Zn-Catalyzed Nicotinate-Directed Transamidations in Peptide Synthesis

Article abstract of DOI:10.1021/acscatal.9b05074

A chemoselective and catalytic transamidation for peptide synthesis is described. Transamidation under Zn catalysis is chemoselectively achieved by amino acid amide/peptidic amide derivatization with a tert-butyl nicotinate (tBu-nic) directing group. The directing group could be easily introduced on protected amino acid amides via Pd-catalyzed amidation with tert-butyl 2-chloronicotinate (tBu-nicCl). Under standard peptide coupling/deprotection conditions, the tBu-nic-equipped amino acid amides proved to be fully inert, allowing them to be easily built-in in complex molecules. The disclosed method was evaluated in the synthesis of diverse dipeptides, in dipeptide segment coupling, in side-chain modification of a solid-supported tetra-/pentapeptide, and in the macrocyclization of a heptapeptide.

Full text of DOI:10.1021/acscatal.9b05074

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Article
Zn-Catalyzed Nicotinate-Directed Transamidations in Peptide Synthesis
Karlijn Hollanders, Evelien Renders, Charlène Gadais, Dario Masullo, Laurent Van Raemdonck, Clarence
Chloë Daniëlla Wybon, Charlotte Martin, Wouter A. Herrebout, Bert U. W. Maes, and Steven Ballet
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b05074 • Publication Date (Web): 10 Feb 2020
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Page 1 of 39
ACS Catalysis
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Zn-Catalyzed Nicotinate-Directed Transamidations in
Peptide Synthesis
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Karlijn Hollanders, †,‡ Evelien Renders, ‡ Charlène Gadais, †,‡ Dario Masullo,‡ Laurent Van Raemdonck,
‡
Clarence C. D. Wybon, ‡ Charlotte Martin,† Wouter A. Herrebout,ꟼ Bert U. W. Maes,*,‡ and Steven
Ballet*,†
†Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel,
Pleinlaan 2, B-1050 Brussels, Belgium
‡Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020
Antwerp, Belgium
ꟼMolecular Spectroscopy, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-
2020 Antwerp, Belgium
ABSTRACT
A chemoselective and catalytic transamidation for peptide synthesis is described. Transamidation under
Zn catalysis is chemoselectively achieved by amino acid amide/peptidic amide derivatization with a tert-
butyl nicotinate (tBu nic) directing group. The directing group could be easily introduced on protected
amino acid amides via Pd-catalyzed amidation with tBu 2-chloronicotinate (tBu nicCl). Under standard
peptide coupling/deprotection conditions, the tBu nic equipped amino acid amides proved to be fully inert
allowing to be easily built-in in complex molecules. The disclosed method was evaluated in the synthesis
of diverse dipeptides, in dipeptide segment coupling, in side chain modification of a solid supported
tetra/pentapeptide, and in the macrocyclization of a heptapeptide.
Keywords: Amide cleavage, Transamidation, Directing group, Peptide, Amino acid amide
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Page 2 of 39
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INTRODUCTION
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The amide functionality is of utmost importance in both biology and chemistry. Molecules sustaining life,
such as peptides and proteins, are composed of repeating amino acid monomers connected by amide
bonds. Their significance as part of therapeutic compounds is demonstrated by the list of FDA-approved
drugs of 2018 in which 69% features an amide entity.1 Consequently, formation of this functional group
is considered to be among the most executed transformations in organic chemistry,2 with a major
application in the synthesis of peptides and peptidomimetics. In the last decades, chemists have made
immense efforts to form amide bonds in an efficient and selective manner. Direct acylation of an amine
with an in situ activated carboxylic acid2-3 remains the most common procedure and accounts for 16% of
all reactions in pharmaceutical synthesis (Scheme 1a).2d,4 This manifests in a well-established catalog of
so-called coupling reagents. Nevertheless, amide formation has yet to overcome the inherent limitations
associated with these coupling reagents, such as elevated prices, potentially explosive properties and
(super)stoichiometric amounts.2d-f Furthermore, the carboxylic acid activation is still linked to risks, like
enolization and oxazolone formation, resulting in the epimerization of chiral centers.2b In certain cases,
such as segment coupling or macrocyclization, activation of a single carbamate N-protected amino acid
is no longer possible which greatly complicates the couplings.2b To address these issues new strategies
focusing on non-classical approaches for amide synthesis have been introduced,2c for instance, through
amine activation5 or via alternative functional groups.6 In the latter strategy major advances involve the
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α-ketoacid-hydroxylamine-ligation, introduced by Bode,6d, 6f and the umpolung strategy of Johnston.6a,
6g-k
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ACS Catalysis
Scheme 1. Peptide synthesis: (a) Traditional approach: carboxylic acid activation and (b) New
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approach: Zn-catalyzed nicotinate-directed transamidation.
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a. Peptide coupling through carboxylic acid activation (classical approach)
Coupling
reagent
(Base)
R1
R2
R1
O
H



R3

PG
OH
X
PG
N
+
N
H2N
R3
N
X
Solvent
H
H
O
O
O
R2
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R2
HOAct
R1
H


X
PG
OAct
H2N
R3
N
H
O
O
b. Peptide coupling by transamidation (new approach, orthogonal with a)
R2
R1
O
O
OtBu
R1
R1
Pd (cat)
base
H
H




R3
Zn(OAc)2 (cat)
Solvent

X
PG
N
+
PG
NH2
PG
N
R3
N
X
+
Cl
H2N
N
N
tBu nic
H
H
H
Solvent
O
O
R2
O
O
N
2
O
OtBu
R1
O
N
OtBu
O
OtBu
Commercially available
H
N

PG
H2N
N
H
O
N
O
R2
H
N
O
N
H
Zn
O

tBu nic
X
O
O
R3
X = O, NH
PG = protective group
Act = activator
NaNO2, NaCl
HCl (aq.), 0°C to rt
Amides themselves have rarely been considered as a carboxylic acid surrogate. Given the prevalence of
the amide functional group, transamidations with amines are potentially interesting reactions to obtain
amides with other substitution patterns. However, these reactions are faced with two main challenges:7 i)
intrinsic stability and poor carbonyl electrophilicity of amides, and ii) the thermodynamically neutral
character of these transformations involving an amine as both nucleophile and by-product as illustrated
by the work of Gellman and Stahl.8 Following the work of Bigg and Bertand reporting transamidations
with unfunctionalized amides and amines and (super)stoichiometric AlCl3,9 various efficient preparative
catalytic transamidations at higher temperature have been published.10 Recent important advances involve
amide activation prior to transamidation, typically allowing milder conditions and a broader scope in both
reaction partners. Garg and Szostak reported Ni- and Pd-catalyzed transamidations of tertiary amides by
N-activation of secondary amides through N-Bocylation or N-Tosylation.11-14 In some cases transition
metal free transamidation reactions of N-activated secondary amides are possible.15 By deprotonation of
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the amine nucleophile with LiHMDS also unactivated tertiary amides have recently been used.16 Mild
transamidation on secondary amides, by activation of primary amides is to the best of our knowledge still
unknown. The cleavage of amides in complex and sensitive molecules such as peptides has been
established in reversible native chemical ligation (N→S acyl shift).17 Nonetheless, a direct transamidation
that introduces an additional degree of orthogonality in peptide synthesis, e.g. for late-stage modification,
segment coupling and macrocyclization, would be exceedingly valuable.18,19
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Recently our group introduced a general protocol for primary amide esterification via derivatization with
a tBu nicotinate (tBu nic) directing group (DG).20 The tBu nic is easily introduced through a Pd-catalyzed
amidation on a primary amide with commercially available tBu 2-chloronicotinate (2) (Table 1).
