Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation

Article abstract of DOI:10.1021/jacs.1c05206

The enantioselective amination of C(sp3)-H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C-H amination, Rh2(esp)2, with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C-H amination of substrates bearing pendant hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex, providing improved yields of product versus Rh2(esp)2 and highlighting the dual role that the cation is playing. These results underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.

Full text of DOI:10.1021/jacs.1c05206

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Enantioselective Intermolecular C−H Amination Directed by a Chiral
Cation
Alexander Fanourakis, Benjamin D. Williams, Kieran J. Paterson, and Robert J. Phipps*
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ABSTRACT: The enantioselective amination of C(sp3)−H bonds is a powerful synthetic transformation yet highly challenging to
achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C−H
amination, Rh2(esp)2, with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired
catalysts enable high levels of enantioselectivity to be achieved in the benzylic C−H amination of substrates bearing pendant
hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex,
providing improved yields of product versus Rh2(esp)2 and highlighting the dual role that the cation is playing. These results
underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.
he ability to form new C−N bonds in a direct and
efficient manner is crucially important due to their
development of a chiral variant could be transformational
but there are few structural opportunities to achieve this.4b,14
In a creative strategy, Bach and co-workers tethered the
bridging aryl ring of (esp), through an alkyne linker, to a chiral
lactam (Figure 1b, right).15 A dual hydrogen bonding
interaction with the substrate permitted benzylic C−H
amination with up to 74% ee.
T
ubiquity in organic molecules. Traditional disconnections are
increasingly supplemented by methods which can use far less
reactive C−H bonds, enabling powerful alternative retro-
synthetic strategies.1 One of the most widely used and versatile
involves the insertion of catalytically generated rhodium
nitrenoids into C(sp3)−H bonds.2 The original catalysts used
for this purpose were dirhodium tetracarboxylates (also
referred to as paddlewheel complexes),3 and extensive
development of this methodology has been undertaken by
Du Bois and co-workers in particular.2a This has culminated in
the development of the versatile and robust strapped
dicarboxylate catalyst Rh2(esp)2 which can perform rhodium-
catalyzed C−H amination intermolecularly on benzylic,
tertiary, and, in some cases, secondary alkyl C−H bonds
(Figure 1a).2a,4 In many instances, C−H amination leads to
the introduction of a new stereocenter and efforts to render
Rh(II)-catalyzed C−H aminations enantioselective have been
ongoing since its early development.5 Due to the ready
availability of chiral carboxylic acids, their incorporation into
paddlewheel complexes has constituted the main strategy,
encompassing important contributions from Hashimoto,6
We recently outlined a strategy for inducing asymmetry in
reactions that use ligand scaffolds which are particularly
challenging to render chiral in the conventional manner. In our
approach, the ligand is made anionic through the attachment
of a sulfonate group which in turn allows association of a chiral
cation with which to exert enantiocontrol (Figure 1c).16 This
strategy provides an opportunity to unite privileged chiral
cations with the diverse reactivity of transition metal
complexes.17 In our first study a distally sulfonated bipyridine
ligand was associated with a quinine-derived cation to impart
enantiocontrol in iridium-catalyzed arene borylation.18 Qua-
ternized cinchona alkaloids provide a well-defined chiral
pocket with ample opportunity for attractive noncovalent
interactions between the substrate and the rich functionality of
the cation.19 Seeking to apply this strategy to C−H amination
we first synthesized an (esp) analogue bearing a methylenesul-
fonate group on each bridging benzene ring. These anionic
handles would then be used to associate with chiral cations to
form a “sulfonesp” family of ion-paired catalysts (Figure 1d).
The “sulfonesp” scaffolds were readily synthesized in a three-
step sequence comprising dialkylation using ester enolates,
displacement of the remaining benzyl bromide with sodium
Mu
̈
ller,7 Davies,8 and Dauban,9 among others (Figure 1b,
left). Additionally, Du Bois developed a chiral carboxamidate
variant for enantioselective intramolecular amination (Figure
1b, middle).10 Despite these advances, as well as related ones
employing alternative transition metals11 and enzymes,12
intermolecular C−H amination via nitrene transfer still
remains extremely challenging to achieve asymmetrically. For
rhodium dimers bearing chiral carboxylate ligands, the chiral
information is located at a considerable distance from the
reactive axial site. Although very successful for enantioselective
carbene C−H insertions,13 for nitrene insertions the develop-
ment of fundamentally different strategies is clearly warranted.
