Received: 12 November 2017 | Revised: 23 January 2018 | Accepted: 25 January 2018

DOI: 10.1002/pep2.24049

REVIEW

Decarboxylative couplings as versatile tools for late-stage

peptide modifications

Lara R. Malins

Research School of Chemistry, Australian

National University, Canberra, ACT 2601,
Australia
Correspondence
Lara R. Malins, Research School of
Chemistry, Australian National University,
Canberra, ACT 2601, Australia.
Email: lara.malins@anu.edu.au
Abstract
While strategies for the late-stage modification of peptides are crucial to the design and synthesis
of new peptide-based materials and therapeutics, synthetic methods have historically focused on
the modification of select, nucleophilic amino acids. This review highlights decarboxylative coupling
strategies as emerging tools for the targeted functionalization of native peptidic acids
—a-carboxylic acids and aspartic/glutamic acid residues—through complexity building CAC and
CAheteroatom bond formations. Decarboxylation strategies employing both activated carboxylic
acids (redox-active esters) and the direct application of unprotected carboxylic acids are discussed.
Emphasis is placed on the scope and limitations of the methodologies as well as their compatibility
with complex peptide substrates.

KEYWORDS
cross-coupling, decarboxylation, peptide modification, transition-metal catalysis, unnatural amino
acids

1 | INTRODUCTION recent developments in peptide synthesis and more broadly, organic

The importance of peptides as biological tools, functional materials, and
promising therapeutics underpins a growing demand—from both aca-
demic and industrial laboratories—for versatile peptide functionalization
strategies.[1,2] Precise structural modifications, particularly the incorpo-
ration of non-native motifs, enable the production of designer peptides
featuring finely tuned biological properties or enhanced therapeutic
capabilities. Such modifications are particularly relevant to drug discov-
ery as tools for minimizing the conventional liabilities associated with
peptide drugs, including a lack of in vivo stability and poor oral bioavail-
ability.[3,4] Although the programmed incorporation of unnatural amino
acid building blocks into peptides through iterative solid- or solution-
phase peptide synthesis is now routine, the selective, late-stage intro-
duction of such important structural modifications onto native amino
acids remains challenging, owing in part to the strict chemoselectivity
and reagent compatibility requirements posed by peptide substrates.
Nevertheless, the rapid generation of modified peptides directly from
native peptide precursors is conceptually appealing as a means of
reducing the synthetic burden associated with the preparation of
orthogonally protected building blocks (typically nontrivial, multistep
syntheses) and the de novo assembly of each designer peptide target.
As such, residue-specific modifications have been a focal point of
methodology development.[5] Tools that have long been exploited for
the functionalization of small molecules (e.g., transition metal-mediated
cross-couplings,[6–8] CAH functionalizations[9,10]) are increasingly being
developed and optimized for the selective modification of peptides.
Historically, strategies for the direct modification of native pep-
tides have mirrored advances in bioconjugation,[11,12] relying exten-
sively on the reactivity of nucleophilic residues such as cysteine (Cys),
lysine (Lys), and tyrosine (Tyr) with carefully tuned electrophiles. Protei-
nogenic alkyl carboxylic acids such as aspartic acid (Asp), glutamic acid
(Glu), and a-carboxylic acid groups, though abundant in peptide sub-
strates, have rarely been exploited as handles for functionalization out-
side of the standard mode of activation and amide bond formation.[5]
An appetite for more diverse means of peptide modification, however,
has fueled a recent surge in decarboxylative functionalizations which
exploit ubiquitous proteinogenic carboxylic acids as versatile starting
points for the introduction of non-native amino acids and functional
groups via CO2 extrusion and subsequent carbonAcarbon or carbon-
Aheteroatom bond formation (Scheme 1). In most cases, such endeav-
ors are intimately linked to powerful advances in the decarboxylative
functionalization of small molecules (including single amino acid sub-
strates), which have been the subject of several recent reviews.[13–16]
Rather than serve as a comprehensive or historical overview of

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C 2018 Wiley Periodicals, Inc. | 1 of 16
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2 of 16 | MALINS
S C H E M E 1 Strategies for the modification of peptides via
decarboxylative couplings
decarboxylative transformations, this review focuses specifically on
advances in decarboxylative couplings for the late-stage modification
of native carboxylic acids within peptide substrates (defined here as
two or more amino acids). Where applicable, readers are referred to
relevant reviews and seminal papers underpinning the described trans-
formations. Herein, synthetic strategies are principally categorized by
their use of activated esters (“redox-active esters”) (path A), or unpro-
tected carboxylic acids (path B), as substrates for the extrusion of CO2
and downstream coupling reactions (Scheme 1). These discrete syn-
thetic pathways are further subdivided by the nature of the bond-
forming reaction (CAC bond formation or CAheteroatom bond forma-
tion). The aim is to provide readers with a detailed guide to the growing
array of accessible decarboxylative modifications as well as provide a
perspective on unmet challenges in the area.
2 | DECARBOXYLATION OF ACTIVATED
ESTERS
2.1 | Historical perspectives
Despite the biosynthetic prevalence of amino acid decarboxylation
reactions, the decarboxylative functionalization of amino acids perhaps
only entered the general lexicon of synthetic chemists in the mid-
SCHEME 2 A, Barton esters as versatile substrates for decarboxylative couplings; B, Proposed radical mechanism
1980s with Sir Derek Barton’s seminal work on the reactivity of amino
acid thiohydroxamate esters 1 (so-called “Barton esters,” see Scheme
2A).[17,18] Prior approaches to the decarboxylation of amino acids, pep-
tides, and proteins relied extensively on heat[19,20] or the intermediacy
of highly unstable acid derivatives (e.g., acyl hypobromites,[21] reminis-
cent of the Hunsdiecker-Borodin reaction). Readily formed from protei-
nogenic carboxylic acids (e.g., 2, Scheme 2A), however, Barton esters 1
are known to fragment under mild conditions in the presence of heat
or light, causing homolysis of the NAO bond and the extrusion of CO2
and 2-pyridylthiyl radical 4 to form an amino acid-derived alkyl radical
intermediate 6 (Scheme 2B). This alkyl radical can engage in a number
of downstream pathways including reduction to the corresponding
alkane 8 in the presence of a hydrogen atom donor, such as tBuSH, or
halogenation with CCl4 or BrCCl3 to afford the Hunsdiecker-Borodin
product 9.[18,22] Giese-type radical addition to an electron deficient ole-
fin followed by incorporation of a pyridylsulfide unit at the a-position
to the electron-withdrawing group affords amino acid derivatives such
as 10 (Scheme 2A) .[23]
Importantly, Barton showed that transformations of this type were
amenable to the modification of both side-chain and a-carboxylic acids,
although a-decarboxylation proved more facile owing to the relative
stability of the a-amino radical formed following loss of CO2.[18] The
versatility of Barton esters for decarboxylative transformations on pep-
tides was further demonstrated by their compatibility with solid-phase
peptide synthesis (SPPS). In 2001, Attardi and Taddei demonstrated
the solid-phase synthesis of peptide Barton esters followed by a light
induced Hunsdiecker-Borodin reaction on the resin-bound substrates
to afford valuable brominated products.[24]
2.2 | Identifying redox-active esters
In the years following Barton’s seminal work, several additional acti-
vated esters were explored as suitable substrates for photolytic decar-
boxylative functionalizations, including benzophenone oxime esters
11[25] and N-hydroxyphthalimide (NHPI) esters 12 (Scheme 3A).[26–28]
MALINS | 3 of 16

