Non- C2-Symmetric Chiral-at-Ruthenium Catalyst for Highly Efficient Enantioselective Intramolecular C(sp3)-H Amidation

Article abstract of DOI:10.1021/jacs.9b09301

A new class of chiral ruthenium catalysts is introduced in which ruthenium is cyclometalated by two 7-methyl-1,7-phenanthrolinium heterocycles, resulting in chelating pyridylidene remote N-heterocyclic carbene ligands (rNHCs). The overall chirality results from a stereogenic metal center featuring either a or Δabsolute configuration. This work features the importance of the relative metal-centered stereochemistry. Only the non-C₂-symmetric chiral-at-ruthenium complexes display unprecedented catalytic activity for the intramolecular C(sp³)-H amidation of 1,4,2-dioxazol-5-ones to provide chiral -lactams with up to 99:1 er and catalyst loadings down to 0.005 mol % (up to 11 ?200 TON), while the C₂-symmetric diastereomer favors an undesired Curtius-type rearrangement. DFT calculations elucidate the origins of the superior C-H amidation reactivity displayed by the non-C₂-symmetric catalysts compared to related C₂-symmetric counterparts.

Full text of DOI:10.1021/jacs.9b09301

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Non‑C2‑Symmetric Chiral-at-Ruthenium Catalyst for Highly Efficient
Enantioselective Intramolecular C(sp3)−H Amidation
Zijun Zhou,†,§ Shuming Chen,‡,§ Yubiao Hong,† Erik Winterling,† Yuqi Tan,† Marcel Hemming,†
Klaus Harms,† K. N. Houk,*,‡ and Eric Meggers*,†
†
̈
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States
S
* Supporting Information
ABSTRACT: A new class of chiral ruthenium catalysts is
introduced in which ruthenium is cyclometalated by two 7-
methyl-1,7-phenanthrolinium heterocycles, resulting in chelating
pyridylidene remote N-heterocyclic carbene ligands (rNHCs). The
overall chirality results from a stereogenic metal center featuring
either a Λ or Δ absolute configuration. This work features the
importance of the relative metal-centered stereochemistry. Only the
non-C2-symmetric chiral-at-ruthenium complexes display unprece-
dented catalytic activity for the intramolecular C(sp3)−H amidation
of 1,4,2-dioxazol-5-ones to provide chiral γ-lactams with up to 99:1
er and catalyst loadings down to 0.005 mol % (up to 11 200 TON),
while the C2-symmetric diastereomer favors an undesired Curtius-
type rearrangement. DFT calculations elucidate the origins of the
superior C−H amidation reactivity displayed by the non-C2-symmetric catalysts compared to related C2-symmetric
counterparts.
nitrogen-containing molecules.6 Recently, Chang introduced a
new γ-lactam synthesis through a direct C−H amidation using
INTRODUCTION
■
The vast majority of chiral transition metal catalysts contain
1,4,2-dioxazol-5-ones as highly attractive nitrene precursors
that can be accessed in two steps (one pot) from ubiquitous
carboxylic acids.7−9 Chang,10 Yu,11 and Chen12 subsequently
reported catalytic enantioselective versions of this intra-
molecular C−H amidation employing well-established chiral
half-sandwich iridium or ruthenium complexes (Figure 1b).
However, despite impressive enantioselectivities, these
methods along with all other catalytic asymmetric C−H
nitrogenations suffer from high catalyst loadings, which renders
an application in the pharmaceutical industry unattractive.
Here we introduce a new class of chiral-at-ruthenium
catalysts3,4 containing two strongly electron-donating remote
N-heterocyclic carbene (rNHC) ligands5 coordinated in a non-
C2-symmetric fashion (Figure 1c). The catalyst displays
unprecedented catalytic activity for the conversion of 1,4,2-
dioxazol-5-ones to chiral γ-lactams at catalyst loadings down to
0.005 mol % (up to 11 200 TON), whereas the C2-symmetric
diastereomer provides a Curtius-type rearrangement13 as the
main product for the same conversion. Density functional
theory (DFT) calculations unravel the role of the ligand
architecture for achieving efficient C−H amidations.
chiral organic ligands in the coordination sphere of the metal.