Given that Rh2(esp)2 is the current state-of-the-art catalyst for
nonenantioselective intermolecular C−H amination, the
Received: May 20, 2021
Published: June 28, 2021
© 2021 The Authors. Published by
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Figure 2. Synthesis (a) and systematic variation of ion-paired
“sulfonesp” ligands on both ligand scaffold (b) and cation (c).
Figure 1. Background to enantioselective C−H amination using Rh
dimers (a, b) and this work (c, d).
difluorobenzene suggests a significant difference in their
respective HOMO−LUMO energy gaps (see Supporting
Information (SI) for further details).21 While such binding
could prevent nitrenoid formation if the binding in solution
were too strong, we anticipated that a weaker, reversible
interaction could actually be beneficial, potentially protecting
the rhodium dimer from decomposition pathways and
extending the catalyst lifetime, as has been shown in a number
of recent studies.4d,22
We began our investigations using 4-phenybutan-1-ol (6a)
as a challenging test substrate (Table 1). This contains
prochiral benzylic C−H bonds and a hydroxyl functionality
that could feasibly hydrogen bond with the catalyst sulfonate
group to provide organization at the transition state. The direct
rhodium-catalyzed intermolecular amination of substrates
containing unhindered primary alcohols has little precedent,
yet the resulting chiral aminoalcohol derivatives could be of
great synthetic utility, particularly since they are an oxidation
away from γ-aminobutyric acids.23 Additionally, the trans-
formation would give rise to products not currently accessible
using Du Bois’ enantioselective intramolecular amination
methodology involving cyclization of sulfamate esters en
route to 1,3-amino alcohols.10 Although Rh2(esp)2 gave a
very low yield (9%) on this substrate under the evaluation
sulfite, and ester hydrolysis to the corresponding diacid (Figure
2a). After assembly of the rhodium dimers, the bisligated
complexes were isolated as the bistetrabutylammonium salts
and it proved straightforward to introduce chiral cations via
intermediate protonation using Amberlite IRC120 H. This
accessed a series of “sulfonesp” scaffolds with varied geminal
dialkyl substitution, both acyclic (A) and cyclic (B−E) (Figure
2b), a steric parameter on the ligand that we anticipated could
be used to tune enantioselectivity. Notably, chirality is
introduced in the final ion exchange, enabling rapid access to
libraries of ion-paired catalysts.20 We initially synthesized the
gem-dimethyl ligand scaffold (A) in combination with
dihydroquinine-derived (DHQ-derived, 1) and dihydroquini-
dine-derived (DHQD-derived, 2a) cations that bore the
specific bulky quaternizing benzyl group that had been optimal
in our previous work (Figure 2c).18 Intriguingly, we observed a
striking solution color change from green to red once the chiral
cations were incorporated. This strongly suggested axial
ligation of rhodium, with the quinoline nitrogen of the cations
constituting the most likely ligand. UV−visible studies lent
strong support to this hypothesis: comparing the λmax of
Rh2(D)2·(2a)2 (536 nm) with Rh2(esp)2 (655 nm) in 1,3-
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a
Table 1. Reaction Optimization
b
Entry
Catalyst
Oxidant
Temp (°C)
Solvent
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
Rh2(esp)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
PhIO
−10
−10
−10
−10
−10
−10
−25
−25
−25
−25
−25
−25
−25
−25
−25
−25
1,4-DFB
1,4-DFB
1,4-DFB
1,4-DFB
1,4-DFB
1,4-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
1,3-DFB
9
Rac.
33
Rh2(A)2·(1)2
Rh2(A)2·(2a)2
Rh2(A)2·(3)2
Rh2(A)2·(4)2
Rh2(A)2·(2a)2
Rh2(A)2·(2a)2
Rh2(B)2·(2a)2
Rh2(C)2·(2a)2
Rh2(D)2·(2a)2
Rh2(E)2·(2a)2
Rh2(D)2·(2b)2
Rh2(D)2·(2c)2
Rh2(D)2·(2d)2
Rh2(D)2·(2e)2
Rh2(esp)2
43
35
13
21
46
83
60
75
−71
Rac.