Subsequently, the amide bond is cleaved with alcohols by Zn catalysis. The activation mechanism
involving tBu nic amide chelation by a Zn catalyst is biomimetic with metalloproteases. DGs are
commonly used for C-H bond functionalization, but not for amide activation.21 In the esterification
reaction, tBu 2-aminonicotinate is released. This by-product can be easily transformed into reactant 2
through functional group interconversion involving a diazotization reaction.20 In this work, we disclose
an unprecedented mild transamidation reaction to be used in peptide synthesis which is orthogonal with
classical methods via transamidation of N-protected N-tBu nic amino acid amides, N-activated primary
amides, with amino acid esters/amides (Scheme 1b).
Results and discussion
Boc-protected directing group-bearing amino acid amides 4 were synthesized via our previously
developed Pd-catalyzed amidation protocol of primary amides with commercially available tBu 2-
chloronicotinate (tBu nicCl) (2), based on a Buchwald Pd-G3-dcpf precatalyst with K2CO3 or Cs2CO3 as
base in 2-MeTHF or dioxane at 40-50°C.20,22 This mild method proved generally applicable for amino
acid amides, also those with protected nucleophiles in the side chain, and can even be applied on peptides
(Table 1).20 Sometimes the use of K2CO3 is required to avoid epimerization and a larger excess of base is
beneficial for the reaction rate (“base effect”).23 Pd(OAc)2 in combination with commercially available
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ACS Catalysis
Xantphos as ligand could also be used to introduce the directing group provided a higher reaction
temperature (90°C) is applied.20 In this case higher boiling 1,4-dioxane was selected as solvent. Though
good yields were generally obtained only for some Boc-AA-NH2 1 (L-4d and L,L-4n) significant
epimerization could be avoided (see Supporting Information; Table S13). Pd-G3-dcpf precatalyst which
can be used at 40-50°C is therefore generally preferred as it retains the chiral information. Interestingly,
the compounds of type 4 proved to be bench stable and the tBu nic amide functionality remains untouched
under classical peptide coupling conditions providing full orthogonality as exemplified for the synthesis
of substrates L,L-7, L,L-8, 13, 15.HCl used in the transamidations (see Supporting Information; e.g.
assembly of L,L-7 in Scheme 2a). When L,L-7 was prepared via Pd-catalyzed amidation of Boc-L-Leu-L-
Phe-NH2 with tBu nicCl (2) under the standard conditions a lower yield was obtained (Scheme 2b).
Interestingly, under these conditions without further optimization no epimerization was observed and
unreacted amide was recovered providing a good mass balance. Amides also occur in the side chain of
amino acids and therefore we tested whether the directing group could be introduced on L-glutamine. This
is particularly challenging considering the presence of a free carboxylic acid. Boc-L-Gln(NH-tBu nic)-
OH (L-4o) could be obtained in 60% when the Pd(OAc)2 / Xantphos precatalyst system was used (Scheme
3). In this case Buchwald Pd-G3-dcpf precatalyst did not provide any reaction product L-4o.
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Scheme 2. Synthesis of tBu nic-functionalized dipeptide L,L-7 via application of Boc-L-Phe-tBu nic L-4a
in classical peptide synthesis (a) and Pd-catalyzed amidation of Boc-L-Leu-L-Phe-NH2 with tBu NicCl (2)
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(b).
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1) HCl / 1,4-dioxane (4 M)
rt, 30 minutes
O
N
O
N
(a)
H
N
H
N
Boc
Boc
N
N
H
N
H
H
2)
L
Boc- -Leu-OH (1.1 equiv)
COOtBu
O
COOtBu
Et3N (1 equiv)
EDC.HCl (1.3 equiv)
HOBt.H2O (1.3 equiv)
CH2Cl2, rt, 2 h
L,L-7
L-4a
96 %
(b)
COOtBu
O
O
N
H
N
H
N
3
Pd-G3-dcpf ( ) (10 mol%)
Cl
Boc
Boc
N
NH2
N
H
N
H
+
H
K2CO3 (7.5 equiv)
1,4-dioxane
N
O
O
COOtBu
2
50°C, 30 h
41%
(1.1 equiv)
55% recovered
L,L-7
50% recovered
Scheme 3. Synthesis of Boc-L-Gln(NH-tBu nic)-OH (L-4o) via Pd-catalyzed amidation of Boc-L-Gln-
OH with tBu NicCl (2).
Pd(OAc)2 (5 mol%)
N
O
NH2
COOtBu
COOtBu
Xanthphos (10 mol%)
Cs2CO3 (1.2 equiv)
O
NH
Cl
+
1,4-dioxane
90°C, 24 h
Boc
OH
N
N
H
Boc
OH
O
(1.5 equiv)
2
N
H
60%
O
L-4o
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Table 1. Synthesis of N-Boc N-tBu nic amino acid amides (4) via Pd-catalyzed amidation of N-Boc
amino acid / peptidic amides (1) with tBu nicCl (2).