Recently, we and others demonstrated that effective asym-
metric transition metal catalysis does not rely on chiral
ligands.1,2 We introduced a series of chiral transition metal
catalysts that are exclusively composed of achiral ligands with
the overall chirality being the consequence of a stereogenic
metal center. This chiral-at-metal strategy provides untapped
opportunities for the design of chiral transition metal catalysts
with distinct structural features and electronic properties.
However, the current structural variety is limited as, for
example, all chiral-at-metal catalysts developed in our
laboratory strictly follow the design shown in Scheme 1a,
containing two nonsymmetric bidentate and two monodentate
ligands coordinated to a central metal in a C2-symmetric
fashion. The metal-centered configuration Λ versus Δ then
determines the absolute configuration of the reaction products.
A larger structural diversity might lead to more diverse chiral
catalysts for a broader variety of asymmetric transformations.
For example, one could imagine non-C2-symmetric diaster-
eomers, expecting that the relative metal-centered stereo-
chemistry affects the overall reactivity of such chiral-at-metal
catalysts.
The direct catalytic asymmetric nitrogenation of C−H
bonds through a stereocontrolled insertion of metal nitrenoids
into prochiral C(sp3)−H bonds has emerged as a powerful and
economic tool for the efficient synthesis of chiral nonracemic
Received: August 28, 2019
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of Enantiomerically Pure Chiral-at-
Ruthenium Complexes Λ- and Δ-rNHCRu
Figure 1. Chiral-at-metal complexes and catalysts for enantioselective
C(sp3)−H amidation. (a) Chiral-at-metal complexes with different
symmetry. (b) Catalysts developed in this study. Note that C2-
rNHCRu was only synthesized as a racemic mixture. (c) Previous
studies and this work on enantioselective C(sp3)−H amidations with
1,4,2-dioxazol-5-ones.
RESULTS AND DISCUSSION
■
Catalyst Design and Synthesis. Due to the versatile
catalytic properties of many ruthenium complexes and the
lower cost of ruthenium compared to other platinum-group
metals, our laboratory has an active research program
developing chiral-at-Ru catalysts. We envisioned achieving
high catalytic activity by increasing electron density at the
ruthenium center using rNHC ligands. Such rNHC ligands are
stronger σ-donors compared to standard NHCs.5 Accordingly,
we chose the heterocycle 7-methyl-3-phenyl-1,7-phenanthroli-
nium hexafluorophosphate (1) as our ligand of choice
(Scheme 1).14,15 Reaction of RuCl3 hydrate with 1 in 2-
ethoxyethanol/water (4:1) at 125 °C afforded the racemic
chloro-bridged dimer complex rac-2 (88% yield). Each
ruthenium is cyclometalated by two 1,7-phenanthroline
ligands, which are electronically best described as chelating
pyridyl pyridylidene ligands. The racemic mixture was next
reacted with (R)- or (S)-N-benzoyl-tert-butanesulfinamide (3)
in the presence of K2CO3 to provide the complexes Λ-(S)-4 or
Δ-(R)-4 as single stereoisomers in 46% and 44% yield,
respectively.16,17 Interestingly, in the course of the formation of
the N-sulfinylcarboximidate complexes, an unexpected but
important isomerization of the chelating pyridylidene ligands
occurred. Treatment with the weak acid NH4BF4 and reaction
with pivalonitrile afforded the complexes Λ-rNHCRu and Δ-
rNHCRu in 95% and 94% yield, respectively.
Figure 2. Single-crystal X-ray structure of Λ-Ru3, a derivative of Λ-
rNHCRu (CCDC 1910816). ORTEP drawing with 50% probability
thermal ellipsoids. Solvent and counterion are omitted for clarity.
