Scheme 1).
Our group has an established interest in the chemistry of α-
amino radicals.8 Pioneering studies by Mariano9 and Pandey10
demonstrated that the photosensitized oxidation of amines, α-
amino acids, and α-silylamines offers the most straightforward
method for the production of these highly nucleophilic,
Thus, the optimization of the enantioselective α-amino radical
addition began with an exploration of the reaction between α-
silylmethyl aniline 1 and crotonyl oxazolidinone 2a (Table 1).
Irradiation with a household 23 W fluorescent light bulb in the
presence of 2 mol % Ru(bpy)3Cl2 resulted in the slow formation
of the expected radical conjugate addition product 3a in 28%
yield after 18 h (entry 1). In accord with our initial hypotheses,
Sc(III)-pybox complexes provided both a significant increase in
the rate of the reaction and modest enantioselectivity (entries 2−
Scheme 1. Design Plan for Cooperative Lewis Acid−
Photoredox Catalysis of α-Amino Radical Additions
Received: December 15, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja512746q
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Journal of the American Chemical Society
Communication
successful reaction; N,N-dimethyl aniline produces only a trace
of the conjugate addition product (entry 15), consistent with our
design strategy. Second, we observed the formation of 52% yield
of 3b after 18 h even in the absence of Lewis acid (entry 16).
Thus, the rate acceleration afforded by the Lewis acid catalyst
must be large enough to overcome a significant racemic
background addition in the absence of Lewis acid catalyst.
Table 2 summarizes the effects of structurally varied α-
silylamines under the optimized conditions for enantioselective
Table 1. Optimization of the Asymmetric α-Amino Radical
Addition
a
Table 2. Reactions of Structurally Varied α-Silylamines with
a
Michael Acceptor 2b
[Ru]
yield
b
ee
c
entry acceptor
ligand
none
mol %
additive
none
(%)
(%)
de
,
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2%
2%
2%
2%
2%
2%
5%
15%
2%
2%
2%
2%
2%
2%
2%
2%
0%
2%
28
18
75
15
70
94
93
97
74
91
52
40
80
83
<5
52
0
−
d
d
d
d
tBuPybox (4a)
BnPybox (4b)
iBuPybox (4c)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
sBuPybox (4d)
iBuPybox (4c)
iBuPybox (4c)
none
none
49
27
42
43
50
59
66
59
67
43
46
89
93
−
none
none
none
none
none
none
KCl
10
11
12
13
14
15
16
17
18
Bu4N+Cl−
Bu4N+PF6
−
Bu4N+ClO4
Bu4N+Cl−
Bu4N+Cl−
Bu4N+Cl−
Bu4N+Cl−
Bu4N+Cl−
none
−
f
e
−
−
86
iBuPybox (4c)
iBuPybox (4c)
91
a
Unless otherwise noted, reactions were conducted at 0.05 M in 1 and
irradiated at a distance of 30 cm from a 23 W compact fluorescent light
b
bulb. Yields determined by 1H NMR using an internal standard.
c
d
Enantiomeric excess determined by chiral SFC analysis. Reaction
e
conducted at 0.25 M in 1. Reaction conducted without Lewis acid.
f
Reaction conducted with N,N-dimethyl amine in place of silyl amine
1.
5); the sBuPybox complex gave the optimal combination of yield
and ee in this screen. An examination of reaction concentration
showed that the rate and ee were improved somewhat at lower
concentrations (entry 6). We next made the surprising
observation that the concentration of Ru(bpy)3Cl2 had an effect
on ee (entries 6−8). It seemed unlikely that the photocatalyst
itself could be involved in the stereochemistry-determining
conjugate addition step. Speculating instead that the chloride
counteranion might be responsible for the observed effect on ee,
we found that the addition of either KCl or Bu4N+Cl− also
improved enantioselectivity, while addition of noncoordinating
anions did not (entries 9−12). Finally, inspired by the success of
Sibi’s chiral relay auxiliary in other enantioselective radical
addition processes, we discovered that the use of Michael
acceptor 2b provided substantially higher ee (entry 13). A
rescreening of chiral ligands at this point revealed that iBuPybox
provided the optimal chiral environment with this acceptor,
affording γ-aminocarbonyl adduct 3b in 93% ee (entry 14).