S C H E M E 3 A, Alternative esters capable of photolytic decarboxylation; B, Proposed mechanism of N-hydroxyphthalimide (NHPI) ester
fragmentation to afford alkyl radical 18; C, Representative products following decarboxylation and trapping of the radical intermediate

Okada et al. demonstrated the advantageous stability of the latter, carboxylic acids as a feasible entry point into conventional, metal-
which are readily prepared, easily isolable, and tolerant of aqueous catalyzed cross-couplings,[15,35,36] the Baran laboratory was first to
[26]
reaction media. Upon irradiation of phthalimide esters with visible report the use of activated carboxylic acids such as 22 as robust alkyl
light in the presence of a photosensitizer (e.g., PS, 13, Scheme 3B), sin-
gle electron transfer (SET) from the excited state of the photosensitizer
14 to ester 12 affords the phthalimide radical anion 15. Protonation
followed by homolysis of the weak NAO bond generates carboxyl radi-
cal 17 which spontaneously decarboxylates to afford carbon centered
radical 18. Okada and coworkers demonstrated that radical intermedi-
ate 18 can subsequently engage a variety of radical traps, including
tBuSH, CCl4, and various electron-deficient olefins to afford the corre-
sponding reduced alkanes 19,[26] chloroalkanes 20,[27] and Michael
adducts 21,[28] respectively (Scheme 3C). The ability to forge addition
products such as 21 is a notable advantage over the use of Barton
esters, whereby the intermediate radical formed following Michael
addition reacts preferentially with the Barton ester thiocarbonyl group
to form a-sulfide products such as 10 (see Scheme 2A).[23] In their
2012 second-generation synthesis of the diterpene (–)-aplyviolene,
Schnermann and Overmann masterfully employed an NHPI ester to
facilitate the decarboxylative addition of a tertiary radical to an
a,b-unsaturated ketone.[29] Carried out in the presence of light and
catalytic [Ru(bpy)3Cl2] in aqueous THF, this transformation provided
a mild and selective approach to radical formation and afforded the
target product without incorporation of the 2-pyridylthio group.
Decades after the initial disclosure of decarboxylative transforma-
tions using the versatile activated esters outlined in Schemes 2 and 3,
the synthetic utility of these venerable intermediates became a source
of renewed excitement, owing to the seminal work of several research
groups.[30–33] The pivotal realization—that carbon-centered radicals
(e.g., 18) formed through decarboxylation of activated alkyl esters can
engage in conventional cross-coupling pathways—markedly expanded
the retrosynthetic utility of carboxylic acid derivatives. Unlike conven-
tional metal-catalyzed CAC bond-forming reactions, which rely heavily
SCHEME 4 A, Application of “redox-active esters” in nickel-
on alkyl and aryl halides as starting electrophiles,[34] activated esters
catalyzed decarboxylative cross-couplings with arylzinc reagents; B,
are simple and readily accessible, serving as robust chemical feedstocks
Cross-electrophile coupling employing redox-active esters; C, Pro-
for a vast array of complexity-building reactions. Drawing on earlier posed catalytic cycle involving decarboxylative fragmentation of
studies which demonstrated the decarboxylative metalation of aryl radical anion 28 to form radical intermediate 29
4 of 16 | MALINS
SCHEME 5 Overview of decarboxylative couplings employing peptide redox-active esters (RAEs)
coupling partners in metal-catalyzed CAC bond formation in early
[30]
2016 (Scheme 4A). The authors identified that the radical decarbox-
ylation of Barton esters could be triggered, at room temperature in the
absence of light, through single-electron transfer (SET) from a suitable
transition-metal complex (Scheme 4A). The transition metal catalyst (a
ligated aryl-nickel complex formed from NiCl2, a bipyridine ligand, and
arylzinc reagent 23) could also mediate downstream CAC bond forma-
[30]
tion, affording the valuable alkyl-aryl cross-coupled product 24.
The photosensitivity of Barton esters prompted a search for more
practical activated ester alternatives, or so-called redox-active esters
(RAEs), also capable of accepting an electron from a suitable metal-
catalyst. In addition to Okada’s priviledged phthalimide ester 22-
NHPI,[26–28] and the related tetrachloro-variant 22-TCNHPI, N-hydrox-
ybenzotriazole esters 22-HOBt and 22-HOAt—commonly employed in
[30]
peptide couplings—were also suitable substrates (Scheme 4A). Weix
and coworkers independently reported a concurrent nickel-catalyzed
decarboxylative cross-coupling of N-hydroxyphthalimide esters 25 with
[31]
aryl iodides 26 in the presence of zinc metal (Scheme 4B), serving as
a testament to the generality of such carboxylic acid derivatives as
robust alkyl radical precursors. Mechanistically, such reactions are
thought to proceed through a pathway similar to Okada’s photolytic
decarboxylation (see Scheme 3B). In the absence of light and a photo-
catalyst, however, the key electron-transfer step is thought to be medi-
ated by the metal center. Baran and coworkers proposed that the
nickel-catalyzed arylzinc coupling (outlined in Scheme 4A) involves an
initial transmetalation of arylzinc reagent 23, forming the key ligated
aryl-Ni complex (Scheme 4C).[30] SET from the metal center to the
phthalimide ester 22-NHPI forms radical anion 28 which spontaneously
fragments, losing CO2, and forming alkyl radical 29. Recombination of
the alkyl radical with the Ni complex followed by reductive elimination
forms the cross-coupled product 24, closing the catalytic cycle. The
putative involvement of radical intermediates in this process was con-
firmed through ring-opening of a carboxylic acid bearing a cyclopro-
pane unit.[30]
Given the overlap between redox-active esters (RAEs) and the
intermediates formed using standard peptide coupling reagents, it is
perhaps unsurprising that RAEs have gradually emerged as powerful
tools for the coupling of peptide-based alkyl carboxylic acids. In addi-
tion to a variety of nickel-catalyzed transformations,[30,37–42] concur-
rent work has exploited Okada’s photoinduced fragmentation of
phthalimide esters[26] for the decarboxylative arylation,[32,33,43] thiola-
tion,[44] and selenation[45] of peptide substrates (vide infra). Despite a
conceptual similarity to prior work on decarboxylative functionaliza-
tions, the renewed impetus for the contemporary advancement of
RAE-mediated decarboxylative couplings stems largely from a growing
demand for modified peptides from both academia and industry. New
methods are additionally underpinned by an enhanced understanding
of transition-metal-catalyzed and photochemical processes, setting the
stage for rapid and powerful additions to the repertoire of decarboxyla-
tive functionalizations and allowing access to more diverse peptide
MALINS
SCHEME 6 On-resin nickel-catalyzed decarboxylative alkyl-alkyl couplings employing peptide TCNHPI esters
products. Scheme 5 summarizes very recent methods—most reported
within the past 2 years—for peptide modifications which utilize RAEs,
particularly phthalimide esters, as a starting point for the diverse decar-
boxylative functionalization of peptides. The following sections, subdi-
vided by the nature of the bond-forming reaction, will discuss the
scope and limitations of these methodologies.
2.3 | CAC bond formation
Tools for CAC bond formation are paramount to building molecular
complexity and are amongst the most oft-used strategies in drug dis-
covery.[46] Within the context of peptides, the decarboxylative cross-
coupling of activated esters is quickly emerging as a powerful approach
to the targeted functionalization of peptides, given the relative stability
and abundance of proteinogenic carboxylic acids and their ease of acti-
vation. The following sections outline metal-catalyzed and photochemi-
cal cross-couplings of peptidic alkyl carboxylic acid derivatives with
C(sp3)-, C(sp2)-, and C(sp)-hybridized coupling partners.
3 3
2.3.1 | C(sp )AC(sp ) coupling
Alkylation
Shortly after demonstrating the feasibility of nickel-catalyzed decarbox-
ylative arylations on small-molecule substrates, the Baran laboratory
reported in 2016 a robust method for the decarboxylative alkylation of
resin-bound peptide-RAEs with alkylzinc reagents (Scheme 6).[37] Tak-
ing advantage of the similarities between RAEs and standard peptide
coupling reagents for amide-bond formation, this solid-phase approach
to CAC bond formation utilized peptides forged under standard Fmoc-
solid-phase peptide synthesis (SPPS) conditions on Rink amide resin.
The target carboxylic acids 31 were incorporated as orthogonally
| 5 of 16
protected allyl esters 30 which, following elongation of the target pep-
tide on the solid-phase, could be readily unmasked upon treatment
with Pd(PPh3)4 and phenylsilane. On-resin activation of peptide acids
was preferentially performed using excess DIC and tetrachloro-N-
hydroxyphthalimide (TCNHPI) 32 in the presence of DMAP at 378C.
Treatment of the resin-bound RAE 33 with NiCl2glyme, ligand di-tert-
butylbipyridine, and various alkylzinc reagents then afforded modified
peptides 34-38, following simple washing steps and acidic cleavage from
the resin.[37]
Conventional advantages associated with solid-phase chemistry—
the use of excess reagents (2 equiv. of the nickel/ligand complex, 20
equiv. of the alkylzinc reagent) and ease of purification—facilitated the
rapid diversification of resin-bound substrates. Products derived from
both side-chain (34 and 35) and a-carboxylic (36 and 37) acids were
feasible, as was the dual-functionalization of Asp and Glu (38). Side-
chain modifications proceeded with complete retention of a-chirality,
affording homogeneous peptide products with valuable synthetic han-
dles including alkenes. While transformations generally occurred in
good yields based on the original resin-loading, byproducts associated
with hydrolysis of the activated ester, net reduction via a
decarboxylation-hydrogen-atom abstraction pathway, and aspartimide
or glutimide formation following side-chain activation account for the
mass-balance.[37] Strategies to reduce byproduct formation would sim-
plify iterative couplings, ideally allowing for the robust incorporation of
two or more discrete unnatural variants.
Giese reaction
Drawing from the early successes of Barton[23] and Okada[28] on decar-
boxylative Giese reactions, Baran and coworkers extended their suite
of on-resin, nickel-catalyzed RAE modifications to include reactions
6 of 16 | MALINS