A crystal structure of a simplified derivative of Λ-rNHCRu,
devoid of the two phenyl substituents and bearing two
acetonitriles instead of pivalonitriles (Λ-Ru3), is shown in
Figure 2 and was used to assign the relative and absolute
metal-centered stereochemistry. It is noteworthy that due to
the lacking C2-symmetry of this complex, the two coordinated
B
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a
Table 1. Comparison of Different Ruthenium Catalysts
Scheme 2. Substrate Scope
b
yield (%)
loading
(mol %)
T
(°C)
c
entry
catalyst
6a
7
er
d
d
d
1
2
3
4
5
6
7
Λ-rNHCRu
Λ-Ru2
Λ-Ru3
Λ-Ru4
Λ-Ru5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.05
rt
rt
rt
rt
rt
rt
4
93 (92)
92 (91)
84 (82)
6
7
95:5
94:6
92:8
15
>99
>99
>99
5
Λ-Ru6
d
d
d
Λ-rNHCRu
Λ-rNHCRu
Λ-rNHCRu
95 (95)
95 (95)
93 (93)
96:4
96:4
95:5
e
8
f
4
4
5
7
a
Reactions performed in acetonitrile at room temperature for 8 h
instead of standard conditions.
9
a
Standard conditions: 5 (0.2 mmol) and Ru catalyst (0.05−0.5 mol
%) in 1,2-dichlorobenzene (0.4 mL) stirred at the indicated
b
Scheme 3. Gram-Scale Reaction with Low Catalyst Loading
and Further Transformations: (a) Gram-Scale Synthesis of
(S)-6e and (S)-6i; (b) Synthetic Applications of (S)-6i
temperature for 8 h under an atmosphere of nitrogen. Yields based
c
on 1H NMR analysis. Enantiomeric ratio of the crude product
d
determined by HPLC analysis on a chiral stationary phase. Isolated
yields in brackets. Reaction time of 30 h instead. Reaction time of 48
h instead.
e
f
nitriles are not equivalent. The strong σ-donating pyridylidene
ligand renders the acetonitrile ligand in trans position more
labile, which is evident from an elongated coordinative bond
(Ru1−N34 = 2.115 Å as compared to Ru1−N31 = 2.002 Å).18
To our knowledge, this is the first example of ruthenium
cyclometalated by two 7-alkyl-1,7-phenanthrolinium ions.19
Initial Experiments on Enantioselective C(sp3)−H
Amidations. We investigated the catalytic properties of the
new chiral-at-ruthenium complex and found that Λ-rNHCRu
displays excellent catalytic activity for the intramolecular C−H
amidation of 1,4,2-dioxazol-5-ones. For example, using just 0.5
mol % of Λ-rNHCRu at room temperature catalyzed the
conversion of 5a to the γ-lactam (S)-6a in 92% yield and with
95:5 er (Table 1, entry 1). The related catalysts Λ-Ru2
(acetonitriles instead of pivalonitriles) and Λ-Ru3 (devoid of
phenyl groups and acetonitriles instead of pivalonitriles)
provided lower yields and enantioselectivities for this
conversion and higher yields of side product isocyanate
formation (entries 2 and 3). Importantly, our previous chiral-
at-ruthenium complexes Ru4−Ru6, which were demonstrated
to be very suitable catalysts for enantioselective C−H
aminations of aliphatic azides,20,21 did not afford any
detectable amounts of the C−H amidation product but
instead quantitatively provided the isocyanate compound 7
(entries 4−6). Thus, rNHCRu has very distinct catalytic
properties. The yield and enantioselectivity of rNHCRu-
catalyzed conversion 5a → (S)-6a can be further improved to
95% yield and 96:4 er by performing the reaction at 4 °C. To
demonstrate the exceptional catalytic activity of rNHCRu,
C
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Figure 3. Proposed mechanism and calculated free energies (kcal/
mol) at the M06-D3/6-311++G(d,p)−SDD (Ru), SMD (1,2-
dichlorobenzene)//B3LYP-D3/6-31G(d)−LANL2DZ (Ru) level of
theory, with Ru2 as the catalyst and 5a as the substrate (see
Supporting Information).