+26
−87
−81
−81
−87
9
c
c
10
11
12
13
14
15
16
90
−90
71
46
58
57
58
−86
−53
−76
−82
−74
c
c
17
Rac.
a
Reactions performed on 0.1 mmol scale with respect to 6a using 1.2 equivalents of 5. Reaction concentration = 0.2 M. Yields determined by 1H
NMR with reference to internal standard. ee determined by chiral SFC analysis of the crude reaction. Data corresponds to the isolated sample.
DFB = difluorobenzene.
b
c
Scheme 1. Reaction Scope Exploration
a
b
Reaction performed with 3.0 mol % Rh2(D)2·(2a)2. Reaction performed at −10 °C using 1,4-DFB in place of 1,3-DFB.
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reaction conditions, we were pleased to observe that this
increased significantly (43%) when Rh2(A)2·(1)2 was used.
Further, a low but encouraging ee of 33% was measured (Table
1, entries 1 and 2). Remarkably, when using complex Rh2(A)2·
(2a)2 containing the pseudoenantiomeric DHQD-derived
cation, the ee increased drastically from 33% to −71% (entry
3). Such divergence in the enantiomeric excesses afforded by
the pseudoenantiomers is intriguing but has been noted in
other systems.24 This prompted us to evaluate another set of
diastereomers of the cinchona alkaloid family, namely the epi-
DHQ-derived (3) and epi-DHQD-derived (4) cations, in
which the hydroxyl-bearing stereocenter is inverted on each. In
these cases, the ee outcomes were poor (entries 4 and 5) so we
continued optimization with the DHQD-derived cations. We
were pleased to discover that switching the oxidant from
PhI(OPiv)2 to iodosobenzene (PhIO) increased both con-
version and ee (Table 1, entry 6). Despite the moderate yield,
full conversion of starting material was observed along with a
number of uncharacterized byproducts. A switch to the lower
melting 1,3-difluorobenzene solvent enabled us to reduce the
temperature to −25 °C, which in turn allowed for a more
controlled reaction to give the product in an excellent 83%
yield and −81% ee (entry 7). We next evaluated dimer scaffolds
B−E to systematically explore steric changes near to the active
site which we anticipated might lead to subtle variations in
cation and substrate positioning in the enantiodetermining
transition state (entries 8−11). This revealed that the
cycloheptyl “sulfonesp” scaffold D provided both optimal
yield (90%) and ee (−90%) in the complex Rh2(D)2·(2a)2.
Finally, we returned to evaluate a selection of other
quaternizing groups on the DHQD framework in conjunction
with optimal scaffold D. Replacing the t-Bu groups at the
periphery of the teraryl unit with CF3 (2b) or removing them
completely (2c) was detrimental to the ee (entries 12 and 13),
as was removing the outer two aryl rings of the teraryl unit
(entries 14 and 15). Under the optimal conditions, the ion-
paired catalysts greatly outperformed Rh2(esp)2, which
delivered only a 17% yield (entry 16), underlining the
importance of the chiral cation in improving reaction yield in
addition to its pivotal role in enantioinduction. Indeed, when
4-phenylbutan-1-ol was subjected to the current state-of-the-
art conditions for intermolecular amination using either
PhOSO2NH2 or DfsNH2 as the aminating agents and
Rh2(esp)2 as the catalyst, the desired product was not
observed.4d Only by use of the more reactive perfluorinated
sulfamate ester 5 could ∼20% crude 1H NMR yield be
obtained, emphasizing that 6a is a challenging substrate for C−
H amination (see SI).25
(7x) containing substrates. For products 7q and 7r, a higher
temperature was used for improved conversion and the solvent
was switched from 1,3-difluorobenzene to 1,4-difluorobenzene
since the latter had given a slightly improved enantioselectivity
in initial reaction optimization (Table 1, entries 6 and 7).
Reaction product 7a was readily transformed into protected
2-arylpyrrolidine 8 using Mitsunobu chemistry (Scheme 2a).