S C H E M E 7 Decarboxylative Giese reactions employing peptide NHPI esters. A, Resin-bound carboxylic acid; B, Resin-bound acrylamide
acceptor; C, Solution-phase macrocyclization via an intramolecular Giese reaction

with electron-deficient alkenes (Scheme 7A).[40] Following activation as
the corresponding NHPI-ester, resin-bound acid 39 could be coupled
with phenylvinylsulfone or acrylonitrile in the presence of Ni(acac)2,
LiCl, and Zn powder to afford modified peptides 40 and 41, respec-
tively. Alternatively, solid-supported alkene 43 could be coupled with
an excess of proline-derived RAE 42 to afford peptide 44 incorporating
a g-amino acid (Scheme 7B). Finally, bifunctional peptide 46, bearing an
NHPI ester and a Lys-linked acrylamide moiety could engage in a
solution-phase, intramolecular Giese reaction, forming the structurally
intriguing macrocycle 47 as a mixture of diastereomers at the Pro
a-position (Scheme 7C).[40]

2.3.2 | C(sp3)–C(sp2) and C(sp3)–C(sp) couplings

S C H E M E 8 Arylation of peptide NHPI esters with 2-
isocyanobiphenyl 49 under visible light irradiation
Arylation
In 2016, H. Fu and coworkers reported a collection of high-yielding,
photochemical decarboxylative peptide a-arylations employing NHPI
esters (Scheme 8).[32,43] The authors first disclosed the visible-light
assisted, ruthenium-catalyzed coupling of peptide RAEs such as 48
with 2-isocyanobiphenyl 49 to afford the 8-methylphenanthridine
derivatives 50-52 in excellent yields (Scheme 8).[32] An intriguing modi-
fication of the protocol allowed formation of pentapeptide 52 in the
absence of a conventional photocatalyst.[43] The reaction was instead
carried out in the presence of Cs2CO3 and catalytic 4-(trifluoromethyl)
thiophenol under visible-light irradiation to afford the arylated product.
In the same study, the authors also demonstrated thiophenol-catalyzed
decarboxylative aminations and Giese reactions, albeit on single amino
MALINS | 7 of 16