Figure 4. Calculated electronic energy and forming bond lengths
along the IRC of the C−H amidation reaction catalyzed by Ru4 at the
B3LYP-D3/6-31G(d)−LANL2DZ (Ru) level of theory.
Scheme 4. Control Experiments for Elucidating the
Mechanism
phenyl moiety provided an almost quantitative yield but with a
reduced enantioselectivity (6c). An electron-withdrawing nitro
substituent at the para-position of the phenyl moiety gave 84%
yield with 95:5 er (6d). Halogen substituents at the para-
position of the phenyl moiety were also well tolerated and
provided high yields and good enantioselectivities (6e, 6f). Of
note, both the brominated (6e) and iodinated (6f) γ-lactam
products were improved to >99:1 er after a single
recrystallization in ethyl acetate (see SI for details).22
Replacing the phenyl moiety with a sterically more demanding
naphthyl moiety provided the desired lactam product (6g)
with 95% yield and 92:8 er. A substrate with the
heteroaromatic thiophene (6h) afforded a lower yield with
94:6 er.
Next, we performed reactions of 1,4,2-dioxazol-5-ones with
alkynyl substituents adjacent to the γ-C−H group, which
afforded chiral γ-alkynyl lactams in 61−81% yield and with up
to 95:5 er (6i−m). It is noteworthy that a terminal alkyne (γ-
lactam 6i) and trimethylsilyl (TMS)-functionalized alkyne (γ-
lactam 6m) were not included in previous reports on the direct
enantioselective C−H amidation using 1,4,2-dioxazol-5-
ones.10−12 Finally, with respect to substrate scope, a vinyl
group next to the γ-C−H afforded the γ-vinyl lactam 6n with
modest 42% yield and 80:20 er. If the γ-C−H is not activated
by a π-system, the yields are low, as shown for the adamantyl
product 6o.23 The synthesis of a chiral isoindolinone (6p) and
a desymmetrization generating two stereocenters (6q) are also
shown in Scheme 2.
Gram-Scale Reactions and Synthetic Applications.
The practical value of our developed C−H amidation catalyst
was demonstrated in a gram-scale synthesis of (S)-6e with a
catalyst loading of 0.02 mol % (Scheme 3a). Interestingly, the
isolation of the desired C−H amidation product was
performed without column chromatography by only precip-
itation24 and crystallization in 74% yield and with >99:1 er. It
is noteworthy that the catalyst loading can be further reduced
to merely 0.005 mol % to provide (S)-6e with 56% yield and
>99:1 er (TON number = 11 200) at the same reaction scale.25
We believe this is the highest TON number reported for
asymmetric transition metal complex catalyzed ring-closing C−
catalyst loading was further reduced (entries 7−9). At a
catalyst loading of just 0.05 mol % the intramolecular C−H
amidation still occurred with 93% yield and 95:5 er.
Substrate Scope. With the optimized catalyst and reaction
conditions in hand, we performed a substrate scope (Scheme
2). A methyl group in para-position of the phenyl moiety was
well tolerated and provided 96% yield with 95:5 er (6b). An
electron-donating methoxy group in the para-position of the
D
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Figure 5. Calculated structures of ruthenium nitrene complexes at the B3LYP-D3/6-31G(d)−LANL2DZ (Ru) level of theory. Interatomic
distances are in angstroms (Å). Bolded numbers in orange indicate Hirshfeld charges on individual atoms.
H nitrogenations. A gram-scale synthesis was also demon-
strated for the terminal alkyne-functionalized γ-lactam (S)-6i,
obtained in 60% yield with 92:8 er.
(IV), and subsequent release of the lactam product finishes the
whole catalytic cycle.