Scheme 2. Practical Considerations and Control
Experiments
N-Deprotection of 8 allowed assignment of the absolute
stereochemistry of the products by comparison of the optical
rotation of 9 with literature values (all other amination
products were assigned by analogy). Our earlier observation
that the precise diastereomer of the cinchona alkaloid scaffold
used greatly impacted the enantioselectivity was curious, but
also a practical limitation if the opposite product enantiomer is
required. Assuming that the ethyl group in DHQ-derived 1
causes an unfavorable steric interaction at the transition state,
we removed it by devinylation of quinine.24 We were pleased
to find that the resulting catalyst Rh2(D)2·(10)2 gave the
product ent-7a with almost exactly the opposite sense of
enantioinduction and with only a small reduction in yield
(Scheme 2b). To probe the importance of the proposed
hydrogen bonding between the substrate hydroxyl and the
catalyst sulfonate, we evaluated the amination of phenylbutane
(Scheme 2c, left). This showed drastically reduced reactivity
and enantioselectivity suggesting that the attractive interaction
is crucial for both outcomes. We also carried out the amination
using Rh2(esp)2 in combination with 2a·Br to examine the
effect of severing the ionic link between ligand and cation. This
resulted in poor enantioselectivity (19% ee, Scheme 2c, right).
Interestingly, the yield was significantly improved compared
with Rh2(esp)2 alone (51% vs 17%) which provides support for
beneficial axial ligation by the quinoline of the cation, even
when the cation is not associated with the ligand. Further
support for this fortuitous benefit provided by the cinchona
With the optimized conditions in hand we evaluated the
tolerance to various arene substituents (Scheme 1). An ester at
the meta position was well tolerated (7b) as were methyl
groups at the ortho and meta positions (7c, 7d). Substrates
with fluorine atoms in all three positions also gave very high
levels of enantioselectivity (7e−7g). With meta-substituted
substrates (7h−7l), we were pleased to see that high
enantioselectivity was maintained although in these cases,
increasing the catalyst loading to 3.0 mol % was beneficial for
conversion. Substitution at the ortho position with chlorine
gave a reduced yield (7m) although the enantioselectivity
remained high. Substitution at the para position gave a slightly
reduced enantioselectivity in the case of methoxy (7n), but not
chloride (7o). Finally, a range of disubstituted arenes (7p−7v)
were compatible as well as naphthalene (7w) and thiophene
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alkaloid-based chiral cations was provided by the poor yield
(7%) obtained using an ion-paired ligand bearing tetrabuty-
lammonium in place of the quinoline-containing chiral cation.
We next tested substrate 12, in which the hydroxyl is
replaced by a carboxylic acid to evaluate its ability to interact
productively with the catalyst. Here PhIO as the oxidant led to
only racemic products, but switching to PhI(OPiv)2 afforded
the product with an encouraging level of enantioenrichment
(78% ee), albeit in low yield in these initial investigations
(Scheme 3a). We also evaluated shorter (three carbon) and
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05206.
■
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Full experimental details, characterization data for
compounds and details of UV−vis studies (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Robert J. Phipps − Yusuf Hamied Department of Chemistry,
University of Cambridge, Cambridge CB2 1EW, United
Kingdom; orcid.org/0000-0002-7383-5469;
Email: rjp71@cam.ac.uk
Scheme 3. Further Substrate Exploration
Authors
Alexander Fanourakis − Yusuf Hamied Department of
Chemistry, University of Cambridge, Cambridge CB2 1EW,
United Kingdom
Benjamin D. Williams − Yusuf Hamied Department of
Chemistry, University of Cambridge, Cambridge CB2 1EW,
United Kingdom
Kieran J. Paterson − Yusuf Hamied Department of Chemistry,
University of Cambridge, Cambridge CB2 1EW, United
Kingdom
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05206
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.F. is grateful to the Cambridge Trust and Wolfson College
Cambridge for a Vice-Chancellor’s & Wolfson College
Scholarship. B.D.W. is grateful to the Cambridge Trust and
Sidney Sussex College Cambridge for a PhD studentship. We
are grateful to the Royal Society for a University Research
Fellowship (R.J.P.), the ERC (Starting Grant NonCovRegioSi-
teCat, 757381), and the EPSRC (EP/N005422/1). We are
very grateful to Dr. Georgi R. Genov for useful discussions and
the synthesis of several chiral cations used in this study. We are
grateful also to Duncan J. Howe and Andrew Mason for their
assistance in acquiring NMR spectra.
