Asymmetric Synthesis of Protected Unnatural α-Amino Acids via Enantioconvergent Nickel-Catalyzed Cross-Coupling

Article abstract of DOI:10.1021/jacs.1c03903

Interest in unnatural α-Amino acids has increased rapidly in recent years in areas ranging from protein design to medicinal chemistry to materials science. Consequently, the development of efficient, versatile, and straightforward methods for their enanti

Full text of DOI:10.1021/jacs.1c03903

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Asymmetric Synthesis of Protected Unnatural α‑Amino Acids via
Enantioconvergent Nickel-Catalyzed Cross-Coupling
Ze-Peng Yang,† Dylan J. Freas,† and Gregory C. Fu*
Cite This: J. Am. Chem. Soc. 2021, 143, 8614−8618
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ABSTRACT: Interest in unnatural α-amino acids has increased rapidly in recent years in areas ranging from protein design to
medicinal chemistry to materials science. Consequently, the development of efficient, versatile, and straightforward methods for their
enantioselective synthesis is an important objective in reaction development. In this report, we establish that a chiral catalyst based
on nickel, an earth-abundant metal, can achieve the enantioconvergent coupling of readily available racemic alkyl electrophiles with a
wide variety of alkylzinc reagents (1:1.1 ratio) to afford protected unnatural α-amino acids in good yield and ee. This cross-coupling,
which proceeds under mild conditions and is tolerant of air, moisture, and a broad array of functional groups, complements earlier
approaches to the catalytic asymmetric synthesis of this valuable family of molecules. We have applied our new method to the
generation of several enantioenriched unnatural α-amino acids that have previously been shown to serve as useful intermediates in
the synthesis of bioactive compounds.
he development of effective and straightforward methods
The development of radical-based methods in organic
Tto access enantioenriched unnatural (non-canonical) α- synthesis, which may complement polar/heterolytic processes,
amino acids is a highly important objective, as these amino
acids are finding widespread use in fields such as biology,
biochemistry, pharmaceutical science, and materials sci-
ence;1−5 furthermore, they can readily be transformed into
other useful families of chiral molecules, including β-amino
alcohols (Figure 1).6,7 Catalytic asymmetric routes to
unnatural α-amino acids are especially attractive,5,8,9 and
numerous approaches have been described, such as hydro-
genations of olefins and imines,10,11 electrophilic aminations
of enolates,12 electrophilic alkylations of glycine derivatives,13
and nucleophilic additions to α-imino esters.14
has expanded dramatically in recent years,15,16 but to our
knowledge no such methods have been described for the
catalytic asymmetric synthesis of unnatural α-amino acids. We
envisioned that nickel-catalyzed enantioconvergent cross-
couplings of alkyl electrophiles, which are emerging as a
powerful tool in asymmetric synthesis and typically proceed
through radical intermediates,17−23 might provide a straight-
forward route to protected α-amino acids from readily
available coupling partners. In this report we describe the
realization of this objective, specifically, that a chiral nickel/
pybox catalyst can achieve the coupling of an array of
organozinc reagents with racemic α-haloglycine derivatives,
enabling ready access to a wide variety of protected α-amino
acids (eq 1), including several that have been applied to the
synthesis of bioactive target molecules.
Received: April 14, 2021
Published: June 3, 2021
Figure 1. Diverse applications of unnatural α-amino acids.
https://doi.org/10.1021/jacs.1c03903
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To our knowledge, α-halo-α-amino acid derivatives have
not been employed as electrophiles in metal-catalyzed
asymmetric cross-coupling reactions,24−27 although they have
been utilized as precursors to iminium ions in two
organocatalytic processes (nucleophiles: enolates of 1,3-
dicarbonyl compounds and allylmetal reagents).28−30 By
following a procedure reported by Roche,31 Cbz-protected
α-chloroglycine ester A can be obtained in a single step on a
multigram scale, and it can be stored at 0 °C for at least 6
months without degradation. When this racemic electrophile
is treated with an alkylzinc reagent (1:1.1 ratio, despite a
potentially labile N-bound proton) in the presence of a chiral
nickel/pybox catalyst, alkyl−alkyl coupling proceeds to
generate the desired protected α-amino acid in good yield
and enantioselectivity (84% yield and 97% ee; entries 1 and 2
of Table 1).
water (entries 12 and 13; carbon−carbon bond formation is
faster than protonation of the organozinc reagent and
hydrolysis of the electrophile) or by air (entry 14).
This straightforward method for the catalytic enantiocon-
vergent synthesis of protected unnatural α-amino acids is
compatible with an array of substituents on the nitrogen (R1;
Figure 2, products 1−5) and on the oxygen (R2; products 1
and 6) of the electrophile, providing a range of products with
good yield and high ee. The scope of the coupling is also
broad with respect to the nucleophile. For example, the R
substituent can range in size from methyl to isobutyl
(products 7−11; the use of a secondary alkylzinc reagent
leads to little product under our standard conditions).
Furthermore, a wide variety of functional groups are
compatible with the method, including a silyl ether, ether,
nitrile, imide, alkyne, unactivated primary alkyl fluoride/
chloride, alkene, carbonate, and acetal (products 12−33; we
have also established that an aldehyde, aryl iodide, benzofuran,
benzonitrile, benzothiophene, epoxide, α-ketoester, ketone,
nitroarene, unactivated secondary alkyl bromide, and thioether
are compatible; see the Supporting Information). In the case
of several nucleophiles that bear one or more stereocenters,
the stereochemistry of the catalyst, rather than that of the
nucleophile, predominantly controls the stereochemistry of
the product (products 22−33). On a gram scale (1.48 g of
product), the coupling to generate product 1 proceeds in