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7
8
9
R1
COOtBu
R1
COOtBu
H
3
Pd-G3-dcpf ( ) (5 mol%)
Cl
Boc
N
Boc
NH2
N
N
+
Cs2CO3 or K2CO3
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H
H
N
O
N
O
2-MeTHF (0.16 M)
40°C, 24 h
4
1
2
(1.1 equiv)
Pd-G3-dcpf
H2N
P
Pd
Fe
P
MsO
3
Equivalents
of base
Yield
[%][a]
Entry
Boc-AA-NH-tBu nic 4
Base
%ee[e]
1
2
Boc-L-Phe-NH-tBu nic L-4a
Boc-L-Ala-NH-tBu nic L-4b
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
7.5
7.5
7.5
1.2
7.5
2
93[b]
71[b]
94[b]
80
99
100
100
100
100
-
3
Boc-L-Tyr(tBu)-NH-tBu nic L-4c
Boc-L-Pro-NH-tBu nic L-4d
Boc-L-Met-NH-tBu nic L-4e
Boc-βAla-NH-tBu nic 4f
4
5
93[b,c]
99
6
7
Boc-Gly-NH-tBu nic 4g
1.2
2
83
-
8
Boc-L-Val-NH-tBu nic L-4h
Boc-L-Ile-NH-tBu nic L-4i
Boc-L-Ser(tBu)-NH-tBu nic L-4j
96
96
9
2
82
100[f]
99
10
6
72[b]
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Boc-L-Lys(Boc)-NH-tBu nic L-4k
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
1.2
7.5
1.2
2
79
89[b]
56[d]
99
100
100
98
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2
3
4
5
6
7
8
Boc-L-Cys(tBu)-NH-tBu nic L-4l
Boc-L-His(trt)-NH-tBu nic L-4m
9
Boc-L-Pro-L-Leu-Gly-NH-tBu nic
100[f]
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L,L-4n
[a] Isolated yield. [b] Pd-G3-dcpf (10 mol%) in 1,4-dioxane, 50°C, 30 h. [c] 60°C. [d] Pd-G3-dcpf (10
mol%), 16 h, 50v/v% 2-MeTHF/DMF, 16 h. [e] %ee measured using HPLC with n-hexane:i-propanol on
a Diacel Chiralpak IA column. [f] %de calculated based on 1H NMR analysis.
As model system for the optimization of the transamidation, the synthesis of Boc-L-Phe-L-Phe-OMe (L,L-
6a) from Boc-L-Phe-NH-tBu nic (L-4a) and H-L-Phe-OMe (L-5a) was selected. The reaction conditions
of the alcoholysis, previously developed in our laboratories, were used as a starting point.20 A solvent
screen revealed THF to be the most suitable solvent with respect to solubility and conversion (Table S1).
With 10 mol% Zn(OAc)2, full conversion was obtained in 24 h at 60°C (Table 2, Entry 1-2). α-Amino
esters and derivatives are typically sold as their HCl salts and require liberation of the free amine prior to
the transamidation. In situ amine release from these salts is therefore desirable. Interestingly, a
combination of L-5a.HCl with DIPEA showed to have no effect on the conversion (Table 2, Entry 3;
Table S3). As a base was not required in our esterification protocol20 a selection of catalysts, featuring
various MIIOAc2 (Zn, Co, Ni, Cu) and ZnX2 salts (OAc, Acac, formate, OTf, Cl) that performed well in
the alcoholysis was tested with DIPEA as base (Table S5). Interestingly, Zn formate.2H2O, Cu(OAc)2
and Ni(OAc)2 performed well, although less efficient than Zn(OAc)2. ZnCl2 performed significantly
worse than Zn(OAc)2 which supports the hypothesis that the acetate ligand contributes to the reaction’s
efficiency by activation of the nucleophile with hydrogen bonding, in accordance with the computed
alcoholysis mechanism (Scheme 1b).20 The best catalysts were then cross-checked with different tertiary
amines as bases (Table 2, Entry 4-5; Table S6). This revealed Zn(OAc)2/Et3N as an optimal catalyst/base
system, giving full conversion at 50°C (Table 2, Entry 5). The excess of amino acid ester could be reduced
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to 1.1 equivalents providing a higher temperature (70°C) and catalyst loading (20 mol%) were used (Table
2, Entry 6-8). Considering Zn(OAc)2 is cheap and an authorized food additive (E650) a lower loading of
nucleophile L-5a.HCl is more interesting.
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2
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4
5
6
7
8
9
Safeguarding amino acid stereochemistry is crucial in peptide synthesis. The effect of the transamidation
on the chirality of both the tBu nic amide and amino acid ester hydrochloride was therefore evaluated.
Under the optimized reaction conditions, the chirality was jeopardized, showing a mixture of L,L-6a and
D,L-6a in an 88:12 ratio (Table 2, Entry 8; Scheme S1). This led us to further investigate the effect of base
on the reaction (Table S10). Gratifyingly, NaOAc turned out to allow full conversion without
epimerization (Table 2, Entry 9).
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Table 2. Selected optimization steps of the transamidation with model system L-4a and L-5a.HCl.[a]
L
H- -Phe-OMe.HCl
L-5a.HCl
X
(
equiv)
O
H
Z
Zn(OAc) ( mol%)
COOtBu
2
Boc
N
H
N
OMe
Boc
N
H
Y
Base ( equiv)
N
O
H
THF (0.5 M)
O
N
T
, 24 h
L 4a
-
L,L
-6a
Amine Form
Zn(OAc)2
Yield L-4a Yield 6a
Entry
1
Base[b]
T [°C]
(X equiv)
(Z mol%)
[%]
[%]
L-5a
-
10
40
23
77
(3 equiv)
2
3
L-5a
-
10
10
60
60
0
0
quant.
quant.
(3 equiv)
L-5a.HCl
DIPEA
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(3 equiv)
L-5a.HCl
(3 equiv)
1
2
3
4
5
6
7
8
4
5
6
7
8
9
DIPEA
Et3N
10
10
10
10
20
20
50
50
50
70
70
70
17
0
83
quant.
75
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L-5a.HCl
(3 equiv)
L-5a.HCl
(1.1 equiv)
L-5a.HCl
(1.1 equiv)
L-5a.HCl
(1.1 equiv)
L-5a.HCl
(1.1 equiv)
Et3N
25
14
0
Et3N
86
quant.
(67[c])
Et3N
quant.
(79[d])
NaOAc
0
[a] Reaction conditions: Boc-L-Phe-tBu nic (L-4a) (0.25 mmol), H-L-Phe-OMe.HCl (L-5a) or L-5a.HCl
(X equiv), base (Y equiv), Zn(OAc)2 (Z mol%), THF (0.5 ml). 1H NMR with 1,3,5-trimethoxybenzene as
an internal standard. Isolated yield between brackets. [b] equiv of base in a 1:1 ratio to amine. [c] HPLC
with n-hexane:ethanol (65:35) on a Diacel Chiralpak IA column shows a mixture of L,L:D,L-6a (88:12).
