Copper(I)‐Mediated Denitrogenative Macrocyclization for the Synthesis of Cyclic α3β‐Tetrapeptide Analogues

Abstract

A copper(I)‐mediated denitrogenative reaction has been successfully developed for the preparation of cyclic tetrapeptides. The key reactive intermediate, ketenimine, triggers intramolecular cyclization through attack of the terminal amine group to generate an internal β‐amino acid with an amidine linkage. The chemistry developed herein provides a new synthetic route for the preparation of cyclic α3β‐tetrapeptide analogues that contain important biological properties and results in rich structural information being obtained for conformational studies. With the success of this copper(I)‐catalyzed macrocyclization, two histone deacetylase inhibitor analogues consisting of the cyclic α3β‐tetrapeptide framework have been successfully synthesized.

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Synthesis Design
Copper(I)-Mediated Denitrogenative Macrocyclization for the
Synthesis of Cyclic a3b-Tetrapeptide Analogues
Chun-ChiChen,Sheng-Fu Wang,Yung-YuSu, Yuya A. Lin, and Po-Chiao Lin*[a]
Abstract: Acopper(I)-mediated denitrogenative reaction has
been successfully developed for the preparation of cyclic tet-
rapeptides. The key reactive intermediate, ketenimine,trig-
gers intramolecular cyclization through attack of the termi-
nal amine group to generate an internal b-amino acid with
an amidinelinkage. The chemistry developed herein pro-
vides anew synthetic route for the preparation of cyclic a3b-
tetrapeptide analogues that contain important biological
properties and results in rich structural information being
obtained for conformational studies.With the successofthis
copper(I)-catalyzedmacrocyclization, two histonedeacety-
lase inhibitor analogues consisting of the cyclic a3b-tetra-
peptideframework have been successfully synthesized.
Introduction
Discovery and characterization of bioactive macrocycles have
inspiredchemists in the field of medicinal chemistry.Cyclic
peptides are of particular significance owing to the remarkable
capacityfor functional fine-tuning.[1] Compared with linear
peptides, peptidecycles retain the variability in amino acid res-
idues with additional tuning in ring size, and can significantly
resist degradation by exo- and endoproteases to enablethe
practical use of cyclic peptides as therapeutic agents.[2] Cyclic
peptides, particularly cyclic tetrapeptides (CTPs), are important
model ligandsthat act as reverse-turn analoguesfor protein-
specific recognition.[3] Reverse turns are loop-shaped motifs
that contribute toward the structural stabilityofproteins by
connecting residues of ahelicesand bstrands.[4] The structural
rigidity and protein surface location of reverse turns make
these ideal sites for receptor recognition.Many natural cyclic
peptides have been characterizedtocontain biological activi-
ties towardmultiple unrelated classes of receptors, which
might be ascribed to the idea that reverse-turn motifs could
be ligandsfor more than one receptor.[5] Therefore, the synthe-
sis of aconformationally diverse library of CTPs and their ana-
logues is certainly of great significance for the discoveryofbio-
logical active peptides.
Accordingly,the development of facile synthetic strategies
for cyclic peptides is in high demand for rapid compound gen-
eration with various ring sizes and side-chain functionalities.[6]
Ring size is crucial for successful head-to-tail peptide macro-
cyclization;the cyclization of peptides containing more than
seven amino acids is generally feasible. However,the synthesis
of small-to-medium-sized cyclic peptides can be obstructed by
trans-amide bonds that go againstthe ring-like conformation
required for cyclization.[7] To overcomethis limitation, cycliza-
tion of long peptidesisknown to be accelerated by the forma-
tion of intrapeptide hydrogen bonds and transient b-sheet
structure. Moreover,the introduction of a cis-amide bond in
the middle of peptidechain may provide asuitable geometry
for cyclization. To this end, proline/pseudo-proline and modi-
fied heterocyclic amino acids have been incorporated in the
sequence to induce the cisoid conformation andfacilitatesub-
sequent peptidecyclization.[8] Furthermore, the incorporation
of C-terminal d-aminoacids[9] and N-methyl amino acids[10]
could also exert turn-inducing effects creatinganappropriate
stereochemical configuration of the peptide backbones in sub-
sequent cyclization. The use of metal ions provides another
noncovalent, auxiliary-based strategy which may conformation-
ally preorganize apeptide formacrocyclization. Metals ions,
such as palladium(II), nickel(II), copper(II),[11] lithium,[12]
sodium,[13] and silver(I),[14] have been reported to promote pep-
tide macrocyclization by forming complexes with the peptides
of interest.
