Direct enantioselective C(sp3)-H acylation for the synthesis of α-amino ketones

Article abstract of DOI:10.1021/jacs.0c10471

A direct enantioselective acylation of α-amino C(sp3)-H bonds with carboxylic acids has been achieved via the merger of transition metal and photoredox catalysis. This straightforward protocol enables cross-coupling of a wide range of carboxylic acids, one class of feedstock chemicals, with readily available N-alkyl benzamides to produce highly valuable α-amino ketones in high enantioselectivities under mild conditions. The synthetic utility of this method is further demonstrated by gram scale synthesis and application to late-stage functionalization. This method provides an unprecedented solution to address the challenging stereocontrol in metallaphotoredox catalysis and C(sp3)-H functionalization. Mechanistic studies suggest the α-C(sp3)-H bond of the benzamide coupling partner is cleavage by photocatalytically generated bromine radicals to form α-amino alkyl radicals, which subsequently engages in nickel-catalyzed asymmetric acylation.

Full text of DOI:10.1021/jacs.0c10471

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Direct Enantioselective C(sp3)−H Acylation for the Synthesis of
α‑Amino Ketones
Xiaomin Shu,† Leitao Huan,† Qian Huang, and Haohua Huo*
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ABSTRACT: A direct enantioselective acylation of α-amino C(sp3)−H bonds with carboxylic acids has been achieved via the
merger of transition metal and photoredox catalysis. This straightforward protocol enables cross-coupling of a wide range of
carboxylic acids, one class of feedstock chemicals, with readily available N-alkyl benzamides to produce highly valuable α-amino
ketones in high enantioselectivities under mild conditions. The synthetic utility of this method is further demonstrated by gram scale
synthesis and application to late-stage functionalization. This method provides an unprecedented solution to address the challenging
stereocontrol in metallaphotoredox catalysis and C(sp3)−H functionalization. Mechanistic studies suggest the α-C(sp3)−H bond of
the benzamide coupling partner is cleavage by photocatalytically generated bromine radicals to form α-amino alkyl radicals, which
subsequently engages in nickel-catalyzed asymmetric acylation.
hiral α-amino ketone is a privileged motif found in many
the C−H cleavage proceeds through the single electron
transfer (SET) or hydrogen atom abstraction (HAT) process,
which overcomes the limitations often associated with classic
C−H activation, including the requirements for coordinating
directing groups and high reaction temperatures. Although
substantial efforts have been devoted to the realm of
metallaphotoredox catalysis, enantioselective metallaphotore-
dox catalysis remains underexplored,11 especially for C(sp3)−
H functionalization.12 Herein, we report an unprecedented
metallaphotoredox-mediated enantioselective C(sp3)−H acy-
lation reaction for the synthesis of highly valuable and
enantienriched α-amino ketones from readily available
materials (Figure 1c). We envision that a photocatalyst-
induced hydrogen atom abstraction (HAT) of an α-amino
C(sp3)−H bond would produce a prochiral α-amino radical.
Meanwhile, a chiral nickel catalyst could engage sequentially
with the acyl electrophiles formed in situ from carboxylic acids
and α-amino radicals through oxidative addition and radical
capture. The resulting diorganonickel adduct would undergo
reductive elimination to produce enantioenriched α-amino
ketones.
C
important pharmaceutically active agents (Figure 1a).1
Despite its importance in medical science, the development of
direct yet robust strategies for the enantioselective synthesis of
this pharmacophore remains an important challenge in organic
synthesis.2 Limited successful examples generally rely on
asymmetric electrophilic or nucleophilic amination of carbonyl
compounds (Figure 1b). However, asymmetric electrophilic α-
amination of ketone enolates (top of Figure 1b) often suffers
from mixed enolate formation for dialkyl ketones and requires
specific nitrogen electrophiles (e.g., azodicarboxylates) to
deliver products that necessitates additional transformation
to deliver synthetic useful compounds.3 Recently, several
elegant approaches for nucleophilic α-amination have been
described by employing free amines as the nitrogen source
(bottom of Figure 1b).2 These methods require additional
steps to prepare α-functionalized carbonyl compounds such as
α-bromo cyclic ketones, α-diazo ketones, and α-carbonyl
sulfonium ylides.