identical yield and ee as for a reaction conducted on a 0.6
mmol scale (83% yield, 97% ee).32,33
Because the α-haloglycinate coupling partner can generally
be prepared in one step, this nickel-catalyzed enantioconver-
gent alkyl−alkyl coupling provides an unusually versatile and
efficient method for the generation of a wide array of
unnatural α-amino acid derivatives, which are common
building blocks in the synthesis of bioactive compounds. For
example, Boc-protected α-amino acid 34 (Figure 3), which
serves as an intermediate in the synthesis of a histone
deacetylase (HDAC) inhibitor, has previously been generated
in four steps via an enzymatic kinetic resolution.34
Alternatively, a nickel-catalyzed enantioconvergent cross-
coupling affords α-amino acid 34 in two steps in good yield
and ee (70% overall yield, 95% ee).
Table 1. Catalytic Enantioconvergent Synthesis of a
Protected α-Amino Acid: Effect of Reaction Parameters
a
b
c
entry
variation from the standard conditions
none
30 min, instead of 4 h
no NiBr2·glyme
no L1
L2, instead of L1
L3, instead of L1
L4, instead of L1
L5, instead of L1
5.0 mol% NiBr2·glyme, 6.0 mol% L1
2.5 mol% NiBr2·glyme, 3.0 mol% L1, 24 h
r.t., instead of 0 °C
0.5 equiv H2O added
1.0 equiv H2O added
under air in a closed vial
yield (%) ee (%)
1
2
3
4
5
6
7
8
84
86
10
40
60
71
67
47
82
61
80
80
53
77
97
97
<1
−
96
80
15
41
96
92
95
96
93
96
9
10
11
12
13
14
Similarly, protected unnatural α-amino acid 35 (Figure 3),
which has been employed as an intermediate in the synthesis
of a calpain-1 inhibitor, was originally produced in four steps
from a derivative of pyroglutamic acid.35 Through the nickel-
catalyzed asymmetric coupling method described herein,
target 35 can be generated in two steps in 65% overall yield
and with high enantioselectivity (97% ee).
Furthermore, ketone-bearing α-amino acid 37, an inter-
mediate in the synthesis of cyclic peptide apicidin A, which
exhibits anti-malarial activity, can be produced in three steps
via an enantioconvergent alkyl−alkyl cross-coupling (prior
route: six steps from glutamic acid).36 Finally, our method
provides protected unnatural α-amino acid 38 (Figure 3),
bearing a cyano substituent, in two steps; compound 38 has
previously been generated in six steps from lysine en route to
L-indospicine, a component in tropical legumes in the genus
Indigofera.37
In conclusion, we have developed a straightforward,
versatile method for the asymmetric synthesis of protected
unnatural α-amino acids, an important family of target
molecules, via nickel-catalyzed enantioconvergent cross-
couplings of readily available racemic alkyl halides with
a
b
All data are the average of two experiments. Determined through
c
LC-MS analysis using an internal standard. Determined through SFC
analysis.
In the absence of NiBr2·glyme or of ligand L1, only a small
amount of product is observed (racemic; entries 3 and 4 of
Table 1). Although a variety of other chiral ligands are less
effective than ligand L1 (entries 5−8), it is worth noting that
commercially available pybox ligand L2 affords a reasonable
yield and high enantioselectivity (entry 5). A lower catalyst
loading can be used (entries 9 and 10), and the method
performs well at room temperature (entry 11). The coupling
process is robust, only modestly inhibited by small amounts of
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Figure 2. Scope of catalytic enantioconvergent synthesis of protected unnatural α-amino acids. All couplings were conducted on a 0.6 mmol scale
(unless otherwise noted), and all yields are of purified products.
Figure 3. Catalytic enantioconvergent synthesis of protected unnatural α-amino acids: applications to the synthesis of bioactive compounds. All
data are the average of two experiments, and all yields are of purified products.
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alkylzinc reagents (1:1.1 ratio). These couplings can be
achieved under mild, convenient conditions and are tolerant
of air, moisture, and a wide variety of functional groups,
including alkenes and alkynes (cf. asymmetric hydrogenation).
The usefulness of the new method has been demonstrated by
its application to the efficient synthesis of unnatural α-amino
acid derivatives that have previously been employed as
intermediates en route to bioactive compounds. The develop-
ment of additional catalytic asymmetric processes based on
nickel, an earth-abundant metal, is underway.
Generation Educator Fund (grant to Caltech). We thank
Lawrence M. Henling and Dr. Michael K. Takase (Caltech X-
Ray Crystallography Facility), Dr. Asik Hossain, Dr. Paul H.
Oyala (Caltech EPR Facility), Dr. Felix Schneck, Dr. David G.
VanderVelde (Caltech NMR Facility), and Dr. Scott C. Virgil
(Caltech Center for Catalysis and Chemical Synthesis) for
assistance and helpful discussions.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03903.
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AUTHOR INFORMATION
Corresponding Author
Gregory C. Fu − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0002-
0927-680X; Email: gcfu@caltech.edu
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Authors
Ze-Peng Yang − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0003-
0248-1963
Dylan J. Freas − Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena,
California 91125, United States; orcid.org/0000-0003-
0611-7907
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Complete contact information is available at:
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Substitution Reactions: A Radical Alternative to SN1 and SN2
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Author Contributions
†Z.-P.Y. and D.J.F. contributed equally.
Notes
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The authors declare no competing financial interest.
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This paper is dedicated to Professor David A. Evans on the
occasion of his 80th birthday. Support has been provided by
the National Institutes of Health (National Institute of
General Medical Sciences; grant R01-GM062871), the
National Science Foundation Graduate Research Fellowship
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