In addition, cis/trans isomerization of amide bonds usually
results in CTPs staying in aconformationally dynamic state in
aqueous solution.[15] The ring strain in 12-membered cyclic
structures leads to amarked increaseofcis-amide population,
and therefore, induces distortion of the amide-bond geome-
try.[4,16] The lowered barrier of cis/trans amide isomerization can
result in conformational heterogeneity of CTPs. Incorporation
of a b-amino acid into the tetrapeptide sequence resultsin
aless strained 13-membered cyclic transition state andde-
creased amide isomerization;this allows CTPs to be more
easily synthesized with conformational homogeneity.[17] The
a3b-CTPs are more resistant to hydrolysis. Yudin et al. reported
achemical strategy for the construction of a3b-CTPs through
[a] C.-C. Chen, S.-F.Wang, Y. -Y.Su, Y. A. Lin, Prof. P. -C. Lin
Department of Chemistry,Nation Sun Ya t-sen University
70 Lienhai Rd.,Kaohsiung 80424 (Taiwan)
E-mail:pclin@mail.nsysu.edu.tw
Supportinginformation for this article can be found under :
https://doi.org/10.1002/asia.201700339.
Chem. Asian J. 2017,12,1326 –1337 T2017 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim1326
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DOI:10.1002/asia.201700339

the transformation of the aziridine group into b-aminoacids.[18]
The crucial N-acylaziridine group facilitatesmacrocyclization
and the subsequent ring-opening reaction with nucleophiles
gives site-specific b-amino acid incorporated CTPs.[19] Moreover,
C-linkedcarbohydrate-b3-amino acids have been incorporated
into the synthesis of CTPs that exhibit stable bor gstruc-
tures.[20] Recently,Wong et al. reportedanew approach to syn-
thesize 15-membered CTPs from aprolinemotif by reductive
cleavage with SmI2.[21]
Ghadiri et al. reported aseries of b-amino acids containing
CTPs as potent and selective inhibitors of histone deacetylase
(HDAC).[22] HDACs are Zn2+-dependent enzymes that catalyze
the removal of acetyl groups from e-N-acetyllysine of histones.
Acetylation anddeacetylation of lysine modulate packing of
the chromatin complex and thereby modulate gene transcrip-
tion.[23] The development of HDAC inhibitors opens up aprom-
ising avenue to further understand epigenetic regulation and
the treatment of cancers. The proposed 13-membered a3b
CTPs have abackbone similartothat of azumamides, which
are naturally occurring HDACinhibitors that contain asingle
b3-amino acid,[24] and side chains through rational design in-
spired by the fungal metabolite apicidin A.[5c] Scaffolds for the
inhibition of HDAC isolated from HeLa cells have been opti-
mized by systematicallyscreening the chirality of the amino
acids and the position of the b-amino acid.[22] Avariety of side-
chain functionalities were also investigatedbyelaborate
design.The synthesis of one-bead–one-compound combinato-
rial libraries[25] of a3b-CTPs could further allow the discovery of
potent HDAC ligands by using aconvenientscreening plat-
form. In this research, acopper(I)-catalyzeddenitrogenative an-
nulationisproposed to enable macrocyclization of tetrapepti-
des through the formation of b-aminoacid linkages.
