Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic meso-Anhydrides

Article abstract of DOI:10.1002/anie.201700097

The enantioselective desymmetrization of cyclic meso-anhydrides with benzyl trifluoroborates under nickel-photoredox catalysis is described. The reaction tolerates a variety of sterically and electronically different trifluoroborates, as well as structurally unique cyclic anhydrides. The trans isomer of the keto-acid products is also observed at varying levels dependent on the trifluoroborate identity and relative catalyst loading. A mechanism involving decarbonylation and Ni?C bond homolysis of a Ni^II adduct is proposed. This feature allows access to a trans keto-acid as the major product in high enantioselectivity from a cis meso anhydride.

Full text of DOI:10.1002/anie.201700097

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201700097
German Edition: DOI: 10.1002/ange.201700097
Asymmetric Synthesis
Hot Paper
Dual Nickel- and Photoredox-Catalyzed Enantioselective
Desymmetrization of Cyclic meso-Anhydrides
Erin E. Stache, Tomislav Rovis,* and Abigail G. Doyle*
Abstract: The enantioselective desymmetrization of cyclic
meso-anhydrides with benzyl trifluoroborates under nickel-
photoredox catalysis is described. The reaction tolerates
a variety of sterically and electronically different trifluorobo-
rates, as well as structurally unique cyclic anhydrides. The trans
isomer of the keto-acid products is also observed at varying
levels dependent on the trifluoroborate identity and relative
achieve a highly enantioselective methodology using Ni
catalysts were unsuccessful.
Knochel first introduced electron-deficient olefins as
ligands in alkyl cross-coupling reactions, and proposed that
they accelerate reductive elimination by withdrawing electron
density from the metal center.[5,6] Previous studies from the
Rovis group had identified a qualitative acceleration effect of
electron-deficient olefin additives (Figure 1).[3b] We hypothe-
catalyst loading. A mechanism involving decarbonylation and
II
À
Ni C bond homolysis of a Ni adduct is proposed. This feature
allows access to a trans keto-acid as the major product in high
enantioselectivity from a cis meso anhydride.
A
pplication of photoredox catalysis to transition metal-
catalyzed cross-coupling has rapidly gained prominence as
a strategy that enables a broad range of novel bond-forming
reactions.[1] In this approach, a photoredox catalyst is used to
modulate the oxidation state of the transition metal catalyst
by single-electron transfer and/or generate a radical coupling
partner that engages the transition metal in fragment
coupling. By re-directing the elementary steps of cross-
coupling away from traditional two-electron processes, this
reaction manifold can overcome difficult oxidative additions,
transmetalations, and reductive eliminations.[2] Recently, our
two labs questioned whether the combination of photoredox
and transition metal catalysis could also offer solutions to
challenges in stereoselective cross-coupling.
Beginning in 2002, the Rovis group developed a collection
of transition metal-catalyzed cross-coupling methods for the
ring opening of cyclic carboxylic anhydrides.[3] A primary
attribute of this methodology is the capacity to convert simple
synthetic building blocks to complex keto-acids possessing
a stereodefined backbone through desymmetrization of meso
precursors. Nickel catalysts were found to impart broad scope
and good reactivity. Mechanistic studies with a Ni bipyridine
catalyst system were most consistent with rate-limiting
reductive elimination from a nickel(II) species.[4] Efforts to
Figure 1. a) Use of electron-deficient olefins as ligands in nickel
catalysis. b) Alternative nickel(III) reaction manifold. c) Nickel-photo-
redox for the desymmetrization of meso anhydrides.
sized that single-electron oxidation of a NiII to a NiIII species
could mimic, and perhaps accentuate, the effect of the
electron-deficient olefin on the rate and selectivity of this
À
C C bond-forming reaction. Such a nickel and photoredox-
catalyzed desymmetrization of meso anhydrides would pro-
vide an attractive complement to the precious-metal alter-
natives utilizing Pd and Rh catalysis that the Rovis group
ultimately developed in its stead.[7] Nickel catalysts are
inexpensive and abundant, and most chiral ligand frameworks
for Ni feature similar attributes, as they are diamine or
diimine derivatives of amino acids. Furthermore, the original
chemistry with Ni, Pd, and Rh catalysis was limited to
relatively harsh organometallic nucleophiles, such as aryl and
alkyl zinc reagents. In a dual catalysis manifold, a broad range
of air-stable, easily accessible, and functional group tolerant
coupling partners have been shown to deliver fragments to
Ni.[8]
[*] E. E. Stache, Prof. A. G. Doyle
Department of Chemistry, Princeton University
120 Washington Road, Princeton, NJ 08544 (USA)
E-mail: adoyle@princeton.edu
E. E. Stache, Prof. T. Rovis
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
E-mail: tr2504@columbia.edu
Prof. T. Rovis
Department of Chemistry, Columbia University
New York, NY 10027 (USA)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201700097.
