Enantioselective Synthesis of γ-Oxycarbonyl Motifs by Conjugate Addition of Photogenerated α-Alkoxy Radicals

Article abstract of DOI:10.1021/acs.orglett.1c01790

Enantioselective catalytic Giese addition of photogenerated α-alkoxy radicals to acyl pyrazolidinones can be accomplished using a tandem Sc(III) Lewis acid/photoredox catalyst system. Surprisingly, the excited-state oxidation potential was not the only important variable, and the optimal photocatalyst was not the strongest oxidant screened. Our results show that both the oxidation and reduction potentials of the photocatalyst can be important for the reaction outcome, highlighting the importance of holistic considerations in designing photochemical reactions.

Full text of DOI:10.1021/acs.orglett.1c01790

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Letter
Enantioselective Synthesis of γ‑Oxycarbonyl Motifs by Conjugate
Addition of Photogenerated α‑Alkoxy Radicals
Xiao Dong, Qi Yukki Li, and Tehshik P. Yoon*
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ABSTRACT: Enantioselective catalytic Giese addition of photo-
generated α-alkoxy radicals to acyl pyrazolidinones can be
accomplished using a tandem Sc(III) Lewis acid/photoredox
catalyst system. Surprisingly, the excited-state oxidation potential
was not the only important variable, and the optimal photocatalyst
was not the strongest oxidant screened. Our results show that both
the oxidation and reduction potentials of the photocatalyst can be
important for the reaction outcome, highlighting the importance of
holistic considerations in designing photochemical reactions.
etrosynthetic disconnections are often defined by the
relative disposition of oxygen-containing functional
example using a photogenerated α-alkoxy radical was
described, but the generality of this process was not studied.
We hypothesized that a Lewis acid cocatalyst might expand the
scope of this reaction to include less electrophilic acceptors
and provide an opportunity for stereocontrol in the Giese
addition of oxyfunctionalized organoradical intermediates.
Subjecting α-silyl ether 1a and pyrazolidinone 2a to
conditions optimized for radical conjugate addition of α-silyl
amines gave only returned reactants (Table 1, entry 2),
indicating that the excited-state photocatalyst [Ru*(bpy)3]2+ is
unable to oxidize 1a to produce the requisite radical
intermediate. We hypothesized that a more oxidizing photo-
catalyst might be able to initiate the reaction and conducted a
screen of several candidates commonly utilized in oxidative
photoredox catalysis. Surprisingly, there was no correlation
between the excited-state oxidation potential of the photo-
catalyst and the yield of 3a (Table 1, entries 3−5); the most
oxidizing transition-metal and organic photocatalysts in our
screen afforded poor conversions after 12 h. The Fukuzumi
acridinium salt, a common oxidizing photocatalyst,12 produced
somewhat better results (entry 4). The highest yield, however,
was obtained using [Ir(dFCF3ppy)2(dtbbpy)]PF6 (Ir), which
possesses a comparatively modest excited-state oxidation
potential.13 Lowering the reaction temperature improved the
mass balance and enantioselectivity of the reaction (entry 6).
Control experiments (entries 7−9) showed that no product is
formed in the absence of light, photocatalyst, or Lewis acid.
R
groups.1 The 1,3-dioxygenation pattern is perhaps the most
iconic of these retrons, suggestive of aldol or Claisen
disconnections, and the development of stereocontrolled
aldol reactions has figured prominently in the history of
asymmetric synthesis.2 Similarly, 1,5- and 1,2-dioxygenation
patterns, suggestive of Michael addition or Rubottom
oxidation retrons, respectively, have also been targeted by
enantioselective catalytic methods (Figure 1A).3 The enantio-
controlled catalytic synthesis of 1,4-dioxygenation patterns,
however, has remained a conspicuous challenge with few
highly effective solutions,4 despite their presence in many
medicinal lead compounds.5
Our laboratory has a long-standing interest in stereo-
controlled reactions of photogenerated radicals. We demon-
strated that Giese addition of α-silyl amines to Michael
acceptors, a classical photoreaction studied in detail by
Mariano,6 could be made highly enantioselective using a dual
catalyst protocol.7 This method utilizes a Ru(II) photoredox
catalyst that initiates the oxidative desilylation of an α-silyl
amine pronucleophile and a chiral Lewis acid cocatalyst that
activates the Michael acceptor and dictates the facial selectivity
of the radical addition (Figure 1B). We reasoned that the use
of α-silyl ether pronucleophiles might offer an analogous
strategy for the generation of chiral γ-alkoxycarbonyl adducts.