[d] HPLC with n-hexane:ethanol (65:35) on a Diacel Chiralpak IA column shows only L,L-6a.
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ACS Catalysis
With these optimized conditions in hand (Table 2, Entry 9), we set out to examine the scope of the
transamidation reaction through the synthesis of different dipeptides (Table 3). Amino acid amides and
esters featuring side chains with different sterical hindrance and functional groups, both at the level of the
substrate and nucleophile, were used successfully (Table 3). Transamidation of the challenging proline
amide L-4d (Table 3, Entry 4) as well as a reaction with H-L-Trp-OBn.HCl (L-5e.HCl) nucleophile (Table
3, Entry 5), possessing an unprotected indole in the side chain, were tolerated. When using amino acid
amides as the nucleophile, featuring a primary amide, full conversion could be obtained by prolonging
the reaction time to 48 h (Table 3, Entry 6) or by using 3 equiv nucleophile (Table 3, entry 7 and 8). The
latter conditions were also suitable to perform reactions with rarely used and epimerization sensitive
amino acid amides. Boc-L-Cys(tBu)-NH-tBu nic (L-4l) and Boc-L-His(trt)-NH-tBu nic (L-4m) smoothly
reacted with H-L-Lys(Cbz)-OMe.HCl (L-5h.HCl) giving 57% and 72% yield (Table 3, entry 10 and 11).
Challenging H-L-Pro-OMe.HCl (L-5g.HCl) involving a secondary amine resulted in only 50% conversion
in 24 h with 3 equiv nucleophile. An additional increase in temperature to 100°C was required to obtain
full conversion in 24 h (Table 3, Entry 9). The substrate can also be a peptide as exemplified by coupling
of L,L-4l with H-L-Phe-OMe.HCl (L-5a.HCl) giving the tetramer L,L,L-6k in 88% isolated yield (Table
3, Entry 12). Interestingly, in all the transamidations of Table 3 no sign of epimerization was observed as
judged by HPLC and NMR analysis.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
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Table 3. Scope of the transamidation reaction for the synthesis of various dipeptides 6 from L-4 and L-
5.HCl.[a]
1
2
3
4
5
6
7
8
9
3
5.HCl
H-AA-XR .HCl (1.1 equiv)
Zn(OAc)2 (20 mol%)
R1
COOtBu
R1
O
H
H
Boc
N
Boc
N
N
N
XR3
NaOAc (1.1 equiv)
THF (0.5 M)
H
H
O
N
O
R2
4
6
70°C, 24 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
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35
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60
Entry Boc-AA-NH-tBu nic 4
Amine 5.HCl
6
Yield [%][b]
Boc-L-Phe-NH-tBu nic H-L-Phe-OMe.HCl L-
1
2
3
4
5
6
7
8
95
L,L-6a
L,L-6b
L,L-6c
L,L-6d
L,L-6e
L,L-6f
L,L-6f
L,L-6g
L-4a
5a.HCl
Boc-L-Ala-NH- tBu nic
H-L-Leu-OAll.HCl
99
85
L-4b
L-5b.HCl
Boc-L-Tyr(tBu)-NH-
tBu nic L-4c
H-L-Val-OtBu.HCl
L-5c.HCl
Boc-L-Pro-NH-tBu nic
H-L-Leu-OMe.HCl
95
L-4d
L-5d.HCl
Boc-L-Met-NH-tBu nic
H-L-Trp-OBn.HCl
80
L-4e
L-5e.HCl
Boc-βAla-NH-tBu nic
H-L-Phe-NH2.HCl
72[c]
74[d]
89[d]
4f
L-5f.HCl
Boc-βAla-NH-tBu nic
H-L-Phe-NH2.HCl
4f
L-5f.HCl
Boc-L-Met-NH-tBu nic
H-L-Phe-NH2.HCl
L-4e
L-5f.HCl
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ACS Catalysis
H-L-Pro-OMe.HCl
L-5g.HCl
Boc-L-Ala-NH- tBu nic
1
2
3
9
68[d,e]
L,L-6h
L,L-6i
L-4b
4
5
6
7
8
Boc-L-Cys(tBu)-NH-
tBu nic L-4l
H-L-Lys(Cbz)-OMe.HCl
10
57%[d]
L-5h.HCl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H-L-Lys(Cbz)-OMe.HCl
L-5h.HCl
Boc-L-His(trt)-NH-tBu
nic L-4m
11
12
72%[d]
L,L-6j
H-L-Phe-OMe.HCl
L-5a.HCl
Boc-L-Pro-L-Leu-Gly-
88
L,L,L-6k
NH-tBu nic L,L-4n
[a] Reaction conditions: Boc-L-AA-tBu nic (4), Amine (L-5a.HCl) (1.1 equiv), NaOAc (1.1 equiv),
Zn(OAc)2 (20 mol%), THF (0.5 M). [b] Isolated yield. [c] 48 h. [d] 3 equiv of the amine and 3 equiv of
NaOAc. [e] T = 100°C.
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Segment condensation was subsequently studied. tBu nic derivatized dipeptides L,L-7 and L,L-8 were
assembled from the corresponding N-Boc N-tBu nic amino acid amides, L-4a and L-4b, respectively with
standard coupling/deprotection protocols (e.g. Scheme 2a for the synthesis of L,L-7). These dipeptides
were engaged in a segment condensation through transamidation with, respectively, H-L-Leu-L-Val-
OtBu.HCl (L,L-9.HCl) and H-L-Ala-L-Phe-OtBu.HCl (L,L-10.HCl) under standard conditions (Scheme
4). Both tetramers L,L,L,L-11 and L,L,L,L-12 could be isolated in a good yield, without loss of chiral
information (see Supporting Information, Section 5.4).
