Bio- And Medicinally Compatible α-Amino-Acid Modification via Merging Photoredox and N-Heterocyclic Carbene Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c02202

An N-heterocyclic carbene and photoredox cocatalyzed α-amino-acid decarboxylative carbonylation reaction is presented. This method displays good scope generality, providing a direct pathway to access various downstream α-amino ketones under bio- and medicinally compatible conditions. Moreover, this strategy is appealing to chemical biology because it has great potential for the chemical modification of peptides or the late-stage synthesis of keto-peptides.

Full text of DOI:10.1021/acs.orglett.0c02202

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Letter
Bio- and Medicinally Compatible α‑Amino-Acid Modification via
Merging Photoredox and N‑Heterocyclic Carbene Catalysis
Ding Du,* Kuili Zhang, Rui Ma, Lei Chen, Jian Gao, Tao Lu, Zhihao Shi,* and Jie Feng*
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ABSTRACT: An N-heterocyclic carbene and photoredox cocata-
lyzed α-amino-acid decarboxylative carbonylation reaction is
presented. This method displays good scope generality, providing
a direct pathway to access various downstream α-amino ketones
under bio- and medicinally compatible conditions. Moreover, this
strategy is appealing to chemical biology because it has great
potential for the chemical modification of peptides or the late-stage
synthesis of keto-peptides.
Scheme 1. Preparation of α-Amino Ketones from α-Amino
Acids
ecause they widely exist in synthetic intermediates, natural
Bproducts, and bioactive compounds, α-amino ketones
represent a class of important motifs.1 The synthesis of α-
amino ketones heavily relies on several traditional methods,
such as the hydrogenation of α-ketoketimines,2 cross-coupling
between aldehydes and imines,3 the amination of enols,4 and
suitable chemistry using ketones as precursors that incorporate
the handling of C−N bond formation.5 Considering that α-
amino acids are the fundamental fragments of peptides and
proteins, which belong to a class of feedstock chemicals that
are abundant in nature,6 the direct transformation from α-
amino acids to α-amino ketones is one of the most appealing
methods (Scheme 1a). Actually, chemical modifications of α-
amino acids or peptides have emerged as an invaluable tool in
chemical biology, affording various targeted bioactive com-
pounds. This has enabled the precision engineering of new
structures and functions into biomolecules.7
The ideal bio- and medicinally compatible reactions are
supposed to meet some requirements such as good functional
group tolerance at (or near) neutral pH and room temperature
as well as no use of metal reagents and toxic additives.8
However, classic transformations from amino acids to amino
ketones usually involve a multistep protocol that requires the
presynthesis of amide or thioester precursors followed by the
treatment of air- and moisture-sensitive organometallic
reagents or followed by transition metal-catalyzed couplings
(Scheme 1a). Thus the development of a facile protocol to
synthesize these biologically relevant motifs from readily
accessible α-amino acids under ambient conditions is highly
desired.
aldehydes.9 The cooperation of NHC catalysis with other
catalytic strategies has offered new reactivity beyond single
catalysis.10
Received: July 3, 2020
N-Heterocyclic carbenes (NHCs) have emerged as one of
the leading organocatalysts, enabling umpolung reactivity of
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In recent years, NHC-catalyzed reactions via a radical
process has opened up a new area in the field of NHC
catalysis.11 Visible-light-driven photoredox catalysis is fre-
quently used for the generation of radical intermediates,12
and the cooperative NHC/visible-light photoredox catalysis
has enabled various invaluable chemical transformations.13
Pioneering work was conducted by Rovis using photo/NHC
dual catalysis for the α-acylation of tertiary amines with
aldehydes.13a Recently, Sun disclosed an example of the
photo/NHC-cocatalyzed γ-dichloromethylenation of enals.13b
In 2020, Hopkinson described a useful photoenolization/
Diels−Alder reaction via merged photo-NHC catalysis.13c
During the same period, Ye reported elegant series work,
including the NHC-catalyzed photoredox γ- and ϵ-alkylation of
γ-preoxidized enals,13d the Smiles rearrangement of O-aryl
salicylaldehydes,13e and the intramolecular cross-dehydrogen-
ative coupling of tetrahydroisoquinoline-tethered aldehydes.13f
Very recently, Scheidt described a single-electron transfer
(SET) reduction of acyl azoliums, followed by a radical−
radical coupling, using merged NHC-photoredox catalysis.13g
Ohmiya14 discovered the NHC-catalyzed decarboxylative
coupling of aryl aldehydes with alkyl carboxylic-acid-derived
redox-active esters (Scheme 1b). Herein we report the rapid
synthesis of structurally diverse α-amino-ketones through the
direct decarboxylative modification of α-amino acids or
peptides with aldehydes via NHC/photo cocatalysis (Scheme
1c,d). This strategy features readily accessible starting
materials, mild reaction conditions, good functional group
compatibility, and biologically useful products.