This strategy is inspired by our previouswork on the prepa-
ration of b-and b3-amino acids directly from the correspond-
ing a-aminoacids.[26] As shown in Figure 1a, N-propargylben-
zamide (i), directly transformed from a-aminoacids, reacts with
TsN3in the presence of acatalytic amountofCuI and K2CO3to
generate ahighly reactive ketenimine intermediate (ii), which
immediately undergoes cyclization to form 4-sulfanimido-1,3-
oxazines(iii). Aring-opening/-closing process leads to arapid
equilibrium that ultimately gives the more stable dihydropyri-
midin-4-ones as the exclusive products. The resulting dihydro-
pyrimidin-4-ones could then be converted into b-and b3-
amino acid analogues through nucleophilic attack. This cop-
per(I)-catalyzed strategy provided an important route to pre-
pare b-amino acids with well-defined stereochemistry that was
preserved from the starting a-aminoacids. The copper(I) cata-
lyst was first involved in the formationofasulfonyl triazole in-
termediate and subsequently participated in the equilibrium
with a-imino diazo species. Through aWolff-type rearrange-
ment, the a-imino diazo intermediate can be converted into
ahighly reactive ketenimine intermediate;these have been
used in many synthetic applications.[27] Notably,the linear sp-
hybrid centerofthe ketenimine intermediate is highly reactive
towardsnucleophiles, even those with considerable sterichin-
drance.Therefore, the introductionofketenimine as akey in-
termediate in the peptide cyclization shouldbeofgreat signifi-
cance to improvecyclization efficiency and facilitatethe expan-
sion of structural diversity.
Results and Discussion
Accordingly,alinear a2ba2-pentapeptide composed of four l-
a-glycine and a b-glycine was first selected as amodel to eval-
uate the applicabilityofthis newly developed chemistry in the
preparation of b-amino acid containing linear or cyclic pep-
tides. The general principle of this strategy is illustrated in Fig-
ure 1b,inwhich the ketenimine intermediate is subjected to
nucleophilic addition by the Nterminus of another peptide
fragment. The desired linear a2ba2-pentapeptide would be ob-
tained with an amidine linkage. To synthesize the peptide pre-
cursors,asillustrated in Scheme 1, Boc-protected glycine 1was
coupled with propargylamine to provide 2(93 %). After remov-
al of the protecting groups, amino compound 3was further
coupled with Boc-protected glycine 1to give dipeptide 4
(85%). On the other hand, Boc-protected glycine methyl ester
5was prepared by treating 1with methyliodide and isolated
in ayield of 97 %. After removal of the Boc group, amino com-
pound 6was coupled with 1by using HOBt and EDC to obtain
Boc-protected dipeptide 7(95 %). Subsequently,treatment
with TFAled to complete removalofthe Boc group to provide
the nucleophilic amino dipeptide 8.
The ketenimine-directed coupling reaction was initiatedby
activation of the terminal alkyne in 4.Inthe presenceofCuI
catalyst, K2CO3,and Ts N 3,the ketenimine intermediate immedi-
Figure 1. a) Reported strategy for the preparation of b-aminoacid ana-
logues. b) The methodproposed herein to synthesize b-amino acid contain-
ing peptides.Boc =tert-butyloxycarbonyl, Ts =tosyl.
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ately reacted with dipeptide 8to give the desired pentapep-
tide 9.Details of the reaction conditions have been carefully
studied and are summarized in Ta ble 1. First, it was found that
acatalytic amount of copperiodide (0.1equiv) in DCM with
K2CO3(2 equiv)enabled successfulcoupling between 4and 8
to obtain the desired a2ba2-pentapeptide 9though in alow
yield of 32%(Table1,entry 1). To optimize the reactioneffi-
ciency,the amounts of CuI and K2CO3,aswell as the reaction
solvents werecarefully screened. The fact that excessK
2CO3
(5 equiv) cannot improvethe yield may be due to the decom-
position of TsN3in the presence of excess base. The use of
ACN as asolvent would retard the reaction, whereas the use
of DMFwith two equivalents of K2CO3could improvethe yield
to 40%(Table 1, entries 5and 6, respectively). Accordingly,an
attempttouse acosolventsystem consisting of DMF and DCM
in the ratio of 1:1successfully increased the yield to 48 %
(Table 1, entry 8). Under theseoptimal conditions, ashort aba-
tripeptide, 10,which was prepared from 2and 6,could be iso-
lated in yields of up to 85 %(Table 1, entry 9).
