Biocompatible Photoinduced Alkylation of Dehydroalanine for the Synthesis of Unnatural α-Amino Acids

Article abstract of DOI:10.1021/acs.orglett.1c01781

A site-selective alkylation of dehydroalanine to access protected unnatural amino acids is described. The protocol is characterized by the wide nature of alkyl radicals employed, mild conditions, and functional group compatibility. This protocol is further extended to access peptides, late-stage functionalization of pharmaceuticals, and enantioenriched amino acids.

Full text of DOI:10.1021/acs.orglett.1c01781

pubs.acs.org/OrgLett
Letter
Biocompatible Photoinduced Alkylation of Dehydroalanine for the
Synthesis of Unnatural α‑Amino Acids
̃
José A. C. Delgado, José T. M. Correia, Emanuele F. Pissinati, and Márcio W. Paixao*
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ABSTRACT: A site-selective alkylation of dehydroalanine to
access protected unnatural amino acids is described. The protocol
is characterized by the wide nature of alkyl radicals employed, mild
conditions, and functional group compatibility. This protocol is
further extended to access peptides, late-stage functionalization of
pharmaceuticals, and enantioenriched amino acids.
quently, new strategies for Dha’s modification have been
ew synthetic methodologies to access derivatized amino
Nacids offer medicinal and biological chemists an significantly investigated.10
Among the recent reports, photocatalytic transformations
expanded toolbox toward the synthesis of biologically relevant
molecules.1 These privileged motifs have been found as
building blocks in drug development2 and are used as a chiral
pool for ligand preparation and catalyst design owing to their
wide structural diversity (Scheme 1A).3 In the context of drug
design, the straightforward synthesis of non-natural amino
acids through amino acid side chain modification can
remarkably improve the drug absorption−distribution−metab-
olism−excretion−toxicity (ADMET) properties.4 As such,
methods that provide site-selective or site-specific amino
acid/peptide modifications under biocompatible conditions are
essential for drug development, especially for those drug
programs based on the modification of proteins, antibodies,
and DNA.5 Nowadays, classical synthetic methodologies
generally rely on higher-energy systems, either through highly
reactive organometallic reagents6 or UV-irradiation,7 to reach
the desired reaction outcome. On the other hand, contempo-
rary synthetic methodologies have focused on selective and
mild conditions. Visible-light mediated catalytic methodologies
have offered an innovative solution to forge similar bonds as
enabled by classical methodologies but with the advantages of
using a low-energy source, which allows for selective and
controlled reactions.8
have taken advantage of radical addition to Dha species,
employing a variety of precursors.11 In this regard, the use of
abundant and cheap radical feedstocks, such as carboxylic acids
and their derivatives, e.g., N-hydroxyphthalimides (NHPI)
esters and oxalates, for radical generation opened a new
perspective for the development of sustainable methodologies
(Scheme 1B).12 Moreover, the replacement of highly reactive
organometallic reagents is one of the important advantages of
these strategies.13
Recently, our group has been involved in developing
photoinduced processes enabled by EDA complexation.14,15a
Inspired by these studies, we have now developed a simple,
mild, biocompatible, and scalable protocol for the alkylation of
Dha’s through the implementation of aliphatic amines16 and
carboxylic acid redox-active derivatives17 (Scheme 1C).
Complementary to previous photoredox protocols, this
approach is metal- and catalyst-free, and it demonstrates high
functional group tolerance to afford a large family of unnatural
amino acids in moderate to good yields.
We started our investigation by studying the reaction
between the proline NHPI ester derivative 1a and
dehydroalanine 2a, in the presence of Hantzsch ester 3a,
under blue LED irradiation. After a set of preliminary
experiments (see SI for details), we have found that the
Of the synthetic precursors to amino acids, dehydroalanine
(Dha) offers tremendous opportunities as it contains a double
bond, which behaves as a nucleophile or electrophile. This
reactivity has found particular success in reactions with
nucleophiles and allows stereoselective transformations (i.e.,
employing a modified Dha called Karady−Beckwith alkene).9
These features have made Dha an excellent synthon for the
selective synthesis of noncanonical amino acids and the late-
stage decoration of biologically relevant peptides; conse-
Received: May 27, 2021
Published: June 21, 2021
https://doi.org/10.1021/acs.orglett.1c01781
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5251−5255
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Entries 2−6 summarize some deviations from the optimized
conditions. The absence or the use of a smaller amount of 3a
was shown to be detrimental to the reaction outcome (entries
2 and 3). A slight erosion in the reaction efficiency was further
observed when DIPEA was used as a second additive (entry 4).
A control experiment in the absence of 3a but with 1.5 equiv of
DIPEA afforded 4a in a very low yield (entry 5). Moreover, the
presence of 1 mol % of commercially available [Ru(bpy)3]-
(PF6)2 as a photoredox catalyst did not alter the reaction
performance (entry 6). As a control experiment, we performed
the reaction in the dark, and no formation of desired product
was observed (entry 7).