Control experiments verified the necessity of each reaction
component (entries 15−18). Two experiments are particularly
notable. First, the electrofugal silyl substituent is critical for
a
Unless otherwise noted, reactions were conducted using 1.5 equiv of
2, 2 mol % Ru(bpy)3Cl2, 15 mol % Sc(OTf)3, 20 mol % (S,S)-4c, and
30 mol % Bu4N+Cl− in degassed MeCN (0.05 M) and were irradiated
b
using a 23 W compact fluorescent light bulb. Values represent the
averaged isolated yields of two reproducible experiments. Enantio-
meric excess determined by chiral SFC analysis. Enantiomeric excess
of the corresponding alcohol. Reaction conducted using (R,R)-4c to
c
d
e
facilitate measurement of ee.
conjugate addition. A variety of electron-withdrawing para
substituents are easily accommodated on the N-aryl moiety
(entries 2−4). Modestly electron-donating substituents slow the
rate of the reaction without negatively impacting ee (entry 5).
Strongly electron-donating para substituents inhibit reactivity
altogether (entry 6), which is consistent with Mariano’s
B
DOI: 10.1021/ja512746q
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Journal of the American Chemical Society
Communication
observation that electron-releasing p-methoxy groups retard the
desilylation of α-silylmethyl anilines by an order of magnitude
compared to their unsubstituted analogues.16 A meta-methoxy
substituent, however, is well tolerated and provides the desired
product in good yield and with excellent enantioselectivity (entry
7). Gratifyingly, substitution in the ortho position is also
tolerated (entries 8 and 9). We found that successful Michael
reaction required the presence of one N-aryl substituent;
aliphatic amines undergo protodesilylation without adding to
the Michael acceptor (entry 10). However, both N,N-diaryl and
mixed N-alkyl-N-aryl α-silylamines participate in this reaction
(entries 11 and 12) although sterically bulky α-amino radicals
react sluggishly. Unfortunately, substrates bearing N-acyl groups
were recovered unchanged, consistent with the greater difficulty
with which they are oxidized (entry 14).
none auxiliary (Scheme 2). Standard conditions for hydrolysis
and reduction of imides proved to be unselective, producing
Scheme 2. Auxiliary Removal
The generality of the reaction with respect to the Michael
acceptor is outlined in Table 3. A variety of aliphatic acceptors
Table 3. Reactions of Structurally Varied Michael Acceptors
a
with α-Silylamine 1
mixtures of acyl cleavage products. However, the auxiliary can be
cleanly cleaved upon reaction with ethanethiolate, providing
thioester 5 in quantitative yield with no erosion of
enantioselectivity (eq 1). Importantly, the auxiliary (6) can be
recovered in 95% yield after this cleavage step. Auxiliary cleavage
can also be induced in an intramolecular fashion by a sufficiently
nucleophilic moiety in the product.17 For example, when
secondary aniline 7 is subjected to the optimized conditions,
the conjugate addition product undergoes spontaneous intra-
molecular transacylation in situ to afford pyrrolidinone 8 in very
high yield and excellent ee (eq 2).18
An intriguing unexpected result for our investigations was the
observation that added chloride salts were required for optimal
ee.19 We quickly ruled out the possibility of an electrolyte effect,
as addition of other ammonium salts bearing noncoordinating
ions had no impact on ee (Table 1, entries 11 and 12). We then
examined the influence of chloride on the background and the
Lewis-acid-free reaction between 1 and 2b, and observed no
measurable change in the rate of product formation upon the
addition of 30 mol % Bu4N+Cl− to a reaction conducted in the
absence of Lewis acid. Thus, we conclude that chloride does not
have a significant impact on the photooxidation or desilylation
steps leading to formation of the key α-amino radical
intermediate. Instead, chloride must be interacting intimately
with the Lewis acid. One would expect a scandium(III) chloride
complex to be a weaker Lewis acid than its triflate analogue;
indeed, a (pybox)ScCl3 complex proved to give rates inferior to
those of the optimized triflate catalyst. However, analysis of
(pybox)Sc(OTf)3-catalyzed reactions at incomplete conversions
revealed that the addition of exogenous Bu4N+Cl− significantly
increased the rate of formation of adduct 3b under catalytic
conditions.