As an alternative to α-amination processes, asymmetric
acylation of α-amino C(sp3)−H bonds provides straightfor-
ward and modular access to α-amino ketones via C−C bond
construction.4 Whereas transition-metal-catalyzed enantiose-
lective C(sp3)−H functionalization is a persistent challenge in
asymmetric catalysis,5,6 there is a growing need for the
development of new C−H bond activation and late-stage
functionalization reactions that proceed with nontraditional
disconnections.7
Our investigation began with optimizing reaction conditions
for the cross-coupling of commercially available butyric acid
and N-pentyl benzamide (Figure 2).13 We chose dimethyl
dicarbonate (DMDC) as the activator to convert butyric acid
to a mixed anhydride in situ. This elegant acid activation
strategy has been previously employed in ketone synthesis.14
Notably, commercially available, bench-stable carboxylic acids
In recent years, transition metal and photoredox dual
catalysis, particularly photoredox nickel catalysis, has emerged
as a powerful tool to construct chemical bonds that are difficult
to form via traditional two-electron pathways.8 For examples,
nickel-mediated photoredox catalysis has enabled the direct
C(sp3)−H functionalization of both feedstock hydrocarbons
and complex molecules by leveraging nickel’s unique ability in
alkyl fragment couplings.9 In these photochemical methods,10
Received: September 30, 2020
https://dx.doi.org/10.1021/jacs.0c10471
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© XXXX American Chemical Society
A

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Figure 1. Bioactive α-amino ketone motifs and approaches for their
asymmetric synthesis. (a) Examples of pharmaceutically active agents
possessing α-amino ketone motifs. (b) Classic approaches for the
asymmetric synthesis. (c) This study.
Figure 2. Effect of reaction parameters for photocatalytic
enantioselective acylation.
when the carboxylic acid was functionalized with a variety of
functional groups, including a phenyl group, a trifluoromethyl
group, a nitrile, an ester, an alkyl chloride, an alkyl bromide,
and a thiophene (9−15). Our protocol allowed for the
coupling of not only alkyl carboxylic acids but also aromatic
carboxylic acids with diverse electronic properties (16−21),
complementing existing methods for asymmetric synthesis of
α-amnio ketones based on organocatalytic α-amination
reactions.2,3
The acylation reaction tolerated benzamides bearing alkyl
groups with different steric properties (22−26). Various
functional groups, such as an ester, an alkyl chloride, an alkyl
bromide, an alkyl ether, a silyl ether, and an acetate, were well
compatible (27−32). The alkyl halides provided versatile
synthetic handles for further functionalization. The R
substituent at the nitrogen protected group could be varied
as well (33−37).
can offer practical advantages over other acyl surrogates such
as chemically sensitive anhydrides, acyl halides, preformed
thioesters and amides.15 After extensive investigation (also see
Supporting Information), it was revealed that a chiral nickel/
(bis-oxazoline) catalyst and a known Ir-photocatalyst could
accomplish the desired acylation to deliver the aminoketone
product in 90% yield and 92% ee (entry 1). Control
experiments showed that nickel, chiral ligand, photocatalyst,
and light are essential for product formation (entries 2−4).
The reaction run under air in a closed vial or without NH4Cl
afforded unaltered enantioselectivity, albeit with slightly
reduced yield (entries 5 and 6). Raising the reaction
temperature to room temperature had almost no effect on
the acylation reaction (entry 7). While Boc2O was less effective
than DMDC (entry 8), the use of EA or dioxane as solvent led
to a comparable outcome (entries 9 and 10). Two other
commercially available chiral ligands L1 and L2 can deliver the
product in good yield but with poor asymmetric induction
(entries 11 and 12).