To apply this strategy in the synthesis of CTPs, two a3b-ami-
dine analogues of apicidin A, CTP 1and 2,wereselected as
targets.The retrosynthesis is illustrated in Figure 2. Target CTP
1is composed of three a-aminoacids, glycine (amino acid 1),
tryptophan (amino acid 2), and alanine (amino acid 4), and
ab-homoleucine (amino acid 3). The key copper(I)-catalyzed
denitrogenative reaction triggershead-to-tailcyclization and
thereby connects residues 3and 4with a b-linked amidine.
With traditional solution-phase peptide synthesis, linear tetra-
peptide 14 was synthesized through the coupling of 11 and
12.Anunusual amino acid analogue, 5-methylhex-1-yn-3-
amine (blue moiety in 11), can be prepared from a-leucine by
areported procedure.[26] The target structure is aHDAC inhibi-
tor analogue, which usually carriesacriticalZn
2+-coordinating
amino acid side chain, such as epoxyketone, ethylketone,
amide, or carboxylic acid.[22b, 28] Modificationofthe zinc-coordi-
nating functionality can significantly affect the binding affinity
of CTPs to HDACs.[28] For this purpose, an O-allyl group has
been introduced into the side chains of the CTP analogueto
form CTP 2,which demonstrates facile structuralexpansion of
the zinc-coordinatingmotif.
The synthesis of dipeptide buildingblock 11 is initiated with
the conversion of Boc-l-Leu to the corresponding Weinreb
amide (Scheme 2). As-obtained 16 was then reduced with LAH
Scheme1.Synthetic pathway of linear a2ba2-tetrapeptide precursors.
DMF=N,N-dimethylformamide,EDC =N-(3-dimethylaminopropyl)-N’-ethyl-
carbodiimide, HOBt =1-hydroxybenzotriazole hydrate, TFA=trifluoroacetic
acid, DCM=dichloromethane,TEA =triethylamine.
Table 1. Optimization of conditionsfor the synthesis of linear an–b–an
peptides.
Entry CuI
[equiv]
K2CO3
[equiv]
Solvent[a] Yield
[%]
10.1 2DCM 32
20.1 2ACN trace
30.5 2DCM 36
40.5 5DCM 21
50.5 2ACN trace
60.5 2DMF40
70.5 2ACN/DMF(1/1) 45
80.5 2DCM/DMF(1/1)48
9[b] 0.5 2DCM/DMF(1/1) 85
[a] ACN=acetonitrile. [b] Optimizedconditions in the synthesis of aba-
linear tripeptide 10 from 2and 6.
Figure 2. Retrosynthesis of CTPs through copper(I)-catalyzed denitrogenative
cyclization.
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to give aldehyde 17.Subsequently,the aldehydewas subject-
ed to homologation by using Bestmann–Ohira reagent to pro-
duce Boc-protected amino alkynes (18;60% over two steps).
Removalofthe Boc group afforded the free amine (19 ;quanti-
tative yield), which was then set up for coupling with Boc-Trp-
OH to give the dipeptide buildingblock 20.Finally,removal of
the Boc protecting group led to dipeptide building block 11,
which contained afree amine and aterminal alkyne group for
furthercoupling reactions.
In Scheme 3, glycine and O-allyl-substituted l-serine were
coupled with l-alanine to construct dipeptide building blocks
12 and 13.ToprepareO-allyl-substituted serine, l-serine
methylester hydrochloride was protected with atriphenyl-
methylgroup to afford N-trityl-l-serine methyl ester,which
was then subjected to O-allylation. After removal of the trityl
group, compound 21 was ready for use in the synthesis of di-
peptide 13.[29] Glycine 6andO-allyl serine 21 were then react-
ed with Boc-Ala-OHtoobtain protected dipeptides 22 (99%)
and 23 (84%). Subsequently,basic hydrolysis of the ester
groups with diluted sodium hydroxide gave the corresponding
dipeptides 12 (90 %) and 13 (92 %) and exposed the carboxylic
acid group for subsequentamide-bondformation.