We started our mechanistic study by investigating the
influence of the relative stereochemistry of the new ruthenium
catalyst scaffold on promoting C−H amidation reactivity. The
complex rNHCRu features non-C2-symmetry, whereas all
catalysts previously developed in our group for asymmetric
C−H aminations (Ru4-Ru6) display C2-symmetry, but only
provide the undesired Curtius-type rearrangement products
(Table 1, entries 4−6). To evaluate the importance of the
relative stereochemistry around the metal center and the
potential electronic role of the rNHC ligands, we synthesized
the C2-symmetric diastereomer of rNHCRu (C2-rNHCRu,
Figure 1c) and subjected it to standard reaction conditions
with dioxazolone 5a. Revealingly, the Curtius-type rearrange-
ment product 7 was formed as the major reaction product in
60% yield with only 38% C−H amidation, demonstrating that
the relative stereochemistry of rNHCRu has a significant effect
on the reaction outcome (Scheme 4a).
Chiral γ-lactams are useful intermediates for the synthesis of
bioactive molecules such as natural products and drugs. For
example, the γ-lactam (R)-6e has been reported as an
intermediate for the synthesis of a compound for the treatment
of inflammatory disorders and a hydroxamate-based inhibitor
of deacetylases B.26 Chiral γ-lactam (S)-6i, containing a
terminal alkyne, was reported as a synthetic intermediate used
in the total syntheses of the natural products (−)-isoretrone-
canol, (−)-heliotridane,27 and the GABA aminotransferase and
glutamic acid decarboxylase inhibitor (S)-(+)-4-amino-5-
hexynoic acid28 (Scheme 3b). (S)-6i was previously synthe-
sized in multiple steps starting from chiral amino acids or
amino esters.27,28
Mechanistic Studies. The proposed mechanism is shown
in Figure 3. The reaction is initiated by ruthenium (I)
coordination to the 1,4,2-dioxazol-5-one (intermediate II). A
subsequent fragmentation and release of CO2 gas generates the
ruthenium-imido intermediate III, followed by stereocon-
trolled insertion of the nitrene moiety into the C−H bond
An intermolecular KIE value of 1.2 was determined by
measuring initial C−H amidation rates of nondeuterated and
bis-deuterated substrates (Scheme 4b).29 The C−H amida-
tions with a substrate bearing a benzylic-CHD stereocenter
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Figure 6. Calculated C−H amidation and Curtius rearrangement transition states at the M06-D3/6-311++G(d,p)−SDD (Ru), SMD (1,2-
dichlorobenzene)//B3LYP-D3/6-31G(d)−LANL2DZ (Ru) level of theory. Interatomic distances are in angstroms (Å). Energies are in kcal/mol.
Activation barriers are calculated with respect to the lowest-energy conformers of Ru nitrene intermediate III.
were tested by using different rNHCRu catalysts. Both Λ- or
Δ-rNHCRu gave a KIE value of 1.1, while C2-rNHCRu, the
C2-symmetric diastereomer of rNHCRu, afforded a KIE value
of 1.3. Low KIE values were also obtained in related work by
Chang, Yu, and Chen using dioxazolones as nitrene
precursors.7,10−12 These results indicate a singlet nitrene
insertion with a concerted N−C and N−H formation
pathway,30 although a stepwise radical reaction through a
triplet nitrene cannot be totally excluded. We also tested the
stereochemistry of the reaction by subjecting the nonracemic
(99:1 er) chiral substrate (R)-5a-Me to the C−H amidation
conditions. As a result, (S)-6a-Me with retention of
configuration at the reacted carbon was obtained as the
major product with both Λ- and Δ-rNHCRu, but the Λ-
catalyst reacts significantly faster with higher yield and affords
the γ-lactam with a higher enantiomeric excess, thus revealing a
high stereochemical discrimination between the two enantio-
topic C−H bonds (Scheme 4c).