The exceptionally mild conditions and fairly broad func-
tional group tolerance of our method prompted us to apply it
to late-stage functionalization of natural products and drug
molecules. Indeed, the present method could be used to
produce an array of chiral α-amino ketones containing a
pharmacophore or bioactive fragments in good stereo-
selectivities (38−49).
With the optimized reaction conditions in hand, we
investigated the scope of direct cross-coupling of carboxylic
acids and N-alkyl benzamides (Figure 3). Carboxylic acids with
different steric properties were suitable acyl donors (1−8).
Remarkably, good yields and enantioselectivities were obtained
To further demonstrate the synthetic utility of the present
method, a gram-scale synthesis of 20 was performed with
B
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Figure 3. Catalytic enantioselective acylation of α-amino C(sp3)−H bonds with carboxylic acids. All data represent the average of two experiments.
Unless otherwise stated, reactions were conducted on a 0.5 mmol scale under standard conditions. aIn lieu of the standard conditions, 10% Ni and
13% chiral ligand were used. bIn lieu of the standard conditions, dioxane was used as solvent. cIn lieu of the standard conditions, the reaction was
conducted at 25 °C.
C
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excellent ee and synthetically useful yield (Figure 4). This
aminoketone product could be directly converted through
Figure 4. Gram-scale reaction and synthetic transformations. All data
represent the average of two experiments. Reaction conditions: (a) 4-
CF3PhMgBr, THF; (b) Cp2ZrHCl (1.2 equiv), THF; (c) DIAD,
Ph3P, DCM; (d) Cp2ZrHCl (4.0 equiv), THF.
single-step reactions into other useful enantioenriched building
blocks, such as β-amino tertiary alcohol 50, β-amino secondary
alcohol 51, chiral oxazoline ligand framework 52,16 and β-
benzyl amine 53.
To provide some insights into the reaction mechanism,
preliminary studies were conducted (Figure 5). Addition of 1
equiv of allylic sulfone to the model reaction led to a racemic
adduct 55 in 21% yield without formation of α-amino ketone
product (Figure 5a). This observation suggested that the
reaction may involve formation of α-amino radicals.
Furthermore, a primary kinetic isotope effect (KIE) was
obtained by parallel (KIE = 3.1) and competition reactions
(KIE = 4.3), which indicated that C−H cleavage has a
significant contribution to the rate-determining step (Figure
5b). The use of the nickel precatalyst free of bromide led to
less than 10% product formation (Figure 5c, entries 2 and 4).
Interestingly, the product formation could be restored by
addition of NaBr (Figure 5c, entries 3 and 5), alluding to the
crucial role of the bromide anion in the coupling reaction. It
has been reported that photocatalytic oxidation of bromide
anion, a dissociable ligand on nickel, could generate bromine
radicals for hydrogen atom abstraction from C(sp3)−H
bonds.17
Figure 5. Preliminary mechanistic studies. (a) α-Amino alkyl radical
trapping experiment. (b) Kinetic isotope effect experiments. (c) Ni-
precatalyst control experiments.
According to our mechanistic studies (also see Supporting
Information) and literature precedent,17 a possible mechanism
is proposed (Figure 6). The reaction is initiated by oxidative
addition of Ni(0) intermediate I to acyl electrophile formed in
situ to provide Ni(II) intermediate II. Concurrently, an
oxidatively generated bromine radical (E1/2[Ir(III*/II)] = +
ox
1.21 V vs SCE in CH3CN; for bromide: E1/2 = + 0.80 V vs
Figure 6. Putative catalytic cycle. R. E. = reductive elimination, O. A.
= oxidative addition.