S C H E M E 1 0 Nickel-catalyzed peptide alkenylation and

alkynylation employing NHPI redox-active ester 58

photocatalytic approach by H. Fu and coworkers utilizes amino acid

SCHEME 9 Decarboxylative arylation of a-carboxylic acids via a-NHPI esters and a variety of terminal alkynes in the presence of
direct CAH coupling of heteroarenes [Ru(bpy)3]Cl2/CuI to accomplish the decarboxylative alkynylation of
single amino acid derivatives.[53] Though not yet employed as a
acid substrates.[43] Employing a more conventional photocatalytic sys-
means of peptide modification, the ability to utilize terminal alkynes,
tem, Shang, Y. Fu, and coworkers later demonstrated the coupling of
rather than preformed alkynylzinc reagents, is an attractive feature
diverse heteroarenes with peptide acids via co-catalysis with iridium
of this approach.
photocatalyst 54 and phosphoric acid PA-1 under irradiation with blue
LEDs (Scheme 9).[33] Products 55-57, bearing valuable, pharamaceuti- 2.3.3 | Advances in RAE synthesis for CAC bond formation
cally relevant heteroaryl motifs, have promising applications in peptide In a recent effort to streamline nickel-catalyzed decarboxylative pep-
drug discovery. While differing in the precise mode of photoexcitation, tide cross-couplings into a facile one-pot protocol and overcome diffi-
each arylation reaction described above is mechanistically linked by a culties with the sluggish in-solution activation of peptides using DIC
putative alkyl radical intermediate formed following decarboxylation—a and TCNHPI (32, see Scheme 6), Baran and coworkers developed a
process reminiscent of the photoinduced phthalimide fragmentation versatile new reagent for RAE synthesis. Inspired by the superior reac-
reported by Okada and coworkers.[26–28] tivity of uronium-based, “all-in-one” peptide coupling reagents such as
HATU, the group reported the multi-kilogram scale synthesis of tetra-
Alkenylation
chloro-N-hydroxyphthalimide tetramethyluronium hexafluorophos-
The direct incorporation of alkenes into peptide substrates facilitates
phate (CITU) 63, a tetramethyluronium derivative of TCNHPI (Scheme
an array of important downstream modifications, including applications
11).[41] The bench-stable coupling reagent facilitates a host of decar-
relevant to peptide stapling[47] and thiol-ene couplings.[48–50] In early
boxylative nickel-catalyzed transformations, including solid-phase
2017, the Baran lab reported a nickel-catalyzed decarboxylative alkeny-
lation strategy employing peptide RAEs.[38] Using various alkenylzinc
reagents, the method allows for the stereoselective incorporation of
substituted olefins. Application to the late-stage modification of an
unprotected peptide-NHPI ester 58 provided the valuable isopropenyl
(59) and styrenyl (60) peptide products (Scheme 10).