Importantly, the methodology’s compatibility with a solid support was also confirmed. The side chain of
Gln of solid phase assembled and resin-bound tetrapeptide Boc-Gln(tBu nic)-Phe-Lys(Boc)-Phe-NH-
Rink amide resin (13) was coupled with H-Ala-OtBu.HCl (L-5h.HCl) (5 equiv) (Scheme 5). By
application of 5 equiv NaOAc as base and 20 mol% of Zn(OAc)2 in THF as solvent, full conversion was
noted after 48 h reaction time at 90°C. The pentapeptide 14.TFA was isolated upon TFA/TIS/H2O
cleavage of the resin with a yield of 59% (preparative HPLC). Hereafter, the compatibility of the
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functionalized amide with Fmoc deprotection was established by using Fmoc-L-Gln(tBu nic)-OH (L-4p)
in the synthesis of Boc-L-Phe-L-Gln(tBu nic)-L-Phe-L-Lys(Boc)-L-Phe-NH-Rink amide resin (15) through
solid phase synthesis (SPPS). Subsequent amide cleavage was demonstrated under the same conditions
as used for 13, yielding peptide 16.TFA in 50% yield (Scheme 5). These examples demonstrate that solid
supported reactions are within reach and chemoselective side chain derivatization, through use of the Boc-
(L-4o) and Fmoc-Gln(tBu nic)-OH (L-4p) building blocks, fully orthogonal to classical peptide synthesis
is possible.
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5
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9
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17
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Macrocyclization via our transamidation was demonstrated by the synthesis of an allylated analog of
Stylissatin A. This cyclic heptapeptide natural product, first isolated from the Papua New Guinean marine
sponge, Stylissa massa, was reported to possess inhibitory activity on nitric oxide production.24
Cyclization of linear precursor tBu nic equipped peptide 17.HCl was smoothly achieved at 100°C. Full
conversion was obtained within 24 h and the cyclic 7-mer 18 was isolated by means of preparative HPLC
purification (Scheme 6). To the best of our knowledge this is the first cyclic peptide synthesis based on a
transamidation.
Scheme 4. Application of the methodology through dipeptide segment condensations.
L
L-
H- -Leu- Val-OtBu.HCl
L,L-9.HCl
(1.1 equiv)
O
N
O
O
H
N
H
N
H
N
Zn(OAc)2 (20 mol%)
Boc
Boc
N
N
H
N
H
N
OtBu
H
H
NaOAc (1.1 equiv)
THF (0.5 M)
70°C, 24 h
83 %
O
COOtBu
O
O
L,L 7
L,L,L,L-11
-
tBu
L
L
H- -Ala- -Phe-OtBu.HCl
L,L 10.HCl
tBu
O
-
(1.1 equiv)
O
O
O
H
N
H
N
Zn(OAc)2 (20 mol%)
O
N
Boc
H
N
N
N
H
OtBu
Boc
H
NaOAc (1.1 equiv)
N
H
N
H
O
O
THF (0.5 M)
70°C, 24 h
74 %
O
COOtBu
L,L-8
L,L,L,L-12
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Scheme 5. Application of the methodology through solid-phase side chain derivatization of peptide 13
and 15 involving Boc-Gln(tBu nic)-OH (L-4o) (a) and Fmoc-Gln(tBu nic)-OH (L-4p) (b) building blocks
1
2
3
4
5
6
a) Application of Boc-L-Gln(tBu nic)-OH L-4o
7
8
9
HO
1) H-L-Ala-OtBu.HCl
Boc
N
L-5h
TFA.H2N
(5 equiv)
HN
O
COOtBu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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41
42
43
44
45
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50
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58
59
60
Zn(OAc)2 (20 mol%)
NaOAc (5 equiv)
THF, 90°C, 48 h
NH
NH
O
O
Rink amide
resin
O
O
O
O
H
H
H
H
N
N
N
2)TFA/TIS/H2O
rt
N
NH2
Boc
N
N
TFA.H2N
N
H
H
H
O
O
O
O
59%
(preparative HPLC)
13
14.TFA
b) Application of Fmoc-L-Gln(tBu nic)-OH L-4p
Boc
N
Boc
HN
COOtBu
N
HN
COOtBu
NH
O
O
NH
O
Rink amide
resin
SPPS
Rink amide
resin
O
O
O
H
O
H
N
H
H
N
H
N
N
N
H
N
Fmoc
N
Boc
N
1) 4-methylpiperidine
(20% in DMF), rt, 20 min
2) Boc-L-Phe (3 equiv)
HBTU (3 equiv)
DIPEA (5 equiv)
DMF, rt, 40 min
N
H
O
H
O
H
O
O
15
1) H-L-Ala-OtBu.HCl
L-5h
2)TFA/TIS/H2O
rt
(5 equiv)
Zn(OAc)2 (20 mol%)
NaOAc (5 equiv)
THF, 90°C, 48 h
OH
O
TFA.H2N
NH
O
O
O
O
H
N
H
N
TFA.H2N
NH2
N
N
H
O
H
O
16.TFA
50%
(preparative HPLC)
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1
2
3
4
5
Scheme 6. Application of the methodology through macrocyclization of heptapetide 17.HCl
6
7
8
9
COOtBu
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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38
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59
60
H
N
N
HN
N
O
N
O
O
O
O
HN
N
HN
Zn(OAc)2 (20 mol%)
HClH2N
O
O
O
O
O
O O
NH
NaOAc (1 equiv)
THF (0.4 M)
HN
N
O O
NH
NH
100°C, 24 h
N
NH
26 %
(preparative HPLC)
OAll
OAll
18
17.HCl
To further demonstrate the chemoselectivity of our transamidation, we selected L,L-19, a substrate
containing five electronically and sterically different amides (primary, secondary and tertiary amides
derived from aromatic and aliphatic carboxylic acids, both N-alkyl and N-aryl variants) (Scheme 7).
Reaction of L,L-19 with H-L-Ala-OMe.HCl (L-5i.HCl) as the nucleophilic partner resulted in full
conversion and an excellent 93% yield. No other amides, even the aromatic, beside the acyl-L-Phe-NH-
tBu nic one cleaved under these reaction conditions. Also, tertiary N-methyl-N-phenylbenzamide, which
is known to be activated under Ni-catalysis,13a does not cleave. In fact, an aliphatic amide selectively
transamidates in the presence of aromatic amides. Calculations of the resonance energies of the 5 amides
supported the L-Phe-NH-tBu nic moiety to be the most reactive in transamidation (Scheme 8).25
Interestingly, conformational analysis in L,L-19 revealed several intramolecular interactions, responsible
for the lowering of the resonance energies in comparison with simple model reference amides.