Scheme 1. Photocatalytic Hydroalkylation of
Dehydroalanine
a
Next, we turned our attention to exploring the scope and
limitations of this metal-free hydroalkylation protocol (Scheme
2). A variety of cyclic and acyclic amino acid NHPI esters
(4a−4g) were successfully employed, showing a remarkable
tolerance to both protected alcohols and amines as well as
aromatic and steric encumbrance. Moreover, cycloalkyl NHPI
esters (4h−4k) were successfully applied under the reaction
conditions, where a minor relationship between the ring size
and chemical yield could be observed. Consistent with this
relationship, the highest yielding substrate of this series is 4k
(70%), which comes from the most stable cyclohexyl radical.
In addition, the 4-carboxyl-piperidine derivative afforded the
corresponding amino acid 4l in 47% yield. Next, acyclic
secondary NHPI esters were also evaluated, affording the
silylated 4m and lipidic 4n derivatives in 70% and 48% yields,
respectively. Moving to tertiary alkyl NHPI esters (4o−4u),
the reaction also tolerated sterically hindered quaternary
carbon centers with good generality. As previously observed,
radical stability had an appreciable effect on chemical yields,
with adamantyl NHPI ester affording 4q in 95% yield. The
generation of the tertiary radical through a radical-relay
process, starting from the citronellic acid NHPI ester,
efficiently gave access to the amino acid 4u in 61% yield.
Primary alkyl and benzylic NHPI esters were also successfully
employed under the optimized reaction conditions, albeit in
lower yields, affording the respective homoallylic, homoben-
zylic, and benzylic unnatural amino acids 4v−4z (Scheme 2).
Envisioning applications in bioconjugation, the incorpora-
tion of pharmaceutically active ingredients was also inves-
tigated. While gemfibrozil (used for dyslipidemia treatment)
residue could be efficiently coupled, affording the modified
amino acid 4aa in good chemical yield (77%), the use of the
nonsteroidal anti-inflammatory etodolac’s NHPI ester afforded
4ab in 15%. The lower yield observed for 4ab is probably due
to the steric hindrance of the neopentylic radical involved in
the process. Gratifyingly, peptide residues were also success-
fully incorporated into the Dha, with the unnatural dipeptide
4ac and tripeptide 4ad being afforded in 65% and 76% yields,
respectively. To summarize, the results described in Scheme 2
demonstrate the generality of our method, showing its
applicability toward the preparation of a wide range of
unnatural amino acids, including derivatives decorated with
bioactive molecules, and its great potential for peptide
functionalization.
a
−
EDA = R-CO2Phth + HE and R-TPPy+BF4 + HE.
optimum conditions involving 1.0 equiv of 1a, 1.5 equiv of 2a,
and 2.1 equiv of 3a in DMSO/H2O (9:1) afforded the desired
product (4a) in excellent yield, after 20h of irradiation (Table
1, entry 1).
Table 1. Optimization of Reaction Parameters
a
entry
deviation from optimum conditions
yield of 4a
1
2
3
4
5
6
7
none
without 3a
1.5 equiv of 3a
90%
0%
75%
85%
32%
70%
0%
addition of 1.5 equiv of DIPEA
1.5 equiv of DIPEA instead of 3a
1 mol % of [Ru(bpy)3](PF6)2
without light
We then decided to evaluate the scalability of this new
metal-free photochemical protocol. By using conditions similar
to those previously applied, a 2 mmol scale experiment
employing the N-Boc-amino isobutyric acid NHPI ester
successfully afforded the amino acid 4c in 82% yield (see SI
for further information).
a
Isolated yields. Diastereoselectivities were determined by NMR and
corresponded to 1:1 in all cases.
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a
Scheme 2. Scope of NHPI Esters
a
Reaction conditions: 1a−ad (0.2 mmol), 2a (0.3 mmol), 3a (0.42 mmol) in DMSO/H2O (9:1) (0.15 M). Yields of isolated products.
1
Diastereomeric ratios were determined by H NMR analysis from the crude reaction mixture and corresponded to 1:1 in all cases where
diastereomers were formed. 2 mmol scale experiment.
b
Aiming at expanding the scope and the generality of these
reactions to other radical precursors, we envisioned that
functionalized alkylpyridinium salts would be compatible to
the conditions previously optimized for the achieved NHPI
esters.16b Pleasingly, this reactivity enabled the direct
construction of a range of non-natural α-amino acids 4k, 4z,
and 6a−f in good chemical yields (Scheme 3).
We further examined pyridinium salts derived from cyclic
secondary alkyl amines, which afforded the respective desired
products 4k and 6a, in 80% and 67% yields, respectively. The
acyclic secondary pyridinium salts containing the O-acetylated-
phenol moiety furnished hydrolyzed product 6b in 68% yield.