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We report here an enantioselective Ni and photoredox-
catalyzed desymmetrization of meso-succinic anhydrides with
C(sp3)-organotrifluoroborates. Notably, enantioselective met-
allophotoredox reactions have remained largely elusive.[9] To
date, only a single example of a highly enantioselective
method has been reported.[2a,10] The MacMillan and Fu
groups described a synthesis of enantioenriched benzylic
amines by stereoconvergent decarboxylative coupling of
amino acids with aryl iodides. In their reaction, the radical
intermediate is the prochiral component. The reaction
reported herein demonstrates that a chiral Ni catalyst is also
capable of inducing asymmetry on the electrophilic coupling
partner.
benefits from air/moisture stability and low cost compared to
Ni(cod)2 provides product in good yield albeit low asymmet-
ric induction (entry 6).[13] An attractive feature of this method
is that the optimal photocatalyst is an inexpensive organic
photocatalyst, recently introduced by the Zhang group for Ni/
photoredox cross-coupling.[11] Under the optimized condi-
tions, use of [Ir(dFCF3ppy)2dtbppy]PF6 instead of 4CzIPN
affords 2 in modest yield and slightly reduced selectivity
(entry 7). Excellent enantioselectivity can be obtained with
the Ir photocatalyst using THF as solvent, although the yield
of the transformation remains low (entry 8). In the absence of
nickel, light or photocatalyst, no product is observed
(entries 9–11).
We chose to examine benzyl trifluoroborates as a radical
source due to their ready availability and precedent for
coupling in the Ni/photoredox manifold, as introduced by the
Molander group.[2a] After an exploration of conditions using
carboxylic anhydride 1 as a model substrate, we found that
Ni(cod)2, (S,S)-PhBox (L1), and the organophotocatalyst
4CzIPN[11] gave the product in 85% yield and 90% ee after
24 h at room temperature under irradiation with 34 W blue
LEDs (Table 1, entry 1). In the absence of ligand, a modest
amount of racemic product is formed, suggesting a possible
route for erosion of enantioselectivity (see below)
(entry 2).[12] In screening other ligands, we observed inter-
mediate levels of selectivity when using either (S,S)-t-BuBox
(L2) or (R,R)-BnBox (L3), whereas distinct ligand frame-
works, such as (S)-t-BuPyrOx L4, delivered inferior results
(entries 3–5). Employment of a nickel(II) pre-catalyst that
With optimized conditions in hand, we explored the scope
and limitations of the method. As can be seen in Table 2, the
desymmetrization of anhydride 1 proceeds smoothly on larger
Table 2: Anhydride scope.[a,b]
Table 1: Reaction optimization.
[a] Yields and selectivities are an average of two runs, 0.25 mmol scale.
[b] ee and d.r. determined by HPLC using a chiral stationary phase. [c] L3
used (6 mol%). [d] d.r. determined by 1H NMR. [e] Reaction time 48 h.
scale to yield keto-acid 2 in 77% yield, 91% ee and > 20:1 d.r.
favoring the cis isomer (see below).[14,15] Notably, cyclopentyl,
cyclobutyl and cyclopropyl succinic anhydrides are all suitable
electrophiles. However, anhydrides bearing b-substitution
undergo coupling in more modest yield and enantioselectivity
(7). Although these conditions were optimized for bicyclic
anhydrides, they can be applied successfully to monocyclic
succinic anhydrides; acyclic keto-acid 8 was isolated in 70%
yield and 88% ee. Interestingly, benzylation of tetrahydro-
phthalic anhydride occurs in good yield but with reduced
enantioselectivity compared with the parent cyclohexane
carboxylic anhydride (9). We attribute this loss of selectivity
to the ability of the backbone alkene to coordinate to the
nickel center. Indeed, in the formation of product 10, the
Entry
Deviation from standard conditions
Yield[a] [%]
ee[b] [%]
1
2
3
4
5
6
7
8
none
no ligand
L2 (6 mol%)
L3 (6 mol%)
85
7
90
nd
45
25
71
65
64
43
45
0
À43
L4 (6 mol%)
40
NiCl2·glyme (5 mol%)
[Ir(dFCF3ppy)2dtbbpy]PF6 3 (2 mol%)
3 (2 mol%), THF (0.05 m)
no nickel
no light
no photocatalyst
32
78
94
nd
nd
nd
9
10
11
0
0
[a] Yield determined by 1H NMR on 0.1 mmol scale using benzoic acid as
a standard. [b] ee determined by HPLC using a chiral stationary phase.