longer (five carbon) chain alcohols against our five “sulfonesp”
scaffolds A−E, all using cation 2a. This revealed that, for
phenylpropanol, the same scaffold (D) that was optimal for
phenylbutanol was best and cyclobutane-containing B was
poorest (Scheme 3b, 14). However, for the longer chain
phenylpentanol, scaffold B was superior to all others (Scheme
3b, 15). While still preliminary, these encouraging results
provide a compelling demonstration that the modularity of our
ion-paired “sulfonesp” ligands, in terms of both ligand scaffold
and cation, will facilitate matching them with future substrates
of interest. We also tested other functional groups in place of
hydroxyl, which gave poor outcomes (see SI for details).
In conclusion, we have developed a family of ion-paired
chiral catalysts for rhodium-catalyzed C−H amination based
on the (esp) ligand scaffold and have applied them successfully
to the enantioselective intermolecular C−H amination of 4-
arylbutanols. Furthermore, the optimal ion-paired catalyst also
results in significantly improved yields compared with
Rh2(esp)2. We believe that this is due to a combination of
axial coordination by the chiral cation and a network of
noncovalent interactions between ligand and substrate which
promote the desired benzylic amination. These results form
the basis of a catalyst design principle that we anticipate, with
further development, should be applicable to intermolecular
amination reactions of other challenging substrate classes.
More broadly, this demonstrates the potential of using ion-
paired ligands bearing chiral cations to tackle challenging
transition-metal-catalyzed reactions.
REFERENCES
■
(1) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C−H
Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017,
117, 9247−9301.
(2) (a) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Metal-Catalyzed
Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C−
H Bonds. Acc. Chem. Res. 2012, 45, 911−922. (b) Dequirez, G.; Pons,
V.; Dauban, P. Nitrene Chemistry in Organic Synthesis: Still in Its
Infancy? Angew. Chem., Int. Ed. 2012, 51, 7384−7395. (c) Darses, B.;
Rodrigues, R.; Neuville, L.; Mazurais, M.; Dauban, P. Transition
metal-catalyzed iodine(iii)-mediated nitrene transfer reactions:
efficient tools for challenging syntheses. Chem. Commun. 2017, 53,
493−508.
(3) (a) Breslow, R.; Gellman, S. H. Intramolecular nitrene carbon-
hydrogen insertions mediated by transition-metal complexes as
nitrogen analogs of cytochrome P-450 reactions. J. Am. Chem. Soc.
1983, 105, 6728−6729. (b) Nägeli, I.; Baud, C.; Bernardinelli, G.;
̈
Jacquier, Y.; Moraon, M.; Muller, P. Rhodium(II)-Catalyzed CH
Insertions with {[(4-Nitrophenyl)sulfonyl]imino}phenyl-λ3-iodane.
Helv. Chim. Acta 1997, 80, 1087−1105.
10074
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(4) For selected examples, see: (a) Espino, C. G.; Fiori, K. W.; Kim,
M.; Du Bois, J. Expanding the Scope of C−H Amination through
Catalyst Design. J. Am. Chem. Soc. 2004, 126, 15378−15379.
(b) Fiori, K. W.; Du Bois, J. Catalytic Intermolecular Amination of
C−H Bonds: Method Development and Mechanistic Insights. J. Am.
Chem. Soc. 2007, 129, 562−568. (c) Roizen, J. L.; Zalatan, D. N.; Du
Bois, J. Selective Intermolecular Amination of C-H Bonds at Tertiary
Carbon Centers. Angew. Chem., Int. Ed. 2013, 52, 11343−11346.
(d) Chiappini, N. D.; Mack, J. B. C.; Du Bois, J. Intermolecular
C(sp3)−H Amination of Complex Molecules. Angew. Chem., Int. Ed.
2018, 57, 4956−4959.
the Enantiomer Problem. Angew. Chem., Int. Ed. 2012, 51, 8568−
8572. (e) Chen, P.-A.; Setthakarn, K.; May, J. A. A Binaphthyl-Based
Scaffold for a Chiral Dirhodium(II) Biscarboxylate Ligand with α-
Quaternary Carbon Centers. ACS Catal. 2017, 7, 6155−6161.