To reveal how the non-C2-symmetric catalysts improve
selectivity for the desired C−H amidation pathway over the
undesired Curtius rearrangement, we performed DFT
calculations. The electrophilicity of the nitrene fragment is
expected to be an important factor in determining C−H
amidation versus Curtius rearrangement reactivity. Curtius
rearrangements favor electrophilic nitrenes and are well-known
to be catalyzed by Lewis or Brønsted acids.32,33 The C−H
amidation pathway, on the other hand, requires more
nucleophilic nitrenes due to its concerted but asynchronous
nature. The calculated intrinsic reaction coordinate (IRC) for
the C−H amidation catalyzed by Ru4 shows that the N−H
bond formation occurs first, driven by nitrene lone pair
donation into σ*C−H (Figure 4). This is followed by rotation of
the nitrene moiety to align its empty p orbital with the
deprotonated nucleophilic carbon, which allows the N−C
bond to form. A more electron-rich nitrene with stronger
donor ability is therefore essential for lowering the C−H
amidation barrier.7
Transition metal nitrenoids have been reported to transfer
the nitrene fragment to phosphines to furnish iminophosphor-
anes.31 To gain experimental evidence for the formation of an
intermediate ruthenium nitrenoid in our catalytic system, we
performed a trapping experiment with PPh3 using a
dioxazolone substrate (5t) that is not capable of undergoing
an intramolecular δ-C−H insertion (Scheme 4d). As a result,
the expected iminophosphorane 6t was formed in 81% yield
under our standard reaction conditions, which is consistent
with our assumption that the ruthenium-catalyzed reaction
proceeds through an intermediate ruthenium nitrenoid.
Calculated structures of ruthenium N-acylnitrenes (8a−c)
formed with the three model catalysts Ru3, its C2-symmetric
diastereomer C2-Ru3, and Ru4 are shown in Figure 5. Both
Ru3 and C2-Ru3 bear rNHC ligands, while Ru4 has normal
NHC (nNHC) ligands. Hirshfeld charge analysis shows that
rNHC-bearing 8a (from Ru3) and 8b (from C2-Ru3) have
more electron-rich nitrene fragments (highlighted in green)
than 8c.34 This is consistent with the expected higher σ-
donating ability of rNHC over nNHC ligands.5 The calculated
structures also reveal another factor that influences the
electron-richness of the nitrenes, namely, NCH···OC
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1.6 kcal/mol). For Ru4, Curtius rearrangement is more facile
with a barrier of 10.5 kcal/mol, while the C−H amidation
barrier increases to 15.1 kcal/mol. The large ΔΔG⧧ of 4.6
kcal/mol is consistent with the experimental observation that
Ru4 leads exclusively to the Curtius rearrangement product.
Aside from higher nitrene electrophilicity, we hypothesized
that steric factors may also play a role. In Ru4 two mesityl
groups are in close vicinity to the active site and may disfavor
C−H amidation because of the more sterically demanding
transition state, in which the nitrene alkyl chain must fold into
a particular conformation in order to cyclize. To assess the role
of steric effects, we calculated the C−H amidation and Curtius
rearrangement transition states for Ru4-Me, a modified version
of Ru4 in which the large N-Mes groups are replaced with
sterically less demanding N-Me groups (see Supporting
Information). Surprisingly, the Curtius rearrangement pathway
is still favored by 4.3 kcal/mol, only 0.3 kcal/mol less than for
Ru4. These results indicate that nitrene electrophilicity and not
sterics is the dominant factor in determining C−H amidation
versus Curtius rearrangement selectivity.37
Finally, we calculated C−H amidation transition states for
the reaction 5a → 6a catalyzed by Λ-Ru2, leading to different
enantiomers of the lactam product (Figure 7). TS-1, which
leads to the major enantiomer (S)-6a, is favored by 1.8 kcal/
mol, in good agreement with the observed er of 94:6 (ΔΔG⧧ =
1.6 kcal/mol). A stabilizing π−π stacking interaction exists
between the nitrene phenyl group and the rNHC ligand. In
TS-1-ent, the cyclizing nitrene fragment is oriented quite
differently, with two weaker π−π stacking interactions between
the nitrene phenyl group and the phenyl substituents on the
rNHC ligands.