2
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selectivity was nearly restored, presumably because the more
Formation of the trans keto-acid products in Tables 2 and
substituted alkene discourages coordination to nickel.[3b]
A wide array of trifluoroborates are also well tolerated in
the reaction. Electron-deficient and electron-neutral
trifluoroborates react smoothly with anhydride 1 in good
yield and high enantio- and diastereoselectivity (11–13)
3 is also noteworthy from a mechanistic perspective.[19]
Control experiments show that the product is configuration-
ally stable under the reaction conditions.[20] Further, the
nearly identical enantioselectivity of the cis and trans
products suggests that no significant epimerization is occur-
ring on the anhydride substrate, rather that epimerization
occurs on the catalytic cycle after the ee-determining step.[21]
A mechanism wherein the NiII adduct, generated upon ee-
determining oxidative addition of Ni0 to the anhydride, can
Table 3: Trifluoroborate scope.[a,b,c]
À
undergo decarbonylation followed by Ni C bond homolysis
could account for this observation (Figure 2).[22,23] Recombi-
[a] Yields and selectivities are an average of two runs, 0.25 mmol scale.
[b] ee determined by HPLC on a chiral stationary phase. [c] d.r.
1
determined by H NMR. [d] d.r. determined by HPLC on a chiral
stationary phase. [e] Et2O/THF (10:1) used instead of dioxane.
(Table 3). Gratifyingly, cross-coupling proceeds chemoselec-
tively with a para-chloro-substituted benzyl trifluoroborate,
leaving behind a functional group for further derivatization.
Trifluoroborates with meta or ortho substituents also react in
high yield and enantioselectivity; however, ortho-substituted
nucleophiles deliver keto-acids 19 and 20 with significantly
eroded diastereoselectivity (see below). Benzyl trifluorobo-
rates possessing electron-donating substituents are suitable
reaction partners, affording 21 and 22 in good yield and
diastereoselectivity and good to excellent enantioselectivity.
The attenuated enantioselectivity obtained in the case of 21 is
likely due to a more prolific racemic background reaction
with the nucleophilic trifluoroborate;[16] indeed, for 22,
switching from dioxane to the less polar solvent diethyl
ether suppressed the racemic background reaction and raised
the enantioselectivity from 48 to 94% ee.[17]
Based on a computational investigation, Molander and
Kozlowski have put forward a Ni0/I/III mechanism for related
Ni/photoredox cross couplings wherein the C-centered rad-
ical generated from an organotrifluoroborate reacts with Ni0
prior to oxidative addition of aryl halide, and reductive
elimination serves as the stereodetermining step.[9] In our
system, UV studies support oxidative addition of Ni0 to
anhydride 1.[18] As such, a mechanism proceeding first via ee-
determining Ni0 oxidative addition to the anhydride, followed
by interception of the benzylic radical on a NiII species is more
likely.
Figure 2. a) Proposed mechanism and plausible pathway for epimeri-
zation observations. b) Alternative mechanism inconsistent with obser-
vations.
nation and carbonyl insertion from the planar radical
intermediate would regenerate both the cis and trans
diastereomers without erosion in enantioselectivity. Decar-
bonylation, and thus epimerization, should be slow from
a NiIII intermediate due to coordinative saturation, lending
additional support for the involvement of a Ni0/II/III pathway.
Further study into the mechanism of epimerization
showcased a significant correlation between nickel loading
and the degree of epimerization (Table 4). At 2.5 mol% Ni
loading, the cis-2 product was formed exclusively. Simply
increasing the Ni loading to 15 mol% led to the formation of
the trans-2 isomer in nearly 1:1 d.r. with 88% ee. We propose
that at high relative concentrations of the radical (low Ni
loading relative to photocatalyst) high diastereoselectivity is
observed due to efficient trapping of the NiII adduct in the
Ni0/II/III cycle prior to epimerization. The relationship of
diastereoselectivity to the identity of the trifluoroborate, with
more nucleophilic radicals providing high levels of diastereo-
selectivity is further support for this hypothesis (Table 3).