(15) Höke, T.; Herdtweck, E.; Bach, T. Hydrogen-bond mediated
regio- and enantioselectivity in a C−H amination reaction catalysed
by a supramolecular Rh(ii) complex. Chem. Commun. 2013, 49,
8009−8011.
(16) For a related, charge-inverted strategy, see: (a) Ohmatsu, K.;
Ito, M.; Kunieda, T.; Ooi, T. Ion-paired chiral ligands for asymmetric
palladium catalysis. Nat. Chem. 2012, 4, 473−477. (b) Ohmatsu, K.;
Ito, M.; Kunieda, T.; Ooi, T. Exploiting the Modularity of Ion-Paired
Chiral Ligands for Palladium-Catalyzed Enantioselective Allylation of
Benzofuran-2(3H)-ones. J. Am. Chem. Soc. 2013, 135, 590−593.
(17) For selected examples of use of chiral cations with transition
metal catalysis, see: (a) Nakoji, M.; Kanayama, T.; Okino, T.;
Takemoto, Y. Pd-Catalyzed Asymmetric Allylic Alkylation of Glycine
Imino Ester Using a Chiral Phase-Transfer Catalyst. J. Org. Chem.
2002, 67, 7418−7423. (b) Ohmatsu, K.; Imagawa, N.; Ooi, T.
Ligand-enabled multiple absolute stereocontrol in metal-catalysed
cycloaddition for construction of contiguous all-carbon quaternary
stereocentres. Nat. Chem. 2014, 6, 47−51. (c) Wang, C.; Zong, L.;
Tan, C.-H. Enantioselective Oxidation of Alkenes with Potassium
Permanganate Catalyzed by Chiral Dicationic Bisguanidinium. J. Am.
Chem. Soc. 2015, 137, 10677−10682. (d) Mechler, M.; Peters, R.
Diastereodivergent Asymmetric 1,4-Addition of Oxindoles to Nitro-
olefins by Using Polyfunctional Nickel-Hydrogen-Bond-Azolium
Catalysts. Angew. Chem., Int. Ed. 2015, 54, 10303−10307. (e) Ye,
X.; Moeljadi, A. M. P.; Chin, K. F.; Hirao, H.; Zong, L.; Tan, C.-H.
Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium
Diphosphatobisperoxotungstate Ion Pair. Angew. Chem., Int. Ed.
2016, 55, 7101−7105. (f) Zong, L.; Wang, C.; Moeljadi, A. M. P.; Ye,
X.; Ganguly, R.; Li, Y.; Hirao, H.; Tan, C.-H. Bisguanidinium
dinuclear oxodiperoxomolybdosulfate ion pair-catalyzed enantiose-
lective sulfoxidation. Nat. Commun. 2016, 7, 13455. (g) Zong, L.;
Tan, C.-H. Phase-Transfer and Ion-Pairing Catalysis of Pentanidiums
and Bisguanidiniums. Acc. Chem. Res. 2017, 50, 842−856. (h) Paria,
S.; Lee, H.-J.; Maruoka, K. Enantioselective Alkynylation of Isatin
Derivatives Using a Chiral Phase-Transfer/Transition-Metal Hybrid
Catalyst System. ACS Catal. 2019, 9, 2395−2399.
(5) For reviews, see: (a) Muller, P.; Fruit, C. Enantioselective
̈
Catalytic Aziridinations and Asymmetric Nitrene Insertions into CH
Bonds. Chem. Rev. 2003, 103, 2905−2920. (b) Collet, F.; Lescot, C.;
Dauban, P. Catalytic C−H amination: the stereoselectivity issue.
Chem. Soc. Rev. 2011, 40, 1926−1936. (c) Hayashi, H.; Uchida, T.
Nitrene Transfer Reactions for Asymmetric C−H Amination: Recent
Development. Eur. J. Org. Chem. 2020, 2020, 909−916.
(6) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto,
S. Dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate]:
a new chiral Rh(II) catalyst for enantioselective amidation of CH
bonds. Tetrahedron Lett. 2002, 43, 9561−9564.