Our calculations also established the energetic feasibility of
the proposed catalytic cycle (Figure 3). After coordination of
the substrate to the Ru center, extrusion of CO2 to furnish III
is exergonic (−17.9 kcal/mol for Ru2 and 5a). Both C−H
amidation and Curtius rearrangement pathways have low
barriers, consistent with the observation that the reactions
generally proceed at room temperature or below.
Figure 7. Calculated C−H amidation transition states leading to
major and minor lactam enantiomers at the M06-D3/6-311+
+G(d,p)−SDD (Ru), SMD (1,2-dichlorobenzene)//B3LYP-D3/6-
31G(d)−LANL2DZ (Ru) level of theory. Interatomic distances are in
angstroms (Å). Energies are in kcal/mol. Activation barriers are
calculated with respect to the lowest-energy conformer of Ru nitrene
intermediate III.
hydrogen bonds between the carbonyl group of the acylnitrene
and the polarized C−H bond in 2-position of the closeby
pyridyl ligand. This NCH···OC hydrogen bond is
significantly stronger in 8b (2.17 Å) and 8c (2.05 Å), which
are both derived from C2-symmetric catalysts, than in 8a (2.30
Å) derived from a non-C2-symmetric catalyst. In 8a, the metal’s
coordination bond to one of the pyridine nitrogens is
lengthened (2.24 Å, versus 2.15 Å in 8b and 8c) due to
being positioned trans to the strongly σ-donating rNHC
carbene carbon.35,36 The longer Ru−N(pyridine) bond leads
to a more electron-rich pyridine nitrogen and a less acidic α-
CH bond, which consequently weakens the NCH···OC
hydrogen bond in 8a over 8b and 8c. Both Hirshfeld charges
and orbital energies (see Figure 5) show that the overall
nucleophilicity of the nitrene fragment decreases in the order
of 8a > 8b > 8c, predicting that rNHC-bearing, non-C2-
symmetric catalysts should be the most selective for C−H
amidation, in agreement with the experimental results (Table
1, entries 1−3).
CONCLUSIONS
■
In conclusion, we have introduced a new class of chiral
ruthenium catalysts and have elucidated the role of the relative
metal-centered configuration and electronic characteristics of
the coordinated rNHC ligands for catalytic activity. The non-
C2-symmetric scaffold exhibits a unique core structure with two
chelating pyridylidene remote NHC ligands that provide high
electron density at the ruthenium and at the same time are
responsible for the overall chirality through a helical arrange-
ment in the coordination sphere. The catalyst rNHCRu shows
an exceptional catalytic activity for the enantioselective C−H
amidation of 1,4,2-dioxazol-5-ones to chiral γ-lactams, reaching
TONs of up to 11 200 (0.005 mol % catalyst loading). We
believe that such a low catalyst loading is unprecedented for
enantioselective C−H nitrogenations with nonenzymatic
catalysts.38 Interestingly, the C2-symmetric diastereomer of
rNHCRu, as well as previously reported C2-symmetric
ruthenium catalysts suitable for enantioselective C−H
aminations, provides instead an undesired Curtius-type
rearrangement as the main product. DFT calculations reveal
that the combination of strongly electron-donating remote
NHC ligands and the non-C2-symmetric arrangement of these
ligands in the coordination sphere provides an especially
electron-rich ruthenium nitrene intermediate favorable for an
Figure 6 shows the calculated transition states for the C−H
amidation and Curtius rearrangement with substrate 5a and
the catalysts Ru2 (non-C2-symmetry) and Ru4 (C2-symmetry).