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5
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8
9
Scheme 7. Application of the methodology on an peptide derived oligoamide L,L-19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
31
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59
60
N
O
N
O
Ph
Ph
L
H- -Ala-OMe.HCl
L 5i.HCl
-
(1.1 equiv)
Zn(OAc)2 (20 mol%)
NaOAc (1.1 equiv)
THF (0.5 M)
70°C, 24 h
93%
O
NH
O
O
NH
O
N
H
H
N
OMe
N
N
N
H
H
O
O
O
O
O
COOtBu
NH2
NH2
L,L,L-20
L,L-19
Scheme 8. Calculated resonance energies of the amides in L,L-19 and reference amide compounds
Reference compounds:
Oligoamide L,L-19:
Ph
O
Me
N
H
N
O
C
E
B
1.850
2.538
Ph
O
Me
2.022
O
D
O
N
H
N
O
N
A
H
H
O
E
OtBu
H
N
2.050
B
: 84.1 kJ/mol
C
: 82.6 kJ/mol
B
N
H
N
O
1.862
O
D
Ph
O
2
N
O
H
N
O
C
A
H
OtBu
N
H
2.303
H
D
E
: 84.3 kJ/mol
: 58.2 kJ/mol
N
A
D
B
: 72.2 kJ/mol C
: 9.8 kJ/mol
: 64.1 kJ/mol
A
: 27.4 kJ/mol
E
: 67.9 kJ/mol
: 62.4 kJ/mol
hydrogen bonds
CONCLUSIONS
In summary, we have developed a novel transamidation reaction based on N-Boc amino acid amides
equipped with a nicotinate DG 4. The DG can be easily introduced on N-Boc amino acid amides under
mild conditions via Pd-catalyzed amidation with commercially available tBu 2-chloronicotinate (2).
Synthesis of dipeptides via transamidation showed that a wide range of tBu nic-bearing N-Boc-protected
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amino amides 4 were compatible with both amino acid esters and amides 5 as nucleophiles. 4 can be used
as building block under classical peptide coupling conditions, easily allowing complex and challenging
peptide/peptidomimetic substrate synthesis for subsequent transamidation, as illustrated by successful
segment condensations, a reaction on a solid support and a macrocyclization. The protocol is fully
chemoselective for tBu nic bearing amides leaving even the more reactive amides untouched. The use of
a cheap and non-toxic Zn catalyst, used as a food additive, renders this mild transamidation fit for the
chemical modification of biomolecules.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
steven.ballet@vub.be
bert.maes@uantwerpen.be
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Detailed optimization data, experimental procedures, characterization data, and copies of NMR spectra
of all compounds (PDF).
ACKNOWLEDGMENT
This work was financially supported by the Research Foundation Flanders (FWO) (Research Project and
Scientific Research Network (WOG)), the Hercules and the Francqui Foundation, and the University of
Antwerp (BOF).
DEDICATION
In memory of Professor Benjamin Van der Veken (1947–2019)
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REFERENCES
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the Right Coupling Reagent for Peptides: A Twenty-Five-Year Journey. Org. Process Res. Dev. 2018,
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C.; Zhao, J. Ynamides as Racemization-Free Coupling Reagents for Amide and Peptide Synthesis. J. Am.
Chem. Soc. 2016, 138, 13135-13138; (d) Lundberg, H.; Adolfsson, H. Hafnium-Catalyzed Direct Amide
Formation at Room Temperature. ACS Catal. 2015, 5, 3271-3277.
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4. Roughley, S. D.; Jordan, A. M. The Medicinal Chemist's Toolbox: an Analysis of Reactions Used in
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the Pursuit of Drug Candidates. J. Med. Chem. 2011, 54, 3451-3479.
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5. For selected examples: (a) Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. Addressing Mechanistic Issues
in the Coupling of sonitriles and caCrboxylic cids: Potential Routes to Peptidic Constructs. J. Am. Chem.
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Catalysis in the Direct Traceless Staudinger Ligation of Carboxylic Acids and Azides. Angew. Chem., Int.
Ed. 2012, 51, 12036-12040; (c) Suppo, J.-S.; Subra, G.; Berg, M.; Marcia de Figueiredo, R.; Campagne,
J.-M. Inverse Peptide Synthesis via Activated α-Aminoesters. Angew. Chem., Int. Ed. 2014, 53, 5389-
5393; (d) Debnath, P.; Baeten, M.; Lefèvre, N.; Daele, S. V.; Maes, B. U. W. Synthesis of Secondary
Amides from N-Substituted Amidines by Tandem Oxidative Rearrangement and Isocyanate Elimination.
Adv. Synth. Catal. 2015, 357, 197-209; (e) Zhu, Y.-P.; Mampuys, P.; Sergeyev, S.; Ballet, S.; Maes, B.
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6. For selected examples: (a) Shen, B.; Makley, D. M.; Johnston, J. N. Umpolung Reactivity in Amide
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Oxytocin Through the Medium of Isonitriles. J. Am. Chem. Soc. 2012, 134, 13244-13247; (c) Chen, W.;
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12252; (e) Flood, D. T.; Hintzen, J. C. J.; Bird, M. J.; Cistrone, P. A.; Chen, J. S.; Dawson, P. E.
Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in
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Native Chemical Ligation. Angew. Chem., Int. Ed. 2018, 57, 11634-11639; (f) Bode; J. W. Chemical
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Carboxamides and Ureas with Amines. Angew. Chem., Int. Ed. 2012, 51, 3905-3909; (c) Allen, C. L.;
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11. For recent reviews, accounts and perspectives on transition metal-catalyzed reactions with N-activated
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7925; (f) Chaudhari, M. B.; Gnanaprakasam B. Recent Advances in the Metal-Catalyzed Activation of
Amide Bonds. Chem. Asian J. 2019, 14, 76–93; (g) Buchspies, J.; Szostak, M. Recent Advances in Acyl
Suzuki Cross-Coupling. Catalysts 2019, 9, 53; (h) Bourne-Branchu, Y.; Gosmini, C.; Danoun, G. N-Boc-
Amides in Cross-Coupling Reactions. Chem. Eur. J. 2019, 25, 2663-2674.
12. For transition metal-catalyzed transamidation reactions of N-activated secondary amides: (a) Baker,
E. L.; Yamano, M. M.; Zhou, Y.; Anthony, S. M.; Garg, N. K. A Two-tep aApproach to Achieve
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Secondary Amide Transamidation Enabled by Nickel Catalysis. Nat. Commun. 2016, 7, 11554-1159; (b)
Dander, J. E.; Baker, E. L.; Garg, N. K. Nickel-Catalyzed Transamidation of Aliphatic Amide
Derivatives. Chem. Sci. 2017, 8, 6433-6438; (c) Meng, G.; Lei, P.; Szostak, M. A General Method for
Two-Step Transamidation of Secondary Amides Using Commercially Available, Air- and Moisture-
Stable Palladium/NHC (N-Heterocyclic Carbene) Complexes. Org. Lett. 2017, 19, 2158-2161; (d) Zhou,
T.; Li, G.; Nolan, S. P.; Szostak, M. [Pd(NHC)(acac)Cl]: Well-Defined, Air-Stable, and Readily Available
Precatalysts for Suzuki and Buchwald-Hartwig Cross-coupling (Transamidation) of Amides and Esters
by N–C/O–C Activation. Org. Lett. 2019, 21, 3304-3309; (e) Shi, S.; Szostack, M. Pd–PEPPSI: a General
Pd–NHC Precatalyst for Buchwald–Hartwig Cross-Coupling of Esters and Amides (Transamidation)
under the Same Reaction Conditions. Chem. Commun. 2017, 53, 10584-10587.