(7) Fruit, C.; Muller, P. Intramolecular Asymmetric Amidations of
̈
Sulfonamides and Sulfamates Catalyzed by Chiral Dirhodium(II)
Complexes. Helv. Chim. Acta 2004, 87, 1607−1615.
(8) Reddy, R. P.; Davies, H. M. L. Dirhodium Tetracarboxylates
Derived from Adamantylglycine as Chiral Catalysts for Enantiose-
lective C−H Aminations. Org. Lett. 2006, 8, 5013−5016.
(9) (a) Nasrallah, A.; Boquet, V.; Hecker, A.; Retailleau, P.; Darses,
B.; Dauban, P. Catalytic Enantioselective Intermolecular Benzylic
C(sp3)−H Amination. Angew. Chem., Int. Ed. 2019, 58, 8192−8196.
(b) Nasrallah, A.; Lazib, Y.; Boquet, V.; Darses, B.; Dauban, P.
Catalytic Intermolecular C(sp3)−H Amination with Sulfamates for
the Asymmetric Synthesis of Amines. Org. Process Res. Dev. 2020, 24,
724−728.
(10) Zalatan, D. N.; Du Bois, J. A Chiral Rhodium Carboxamidate
Catalyst for Enantioselective C−H Amination. J. Am. Chem. Soc.
2008, 130, 9220−9221.
(11) (a) Zhou, X.-G.; Yu, X.-Q.; Huang, J.-S.; Che, C.-M.
Asymmetric amidation of saturated C−H bonds catalysed by chiral
ruthenium and manganese porphyrins. Chem. Commun. 1999, 2377−
2378. (b) Kohmura, Y.; Katsuki, T. Mn(salen)-catalyzed enantiose-
lective CH amination. Tetrahedron Lett. 2001, 42, 3339−3342.
(c) Nishioka, Y.; Uchida, T.; Katsuki, T. Enantio- and Regioselective
Intermolecular Benzylic and Allylic C-H Bond Amination. Angew.
Chem., Int. Ed. 2013, 52, 1739−1742. (d) Annapureddy, R. R.; Jandl,
C.; Bach, T. A Chiral Phenanthroline Ligand with a Hydrogen-
Bonding Site: Application to the Enantioselective Amination of
Methylene Groups. J. Am. Chem. Soc. 2020, 142, 7374−7378.
(12) Prier, C. K.; Zhang, R. K.; Buller, A. R.; Brinkmann-Chen, S.;
Arnold, F. H. Enantioselective, intermolecular benzylic C−H
amination catalysed by an engineered iron-haem enzyme. Nat.
Chem. 2017, 9, 629−634.
(18) Genov, G. R.; Douthwaite, J. L.; Lahdenperä, A. S. K.; Gibson,
D. C.; Phipps, R. J. Enantioselective remote C−H activation directed
by a chiral cation. Science 2020, 367, 1246−1251.
(19) Fanourakis, A.; Docherty, P. J.; Chuentragool, P.; Phipps, R. J.
Recent Developments in Enantioselective Transition Metal Catalysis
Featuring Attractive Noncovalent Interactions between Ligand and
Substrate. ACS Catal. 2020, 10, 10672−10714.
(20) Ohmatsu, K.; Hara, Y.; Ooi, T. In situ generation of ion-paired
chiral ligands: rapid identification of the optimal ligand for palladium-
catalyzed asymmetric allylation. Chem. Sci. 2014, 5, 3645−3650.
(21) (a) Forslund, R. E.; Cain, J.; Colyer, J.; Doyle, M. P. Chiral
Dirhodium(II) Carboxamidate-Catalyzed [2 + 2]-Cycloaddition of
TMS-Ketene and Ethyl Glyoxylate. Adv. Synth. Catal. 2005, 347, 87−
92. (b) Zalatan, D. N.; Du Bois, J. Understanding the Differential
Performance of Rh2(esp)2 as a Catalyst for C−H Amination. J. Am.
Chem. Soc. 2009, 131, 7558−7559. (c) Berry, J. F. The role of three-
center/four-electron bonds in superelectrophilic dirhodium carbene
and nitrene catalytic intermediates. Dalton Trans 2012, 41, 700−713.