While this modification is conceptually straightforward, it
presents a significant tactical challenge because oxygen
functionalities are substantially harder to oxidize than their
nitrogen counterparts (Figure 1B).8 The use of α-silyl ethers in
racemic conjugate additions has previously been reported by
Steckhan9 and Woo,10 but these reactions have been limited to
highly electron-deficient Michael acceptors. Recently, Mel-
chiorre described enantioselective Giese additions to enals
using organophotoredox/chiral amine dual catalysis.11 A single
Received: June 2, 2021
Published: July 23, 2021
https://doi.org/10.1021/acs.orglett.1c01790
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5703−5708
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a
Table 1. Variations of the Reaction Conditions
deviation from the standard
conditions
Eo*x
entry
(V vs SCE)
yield
e.e.
1
2
3
4
5
6
7
8
none
+1.21
+0.77
+1.45
+2.06
+2.30
+1.21
+1.21
−
82%
0%
0%
45%
16%
71%
0%
95%
−
−
83%
85%
87%
−
[Ru(bpy)3]Cl2 instead of Ir, rt
[Ru(bpz)3]Cl2 instead of Ir, rt
MesAcrMe+ instead of Ir, rt
TPPT instead of Ir, rt
rt instead of −25 °C
no light
no photocatalyst
0%
−
9
10
11
no Sc(OTf)3
no Bu4NCl
ScCl3 instead of Sc(OTf)3
+1.21
+1.21
+1.21
0%
72%
0%
−
90%
−
Figure 1. (A) Retrosynthetic disconnections defined by dioxygena-
tion patterns. (B) Stereocontrolled access to 1,4-dioxygenation
patterns via asymmetric photoredox conjugate addition.
a
Reaction conditions: 1a (0.15 mmol, 1 equiv), 2a (0.225 mmol, 1.5
equiv), photocatalyst (3 × 10−3 mmol, 2 mol %), Sc(OTf)3 and
Bu4NCl (0.0225 mmol, 15 mol %), (S,S)-sBuPybox (0.03 mmol, 20
mol %), MeCN (3.0 mL, 0.05 M), 34 W blue LEDs. Yields were
determined by 1H NMR analysis of the crude reaction mixtures using
mesitylene as an internal standard.
The addition of a soluble chloride salt (Bu4NCl) increased the
yield and enantiometric excess (e.e.) of the conjugate addition,
but the effect was less pronounced than in the α-silyl amine
reaction (entry 10).7 Finally, no product was formed when
insoluble ScCl3 was used in place of Sc(OTf)3 (entry 11).
Figure 2 summarizes studies exploring the scope of the
enantioselective photocatalytic Giese addition. With respect to
the α-silyl ether pronucleophiles, functional groups such as
halogens and boronic acids are well-tolerated under the
reaction conditions, providing handles for further synthetic
manipulation. Steric hindrance led to a lower yield (3ia), while
both mildly electron-donating groups and electron-with-
drawing groups provided good yields and excellent e.e. values.
However, highly electron-rich and electron-deficient pronucle-
philes did not yield the desired conjugate addition products. In
the case of highly electron-rich substrates, we observed
decomposition, while for highly electron-deficient substrates,
we recovered the starting pronucleophiles in good yield.
With respect to the Michael acceptor, we noticed a
sensitivity toward the nature of the β-substituent, while α-
substituents shut down the reactivity. Increasing steric bulk
leads to diminished yields. On the other hand, we were pleased
to see that synthetic handles such as chlorine and a terminal
alkene remained intact during the reaction. Polar functional
groups, including Boc-protected amine, ether, and amino acid
derivatives, are also tolerated. Lewis basic functionalities such
as esters result in decreased e.e. values. Unexpectedly, aromatic
substituents, which were well-tolerated in our previously
reported α-amino radical addition, did not lead to the desired
products. Rather, we observed no further reaction after enone
E/Z isomerization, suggesting that access to the triplet enone is
feasible under the reaction conditions. Nevertheless, the
current system enabled functionalization of moderately
electrophilic Michael acceptors, overcoming a major limitation
in the previous reports by Steckhan9 and Woo.10 The absolute
configuration of 3a was confirmed by X-ray crystallographic
analysis of the corresponding carboxylate salt (see the
Supporting Information).