Alkynylation
A conceptually similar approach to C(sp3)–C(sp) couplings was accom-
plished by Baran and coworkers, through the cross-coupling of
peptide-NHPI ester 58 with ethynylzinc chloride 61 to afford the cov-
eted alkyne moiety (Scheme 10).[39] As expected, terminal alkyne 62
was a suitable substrate for the copper-catalyzed azide-alkyne cycload-
dition (CuAAc) reaction with benzyl azide to afford the corresponding
triazole product. The importance of alkynylated peptide targets for bio-
conjugation[11,12,51] and recent strategies for peptide macrocycliza-
SCHEME 11 CITU 63 as a versatile activating agent for one-pot,
tion[47,52] render this particular methodology a prominent addition to nickel-catalyzed decarboxylative cross-couplings with alkyl, alkenyl
the toolbox of late-stage peptide modifications. An alternative, and alkynyl zinc reagents
8 of 16 | MALINS
SCHEME 12 Nickel-catalyzed decarboxylative borylation of
peptide NHPI esters affording peptide boronate esters and peptide
boronic acids
alkylation and arylation, and solution-phase alkylation (65 and 66), alke-
nylation (59), and alkynylation (62). The reagent outperforms a one-pot
alkylation protocol employing HATU and proved superior to preacti-
vated NHPI esters (see 58, Scheme 10). Importantly, initial evaluation
of the explosivity of the reagent suggests that, unlike benzotriazole-
based coupling reagents,[54] CITU is not explosive. The promising safety
profile renders the reagent an attractive option for the potential scale-
up of decarboxylative couplings.[41]
2.4 | CAheteroatom bond formation
As with CAC bond formation, the introduction of heteroatom function-
alities onto peptide substrates via the decarboxylative cross-coupling
of redox-active esters is a burgeoning area of research. The resulting
peptide products feature valuable nonproteinogenic functionalities,
including boronic acid derivatives,[42] arylsulfides,[44] and aryl- and alkyl-
selenides,[45] incorporation of which would otherwise require the syn-
thesis of challenging unnatural amino acid building blocks.
2.4.1 | C(sp3)–B bond formation
In addition to their limitless potential as substrates for various
organic transformations,[55] boronic acids are intriguing bioisosteric
replacements of peptide carboxylic acids[56] and attractive therapeu-
tic candidates. Two peptide alkyl boronic acid derivatives, Velcade
and Ninlaro, are FDA-approved proteasome inhibitors whose bioac-
tivity is attributed to their C-terminal alkyl boronic acid moieties.[57]
Though conventional syntheses of such molecules rely on a building
block approach—incorporating a preformed amino boronic acid into
the peptide-chain—replacement of a proteinogenic carboxylic acid
with a boronic acid group represents a more efficient and direct dis-
connection strategy.
In 2017, Baran and coworkers accomplished the decarboxylative
cross-coupling of peptide NHPI esters with B2pin2 (Scheme 12)[42] to
rapidly afford peptide boronate esters. The nickel-mediated transfor-
mation was aided by the addition of magnesium salts and the pre-
mixing of B2pin2 with MeLi, which served to activate the boron for
transmetalation. While the method provided initial access to peptide
pinacol boronate esters (e.g., 68), facile hydrolysis also afforded the
analogous boronic acids. Accessible peptide products included Ninlaro
(70), various di- and tripeptide derivatives (71–73)—including precur-
sors to potent new human neutrophil elastase inhibitors—and remark-
ably, a borylated variant of the peptide antibiotic vancomycin (74).
While the general use of the strongly basic MeLi might pose concerns
for base-sensitive motifs, precomplexation of B2pin2 with MeLi ren-
dered the method compatible with standard Fmoc-protecting
groups.[42]
In mid-2017, Aggarwal and coworkers reported a complimentary,
transition-metal free, photoinduced decarboxylative borylation strategy
for the conversion of NHPI esters into the corresponding pinacol boro-
nate esters through irradiation with visible light.[58] Although not dem-
onstrated explicitly on peptide substrates, the successful
decarboxylative borylation of a glutamic acid side-chain suggests that
this methodology may be similarly extendable to the late-stage modifi-
cation of peptides.
2.4.2 | C(sp3)–S and C(sp3)–se bond formation
Concurrent with their work on visible-light induced, thiophenol-
catalyzed CAC bond formation[43] (see 2.3.2), H. Fu and coworkers
reported conditions for the arylthiolation of amino acids and a tri-
peptide substrate (Scheme 13A).[44] Beginning with tripeptide 75
bearing a C-terminal proline a-NHPI ester, photoirradiation in the
presence of Cs2CO3 and a substituted thiophenol derivative
afforded peptide product 76 in 73% yield. The feasibility of the
S C H E M E 1 3 Decarboxylative CAheteroatom bond formation
employing peptide NHPI esters; A, metal-free decarboxylative
arylthiolation, and B, ruthenium-catalyzed decarboxylative selena-
tion of side-chain NHPI esters
MALINS
S C H E M E 1 4 Representative photochemical approach to the direct
radical decarboxylation of carboxylic acids to form radical
intermediate 18
transformation in the absence of an added photocatalyst is attrib-
uted to the ability of a putative Cs2CO3-phthalimide ester complex
to absorb visible light. The excited state phthalimide complex is
thought to accept an electron from an aryl thiolate forming the cor-
responding thiyl radical and a phthalimide radical anion (cf., 15,
Scheme 3B) capable of decarboxylative fragmentation to the key
alkyl radical intermediate. [44]
The same authors employed a more conventional ruthenium pho-
tocatalyst for the visible-light promoted, decarboxylative arylselenation
of an AspPro dipeptide (Scheme 13B).[45] Decarboxylation of the Asp
side-chain NHPI-ester 77 and concomitant coupling with diphenyldise-
lenide afforded modified dipeptide 78. Though not explicitly demon-
strated on additional peptide substrates, the reaction conditions were
also amenable to the functionalization of glutamic acid and the installa-
[45]
tion of diverse aryl- and alkylselenides.
SCHEME 15 Overview of strategies for the direct decarboxylative coupling of peptide carboxylic acids
| 9 of 16
2.5 | Scope and limitations of redox-active ester (RAE)
decarboxylation strategies
As discussed in sections 2.3 and 2.4, emerging RAE-based decarboxylative
coupling strategies are highly versatile, featuring the formation of diverse
CAC bonds and valuable CAheteroatom bonds from activated peptide
carboxylic acids. Methods utilize remarkably mild SET processes—medi-
ated by a transition-metal catalyst or a photocatalytic system—to transfer
an electron into the RAE and promote radical fragmentation. This process
enables the formation of both stabilized a-amino and non-stabilized pri-
mary radical intermediates from a-acids and side-chain acids, respectively.
Notably, transformations on side-chain Asp and Glu retain the a-chirality
of these residues. The installation of unnatural motifs, both in solution and
on the solid-phase, provides rapid access to diverse and high-value peptide
targets, including substrates poised for further functionalization.
The technologies for decarboxylative functionalization of peptide
RAEs described above are rapidly maturing. Nevertheless, the current
methodologies have limitations in scope and applicability that may guide
future developments. One notable drawback associated with RAE cou-
plings is the requirement for a discrete activation step. Although esterifi-
cations of amino acids are generally facile, they lengthen the synthetic
process and limit the overall atom-economy of the decarboxylative
transformation, as the activator is not typically recycled. Recalcitrant sub-
strates can also pose considerable challenges. Inventive coupling
reagents such as CITU[41] (section 2.3.3) are just beginning to streamline
the process and enhance reactivity over standard carbodiimide-based
activations. In addition, the scope of coupling reactions, while broad, has
10 of 16 | MALINS
S C H E M E 1 6 Iridium-mediated photocatalytic decarboxylative Giese reactions employing unprotected carboxylic acids. A, Intermolecular
Giese reaction; B, an intramolecular Giese approach to peptide macrocyclization
not yet been fully vetted on the entire suite of proteinogenic amino
acids. Frequent use of reactive organozinc reagents (which typically
require fresh preparation) may limit compatibility with unprotected resi-
dues. It is therefore envisioned that the extension of RAE-mediated
decarboxylative couplings in the future will focus on the application of
[59]
readily accessible and benign coupling partners, such as boronic acids
[33]
or unfunctionalized arenes and heteroarenes via direct CAH cou-
plings. Promising methods that have thus far only been demonstrated on
single amino acids, including H. Fu’s thiophenol-catalyzed decarboxyla-
tive amination strategy[43] (see section 2.3.2), an approach to substituted
peptide alkynes using alkynyl sulfones,[60] and a recent decarboxylative
silylation manifold,[61] may also serve as important proof-of-concept
studies for the development of new peptide-based methods. Given the
simplicity of routine solid-phase peptide synthesis using various auto-
mated platforms, it is further envisaged that the adoption of decarboxy-
lative transformations would greatly benefit from the development and
optimization of new strategies amenable to automation.
3 | DIRECT DECARBOXYLATION OF
CARBOXYLIC ACIDS
3.1 | Background
In addressing the limitations of RAE-mediated couplings, direct decar-
boxylation is an attractive approach to the modification of peptides as
it allows for the functionalization of native carboxylic acids without the
need for preactivation through RAE formation. Contemporary strat-
egies for direct couplings rely heavily on photo-induced electron trans-
fer (PET) as a means of mildly and selectively triggering the
decarboxylative fragmentation of an unprotected acid (Scheme 14).[62]
Upon irradiation with light, a suitable photocatalyst (traditionally a
high-value iridium or ruthenium-based complex) can accept photons to
generate an excited state complex which is highly oxidizing. Deproto-
nation of the starting carboxylic acid, followed by single-electron oxida-
tion—the transfer of an electron from the carboxylate 79 to the excited
photocatalyst—forms a carboxyl radical 80. Spontaneous fragmentation
leads to the loss of CO2 and formation of radical 18, analogous to that
produced following RAE fragmentation and now poised for subsequent
functionalization (see Scheme 14 for a representative example). Devel-
opments in photocatalytic systems have enabled access to alkyl radicals
using a variety of alternative photosensitizers and under various reac-
tions conditions.[63] Importantly, amino acid alkyl radicals generated in
this manner are also known to engage readily with suitable radical traps
or to be intercepted by standard transition-metal-catalyzed cross-cou-
pling cycles,[63–66] setting the stage for downstream diversification.
Other intriguing approaches to the direct functionalization of
native peptide a-carboxylic acids include chemical and electrochemical
oxidative decarboxylations (see Scheme 24, vide infra). While often not
classified as conventional “coupling” reactions, such oxidative
MALINS | 11 of 16

transformations proceed through reactive acyl iminium intermediates,

which may be trapped with a variety of nucleophiles for the diverse
functionalization of peptides.
The following sections will outline representative transformations
which utilize proteinogenic carboxylic acids for the direct late-stage
modification of peptide substrates. Categorized by the key bond-
forming reaction, particular attention will be paid to developments in
the photocatalytic, electrochemical, and chemical systems used to
accomplish such transformations. An overview of methods to be dis-
cussed is provided in Scheme 15.

