Palladium-Catalyzed Suzuki-Miyaura Reactions of Aspartic Acid Derived Phenyl Esters

Article abstract of DOI:10.1021/acs.orglett.9b02214

Transition-metal-catalyzed transformations of amino acids and peptides could provide a powerful method for their site-selective modification. Here, we report non-decarbonylative Pd-catalyzed Suzuki-Miyaura reactions of phenyl ester derivatives of aspartic acid to form aryl-amino ketones. These products are potentially important in the synthesis of pharmaceuticals, and our methodology represents a new route to access molecules of this type.

Full text of DOI:10.1021/acs.orglett.9b02214

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Suzuki−Miyaura Reactions of Aspartic Acid
Derived Phenyl Esters
Amira H. Dardir, Nilay Hazari,* Scott J. Miller, and Christopher R. Shugrue
The Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: Transition-metal-catalyzed transformations of amino acids
and peptides could provide a powerful method for their site-selective
modification. Here, we report non-decarbonylative Pd-catalyzed Suzuki−
Miyaura reactions of phenyl ester derivatives of aspartic acid to form aryl-
amino ketones. These products are potentially important in the synthesis of
pharmaceuticals, and our methodology represents a new route to access
molecules of this type.
reagents derived from iodoalanine, aspartic acid, or glutamic
eptide-based therapeutics have emerged as a comple-
Pmentary approach to traditional small molecule drugs, acid can be utilized as the nucleophile in Negishi reactions.8
Significant progress has also been made in site-selective
C(sp2)−H and C(sp3)−H functionalization of natural amino
acid and unnatural amino acid derivatives.9 Recently, arylation
chemistry to form X−C(sp2) bonds (X = C, NH, O, or Se) has
been developed to modify amino acids, peptides, or proteins.10
This includes natural amino acids such as cysteine,11 lysine,12
or tyrosine13 which can be chemoselectively modified using
stoichiometric aryl Pd or Au reagents. In related work, arylated
seleno-cysteine can be obtained from oxidized seleno-cysteine
(Se-SR) and boronic acids using Cu reagents.14
At this stage, both stoichiometric and catalytic transition-
metal-mediated processes that target side chain or C-terminal
carboxylic acid functional groups on amino acids are rare, and
they do not conserve the carbonyl moiety. For example, Ir-
mediated photocatalytic couplings of carboyxlic acids15 and
Ni-catalyzed Negishi couplings of carboxylic acids (that have
been converted into redox active esters)16 are decarboxylative
processes. However, the amino ketone motif has proven to be
essential for the functionality of some medicines. For instance,
α-aryl-amino ketones represent a class of therapeutics
employed in the clinical treatment of depression17 and nicotine
dependence18 and exhibit neuroprotective properties in mice
by inhibiting the kynurenine pathway.19 Additionally, bio-
orthogonal reactions of ketones with hydrazines or alkoxy-
amines to form hydrazones or oximes, respectively, have been
used as a handle for further bioconjugation, such as site-
specific in vitro and cell surface protein labeling.4,20
exhibiting high medicinal efficacy, selectivity, and potency, as
well as low toxicity.1 However, one reason their use in
medicinal chemistry has been limited is because it is difficult to
modify their pharmacokinetic properties.1a In recent years,
there have been a number of reports describing transition-
metal-mediated processes to interconvert functional groups on
amino acids and this has the potential to become a powerful
method for peptide modification.2 Changing a functional
group on one or more amino acid residues can alter the
properties of the peptide by enhancing in vivo stability,
solubility, or membrane permeability,3 creating tags that alter
photophysical characteristics, installing handles that enable
additional selective functionalization,4 or facilitating rapid
screening of derivatives to elucidate structure−activity relation-
ships.5
Transition-metal-mediated processes have previously been
utilized to functionalize unnatural, slightly modified, and
natural amino acids (Figure 1a). For example, pseudohalo-
genated tyrosine derivatives and halogenated phenylalanine
derivatives can be used as the electrophile in Suzuki−Miyaura6
and electocatalytic amination reactions,7 while organozinc
Non-decarbonylative Pd-catalyzed Suzuki−Miyaura reac-
tions to form ketones using phenyl esters as the electrophile
were recently discovered.21 Here, we show that this method-
ology can be used to catalytically modify amino acids
containing carboxylic acid groups. Specifically, the esterifica-
Figure 1. (a) Previous selective transition-metal-mediated reactions of
amino acids and peptides. (b) This work’s Pd-catalyzed Suzuki−
Miyaura reactions of phenyl ester amino acids.