The most intriguing feature of our optimization studies was
that the yield of the reaction did not correlate with the excited-
state oxidation potential of the photocatalyst. Moreover, the
excited-state oxidation potential of the optimal Ir photocatalyst
(+1.21 V) seems insufficient to directly oxidize the α-silyl ether
nucleophile (+1.45 V), suggesting that the initiation
mechanism of this process is different from that of the α-silyl
amine reaction we reported previously.7 We thus elected to
study the mechanism of this process in greater detail.
We first conducted a Stern−Volmer study to interrogate the
abilities of the two reactants to quench the excited state of the
photocatalyst, either alone or in the presence of added Lewis
acid (Figure S1).13 The photoluminescence of the photo-
catalyst does not change significantly with varying concen-
trations of the α-silyl ether either with or without added
Sc(OTf)3. These results indicate that one-electron photo-
oxidation of the α-silyl ether does not initiate this photo-
reaction. In contrast, we observed a concentration-dependent
increase in photoluminescence quenching in the presence of
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Figure 2. Reaction scope studies. Standard conditions: 1 (0.50 mmol, 1 equiv), 2 (0.75 mmol, 1.5 equiv), Ir (0.01 mmol, 2 mol %), Sc(OTf)3 and
a
Bu4NCl (0.075 mmol, 15 mol %), (S,S)-sBuPybox (0.10 mmol, 20 mol %), MeCN (10.0 mL, 0.05 M), 34 W blue LEDs, 24 h. 18 h.
Figure 3. Possible (A) energy-transfer and (B) photoredox mechanisms for asymmetric photocatalysis.
Michael acceptor 2a, and the degree of quenching is
significantly greater in the presence of added Sc(OTf)3 (Figure
S1). Thus, the principal photocatalytic quenching process in
this reaction is between the excited-state photocatalyst and the
Sc-bound complex of Michael acceptor 2a.
considered both possibilities (Figure 3). First, we recently
discovered that Lewis acid cocatalysts can accelerate energy
transfer from excited-state Ru(II) and Ir(III) photocatalysts to
enone acceptors, producing Lewis acid-bound triplet-state
enones that undergo enantioselective [2 + 2] cycloadditions.14
Mariano15 and Melchiorre16 reported desilylative conjugate
additions initiated by excited-state Michael acceptors. We
Because Stern−Volmer analysis does not distinguish
between energy- and electron-transfer mechanisms, we
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a
Table 2. Reaction Outcomes with Photocatalysts Having Similar Triplet Energies
entry
photocatalyst
ET (kcal/mol)
E
1/2(M*/M+) (V vs SCE)
E
1/2(M+/M) (V vs SCE)
yield (e.e.)
1
2
3
4
5
[Ir(dFCF3ppy)2(dtbbpy)]PF6
Ir(4-F,4′-tBuppy)3
Ir(ppy)3
[Ir(dFppy)2(bpy)]PF6
[Ru(bpz)3](PF6)2
60.1
59.4
55.2
54.7
48.4
−0.89
−1.27
−1.97
−0.80
−0.26
+1.69
+0.98
+0.78
+1.49
+1.86
82% (95%)
0%
4%
68% (80%)
0%
a
Reaction conditions: 1a (0.15 mmol, 1 equiv), 2a (0.225 mmol, 1.5 equiv), photocatalyst (3 × 10−3 mmol, 2 mol %), Sc(OTf)3 and Bu4NCl
(0.0225 mmol, 15 mol %), (S,S)-sBuPybox (0.03 mmol, 20 mol %), MeCN (3.0 mL, 0.05 M), 34 W blue LEDs. Yields were determined by H
1
NMR analysis of the crude reaction mixtures using mesitylene as an internal standard.
wondered whether this reaction might proceed via initial Lewis
acid-catalyzed energy transfer (Figure 3A). The key activation
step would be the formation of the Lewis acid-bound triplet-
state 2a, which might oxidize α-silyl ether 1a to the requisite α-
alkoxy radical. However, we quickly determined that this
electron-transfer step would be endergonic. The excited-state
redox potential of a compound can be estimated using the
ground-state reduction potential and the energy of the triplet
excited state. Cyclic voltammetry experiments using 2a gave
irreversible reduction features with estimated Ep values of −1.1
and −1.2 V vs SCE in the absence and presence of Sc(OTf)3,
respectively (see the Supporting Information). Unfortunately,
we were not able to ascertain the triplet-excited-state energies
of 2a either experimentally or computationally. Because
efficient energy transfer depends on the thermodynamics in
the exchange event, however, the maximum value for the
triplet energies cannot be substantially higher than the triplet
energy of the Ir sensitizer (2.6 eV).12 Given this limiting
condition, the maximum excited-state reduction potential
available from the Sc-bound complex of 2a cannot be
significantly more positive than +1.4 V. One-electron oxidation
of the α-silyl ether pronucleophile by excited-state 2a is thus
thermodynamically unfavorable by at least 370 mV and
potentially more.