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13. For transition metal-catalyzed and transition metal free esterification reactions of N-activated
secondary amides: (a) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong, X.; Yang, Y.-F.; Liu,
P.; Houk, K. N.; Garg, N. K. Conversion of Amides to Esters by the Nickel-Catalyzed Activation of
Amide C–N Bonds. Nature 2015, 524, 79-83; (b) Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers, J.-
N.; Senanayake, C.; Garg, N. K. Nickel-Catalyzed Esterification of Aliphatic Amides. Angew. Chem. Int.
Ed. 2016, 55, 15129-15132; (c) Weires, N. A.; Caspi, D. D.; Garg, N. K. Kinetic Modeling of the Nickel-
Catalyzed Esterification of Amides. ACS Catal. 2017, 7, 4381-4385; (d) Bourne-Branchu, Y.; Gosmini,
C.; Danoun, G. Cobalt-Catalyzed Esterification of Amides. Chem. Eur. J. 2017, 42, 10043-10047; (e) Li,
G.; Lei P.; Szostak, M. Transition-Metal-Free Esterification of Amides via Selective N-C Cleavage under
Mild Conditions. Org. Lett. 2018, 20, 5622-5625; (f) Wu, H.; Guo, W.; Daniel, S.; Li, Y.; Liu, C.; Zeng,
Z. Fluoride-Catalyzed Esterification of Amides. Chem. Eur. J. 2018, 24, 3444-3447.
14. An aryl group at the amide nitrogen is an alternative manner to activate N-alkylbenzamides for TM
catalysis: (a) N-alkyl-N-phenylbenzamide: See reference 13a; (b) N-methyl-N-pyrimidylbenzamide:
Meng, G.; Lalancette, R.; Szostak, R.; Szostak, M. N-Methylamino Pyrimidyl Amides (MAPA): Highly
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Reactive, Electronically-Activated Amides in Catalytic N–C(O) Cleavage. Org. Lett. 2017, 19,
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15. (a) Liu, Y.; Shi, S.; Achtenhagen, M.; Liu, R.; Szostak, M. Metal-Free Transamidation of Secondary
Amides via Selective N–C Cleavage under Mild Conditions. Org. Lett. 2017, 19, 1614-1617; (b) Li, G.;
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at Room Temperature. Nat. Commun. 2018, 9, 4165-4172.
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16. Li, G.; Ji, C.-L.; Hong, X.; Szostak, M. Highly Chemoselective, Transition-Metal-Free
Transamidation of Unactivated Amides and Direct Amidation of Alkyl Esters by N–C/O–C Cleavage. J.
Am. Chem. Soc. 2019, 141, 11161-11172.
17. (a) Ollivier, N.; Blanpain, A.; Boll, E.; Raibaut, L.; Drobecq, H.; Melnyk, O. Selenopeptide
Transamidation and Metathesis. Org. Lett. 2014, 16, 4032-4035; (b) Ruff, Y.; Garavini, V.; Giuseppone,
N. Reversible Native Chemical Ligation: A Facile Access to Dynamic Covalent Peptides. J. Am. Chem.
Soc. 2014, 136, 6333-6339; (c) Brea, R. J.; Rudd, A. K.; Devaraj, N. K. Nonenzymatic Biomimetic
Remodeling of Phospholipids in Synthetic Liposomes. Proc. Natl. Acad. Sci. 2016, 113, 8589-8594.
18. For accounts and reviews on the use of transition metal catalysis on amino acids and peptides: (a)
Willemse, T.; Schepens, W.; Vlijmen, H.; Maes, B. U. W.; Ballet, S. The Suzuki–Miyaura Cross-
Coupling as a Versatile Tool for Peptide Diversification and Cyclization. Catalysts 2017, 7, 74-106; (b)
Malins, L. R. Peptide Modification and Cyclization via Transition-Metal Catalysis. Curr. Opin. Chem.
Biol. 2018, 46, 25-32; (c) Wang, W.; Lorion, M.; Shah, J.; Kapdi, A. R.; Ackermann, L. Late-Stage
Peptide Diversification by Position-Selective C-H Activation. Angew. Chem., Int. Ed. 2018, 57, 14700-
14717; (d) Kotha, S.; Meshram, M.; Panguluri, N. R. Advanced Approaches to Post-Assembly
Modification of Peptides by Transition-Metal-Catalyzed Reactions. Synthesis 2019, 51, 1913-1922.
19. For examples on the use of transition metal catalysis on amino acids and peptides: (a) Willemse, T.;
Van Imp, K.; Goss, R. J. M.; Van Vlijmen, H. W. T.; Schepens, W.; Maes, B. U. W.; Ballet, S. Suzuki-
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Miyaura Diversification of Amino Acids and Dipeptides in Aqueous Media. ChemCatChem 2015, 7,
2055-2070; (b) Ruan, Z.; Sauermann, N.; Manoni, E.; Ackermann, L. Manganese-Catalyzed C-H
Alkynylation: Expedient Peptide Synthesis and Modification. Angew. Chem., Int. Ed. 2017, 56, 3172-
3176; (c) Andersen, T. L.; Nordeman, P.; Christoffersen, H. F.; Audrain, H.; Antoni, G.; Skrydstrup, T.
Application of Methyl Bisphosphine-Ligated Palladium Complexes for Low Pressure N-11C-Acetylation
of Peptides. Angew. Chem., Int. Ed. 2017, 56, 4549-4553; (d) Reay, A. J.; Hammarback, L. A.; Bray, J.