Received: June 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
tion of carboxylic acids via a simple base-mediated process to
form phenyl ester derivatives22 is followed by Pd-catalyzed
non-decarbonylative cross-coupling to form ketone derivatives
of aspartic acid. To the best of our knowledge, this work is the
first example of a catalytic cross-coupling reaction to transform
amino esters to amino ketones.
rapid activation of this system.21c,23 The IPr ancillary ligand is
important, as utilization of other common NHC ligands, such
as SIPr, IMes, and IPent (entries 5−7), resulted in a decrease
in yield. Additionally, precatalysts containing several common
phosphine ligands gave negligible yields (see the Supporting
Information). The use of K2CO3 as the base is crucial, as other
common inorganic bases, including K3PO4, Na2CO3, and
Cs2CO3, showed minimal product formation (entries 8−10).
Small amounts of water (10 equiv) can result in a large
decrease in yield due to hydrolysis of the phenyl ester (entry
11 and see the Supporting Information). The choice of N-
terminal protecting group for aspartic acid is also important.
For example, when a carboxybenzyl (Cbz) protecting group is
Motivated by previous work demonstrating that (η3-1-tBu-
indenyl)Pd(IPr)(Cl) (1) is an active catalyst for Suzuki−
Miyaura reactions of organic phenyl esters,21b,c this precatalyst
was selected for the coupling of a phenyl ester derivative of a
protected aspartic acid, Boc-Asp(OPh)-OtBu, with 4-methox-
yphenylboronic acid. Our initial reactions indicated that
hydrolysis of the phenyl ester to form Boc-Asp-OtBu was a
significant problem. While changing the phenyl group on the
ester to electronically and sterically different aryl groups led
only to comparable or lower yields, careful optimization of the
reaction conditions minimized hydrolysis (see the Supporting
Information). Under our optimized conditions, near quantita-
tive coupling of Boc-Asp(OPh)-OtBu with 4 equiv of 4-
methoxyphenylboronic acid was observed using 10 mol % of 1
and 4.4 equiv of K2CO3 as the base in THF at 60 °C (Table 1,
t
used instead of a Buoxycarbonyl (Boc) group, 73% of the
cross-coupled product is observed under the standard
conditions (eq 1). Finally, the coupling of alkyl esters is
Table 1. Optimization of a Pd-Catalyzed Suzuki−Miyaura
Coupling with a Phenyl Ester Derivative of Protected
Aspartic Acid
a
significantly more difficult than the coupling of aryl esters, so
the protection of the C-terminus of aspartic acid as a tBu or Me
ester prevented deleterious side reactivity at this position.24
Using our optimized conditions, the scope of the boronic
acid was explored (Figure 2). Substrates with electron-neutral,
electron-donating, or mildly electron-withdrawing substituents
on the arylboronic acid were coupled in good to high yields
b
entry
deviation from optimized conditions
yield (%)
1
2
3
4
5
6
7
8
no change
no precatalyst
(η3-cinnamyl)Pd(IPr)(Cl) instead of 1
PEPPSI-IPr instead of 1
SIPr instead of IPr
IMes instead of IPr
IPent instead of IPr
Na2CO3 instead of K2CO3
Cs2CO3 instead of K2CO3
K3PO4 instead of K2CO3
96
<1
65
69
60
83
60
29
6
9
10
11
12
29
c
10 equiv of water
a
Conditions: Boc-Asp(OPh)-OtBu (0.0547 mmol), 4-methoxybor-
onic acid (0.219 mmol), base (0.241 mmol), precatalyst (0.0547
b
mmol), THF (0.5 mL). Yields are the average of two runs
determined by LCMS on the basis of the calibration curve versus
c
1,2,4,5-tetramethylbenzene. Total volume (THF + H2O) of 0.5 mL.
IPr = 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-yli-
dene, SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-
ylidene, IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene,
IPent = 1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene, PEPPSI =
[1,3-bis(2,6-diispropyl)imidazole-2-ylidene](3-chloropyridyl)-
palladium(II) dichloride.
entry 1). Analysis of the product using chiral HPLC indicates
that there was no racemization of the amino acid during the
reaction and only a single stereoisomer of the amino ketone
was formed (see the Supporting Information).
Precatalyst 1 resulted in higher yields compared to other
commonly used precatalysts, such as (η3-cinnamyl)Pd(IPr)-
(Cl) and PEPPSI-IPr (entries 3 and 4), presumably due to the
Figure 2. Isolated yields of products in Suzuki−Miyaura reactions
using Boc-Asp(OPh)-OtBu. Conditions: amino acid (0.1 mmol),
boronic acid (0.4 mmol), K2CO3 (0.44 mmol), 1 (0.01 mmol), THF
(1 mL), 60 °C, 4 h. aTHF (0.98 mL), H2O (0.02 mL). Yields are the
b
average of two runs. Yield from a single trial performed on a 1.0
mmol scale relative to amino acid.