To start this work, acetylphenylalanine-derived redox-active
ester 1a′ (NIPH ester) was initially synthesized and was
further used for the reaction with benzaldehyde 2a as a model
reaction (Figure 1a, condition A). The presence of an NHC
along with a photocatalyst was crucial to the reaction. The
orthogonal screening of different NHCs and photocatalysts
using blue light-emitting diodes (LEDs) as the light source
indicated that NHC-E and photocatalyst Ir(ppy)2dtbpy were
the best combination, with up to 86% yield (Figure 1b).
DPAIPN incorporated with NHC-E gave a slightly decreased
yield. Other screened photocatalysts always gave inferior
results. The presence of an NHC proved to be essential for
this transformation. Further screening of the bases, solvents,
and light sources identified CH3CN, Cs2CO3, and blue LEDs
as the optimal solvent, base, and light source, respectively. (See
the SI.) During the research period, an issue that needed to be
considered was the isolation and purification of α-amino-acid-
derived NIPH esters. Some α-amino-acid-derived NIPH esters
were unstable and difficult for isolation and preservation. On
the contrary, multistep preparation would always lead to some
uncertainties and potential workup impurities, which were not
suitable for biologically and medicinally directed synthesis.
Thus an in situ activation strategy, as shown in condition B
(Figure 1a), was further developed. In this case, the formation
of ester 1a′ was achieved by the in situ activation of the acid 1a
with a peptide coupling reagent (PCR). Accordingly, the
reaction condition was slightly modified based on the former
condition (Figure 1c). NHC-E and photocatalyst DPAIPN,
along with a weak base (Na2CO3), were found to be the
optimal combination. Additionally, white LEDs were more
effective than blue LEDs. By comparison, the latter metal-free
and weak base system in the presence of white LEDs seemed
preferable for meeting the demand of bio- and medicinally
targeted synthesis.
Figure 1. Optimization of the reaction conditions. Condition A: 1a′
(0.2 mmol), 2a (0.3 mmol), Ir(ppy)2dtbpy(PF6)2 (0.01 mmol),
NHC-E (0.02 mmol), Cs2CO3 (0.3 mmol), CH3CN (5 mL), blue
LEDs, rt, 16 h. Condition B: Pht−OH (0.3 mmol), 1a (0.3 mmol),
DCC (0.3 mmol), DMF, rt, 1 h, then 2a (0.2 mmol), DPAIPN (0.01
mmol), NHC-E (0.02 mmol), Na2CO3 (0.3 mmol), DMF (5 mL),
white LEDs, rt, 16 h.
With the optimized conditions in hand, the substrate scope
was then investigated. The reaction of diversely substituted
benzaldehydes with acetylphenylalanine 1a or its derived
redox-active esters 1a′ was first tested using both conditions A
and B (Scheme 2). Overall, both conditions A and B showed
good tolerance with the isolated yield range from 42 to 86%
(3a−n). Superior yields were commonly obtained with
condition A. However, the merit of condition B lies in the
fact that the prepreparation of NIPH ester is not required,
which may provide synthetic convenience. It was also found
that the electronic and steric effects had a significant influence
on the yields. It seemed that electron-donating substrates
usually gave inferior yields, perhaps owing to the lower
reactivity of combining with the NHC (3h, 3i, and 3o). The
more sterically hindered 2-chlorobenzaldehyde was also
inapplicable to this protocol (3p). Next, 4-phenyl-substituted
benzaldehyde, 1- and 2-naphthaldehyde, as well as an aromatic
B
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Scheme 2. Substrate Scope for Diverse Aldehydes
Scheme 3. Substrate Scope for α-Amino Acids
Scheme 4. Investigation of the Impact of N-Protecting
Groups
heterocyclic aldehyde were further examined. Unfortunately,
the more sterically hindered 1-naphthaldehyde was unsuitable
for this reaction (3s), whereas others afforded the desired
products in moderate to good yields (3q, 3r, and 3t). To
further demonstrate the utility of this protocol, some
synthesized valuable benzaldehydes bearing bioactive frag-
ments were then screened. Gratifyingly, the desired products
3u−w were obtained in moderate yields under condition A or
B. It is noteworthy that aliphatic aldehydes always showed
specific reactivity and were unsuitable for this method. (See
the SI.)