For Ru2, C−H amidation proceeds with a barrier of 11.4 kcal/
mol, 1.4 kcal/mol lower than for the Curtius rearrangement
pathway. This result is in excellent agreement with the
experimentally observed product ratio (6a:7 = 92:7, ΔΔG⧧ =
G
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relative metal-centered stereochemistry (non-C2- vs C2-
symmetry) is therefore crucial for the reactivity and fate of
the catalyzed reaction, while the absolute metal-centered
stereochemistry (Λ vs Δ) determines the absolute config-
uration of the C−H amidation product. Thus, whereas C2-
symmetric chiral transition metal catalysts are typically
desirable for reducing the number of competing processes
and transition states, in this catalyst architecture only the
diastereomer with lower symmetry provides the desired
catalytic activity. Future work will investigate other chiral
ruthenium catalyst architectures with decreased symmetry for
applications in asymmetric catalysis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b09301.
■
S
Experimental procedures, compound characterization
data, NMR spectra, HPLC traces, crystallographic data,
and details of the computational study (PDF)
Crystallographic data for (S)-6e (CIF)
Crystallographic data for Λ-Ru3 (CIF)
Crystallographic data for Λ-(S)-S12 (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*houk@chem.ucla.edu
*meggers@chemie.uni-marburg.de
ORCID
Shuming Chen: 0000-0003-1897-2249
K. N. Houk: 0000-0002-8387-5261
Eric Meggers: 0000-0002-8851-7623
Author Contributions
§Z.Z. and S.C. contributed equally.
(8) For 1,4,2-dioxazol-5-one as nitrene precursor for intermolecular
allylic C-H amidations, see: (a) Lei, H.; Rovis, T. Ir-catalyzed
intermolecular branch-selective allylic C-H amidation of unactivated
terminal olefins. J. Am. Chem. Soc. 2019, 141, 2268. (b) Knecht, T.;
Mondal, S.; Ye, Y.; Das, M.; Glorius, F. Intermolecular, branch-
selective, and redox neutral Cp*IrIII-catalyzed allylic C-H amidation.
Angew. Chem., Int. Ed. 2019, 58, 7117. (c) Burman, J. S.; Harris, R. J.;
Farr, C. M. B.; Bacsa, J.; Blakey, S. B. Rh(III) and Ir(III)Cp*
complexes provide complementary regioselectivity profiles in
intermolecular allylic C-H amidation reactions. ACS Catal. 2019, 9,
5474.
(9) For earlier work on utilizing 1,4,2-dioxazol-5-ones as nitrene
precursors, see: (a) Zhong, C. L.; Tang, B. Y.; Yin, P.; Chen, Y.; He,
L. Synthesis of 2,5-disubstituted oxazoles and oxazolines catalyzed by
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ruthenium-catalyzed nitrene transfer reactions: a photochemical
approach towards N-acyl sulfimides and sulfoximines. Angew. Chem.,
Int. Ed. 2014, 53, 5639. (c) Wang, H.; Tang, G.-D.; Li, X.-W.
Rhodium(III)-catalyzed amidation of unactivated C(sp3)-H bonds.
Angew. Chem., Int. Ed. 2015, 54, 13049. (d) Wang, F.; Jin, L.; Kong,
L.; Li, X.-W. Cobalt(III)- and Rhodium(III)-catalyzed C-H amidation
and synthesis of 4-quinolones: C-H activation assisted by weakly
coordinating and functionalizable enaminone. Org. Lett. 2017, 19,
1812. (e) Hermann, G. H.; Bolm, C. Mechanochemical rhodium(III)-
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Y.; Xie, F.; Jia, A.-Q.; Li, X.-W. Cp*Co(III)-catalyzed amidation of
Notes
The authors declare no competing financial interest.
Crystallographic data for (S)-6e, Λ-Ru3, and Λ-(S)-S12 have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
1910815, 1910816, and 1910817, respectively.
ACKNOWLEDGMENTS
■
E.M. gratefully acknowledges funding from the Deutsche
Forschungsgemeinschaft (ME 1805/15-1). K.N.H. is grateful
to the National Science Foundation (Grant CHE-1764328) for
financial support. Calculations were performed on the
Hoffman2 cluster at the University of California, Los Angeles,
and the Extreme Science and Engineering Discovery Environ-
ment (XSEDE), which is supported by the National Science
Foundation (Grant OCI-1053575).
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