T. W.; Sheridan, T.; Turnbull, D.; Whitwood, A. C.; Fairlamb, I. J. S. Mild and Regioselective Pd(OAc)2-
Catalyzed C-H Arylation of Tryptophans by [ArN2]X, Promoted by Tosic Acid. ACS Catal. 2017, 7,
5174-5179; (e) Skogh, A.; Friis, S. D.; Skrydstrup, T.; Sandström, A. Palladium-Catalyzed
Aminocarbonylation in Solid-Phase Peptide Synthesis: A Method for Capping, Cyclization, and Isotope
Labeling. Org. Lett. 2017, 19, 2873-2876; (f) Sharma, S. V.; Tong, X.; Pubill-Ulldemolins, C.; Cartmell,
C.; Bogosyan, E. J. A.; Rackham, E. J.; Marelli, E.; Hamed, R. B.; Goss, R. J. M. Living GenoChemetics
by Hyphenating Synthetic Biology and Synthetic Chemistry in vivo. Nat. Commun. 2017, 8, 229-239.
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20. Wybon, C. C. D.; Mensch, C.; Hollanders, K.; Gadais, C.; Herrebout, W. A.; Ballet, S.; Maes, B. U.
W. Zn-Catalyzed tert-Butyl Nicotinate-Directed Amide Cleavage as a Biomimic of Metallo-
Exopeptidase Activity. ACS Catal. 2018, 8, 203-218.
21. For recent reviews on directed transition metal-catalyzed C-H functionalization: (a) Gandeepan, P.;
Ackermann, L. Transient Directing Groups for Transformative C–H Activation by Synergistic Metal
Catalysis. Chem 2018, 4, 199-222; (b) Sambiagio, C.; Schönbauer, D.; Blieck, R.; Dao-Huy, T.;
Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.;
Schnürch, M. A Comprehensive Overview of Directing Groups Applied in Metal-Catalysed C–H
Functionalisation Chemistry. Chem. Soc. Rev. 2018, 47, 6603-6743.
22. For selected contributions on Buchwald Pd G3 precatalysts: (a) Bruno, N. C.; Tudge, M. T.; Buchwald,
S. L. Design and Preparation of New Palladium Precatalysts for C–C and C–N Cross-Coupling Reactions.
Chem. Sci. 2013, 4, 916-920; (b) Bruneau, A.; Roche, M.; Alami, M.; Messaoudi, S. 2-Aminobiphenyl
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Palladacycles: The “Most Powerful” Precatalysts in C–C and C–Heteroatom Cross-Couplings. ACS
Catal. 2015, 5, 1386-1396; (c) Ruiz-Castillo, P.; Buchwald, S. L. Applications of Palladium-Catalyzed
C–N Cross-Coupling Reactions. Chem. Rev. 2016, 116, 12564-12649; (d) Hazari, N.; Melvin, P. R.;
Beromi, M. M. Well-Defined Nickel and Palladium Precatalysts for Cross-Coupling. Nat. Rev. Chem.
2017, 1, 0025.
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23. For the 'base effect' in Pd-catalyzed amination reactions: (a) Komrlj, J.; Maes, B. U. W.; Lemière, G.
L. F.; Haemers, A. The First Pd-Catalyzed Aminations of 4-Chloro-3(2H)-Pyridazinones. Synlett 2000,
1581-1584; (b) Jonckers, T. H.; Maes, B. U. W.; Lemière, G. L. F.; Dommisse, R. Selective Palladium-
Catalyzed Aminations on Dichloropyridines. Tetrahedron 2001, 57, 7027-7034; (c) Maes, B.U.W.;
Loones, K. T. J.; Jonckers, T. H. M.; Lemière, G. L. F.; Dommisse, R. A.; Haemers, A. Selective
Palladium-Catalyzed Aminations on 2-Chloro-3-iodo- and 2-Chloro-5-iodopyridine. Synlett 2002, 1995-
1998; (d) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.; Lemière, G. L. F.; Dommisse, R. A.
Study of a New Rate Increasing “Base Effect” in the Palladium-Catalyzed Amination of Aryl Iodides. J.
Org. Chem. 2004, 69, 6010-6017; (e) Surry, D. S.; Buchwald, S. L. Dialkylbiaryl hosphines in Pd-
Catalyzed Amination: a User's Guide. Chem. Sci. 2011, 2, 27-50; (f) Yadav, A. K.; Verbeeck, S.; Hostyn,
S.; Franck, P.; Sergeyev, S.; Maes, B. U. W. “Base Effect” in the Auto-Tandem Palladium-Catalyzed
Synthesis of Amino-Substituted 1-Methyl-1H-α-carbolines. Org. Lett. 2013, 15, 1060-1063.
24. Shaheen, F.; Jabeen, A.; Ashraf, S.; Nadeem-ul-Haque, M.; Shah, Z. A.; Ziaee, M. A.; Dastagir, N.;
Ganesan, A. Total Synthesis, Structural, and Biological Evaluation of Stylissatin A and Related Analogs.
J. Pept. Sci. 2016, 22, 607-617.
25. For resonance energy calculations of amides, see: (a) Szostak, R.; Shi, S.; Meng, G.; Lalancette, R.;
Szostak, M. Ground-State Distortion in N-Acyl-tert-butyl-carbamates (Boc) and N-Acyl-tosylamides
(Ts): Twisted Amides of Relevance to Amide N–C Cross-Coupling. J. Org. Chem. 2016, 81, 8091-8094;
(b) Szostak, R.; Meng, G.; Szostak, M. Resonance Destabilization in N-Acylanilines (Anilides):
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Electronically-Activated Planar Amides of Relevance in N–C(O) Cross-Coupling. J. Org. Chem. 2017,
82, 6373-6378.
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Graphical abstract
R1 = H
Zn(OAc)2
O
R3
H
Cyclic peptide
N
N
H
R2
O
O
N
OtBu
O
R3
H
H
N
N
R1
N
H
n
R2
O
R1 = Boc
Zn(OAc)2
O
R3
O
R5
H
H
N
N
OR6
m
Orthogonal with ‘classical’
peptide synthesis
Applicable on solid phase
R1
N
N
R5
H
H
O
R2
O
R4
O
H2
N
OR6
m
n
N
H
R4
O
Linear peptide
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Peptide synthesis: (a) Traditional approach: carboxylic acid activation and (b) New approach: Zn-catalyzed
nicotinate-directed transamidation.
237x146mm (300 x 300 DPI)
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Synthesis of tBu nic-functionalized dipeptide L,L-7 via application of Boc-L-Phe-tBu nic L-4a in classical
peptide synthesis (a) and Pd-catalyzed amidation of Boc-L-Leu-L-Phe-NH2 with tBu NicCl (2) (b).
145x46mm (300 x 300 DPI)
ACS Paragon Plus Environment