B
DOI: 10.1021/acs.orglett.9b02214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2a, 2c, 2e, 2f). However, low yields were observed for
strongly electron-withdrawing 4-trifluorophenylbornic acid
(2l). While, 2-substituted arylboronic acids could be coupled
(2b, 2d), 2,6-substituted substrates showed minimal formation
of the product by LCMS (see the Supporting Information). 3-
Heteroaryl boronic good yields (2i, 2j), while 2-heteroaryl
boronic acids, which readily undergo protodeborylation,25
were challenging to couple (2k). For example, 2-thienylbor-
onic acid gave low yields and 2-furylboronic acid showed no
product under optimized conditions. Finally, extended
aromatic boronic acids at the 1- and 2-positions showed
moderate yields (2g, 2h). Overall, these reactions represent the
first examples of non-decarbonylative Suzuki−Miyara reactions
of aspartic acid derivatives and more generally a rare catalytic
reaction targeting carboxylic acid side groups of amino acids.
Additionally, at this stage, organic amino ketones are often
synthesized from carboxylic acids either via stoichiometric
reactions with organolithium or Grignard reagents or via
Friedel−Crafts chemistry,26 neither of which are highly
functional group tolerant. Therefore, our catalytic method
may also be relevant to the synthesis of amino ketones in non-
amino acid-based molecules.
Figure 3. Isolated yields of products in Suzuki−Miyaura reactions of
dipeptide phenyl ester derivatives. Conditions: dipeptide (0.1 mmol),
boronic acid (0.4 mmol), K2CO3 (0.44 mmol), 1 (0.02 mmol), THF
(1 mL). Yields are the average of two runs.
While high yields were obtained in coupling reactions
involving the phenyl ester derivative of aspartic acid, we were
unable to couple the related glutamic acid. Performing the
reaction of Boc-Glu(OPh)-OMe with 4-methoxyphenylbor-
onic acid under the optimized conditions for the aspartic acid
derivative resulted in a mixture of the desired product (6%)
and a five-membered pyroglutamic acid (91%) (eq 2).
Scheme 1. Synthesis of Boc-Asp(4-OMe-Ph)-Met-OtBu via
Initial Cross-Coupling Followed by Standard Peptide
Coupling
Glutamic acid and glutamine are known to generate
pyroglutamic acid in the presence of acid, base, or elevated
temperatures, and this side reaction normally occurs more
rapidly when the residue is at the N-terminus.27
groups on the N-terminus amino acid. Our results provide
proof-of-principle that a coupling reaction that works well in
simple organic molecules can be translated to more
complicated amino acid substrates. Further work in our
laboratories will focus on making these reactions more efficient
and general.
Following our work with single amino acids, we extended
the methodology to dipeptides (Figure 3). Dipeptides with the
phenyl ester derivative of aspartic acid at the C-terminus were
coupled with 4 equiv of 4-methoxyphenylboronic acid, 4.4
equiv of K2CO3, and 20 mol % 1 in THF at 60 °C for 16 h.
The reaction was compatible with nonpolar aliphatic (3a−3c)
and aromatic side chains (3d), including proline and
phenylalanine. Peptides containing protected heteroatoms,
such as serine(OtBu) (3e), and heteroaromatics, such as
tryptophan(Boc) (3f), were also coupled in moderate to good
yields. The cross-coupling reaction was not compatible with
sulfides such as methionine. However, by first performing the
cross-coupling reaction on Boc-Asp(OPh)-OtBu under stand-
ard conditions, followed by methionine coupling, the dipeptide
Boc-Asp(4-OMe-Ph)-Met-OtBu was obtained in 41% overall
yield (Scheme 1). Synthesis of the amino ketone monomer
followed by its incorporation into peptides using standard
methods represents an alternative strategy to generate peptides
with new functionality.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02214.
Experimental procedures and characterizing data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nilay.hazari@yale.edu.
ORCID
Nilay Hazari: 0000-0001-8337-198X
Scott J. Miller: 0000-0001-7817-1318
Christopher R. Shugrue: 0000-0002-3504-9475
In conclusion, we have demonstrated the first examples of
catalytic non-decarbonylative Suzuki−Miyaura cross-coupling
reactions of phenyl ester derivatives of Boc protected aspartic
acids to form amino ketones. The reaction is compatible with
dipeptides containing alkyl, aryl, hetreoaromatic, or ether side
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b02214
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
NIHGMS under Award No. RO1GM120162 and R35
GM132092. We thank Dr. Fabian Menges (Yale University)
for help with mass spectrometry and Brian Koronkiewicz (Yale
University) for valuable discussions. C.R.S. thanks the NSF
GRFP for funding (DGE1122492).
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