According to this proposal, manipulation of the photocatalyst
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Res. 2016, 49, 2261 – 2272; d) M. H. Shaw, J. Twilton, D. W. C.
MacMillan, J. Org. Chem. 2016, 81, 6898 – 6926.
Table 4: Epimerization investigation.
[2] a) J. C. Tellis, D. N. Primer, G. A. Molander, Science 2014, 345,
433 – 436; b) Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G.
Doyle, D. W. C. MacMillan, Science 2014, 345, 437 – 440; c) J. A.
Terrett, J. D. Cuthbertson, V. W. Shurtleff, D. W. C. MacMillan,
Nature 2015, 524, 330 – 334; d) E. B. Corcoran, M. T. Pirnot, S.
Lin, S. D. Dreher, D. A. DiRocco, I. W. Davies, S. L. Buchwald,
D. W. C. MacMillan, Science 2016, 353, 279 – 283.
Entry
Nickel
(mol%)
4CzIPN
(mol%)
Yield[a]
[%]
d.r.[b]
ee cis[c]
[%]
ee trans[d]
[%]
[3] a) E. A. Bercot, T. Rovis, J. Am. Chem. Soc. 2002, 124, 174 – 175;
b) E. A. Bercot, T. Rovis, J. Am. Chem. Soc. 2005, 127, 247 – 254.
[4] J. B. Johnson, E. A. Bercot, J. M. Rowley, G. W. Coates, T. Rovis,
J. Am. Chem. Soc. 2007, 129, 2718 – 2725.
[5] A possible coordination number and geometry change at the
metal cannot be discounted; see: a) R. Giovannini, T. Stꢀde-
mann, G. Dussin, P. Knochel, Angew. Chem. Int. Ed. 1998, 37,
2387 – 2390; Angew. Chem. 1998, 110, 2512 – 2515; b) R. Gio-
vannini, T. Stꢀdemann, A. Devasagayaraj, G. Dussin, P. Knochel,
J. Org. Chem. 1999, 64, 3544 – 3553.
1
2
3
4
5
6
2.5
5
10
15
15
15
2
2
2
2
4
1
91
72
62
56
78
49
99:1
24:1
3.8:1
1.4:1
2.1:1
1:1.2
79
87
90
81
90
86
nd
nd
83
88
85
82
[a] Yield determined by 1H NMR on 0.1 mmol scale using benzoic acid as
a standard. [b] d.r. determined by HPLC on the acid on a chiral stationary
phase. [c] ee of cis-2 determined by HPLC on the methyl ester on a chiral
stationary phase. [d] ee of trans-2 determined by HPLC on the acid on
a chiral stationary phase. [e] Performed on 0.25 mmol scale using
benzoic acid as a standard.
[6] a) J. B. Johnson, T. Rovis, Angew. Chem. Int. Ed. 2008, 47, 840 –
871; Angew. Chem. 2008, 120, 852 – 884.
[7] a) E. A. Bercot, T. Rovis, J. Am. Chem. Soc. 2004, 126, 10248 –
10249; b) M. J. Cook, T. Rovis, J. Am. Chem. Soc. 2007, 129,
9302 – 9303; c) J. B. Johnson, E. A. Bercot, C. M. Williams, T.
Rovis, Angew. Chem. Int. Ed. 2007, 46, 4514 – 4518; Angew.
Chem. 2007, 119, 4598 – 4602.
[8] We recently reported the coupling of acyclic anhydrides with
tertiary amines under a nickel/photoredox manifold: C. L. Joe,
A. G. Doyle, Angew. Chem. Int. Ed. 2016, 55, 4040 – 4043;
Angew. Chem. 2016, 128, 4108 – 4111.
[9] O. Gutierrez, J. C. Tellis, D. N. Primer, G. A. Molander, M. C.
Kozlowski, J. Am. Chem. Soc. 2015, 137, 4896 – 4899.
[10] Z. Zuo, H. Cong, W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan, J.
Am. Chem. Soc. 2016, 138, 1832 – 1835.
loading should also impact the diastereoselectivity by chang-
ing the relative concentration of radical to Ni. Indeed, by
lowering the photocatalyst loading and maintaining the Ni
loading at 15 mol%, trans-2 could be favored in a modest
1.2:1 ratio. This result demonstrates the attractive possibility
of forming either the cis or trans keto-acid products in high
enantioselectivity from a cis-meso anhydride solely through
changes to catalyst loading.