Subsequently, the generality of α-amino acids was
investigated (Scheme 3). As previously mentioned, the
screening of α-amino acids was then conducted under
condition B due to the difficulty of preparing some α-amino-
acid NIPH esters. First, several N-Ac-protected natural α-
amino acids were examined. The reaction of representative
nonpolar natural α-amino acids such as proline, valine, leucine,
isoleucine, norvaline, methionine, and lysine proceeded
smoothly to afford the desired products 4a−g in moderate
yields. However, aspartic acid gave product 4h in a significantly
decreased yield. In terms of tryptophan, the yield of product 4i
was also significantly decreased owing to the formation of the
enamine byproduct 4i′. Next, we turned our attention to the
scope of some synthesized protected α-amino acids. In general,
various linear (4j−m, 4p) and cyclic amino acids (4q, 4r) were
well tolerated, affording the corresponding α-amino ketones in
moderate yields. To our delight, α-quaternary amino acids
were also applicable to this condition, yielding α-quaternary
amino ketones 4n and 4o in acceptable yields.
Similar C−N coupling byproducts 6b and 6c were also
observed for some other N-Boc-protected linear amino acids.
On the contrary, the reaction of cyclic N-Boc-protected proline
afforded the desired product 5a in good yield. It was also found
that the reaction of N-Cbz valine gave the desired product 5b
in a decreased yield compared with N-Ac product 4b. Notably,
a small amount of enamine byproduct was isolated together
with 5b, which were not separable through column
chromatography. Thus it might be concluded that the less
sterically hindered acetyl is the optimal N-protecting group of
amino acids for this transformation.
Another unique feature of this protocol is its ability to access
diverse keto-peptides (Scheme 5). There are two strategies
that can be used to achieve this synthetic target. First, the
direct chemical modification of the carboxy group of peptides
under condition B could afford invaluable keto-peptides 7a−c
(Scheme 5a). Another method involves the late-stage strategy
(Scheme 5b). N-protected α-amino ketone fragments were
initially produced and then underwent deprotection and
condensation with other amino acids to give keto-peptides,
which could be further modified using the previously described
steps to afford larger keto-peptides. It is noteworthy that the
peptide modification process was conducted under near-
Following the substrate screening, N-protecting groups of
amino acids were found to be critical to the yield and
selectivity (Scheme 4). For phenylalanine, protecting groups
such as tosyl, Cbz, Fmoc, and methyl protecting groups were
not suitable for the developed system. N-Boc phenylalanine
exclusively gave the unexpected C−N coupling product 6a.
C
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Scheme 5. Application in the Synthesis of Keto-Peptides
Scheme 7. Control Experiments
found that the reaction of ester 1a′ with benzaldehyde under
heating conditions could afford only a small amount of the
desired product 3a (Scheme 7d). Therefore, the photoexcited
radical−radical coupling mechanism may not be the
determining factor in this case.14,15 Moreover, the preliminary
enantioselective synthesis of α-amino ketone 3a has been
investigated, but the results are unsatisfactory. (See the SI.)
Finally, a proposed radical−polar crossover mechanism is
illustrated based on the experimental results and literature
(Scheme 8).16 Preprepared or in situ formed amino-acid-
neutral, metal-free, heating-free conditions, which might
prevent the possible disaggregation and side reactions of
specific bioactive compounds. Thus this method has the
potential for peptide modification and some biochemistry uses.