(d) Warzecha, E.; Berto, T. C.; Wilkinson, C. C.; Berry, J. F. Rhodium
Rainbow: A Colorful Laboratory Experiment Highlighting Ligand
Field Effects of Dirhodium Tetraacetate. J. Chem. Educ. 2019, 96,
571−576.
(22) (a) Sambasivan, R.; Zheng, W.; Burya, S. J.; Popp, B. V.; Turro,
C.; Clementi, C.; Ball, Z. T. A tripodal peptide ligand for asymmetric
Rh(ii) catalysis highlights unique features of on-bead catalyst
development. Chem. Sci. 2014, 5, 1401−1407. (b) Sarkar, M.; Daw,
P.; Ghatak, T.; Bera, J. K. Amide-Functionalized Naphthyridines on a
RhII−RhII Platform: Effect of Steric Crowding, Hemilability, and
Hydrogen-Bonding Interactions on the Structural Diversity and
(13) (a) Hansen, J.; Davies, H. M. L. High symmetry dirhodium(II)
paddlewheel complexes as chiral catalysts. Coord. Chem. Rev. 2008,
252, 545−555. (b) Davies, H. M. L.; Liao, K. Dirhodium
tetracarboxylates as catalysts for selective intermolecular C−H
functionalization. Nat. Rev. Chem. 2019, 3, 347−360.
(14) For examples of strapped chiral rhodium dicarboxylate
complexes, see: (a) Davies, H. M. L.; Kong, N. Synthesis and
evaluation of a novel dirhodium tetraprolinate catalyst containing
bridging prolinate ligands. Tetrahedron Lett. 1997, 38, 4203−4206.
(b) Davies, H. M. L.; Panaro, S. A. Novel dirhodium tetraprolinate
catalysts containing bridging prolinate ligands for asymmetric
carbenoid reactions. Tetrahedron Lett. 1999, 40, 5287−5290.
(c) Sambasivan, R.; Ball, Z. T. Metallopeptides for Asymmetric
Dirhodium Catalysis. J. Am. Chem. Soc. 2010, 132, 9289−9291.
(d) Sambasivan, R.; Ball, Z. T. Screening Rhodium Metallopeptide
Libraries “On Bead”: Asymmetric Cyclopropanation and a Solution to
10075
https://doi.org/10.1021/jacs.1c05206
J. Am. Chem. Soc. 2021, 143, 10070−10076

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Catalytic Activity of Dirhodium(II) Complexes. Chem. - Eur. J. 2014,
20, 16537−16549. (c) Sheffield, W.; Abshire, A.; Darko, A. Effect of
Tethered, Axial Thioether Coordination on Rhodium(II)-Catalyzed
Silyl-Hydrogen Insertion. Eur. J. Org. Chem. 2019, 2019, 6347−6351.
(d) Anderson, B. G.; Cressy, D.; Patel, J. J.; Harris, C. F.; Yap, G. P.
A.; Berry, J. F.; Darko, A. Synthesis and Catalytic Properties of
Dirhodium Paddlewheel Complexes with Tethered, Axially Coordi-
nating Thioether Ligands. Inorg. Chem. 2019, 58, 1728−1732.
(23) (a) Froestl, W. An historical perspective on GABAergic drugs.
Future Med. Chem. 2011, 3, 163−175. (b) Ngo, D.-H.; Vo, T. S. An
Updated Review on Pharmaceutical Properties of Gamma-Amino-
butyric Acid. Molecules 2019, 24, 2678.
(24) Hu, B.; Bezpalko, M. W.; Fei, C.; Dickie, D. A.; Foxman, B. M.;
Deng, L. Origin of and a Solution for Uneven Efficiency by Cinchona
Alkaloid-Derived, Pseudoenantiomeric Catalysts for Asymmetric
Reactions. J. Am. Chem. Soc. 2018, 140, 13913−13920.
(25) Bess, E. N.; DeLuca, R. J.; Tindall, D. J.; Oderinde, M. S.;
Roizen, J. L.; Du Bois, J.; Sigman, M. S. Analyzing Site Selectivity in
Rh2(esp)2-Catalyzed Intermolecular C−H Amination Reactions. J.
Am. Chem. Soc. 2014, 136, 5783−5789.
10076
https://doi.org/10.1021/jacs.1c05206
J. Am. Chem. Soc. 2021, 143, 10070−10076