3.2 | CAC bond formation

Over the past several years, there has been a surge in the discovery of
photocatalytic methods for the direct decarboxylative coupling of car-
boxylic acids to forge new CAC bonds. Most strategies were originally
disclosed for the diversification of small molecules, often including
a-amino acids as substrates.[14,62,63] However, as modified peptides
have become increasingly important synthetic targets (and excellent
proving-grounds for evaluating reaction chemoselectivity),[5] contem-
porary studies have branched into the development and optimization
of such strategies for late-stage peptide modifications. A summary of
these endeavors is provided in the following sections.

3.2.1 | C(sp3)–C(sp3) coupling

Giese reaction
In 2014, MacMillan and coworkers reported a photocatalyzed, direct
decarboxylative Giese reaction between the electron deficient alkene
81 and several simple dipeptide substrates (Scheme 16A).[67] The meth-
odology employed iridium photocatalyst 54 (see Scheme 9) and visible-
light irradiation to forge a new CAC bond at the peptide C-terminus
(82-84). The extension of this methodology to an intramolecular variant
for peptide macrocyclization was accomplished shortly thereafter[68]
and concurrently with the nickel-catalyzed Giese macrocyclization
approach discussed in section 2.3.1.[40] Subjecting peptide substrates
bearing an N-terminal acrylamide unit and a free carboxylic acid at the
C-terminus (e.g., 85, Scheme 16B) to Ir-catalyzed PET conditions, Mac-
Millan and coworkers were able to successfully access a range of
intriguing macrocyclic peptide variants (86-89). Reactions were selec-
tive for C-terminal acids in the presence of unprotected side-chain
acids (87) owing to the enhanced stability of the a-amino radical inter-
mediate. Several other protected amino acid side-chains were tolerated
in the transformation, as were varying ring-sizes in the products, which
ranged from 11-member ring 89 to a 47-membered (15-amino acid)
[68]
macrocyclic product.
Taking full advantage of the chemoselectivity observed in the
intramolecular Giese reactions depicted in Scheme 16, MacMillan and
coworkers subsequently reported a powerful photocatalytic approach
for the direct and selective decarboxylative modification of C-terminal
peptide and protein carboxylates (Scheme 17).[69] Beginning with small
model peptides (e.g., tetrapeptides such as 90, bearing a diverse range
of amino acids at the N-terminus), the authors optimized novel, water-
soluble flavin-based photocatalytic systems (91 and 92) which allow C-
S C H E M E 1 7 A, Substrate scope of flavin-mediated decarboxyla-
tive Giese reaction on unprotected peptides; B, Selective C-
terminal decarboxylative modification of peptide and protein
targets
terminal modification to take place under high dilution conditions
(1 mM with respect to the peptide substrate), in aqueous buffer and at
room temperature. In phosphate buffer at pH 7, the vast majority of
amino acid side-chain functionalities, including carboxylic acids, were
tolerant to reaction with electrophile 81. Although lower yields were
observed in the presence of Lys, Tyr, and His residues (entries 2, 8, 14,
Scheme 17A), optimization of the reaction pH and/or photocatalytic
system led to marked improvements in reaction yields.[69]
In an impressive exploration of the scope of the chemistry, the
authors successfully modified several peptide targets varying in size
and complexity.[69] Representative examples (e.g., 94-96), bearing sev-
eral side-chain carboxylic acids, are shown in Scheme 17B. In the case
of ZHER affibody, a 58-amino acid peptide binder of HER2, byproducts
resulting from the conjugate addition of internal lysine residues to
Michael acceptor 81 led to the exploration of 3-methylene-2-
norbornanone as an alternative radical trap, affording C-terminally
modified peptide 95 in 31% yield. Employing a 3-methylene-2-
norbornanone derivative bearing a valuable alkyne handle, MacMillan
12 of 16 | MALINS

SCHEME 19 Peptide macrocyclization via photo-induced biradical

couplings of peptides bearing C-terminal carboxylic acids and N-
terminal phthalimides

polymer 109, with an average molecular weight Mn 5 9400.[73] Nota-

bly, the polymerization also proceeded with a-acids, demonstrating the
versatility of the phen/1,4-DCB reaction system for mild and general
decarboxylative modifications.