In addition, O-acylated pyridinium salts prepared from amino
alcohols could also be successfully employed (6c−6e). It is
noteworthy that this reaction has also enabled the installation
of a modified pharmaceutical ingredient (5g) onto the α-
amino acid side chain, affording the bioconjugated α-amino
acid 6e in 78% yield. Next, a benzylic pyridinium salt was
subjected to the optimal conditions, delivering the homo-
phenylalanine 4z in 74% yield. A primary alkylpyridinium salt
derived from β-alanine 5h has also been tested, affording the
protected glutamic ester 6f in 25% yield.
Thereafter, we turned our attention to the hydroalkylation of
the Karady−Beckwith alkene (Scheme 4). This chiral Dha
comprises an efficient entry for the preparation of enantioen-
riched nonproteinogenic amino acids. A set of NHPI redox-
active esters and the benzylic pyridinium salt were evaluated
under previously reported conditions and gave access to
another family of amino acids in good yields and excellent
diastereoselectivities (8a−f). In order to evaluate our protocol
against other Dha residues, experiments using N-Boc-, N-
acetyl-, and N-Boc,Cbz-Dha residues have been performed.
From these studies, no reactivity could be observed for the two
first ones, while the last one afforded the expected product in
82% yield (see Supporting Information for more details). A
plausible explanation for lack of reactivity of the monop-
rotected Dha residues has been previously addressed by
Molander and relies on the conformation of those species,
which dramatically affects their reactivity.11d
Finally, to better understand the reaction mechanism of this
new protocol, additional control experiments were performed.
In consonance with previous studies by Chen,18a Aggarwal,18b
Glorius,18c and our group,14 UV−vis and NMR analysis of
solutions containing 3a combined with different amounts of
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a
reported. This strategy features a good functional group
tolerance, experimental simplicity, and scalability, being a
straightforward and efficient strategy for the incorporation of
biologically relevant scaffolds to α-amino acid side chains. The
protocol is also applicable to the Karady−Beckwith alkene,
opening a new opportunity for the preparation of enantioen-
riched nonproteinogenic amino acids.
Scheme 3. Scope Study of Pyridinium Salts
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01781.
Experimental details (procedures for starting materials
preparation, general procedures for the preparation, as
well as full characterization of all new compounds)
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
a
b
Reaction conditions follow in subsequent notes. 5 (0.2 mmol), 2a
c
(0.3 mmol), 3a (0.42 mmol) in DMSO/H2O (9:1) (0.15 M). 5 (0.1
mmol), 2a (0.15 mmol), 3a (0.21 mmol) in DMSO/H2O (9:1) (0.15
M). Yields of isolated products. Diastereomeric ratios were
determined by H NMR analysis from the crude reaction mixture
and corresponded to 1:1 in all cases where diastereomers were
̃
Márcio W. Paixao − Centre of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao
Paulo 13565-905, Brazil; orcid.org/0000-0002-0421-
2831; Email: mwpaixao@ufscar.br
1
̃
CarlosUFSCar, Sao
̃
formed.
Authors
Scheme 4. Diastereoselective Amino Acid Synthesis Using
the Karady−Beckwith Alkene
a
José A. C. Delgado − Centre of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao
Paulo 13565-905, Brazil
̃
CarlosUFSCar, Sao
̃
José T. M. Correia − Centre of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao
Paulo 13565-905, Brazil
̃
CarlosUFSCar, Sao
̃
Emanuele F. Pissinati − Centre of Excellence for Research in
Sustainable Chemistry (CERSusChem), Department of
Chemistry, Federal University of Sao
Paulo 13565-905, Brazil
̃
CarlosUFSCar, Sao
̃
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01781
Notes
The authors declare no competing financial interest.
a
Radical precursor (0.1 mmol), 7a (0.15 mmol), 3a (0.21 mmol) in
DMSO/H2O (9:1) (0.15 M). Yields of isolated products. The dr
values were calculated from crude H NMR.
ACKNOWLEDGMENTS
1
■
We are grateful to INCT-Catálise/CNPq Grants 444061/
2018-5, FAPESP (14/50249-8, 19/01973-9, and 17/10015-6),
and GSK for financial support. This study was financed in part
the NHPI ester 1a and the pyridinium salt 5d strongly support
the formation of the EDA complex during those processes. We
also observed that the addition of 2a to those reaction mixtures
disrupts the formation of such complexes, ruling out the
possibility of a ternary complexation system (see SI, Figures
S2, S4 and S5, for more details). By carrying out experiments
with deuterium-labeled solvents, product 4a did not afford
high levels of deuterium incorporation, indicating that the
Hantzsch ester should act as the main proton source (see SI,
Scheme S1, for further information). On the basis of these
observations and previous literature reports,18 a plausible
reaction mechanism could be outlined (see SI, Scheme S2, for
further information).
by the Coordenaca̧ o de Aperfeico̧ amento de Pessoal de Nível
̃
SuperiorBrasil (CAPES)Finance Code 001. We also
thank Craig S. Day (ICIQTarragona, Spain) for the critical
proofreading of this manuscript.
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