A reasonable interpretation consistent with these results is that
chloride is involved in accelerating the turnover of the Lewis acid
catalyst.20 Thus, we do not believe that chloride alters the
intrinsic stereoselectivity of the (pybox)Sc(OTf)3-catalyzed
conjugate addition. Rather, the addition of chloride aids the
enantioselective Lewis acid-mediated pathway to out-compete a
slower but still significant rate of racemic background radical
addition. This conclusion highlights an important conceptual
distinction between this method and the asymmetric [2 + 2]
a
Unless otherwise noted, reactions were conducted using 1.5 equiv of
Michael acceptor, 2 mol % Ru(bpy)3Cl2, 15 mol % Sc(OTf)3, 20 mol
% (S,S)-4c, and 30 mol % Bu4N+Cl− in degassed MeCN (0.05 M) and
b
were irradiated using a 23 W compact fluorescent light bulb. Values
represent the averaged isolated yields of two reproducible experiments.
c
Enantiomeric excess determined by chiral SFC analysis.
react smoothly and deliver the expected conjugate addition
products with high ee (entries 1−4). Aromatic acceptors are also
excellent partners for this transformation, and both electron-
poor and electron-rich substrates undergo facile Michael
addition (entries 5−7). Substitution at the ortho position is
well tolerated, with only marginally diminished enantioselectivity
(entry 8). A heterocyclic group was also compatible with the
reaction conditions (entry 9).
To expand the synthetic value of this method, we also
investigated conditions for efficient removal of the pyrazolidi-
C
DOI: 10.1021/ja512746q
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Journal of the American Chemical Society
Communication
cycloaddition recently reported by our laboratory:6 in this new
reaction, the Lewis acid is not directly involved in the
photoinduced electron transfer step. Rather, the chiral Lewis
acids control the rate and selectivity of a step independent of the
photoredox process itself. Thus, this study provides compelling
evidence that the combination of photoredox and chiral Lewis
acid catalysis might be broadly applicable to the design of
enantioselective reactions involving the increasingly wide range
of reactive intermediates known to be readily generated via
photoredox catalysis.
In summary, we have developed the first highly enantiose-
lective intermolecular reaction of α-amino radicals. This process
showcases the ability of chiral Lewis acid catalysts to control the
reactivity of these photogenerated nucleophilic intermediates,
and we expect that the combination of photoredox and chiral
Lewis acid catalysis will provide an approach to control the
stereochemistry of a wide variety of photoinitiated organic
reactions. Studies to expand this concept to other synthetically
useful transformations are currently underway in our laboratory.
(10) (a) Pandey, G.; Kumaraswamy, G.; Bhalerao, U. T. Tetrahedron
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Tetrahedron 1994, 50, 8185.
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(14) For recent reviews of enantioselective conjugate additions using
chiral Lewis acids, see: (a) Evans, D. A.; Rovis, T.; Johnson, J. S. Pure
Appl. Chem. 1999, 71, 1407. (b) Sibi, M. P.; Manyem, S. Tetrahedron
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̈
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data for all new com-
pounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(15) (a) Sibi, M. P.; Ji, J. J. Am. Chem. Soc. 1996, 118, 9200. (b) Sibi, M.
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AUTHOR INFORMATION
Corresponding Author
*tyoon@chem.wisc.edu
■
(16) Mariano, P.S., Ed. Advances in Electron Transfer Chemistry; Jai
Press: Greenwich, CT, 1994.
Notes
(17) Sibi has previously described the cleavage of a pyrazolidinone
auxiliary using an intramolecular transacylation process: Sibi, M. P.; Liu,
M. Org. Lett. 2001, 3, 4181.
The authors declare no competing financial interest.
(18) During the preparation of this manuscript, Nishibayashi reported
the photocatalytic synthesis of racemic pyrrolidinones by a conceptually
similar desilylative conjugate addition−cyclization process: Nakajima,
K.; Kitagawa, M.; Ashida, Y.; Miyake, Y.; Nishibayashi, Y. Chem.
Commun. 2014, 50, 8900.
(19) For an excellent review of dramatic halide effects in catalytic
reactions, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41,
26.
ACKNOWLEDGMENTS
■
We thank Brian Dolinar and Dr. Ilia Guzei of UW−Madison
Molecular Structure Laboratory for performing X-ray crystallog-
raphy. Funding for this research was provided by the NIH
(GM095666) and the Sloan Foundation.
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DOI: 10.1021/ja512746q
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