Macrocyclization via radical-radical coupling

The importance of cyclic peptides as therapeutic candidates has
prompted intense research efforts into the development of new modes
of cyclization (see sections 2.3.1 and 3.2.1.). Reported independently
SCHEME 18 Direct decarboxylative Giese reactions employing a by Griesbeck[74,75] and Mariano,[76] linear peptides bearing an N-
phenanthrene (phen)/dicyanobenzene (DCB) organic photocatalyst terminal phthalimide and a free C-terminal carboxylic acid can undergo
system a novel decarboxylative photocyclization involving a net C(sp3)–C(sp3)
bond formation. Following irradiation of the linear peptide 110 and
excitation of the N-terminal phthalimide group, intramolecular SET can
and coworkers were also able to selectively monoalkylate the A chain
occur, leading to oxidation of the C-terminus, concomitant extrusion of
of human insulin to afford 96 in the presence of three disulfide link-
CO2, and the subsequent formation of biradical 111 (Scheme 19).
ages, several internal Glu residues and, remarkably, the terminal carbox-
Cyclization of the biradical intermediate forms diverse and rigidified
ylate of the insulin B chain. Future studies employing norbornanone
macrocyclic peptide products such as 112[76] and 113.[74]
Michael acceptors incorporating other bioorthogonal handles (e.g.,
azides, biotin) will no doubt expand the scope of this methodology for Allylation
the late-stage functionalization of peptides and proteins.[69] Access to a-allylated dipeptides such as 115–117 via a dual-catalyzed
Yoshimi and coworkers have reported a complimentary approach photochemical transformation was reported by Tunge and coworkers
to direct, photoinduced decarboxylative Giese reactions by employing in 2015 (Scheme 20).[77] C-terminal carboxylic acids were irradiated
phenanthrene (phen) 97 and 1,4- or 1,3-dicyanobenzene—1,4-DCB 98 with blue LEDs in the presence of iridium photocatalyst 54, Pd(PPh3)4,
or 1,3-DCB 99, respectively—as a novel photocatalytic system (Scheme
18).[70,71] Mechanistically, excitation of phen in the presence of light is
followed by SET from the excited state of phen to the DCB derivative,
forming a phen radical cation. Oxidation of the peptide carboxylate by
the phen radical cation forms the same peptide carboxyl radical 80
implicated in standard transition-metal based photocatalytic cycles (see
Scheme 14). Extrusion of CO2 forms the alkyl radical 18, which may
participate in a variety of subsequent radical transformations.[72] The
scope of peptide substrates for the Giese reaction includes the cou-
pling of various tripeptide a-acids with acrylonitrile 100 (products 103-
107),[71] and the coupling of a dipeptide with Val-Val acrylamide 101 to
afford peptide 108, albeit in lower yields.[70] Finally the free radical
polymerization of a tripeptide bearing a free side-chain glutamic acid S C H E M E 2 0 Decarboxylative allylation of C-terminal peptide car-
with excess methyl acrylate (100 equiv.) afforded peptide-capped boxylic acids using dual Pd/Ir-catalysis
MALINS
S C H E M E 2 1 Tandem oxidative decarboxylation-Mannich reaction
under visible-light irradiation
and allyl methyl carbonate 114 to afford designer peptides in moderate
to good yields. Interestingly, amino acid allyl esters were also feasible
substrates in the allylation reaction, allowing for both the direct reac-
tion of unprotected carboxylic acids or utilization of an allyl-protected
variant. Mechanistically, the authors hypothesize that an initial Pd-
mediated deallylation affords the peptide carboxylate and a cationic
palladium-p-allyl species. Single-electron oxidation of the peptide car-
boxylate by a photoexcited iridium catalyst induces radical decarboxyl-
ation to form the alkyl radical intermediate. Allylation is feasible
through two possible pathways: (A) peptide radical coordination with
the palladium p-allyl complex followed by reductive elimination; or (B)
Ir-mediated allyl radical formation and subsequent radical-radical
coupling.[77]
Oxidative Mannich reaction
The enzyme-catalyzed oxidative decarboxylation of carboxylic acids is a
[78]
common transformation in various biosynthetic pathways. Chemical
variations on this theme for the modification of peptides therefore rep-
resent intriguing biomimetic strategies. To this end, a tandem oxidative
decarboxylation-alkylation approach was reported by Hern
andez, Boto,
and coworkers (Scheme 21).[79,80] Treatment of C-terminal peptide
acids with PhI(OAc)2 and I2 under visible-light irradiation facilitated C-
terminal decarboxylation and subsequent oxidation to a valuable N-acyl
iminium intermediate (see Scheme 24, vide infra). Subsequent Mannich
reaction in the presence of silyl ketene acetal 118 and BF3
OEt2 facili-
tated C-terminal alkylation of the iminium intermediate and the intro-
duction of valuable b-amino acid derivatives. The reaction was
demonstrated on a variety of dipeptide substrates, affording products in
good yields (see Scheme 21, 119-121 for representative examples).[80]
3.2.2 | C(sp3)–C(sp2) coupling
Arylation
In 2016, Opatz and coworkers reported a phenanthrene (phen)-based
photochemical strategy for the arylation of a-amino acid derivatives
(Scheme 22).[81] The methodology exploits the phen/1,4-DCB organic
photocatalyst system employed by Yoshimi and coworkers for intermo-
lecular Giese reactions (see Scheme 18),[70,71] taking advantage of the
authors’ observation that 1,4-DCB itself was capable of coupling to a tri-
peptide substrate 124 in the absence of other radical acceptors.[71]
Armed with this knowledge, Opatz and coworkers successfully coupled a
| 13 of 16
variety of aromatic nitriles to a-amino acid derivatives, including Fmoc-
protected dipeptide 122 to afford pyridine substituted peptide 123.[81]
A complimentary, iridium-catalyzed photocatalytic approach to
a-arylation using aryl nitriles was reported by MacMillan and
coworkers.[82] Although demonstrated exclusively on single amino acid
substrates, the relatively broad scope of this transformation should
facilitate its extension to peptide substrates in the future.
3.3 | C–heteroatom bond formation
The following sections discuss approaches to CAH/D and CAO bond
formation through the decarboxylative functionalization of unprotected
aliphatic carboxylic acids. While not all transformations are strictly cou-
pling reactions, their relevance as late-stage, decarboxylative modifica-
tions of peptide substrates warrants their inclusion. Furthermore, the
high-value peptide products accessible using such methodologies
(including, for example, isotope labeled products and access to peptido-
mimetic scaffolds) render these transformations valuable additions to
the peptide modification toolbox.
3.3.1 | C–H or C–D bond formation (via reduction)
The Yoshimi lab has extended the versatility of the phen/DCB organic
photocatalytic system (see section 3.2.1.) to include strategies for the
reductive decarboxylation of peptidic acids.[71] While conceptually similar
to the venerable Barton decarboxylation reaction (see Scheme 2), this
variation does not require a discrete preactivation step. Rather, in the
presence of tert-dodecanethiol, PET-mediated, C-terminal decarboxyl-
ation of native tripeptide 126 proceeded smoothly to afford reduced
peptide variant 127 (Scheme 23A).[71] Interestingly, a modified solvent
system provided a facile strategy for the precise incorporation of a deu-
terium label (Scheme 23B).[83] Proton/deuterium exchange of tert-dodec-
anethiol in D2O allows for the formation of a sulfur-deuterium bond
which can engage the photocatalytically generated peptide alkyl radical
in a deuterium-abstraction event. On tripeptide substrate 128, reduction
occurred to afford 129 in 73% yield with >95% deuterium
incorporation.[83]
An alternative, visible-light mediated approach employing an acri-
dinium photocatalyst system (132) was disclosed by Wallentin and
S C H E M E 2 2 Phenanthrene (phen) mediated arylation of
a-carboxylic acids with aryl nitriles
14 of 16 | MALINS

