Copper-Catalyzed Aerobic Enantioselective Cross-Dehydrogenative Coupling of N-Aryl Glycine Esters with Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.6b01328

A copper-catalyzed enantioselective cross-coupling of a C_sp3-H moiety (N-aryl glycine ester) with a C_sp-H component (terminal alkyne) using molecular oxygen as the terminal oxidant is described for the first time. The sustainable met

Full text of DOI:10.1021/acs.orglett.6b01328

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Aerobic Enantioselective Cross-Dehydrogenative
Coupling of N‑Aryl Glycine Esters with Terminal Alkynes
Zhiyu Xie,†,‡,∥ Xigong Liu,†,∥ and Lei Liu*,†,§
†School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
§School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
‡College of Chemistry and Chemical Engineering, Xuchang University, Xuchang 461000, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed enantioselective cross-cou-
pling of a Csp3−H moiety (N-aryl glycine ester) with a Csp−H
component (terminal alkyne) using molecular oxygen as the
terminal oxidant is described for the first time. The sustainable
method provides an efficient and environmentally friendly
approach to rapidly prepare a diverse array of optically active
non-natural α-amino acids.
he construction of C−C bonds through cross-dehydrogen-
as drug discovery projects. Thus, general methods to prepare
Tative coupling (CDC) of two easily accessible C−H chiral non-natural α-amino acids by direct modifying natural
moieties are highly desirable.8 Glycine is the simplest and
components under oxidative condition has emerged as one of the
cheapest natural amino acid. Therefore, the catalytic enantiose-
lective CDC of glycine derivatives with a variety of commercially
available C−H components would provide a straightforward and
rapid access to a high-quality collection of chiral non-natural α-
amino acids bearing diverse substituents at the α-position for
subsequent manipulation and application.9 The Wang group
established the first catalytic enantioselective CDC of N-aryl
glycine esters with β-ketoesters mediated by DDQ, generating a
series of chiral α-alkylated glycine derivatives.5e Despite great
innovation, two aspects merit further comment. First, DDQ is
moderately expensive and poses modest toxicity concerns (LD50
= 82 mg/kg), the potential for HCN liberation upon exposure to
H2O, and the purification difficulties. The employment of
molecular oxygen as the terminal oxidant would be highly
desirable based on economical and environmental factors.
Second, the ability of the ketoester moieties to engage in the
subsequent manipulation was relatively limited. In contrast,
alkynes are outstanding precursors for functionally diverse
structures due to the ability to participate in numerous
transformations. The Li group reported a nonenantioselective
TBHP-mediated CDC of glycine amides with arylacetylenes.10
However, no reactivities were observed for simple alkyl
acetylenes with broader synthetic utilities as well as the
corresponding glycine esters. To the best of our knowledge, a
catalytic enantioselective CDC of glycine derivatives with
terminal alkynes has not been disclosed to date. Herein, we
report the first aerobic catalytic enantioselective CDC of Csp3−H
moieties with Csp−H components.
most straightforward and economical approaches for increasing
molecular complexity and functional group content with minimal
waste generation.1,2 Despite significant progress, existing CDC
reactions typically require the use of a stoichiometric oxidant
such as DDQ, TBHP, and IBX, which generate undesired waste.
More ideal molecular oxygen as the oxidant in view of
economical and ecological aspects with H2O as the only
byproduct has not been well adopted for the process.3 On the
other hand, the development of the catalytic enantioselective
CDC variant remains a formidable challenge.4,5 Consequently,
only few examples of aerobic enantioselective CDC have been
established to date.6 Cui and Jiao reported an organocatalytic
enantioselective α-alkylation of aldehydes with xantheses.6a Xu
disclosed an enantioselective β-alkylation of aldehydes with
dialkyl malonates by merging oxidative enamine and palladium
catalysis.6b Gong and Meggers documented a rhodium-catalyzed
enantioselective CDC of amines with ketones.6d All these
transformations involve the oxidative coupling of a Csp3−H
component with the other reactive Csp3−H bond adjacent to the
carbonyl moiety. Wang reported an enantioselective olefination
of N-arylated tetrahydroisoquinolines with α,β-unsaturated
carbonyls, involving the aerobic oxidative coupling of the
Csp3−H bond adjacent to amines with the Csp2−H bond adjacent
to the carbonyl group.6e To the best of our knowledge, no
example of aerobic, catalytic enantioselective CDC reaction
involving a Csp−H component like the terminal alkyne has been
established.
Optically active α-amino acids are fundamental subunits
spread across numerous pharmaceutical agents and have been
widely utilized as chiral auxiliaries and catalysts in organic
synthesis.7 More importantly, integrating non-natural (syn-
thetic) amino acids into existing bioactive peptides has been
identified as an effective optimizing strategy in proteomics as well
Initially, the CDC of N-aryl glycine ester 1a with arylacetylene
2a using molecular oxygen as the oxidant was selected as the
Received: May 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01328
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Letter
model reaction for optimization (Table 1). No reaction took
place in the absence of any metal additive (Table 1, entry 1).
explored (Scheme 1). A variety of the electronically varied aryl
acetylenes with different substituent patterns were well
a
a
Table 1. Reaction Condition Optimization
Scheme 1. Scope of the Terminal Alkynes
a
Reaction condition: 1a (0.1 mmol), L4 (0.01 mmol), and Cu(OTf)2
(0.01 mmol) in toluene (1.0 mL) under 1 atm molecular oxygen at 40
°C for 2 h, followed by the addition of 2 (0.2 mmol) under N2
atmosphere overnight.
compatible with the system, providing expected α-alkynylated