α-Amino ketone derivatives represent a class of important
synthetic intermediates and bioactive fragments. An inves-
tigation with downstream applications was then conducted
using 3a as the model substrate (Scheme 6). The reduction of
Scheme 8. Proposed Mechanism
Scheme 6. Derivation of α-Amino Ketone 3a
3a gave α-amino alcohol 8a in 82% yield. The treatment of 3a
with a Grignard reagent afforded a higher order α-amino
alcohol 8b. The amino ketone 3a could be further converted to
N,N-disubstituted product 8c. Moreover, a Z/E mixture of α-
amino oxime 8d could be formed through the condensation
with hydroxylamine. Interestingly, a new transformation of 3a
to azirine 8e under acidic conditions was discovered.
Additionally, the removal of the protecting group of 3a gave
product 8f, whose amino group could be further functionalized
for specific synthetic purposes.
Several control experiments were then carried out to clarify
the possible mechanism. The photo/NHC cocatalyzed
reaction was hampered in the presence of excess TEMPO,
which indicated a possible radical mechanism (Scheme 7a).
Because N-protected enamines were sometimes observed as
the byproducts, the reaction of ester 1a′ in the absence of
benzaldehyde was investigated, and N-styrylacetamide 3a′ was
isolated in 30% yield (Scheme 7b). However, 3a′ cannot react
with benzaldehyde to give product 3a (Scheme 7c). It was also
derived redox-active esters 1′ can be converted into
corresponding alkyl radicals I after decarboxylation in the
presence of a photocatalyst. The radical intermediate I may
undergo another electron transfer realized by the oxidative
staged photocatalyst, affording the α-aminoalkyl carbocation
intermediate II.17 After the deprotonation of II under basic
conditions, the imine intermediates III are formed. Some
imines are trapped by the phthalimide anion to afford
byproducts 6, and some are tautomerized to the corresponding
enamine byproducts. On the contrary, the combination of
aldehydes with carbene NHC-E′ generated upon the
deprotonation of the precatalyst NHC-E with a base gives
Breslow intermediate IV. The subsequent aza-Benzoin
condensation3,18 between IV and imines III affords the desired
products 3, 4, and 5, accompanied by the leaving of a carbene
for the next catalytic cycle.
In summary, we have described an NHC/photoredox
cocatalyzed direct modification of α-amino acids and peptides
with aldehydes to access structurally diverse α-amino ketones.
D
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ASSOCIATED CONTENT
* Supporting Information
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All experimental procedures, characterization, and NMR
spectra for new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
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́
(7) (a) Pinazo, A.; Pons, R.; Perez, L.; Infante, M. R. Ind. Eng. Chem.
Ding Du − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China; orcid.org/0000-
0002-4615-5433; Email: ddmn9999@cpu.edu.cn
Zhihao Shi − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China; Email: sszh163@
163.com
Jie Feng − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China; orcid.org/0000-
0002-8662-2198; Email: 1020162519@cpu.edu.cn
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Authors
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Kuili Zhang − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China
Rui Ma − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China
Lei Chen − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China
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Jian Gao − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China; orcid.org/0000-
0003-0071-1972
Tao Lu − State Key Laboratory of Natural Medicines,
Department of Organic Chemistry, China Pharmaceutical
University, Nanjing 210009, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02202
(13) (a) DiRocco, D. A.; Rovis, T. J. Am. Chem. Soc. 2012, 134,
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The authors declare no competing financial interest.
̈
Agrawal, A.; Ruß, V.; Gotze, J. P.; Hopkinson, M. N. Angew. Chem.,
ACKNOWLEDGMENTS
Int. Ed. 2020, 59, 3190. (d) Dai, L.; Xia, Z. H.; Gao, Y. Y.; Gao, Z. H.;
Ye, S. Angew. Chem., Int. Ed. 2019, 58, 18124. (e) Xia, Z.-H.; Dai, L.;
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■
We thank the National Natural Science Foundation of China
(nos. 21572270, 21702232) and the “Double First-Class”
University Project (CPU2018GY02 and CPU2018GY35) for
financial support.
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2019, 141, 3854.
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