An adaptation of Seebach’s method employing the chemical oxidant

Pb(OAc)4 rather than anodic oxidation facilitated the formation of
acetate derivatives 141-143 (Scheme 24B).[88] Importantly, both sets
of N,O-acetal derivatives were shown to be suitable substrates in
various nucleophilic substitution reactions. For example, treatment
with triphenylphosphite or allyltrimethylsilane in the presence of
TiCl4 leads to functionalized peptide derivatives such as 144[85] or
145[86] (Scheme 24C). The acidic hydrolysis of N,O-acetals also leads
to C-terminally truncated peptide variants following cleavage of the
terminal residue.[85]

3.4 | Scope and limitations of direct decarboxylation

S C H E M E 2 3 Direct photocatalytic decarboxylative reduction of
carboxylic acids. A, Phenanthrene (phen)/dicyanobenzene (DCB)-
mediated CAH bond formation and B, CAD bond formation. C,
Acridinium-mediated approach to CAH bond formation
strategies
The direct decarboxylative coupling strategies described in the previous
sections enable the modification of native peptide carboxylic acids with-
out the need for a preactivation step. Such methods facilitate the for-
mation of diverse CAC bonds, including C-terminal decarboxylative
alkylation and arylation, as well as strategies for CAheteroatom bond
formation. Application of these methodologies to the versatile synthesis
of unnatural amino acids, peptide macrocycles,[68,74–76] peptide func-
tionalized polymers,[73] and even proteins[69] is a powerful testament to
the robust nature of the coupling strategies. The majority of available
methods utilize photocatalytic and, in some cases, electrochemical
approaches to convert carboxylic acids under mild conditions into the
corresponding peptide alkyl radicals following the extrusion of CO2.

coworkers in 2014 (Scheme 23C).[84] In this variation, decarboxylative

alkyl radical formation was followed by hydrogen-abstraction from an
aryl thiol generated in situ from bis(4-chlorophenyl)disulfide (DDDS)
133. The authors demonstrated the scope of the transformation on a
number of a-amino acids as well as a dipeptide substrate 130 (Scheme
23C).[84] Such methods provide an attractive alternative to conven-
tional Barton decarboxylation chemistry as they employ stable and
robust carboxylic acid starting materials (in contrast to the photosensi-
tivity of Barton esters) and avoid additional preactivation steps.

3.3.2 | CAO bond formation (via oxidative decarboxylation)

Under either electrochemical or chemical oxidation conditions, C-
terminal carboxylic acids may be efficiently converted into the corre-
sponding peptide N-acyl iminiums (e.g., 135, Scheme 24) following the
extrusion of CO2. In addition to serving as valuable intermediates en
route to Mannich alkylation products (see Scheme 21),[79,80] reactive
iminium species may be trapped with protic solvents (H2O, MeOH,
AcOH), to facilitate the formation of peptide N,O-acetals. Seebach and
coworkers demonstrated that the initial oxidative decarboxylation reac-
tion[85,86] is readily accomplished using Hofer-Moest electrolysis[87] by
employing a platinum anode under constant current and in the pres-
ence of tertiary amines for the in situ generation of the electrolyte.[85]
S C H E M E 2 4 Oxidative decarboxylation of peptide carboxylic
When reactions are performed in methanol or acetic acid, peptide N,O-
acids using A, anodic oxidation, or B, chemical oxidants, to afford
acetals 136-140 are readily formed (Scheme 24A). Notably, CAO bond
N,O-acetals via reactive N-acyliminium intermediate 135. C,
formation at the C-terminus occurred orthogonally to an unprotected Diverse peptide products formed following nucleophilic attack onto
side-chain glutamic acid residue, albeit in lower yield (137, 25%).[85] N,O-acetals
MALINS
One drawback of direct decarboxylative couplings is a general reli-
ance on the intermediacy of stabilized radicals (e.g., a-amino radicals).
Unprotected side-chain carboxylic acids are typically unreactive under
the photochemical conditions employed as decarboxylation would afford
an unstabilized, primary radical. Although such orthogonality has been
expertly exploited to accomplish remarkably selective C-terminal func-
tionalizations (see Schemes 16–17, and 24), a lack of side-chain function-
alization limits the general scope and applicability of the transformations.
Direct decarboxylative approaches to side-chain modifications are there-
fore promising areas of future research. As with RAE-based transforma-
tions (see section 2.5), it is anticipated that further studies will aim to
expand the scope of promising transformations that have thus far only
been demonstrated on single amino acid substrates, including strategies
for alkenylation,[89] alkynylation,[90] and enantioselective arylation.[91]
Such strategies would further expand the repertoire of direct decarboxy-
lative couplings for peptide modification. Furthermore, extending the
decarboxylative manifold to include on-resin transformations may facili-
tate automation in the future, significantly lowering the barrier to the
routine and widespread adoption of these technologies.
4 | OUTLOOK AND CONCLUSIONS
With growing appreciation for designer peptides as potential therapeu-
tics and novel materials, new strategies for peptide modifications no
longer represent niche market products. Methodologies historically
applied to small molecule synthesis are increasingly being optimized for
the selective functionalization of peptides, blurring the conventional
demarcation between peptide synthesis and organic methodology
development. The strategies covered in this review highlight this young
but burgeoning trend by demonstrating the growing capabilities of
modern synthetic chemistry for the selective decarboxylative function-
alization of peptidic carboxylic acids. Over the past few years, enabling
approaches employing both redox-active esters and native carboxylic
acids have reshaped the landscape of accessible peptide products,
affording strategies for CAC and CAheteroatom bond formation. Such
methods have facilitated the installation of high-value synthetic han-
dles, the cyclization of unprotected precursors, and the precise modula-
tion of peptide structure by exploiting the reactivity of a historically
underutilized functional group for the modification of peptides. It is
anticipated that the continued development and optimization of decar-
boxylative functionalizations will increase the practicality, versatility,
and simplicity of these late-stage peptide modifications, with an eye
toward the ultimate goal of facilitating the routine incorporation of
diverse unnatural amino acids.
OR CID
Lara R. Malins http://orcid.org/0000-0002-7691-6432
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AUTHOR BIOG RAPH Y
DR. LARA MALINS completed her B.A. in chemis-
try at Boston University in 2009 before relo-
cating to The University of Sydney to
undertake her PhD with Professor Richard
Payne on the development of new peptide liga-
tion strategies. In 2015, Lara joined the labora-
tory of Professor Phil Baran at The Scripps
Research Institute as a NIH postdoctoral fellow. She was appointed
Research Fellow at the Research School of Chemistry at the Australian
National University in November 2017.
How to cite this article: Malins LR. Decarboxylative couplings
as versatile tools for late-stage peptide modifications. Peptide
Science. 2018;e24049. https://doi.org/10.1002/pep2.24049