glycine esters 3a−3f in good er value and yields. Classically, the
efficient synthesis of glycine derivatives bearing alkyl acetylenes
at the α-position has proved to be challenging probably due to
the reduced reactivity of alkyl acetylenes.10,11 Excitedly, such
components like 2g−2i participated in the aerobic catalytic
enantioselective CDC process smoothly with even better
enantiomeric ratio (up to 93.5:6.5 er) than aryl acetylenes.
Additionally, alkyl acetylenes with commonly encountered
functional group such as cyclopropyl (2j), silyl ether (2k), and
benzyl ether (2l) were also well tolerated. Given that alkyl
acetylenes are excellent precursors for functionally diverse
structures due to the ability to engage in numerous trans-
formations, the method displays the capability in creating
diversely functionalized chiral non-natural α-amino acid
derivatives in high efficiency.
The scope of glycine derivatives 1 was next explored (Scheme
2). The electronic substituent effect on the aniline moiety was
first studied. Monomethyl substituted aniline 1a in Scheme 1
proved to be the best substrate in terms of the enantiomeric ratio
and yields. Replacing the methyl substituted aniline with either
more electron-rich 4b and 4c or -deficient 4d and 4e led to a drop
in both efficiency and er value. The steric substituent effect of
ester moieties was then investigated. Isopropyl ester 4f provided
better er value than those of ethyl (3b) and isobutyl (4g and 4h)
a
Reaction condition: 1a (0.1 mmol), ligand (0.01 mmol), and
Cu(OTf)2 (0.01 mmol) in toluene (1.0 mL) under 1 atm molecular
oxygen at 40 °C for 2 h, followed by the addition of 2a (0.2 mmol)
under N2 atmosphere overnight. Isolated yield. Determined by
HPLC analysis on a chiral stationary phase. Air instead of oxygen.
n.d. = not determined.
b
c
d
Cu(OTf)2 proved to be able to catalyze the CDC reaction (entry
2). A systematic exploration of chiral ligands L1−L8 and metal
sources revealed that pybox L4 with Cu(OTf)2 should be the
ideal combination in terms of the enantiomeric ratio and the
yield (entries 3−13). The further study on the solvent effect
identified toluene to be optimal (entries 14−17). Replacing
molecular oxygen with air gave an inferior result (entry 18).
The scope of the aerobic catalytic enantioselective CDC of N-
aryl glycine ester 1a with a variety of terminal acetylenes was
B
DOI: 10.1021/acs.orglett.6b01328
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involving the premixing of L4 and Cu(OTf)2 followed by the
addition of 1a and 2a proved to be the best sequence (Scheme
3d), whereas performing the oxidation of 1a with Cu(OTf)2 and
molecular oxygen followed by the introduction of L4 and 2a
afforded an inferior er value (Scheme 3e).
Scheme 2. Scope of the Glycine Esters
The control experiments together with the absolute
configuration of the outcome suggested a preliminary model
for enantioinduction (Scheme 4).11 It was proposed that by
Scheme 4. Proposed Stereochemical Model
coordination of the imino ester to the copper center in a
bidentate fashion, the imino ester is activated for addition
through 6b, providing the expected (R)-3a.12 Significant steric
hindrance between the aryl substituent of the imino ester and the
R1 group of the ligand destabilizes the transition state 6a that
would lead to the opposite enantiomer of the product.
ones. The aryl group linked to the nitrogen was crucial to the
reaction, and no reactivity was observed for N-alkyl glycine ester
4i or N-acyl 4j.
In conclusion, the first catalytic enantioselective cross-
coupling of a Csp3−H component with Csp−H moiety using
molecular oxygen as the terminal oxidant has been described.
The Cu(OTf)2-catalyzed CDC of N-aryl glycine esters with a
wide variety of alkyl as well as aryl acetylenes bearing common
functional groups proceeded smoothly, rapidly providing a large
array of diverse chiral non-natural α-amino acid derivatives in
good efficiency and enantiomeric ratio. We envision that the
sustainable method outlined herein will have potential
applications in increasingly significant proteomics and peptide-
based drug discovery research.
In the presence of pybox L4 and Cu(OTf)2 under molecular
oxygen atmosphere, N-aryl glycine ester 1a was converted to an
intermediate detected by TLC analysis, which was identified as
the α-imino ester 5 (Scheme 3a). Subjecting 5 to the catalytic
Scheme 3. Control Experiments for Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01328.
Experimental details and spectral data for new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: leiliu@sdu.edu.cn.
Author Contributions
∥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
enantioselective alkynylation conditions providing expected 3a
in comparable er value to that of the CDC starting from N-aryl
glycine ester 1a (Scheme 3b), suggesting that 5 should be an
intermediate for the process. Recently, α-imino esters were
disclosed to be prepared through the autoxidation of N-aryl
glycine ester precursors.6d,9f Therefore, the role of Cu(OTf)2 was
next examined. No expected 5 was observed in the absence of
Cu(OTf)2 under molecular oxygen atmosphere, indicating the
involvement of Cu(OTf)2 in the oxidation process (Scheme 3c).
The addition sequence of reaction components proved to be
crucial to the enantioselectivity. The standard procedure
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Science Foundation of
China (21472112), the Program for New Century Excellent
Talents in University (NCET-13-0346), Fok Ying Tung
Education Foundation (151035), the Shandong Science Fund
for Distinguished Young Scholars (JQ201404), and the
Fundamental Research Funds of Shandong University
(2014JC005, 2015JC035). Z.X. acknowledges Xuchang Uni-
versity Research Fund Project (2016088).
C
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(11) The absolute configuration was assigned according to the
literature: Rueping, M.; Antonchick, A. P.; Brinkmann, C. Angew. Chem.,
Int. Ed. 2007, 46, 6903.
(12) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
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