In summary, we report a nickel/photoredox catalyzed
desymmetrization of meso anhydrides affording enantio-
enriched keto-acids.[24] We have identified an epimerization
event on an intermediate in the catalytic cycle that provides
access to trans keto-acid products from cis anhydrides in
modest selectivity.
[11] J. Luo, J. Zhang, ACS Catal. 2016, 6, 873 – 877.
[12] A racemic background reaction is not detected under identical
conditions using Ir (3). This suggests 4CzIPN is promoting the
racemic background. See the Supporting Information (SI) for
more details.
[13] Control experiments suggest COD or DME are not responsible
for this difference in enantioselectivity. We propose the possi-
bility of a competitive Ni0/I/III pathway. See Scheme S1 in SI for
a proposed catalytic cycle.
[14] Epimerization was never observed in previous nickel-, palla-
dium- or rhodium-catalyzed anhydride desymmetrizations. See
Ref. [3] and [7].
[15] Products 4 and 5 will epimerize to the trans product under
extended work-up conditions. See SI for more details.
[16] Hammett analysis shows no correlation between enantiomeric
ratio and s values.
Acknowledgements
We thank NIGMS (GM100985 to A.G.D.) and Princeton
University (to E.E.S.) for support and Phil Jeffrey of Prince-
ton University for X-ray crystallographic structure determi-
nation.
[17] A significant racemic background was observed for more
nucleophilic trifluoroborates under standard reaction conditions.
High enantioselectivity could be obtained for product 21 by
employing Et2O; however, reduced yield was obtained due to
solubility issues. See SI (Section VII) for full details.
[18] Oxidative addition was observed via UV/Vis using Ni(cod)2, L1
and 20 equiv of anhydride. See SI for ligand comparisons and
more details. Also see Ref. [6] for previous demonstrations of
oxidative addition studies.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis · cross-coupling ·
desymmetrization · nickel · photoredox catalysis
[19] Derivatization reactions provided evidence that the ketone
stereocenter is being epimerized, as opposed to the carboxylate
center. See SI for full experimental details.
[20] Extended reaction times or subjecting the product to the
reaction conditions did not result in a significant increase in
the formation of the trans product.
[21] For a related example of decarbonylation under nickel cross-
coupling conditions, see: E. M. OꢁBrien, E. A. Bercot, T. Rovis,
[1] a) J. C. Tellis, C. B. Kelly, D. N. Primer, M. Jouffroy, N. R. Patel,
G. A. Molander, Acc. Chem. Res. 2016, 49, 1429 – 1439; b) M. D.
Levin, S. Kim, F. D. Toste, ACS Cent. Sci. 2016, 2, 293 – 301;
c) M. N. Hopkinson, A. Tiahuext-Aca, F. Glorius, Acc. Chem.
4
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J. Am. Chem. Soc. 2003, 125, 10498 – 10499. For an example of
[24] The reaction was scaled using the Merck photoreactor to
decarboxylation and recombination under photoredox condi-
tions, see C. Le, D. W. C. MacMillan, J. Am. Chem. Soc. 2015,
137, 11938 – 11941.
0.5 mmol for derivatization reactions, providing keto-acid 2 in
75% yield, 90% ee and 19:1 d.r.. The product was purified
further to yield the cis isomer in > 99% ee. See SI for more
details.
[22] A small amount (< 2%) of racemic trans anhydride is present in
the cis anhydride, which accounts for the difference in ee
between the cis and trans products.
[23] C. J. Cordier, R. J. Lundgren, G. C. Fu, J. Am. Chem. Soc. 2013,
135, 10946 – 10949.
Manuscript received: January 4, 2017
Final Article published: && &&, &&&&
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Communications
Asymmetric Synthesis
E. E. Stache, T. Rovis,*
A. G. Doyle*
&&& — &&&
Dual Nickel- and Photoredox-Catalyzed
Enantioselective Desymmetrization of
Cyclic meso-Anhydrides
Catalytic teamwork: Cyclic anhydrides are
efficiently desymmetrized through dual
nickel- and photoredox-catalyzed alkyla-
tion using benzylic trifluoroborates salts
as pronucleophiles. A mechanistic
nuance illustrates that an intermediate in
the catalytic cycle undergoes epimeriza-
tion leading to trans keto-acid products
from cis anhydrides under modified reac-
tion conditions.
6
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