We therefore conclude that product formation in this
reaction is initiated by electron-transfer quenching of the
photocatalyst excited state. A plausible mechanism consistent
with the available data is depicted in Figure 3B. The excited-
state photocatalyst is oxidatively quenched by the Lewis acid-
bound Michael acceptor 2a. While it does not seem reasonable
to expect the radical anion of 2a to be capable of oxidizing α-
silyl ether 1a, the photoinduced electron-transfer event also
generates a ground-state Ir(IV) species with a reported redox
potential of +1.7 V vs SCE,12 from which the oxidative
desilylation of 1a should be thermodyanamically feasible. The
addition of the resulting α-alkoxy radical to Michael acceptor
2a would be accelerated by the chiral Lewis acid, which also
determines the facial selectivity. This proposal is consistent
with experiments examining the effect of the photocatalyst
identity on the outcome of the desilylative conjugate addition
(Table 2). Significant product formation was observed using
only the optimal [Ir(dFCF3ppy)2(dtbbpy)]PF6 photocatalyst
and [Ir(dFppy)2(bpy)]PF6, a photocatalyst with similar
excited-state reduction and ground-state oxidation abilities17
(entries 1 and 4). Both of these electrochemical characteristics
appear to be critical. Ir(ppy)3 features an excited state that can
easily reduce 2a but an Ir(IV) ground-state oxidation potential
insufficient to oxidize 1a, and it gives negligible product (entry
3). [Ru(bpz)3](PF6)2 has an oxidized Ru(III) ground state
capable of oxidizing 1a but an excited state that is unable to
reduce 2a,18 and it is similarly ineffective in this reaction.
Finally, we observe no correlation between the triplet-excited-
state energy of the photocatalyst and the yield of the conjugate
addition product. For example, Ir(4-F,4′-tBuppy)3 features an
excited-state energy1 7 similar to that of [Ir-
(dFCF3ppy)2(dtbbpy)]PF6 but results in the formation of no
conjugate addition product (entry 2), consistent with the
conclusion that triplet sensitization of Michael acceptor 2a is
not part of the product-forming reaction pathway.
In summary, we have developed a highly enantioselective
method for the synthesis of γ-aryloxycarbonyl structures for
which there are limited existing retrosynthetic disconnects.
This transformation is accomplished using a dual chiral Lewis
acid/photoredox catalyst system. An analysis of the energetics
of the possible electron-transfer steps suggests a mechanism in
which oxidative quenching results in an Ir(IV) complex,
initiating an enantioselective radical chain process. An
important feature of this study is the observation that the
most effective catalyst is not the species with the most strongly
oxidizing excited state but rather one with balanced electro-
chemical properties. In view of the range of activation
mechanisms available using photoredox catalysis and the
widely differing photophysical properties of excited-state
compounds in different classes, it seems reasonable to
conclude that no single thermodynamic parameter is likely to
be sufficient to predict the optimal photocatalyst for a given
application. A complete understanding of photoredox mech-
anisms requires a holistic appreciation of many potentially
relevant thermodynamic parameters.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01790.
Detailed experimental procedures, full spectroscopic
data for all new compounds, electrochemical data, and
X-ray crystallographic data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−m, 2d−j, 3aa−aj, 3ba−ma, 4ea, and
5ea (ZIP)
5706
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Accession Codes
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data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
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Tehshik P. Yoon − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3934-4973;
Email: tyoon@chem.wisc.edu
Authors
Xiao Dong − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3700-3606
Qi Yukki Li − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0001-7823-5078
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01790
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Ilia A. Guzei for X-ray structure determination and
Shane D. Lies for measuring the cyclic voltammogram for N-
methyl-N-((trimethylsilyl)methyl)aniline. Funding for this
project was provided by the NIH (GM095666). NMR and
MS facilities at UWMadison are funded by the NIH (1S10
OD020022-1) and a generous gift from the Paul J. and
Margaret M. Bender Fund. X-ray instrumentation was made
possible by funds from the NSF (CHE-1919350) and the
UWMadison Department of Chemistry.
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