SCE in DME)17a abstracts the hydrogen atom from α-amino
C−H bond to afford a stabilized α-amino radical, which is
readily intercepted by intermediate II. The resultant Ni(III)
intermediate III undergoes reductive elimination to generate
the final coupling product and Ni(I) intermediate IV.18 The
subsequent single electron transfer (SET) reduction of
intermediate IV by reduced photocatalyst regenerates the
(BDE = 88 kcal/mol) ensures broad functional group
tolerance of this protocol.19
In summary, a metallaphotoredox-mediated enantioselective
C(sp3)−H acylation reaction has been developed. This robust
method employs abundant, air-stable carboxylic acids and
readily available N-alkyl benzamides as coupling partners,
boasts a fairly broad substrate scope and excellent functional
group tolerance, and provides straightforward access to
red
Ni(0) intermediate I and closes the catalytic cycle (E1/2
[Ir(II/III)] = − 1.37 V vs SCE in CH3CN). This proposal
involving a key HAT process is consistent with our mechanistic
observations. The moderate bond dissociation energy of HBr
D
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important enantiomeric α-amino ketones. The development of
other classes of enantioselective radical C(sp3)−H functional-
ization reactions is underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10471.
■
sı
Crystallographic data for (S)-19 (CIF)
Crystallographic data for (S)-29 (CIF)
Experimental procedures, compound characterization
data, NMR spectra, HPLC traces, crystallographic data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Haohua Huo − State Key Laboratory of Physical Chemistry of
Solid Surfaces, Key Laboratory of Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. China; orcid.org/
0000-0003-1785-4128; Email: hhuo@xmu.edu.cn
Authors
Xiaomin Shu − State Key Laboratory of Physical Chemistry of
Solid Surfaces, Key Laboratory of Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. China
Leitao Huan − State Key Laboratory of Physical Chemistry of
Solid Surfaces, Key Laboratory of Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. China
Qian Huang − State Key Laboratory of Physical Chemistry of
Solid Surfaces, Key Laboratory of Chemical Biology of Fujian
Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10471
Author Contributions
†X.S. and L.H. contributed equally.
(4) For a seminal study based on NHC/Photoredox dual catalysis,
see: DiRocco, D. A.; Rovis, T. Catalytic Asymmetric α-Acylation of
Tertiary Amines Mediated by a Dual Catalysis Mode: N-Heterocyclic
Carbene and Photoredox Catalysis. J. Am. Chem. Soc. 2012, 134,
8094−8097.
Notes
The authors declare no competing financial interest.
Crystallographic data for (S)-19 and (S)-29 have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 2032048 and
2032050, respectively.
(5) For a review, see: (a) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.;
Wu, Q.-F.; Yu, J.-Q. Enantioselective C(sp3)−H Bond Activation by
Chiral Transition Metal Catalysts. Science 2018, 359, No. eaao4798.
(6) For selected examples, see: (a) Reyes, R. L.; Sato, M.; Iwai, T.;
Suzuki, K.; Maeda, S.; Sawamura, M. Asymmetric Remote C−H
Borylation of Aliphatic Amides and Esters with a Modular Iridium
Catalyst. Science 2020, 369, 970−974. (b) Zhang, W.; Wang, F.;
McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G.
Enantioselective Cyanation of Benzylic C−H Bonds via Copper-
Catalyzed Radical Relay. Science 2016, 353, 1014−1018. (c) Zhang,
W.; Wu, L.; Chen, P.; Liu, G. Enantioselective Arylation of Benzylic
C−H Bonds by Copper-Catalyzed Radical Relay. Angew. Chem., Int.
Ed. 2019, 58, 6425−6429. (d) Li, J.; Zhang, Z.; Wu, L.; Zhang, W.;
Chen, P.; Lin, Z.; Liu, G. Site-Specific Allylic C−H Bond
Functionalization with a Copper-Bound N-Centred Radical. Nature
2019, 574, 516−521. (e) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E.
J.; Yu, J.-Q. Pd(II)-Catalyzed Enantioselective C−H Activation of
Cyclopropanes. J. Am. Chem. Soc. 2011, 133, 19598−19601. (f) Xiao,
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ACKNOWLEDGMENTS
■
We are grateful for financial support from the NSFC
(22071203) and the Xiamen University. We thank Prof.
Gregory C. Fu (Caltech), Prof. Eric Meggers (University of
Marburg), Prof. Hai-Chao Xu (Xiamen University), and Prof.
Pei-Qiang Huang (Xiamen University) for insightful dis-
cussion. We also thank Zanbin Wei for assistance in solving the
X-ray structures.
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