Then, dipeptide 11 was coupled with 12 and 13 to form the
desired linear tetrapeptide precursors 24 (75%) and 25 (75 %;
Scheme4). High levelsofepimerization were observed under
generalcoupling conditions in the case of tetrapeptide 25.Ac-
cordingtopreviousreports, epimerization occurredduring
solid-phase peptide synthesis and could produce as much as
80%ofthe unnatural epimer for glycosylated serine-contain-
ing peptides.[30] In contrast, lessthan 1% epimerization was
observed for glycosylated threonine derivatives.[31] Theoccur-
rence of epimerization was considered during the coupling
processes by activation and cyclization,then abstraction of the
a-hydrogen to form the other epimer (Scheme S1 in the Sup-
porting Information). Apparently,adoptingO-allyl-substituted
serine 21 as the second amino acids resulted in rapid abstrac-
tion of the a-hydrogen because the ratio of 25 to undesired
byproduct was determined to be 1:1when using coupling re-
agents HBTU and TEA. To suppress undesired side reactions,
different couplingreagents and bases were evaluated in the
coupling reaction; the resultsare summarized in Table S1 in
the Supporting Information. Finally,mildconditions with HATU,
Scheme2.Synthesis of building block dipeptide 11.LAH =lithiumaluminum
hydride, HBTU =N,N,N’,N’-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexa-
fluorophosphate.
Scheme3.Synthesis of building block dipeptides 12 and 13.DIEA =N,N-dii-
sopropylethylamine.
Scheme4.Synthesis of linear tetrapeptides 14 and 15 as CTP precursors. HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin-ium 3-oxid
hexafluorophosphate, HOAt =1-hydroxy-7-azabenzotriazole, TMP =2,4,6-trimethylpyridine.
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HOAt, and TMP present optimized conditions and result in an
improved ratio of 25 to the undesired byproductof5:1. Fur-
thermore, compound 25 was separated from the undesired by-
product by column chromatography to further improvethe
purity of 25 up to aratio of 15 :1. After removal of the Boc pro-
tecting group with TFA, linear tetrapeptide precursors 14 and
15 were collected ready for the next peptide cyclization.
The cyclization of peptides is expected to be very difficult
relative to the linear peptide coupling reaction. Therefore, the
peptidecyclization conditions were optimized for the synthesis
of the desired CTPs (Table 2). Poor solubilityofthe linear tetra-
peptideinless polar solvents (Table 2, entry 5) causes poor cyc-
lization. Heating the reactionmixture (Table 2, entries 6and 7)
led to undesired decomposition of TsN 3and thereby considera-
bly reduced the cyclization efficiency. In the presence of excess
base or in the presence of an organic base, such as TEA, in-
stead of K2CO3showednosignificant improvementeither.To
improvethe substrate solubility,acosolventsystem of DCM
and DMF,along with an increase in CuI (0.5 equiv), successfully
raised the cyclization yield to 22 %(Table 2, entry 8). Finally,the
optimal reaction conditions were found by increasing the
amount of CuI to one equivalent, while keeping K2CO3
(2 equiv) and the DCM/DMF solventsystem as before.Under
these conditions, the desired product CTP 1could be isolated
in ayield of up to 32%. When the optimized conditions were
appliedinthe synthesis of CTP 2,the product couldbeisolat-
ed in ayield of 35 %(Scheme5).
Considering the reaction mechanism, two possible pathways
may involveinthe CTP cyclization.Ketenimine intermediate I
was generated when linear tetrapeptide 15 was treated with
TsN3in the presence of CuI and K2CO3(Scheme6). The reactive
ketenimine intermediate can then be attacked directly by an
N-terminal amino group to form the desired product CTP 2,as
shown in path ainScheme 6. However, according to our re-
portedmechanism for the synthesisofb-amino acids,[26] kete-
nimine intermediate Imay first trigger the formation of dihy-
dropyrimidin-4-one(II;path binScheme 6). Next, the N-termi-
nal amineinitiates acyl substitution to open the ring to obtain
the isomeric product CTP 2’.Tocharacterize the precise struc-
ture of the obtained product, several2DNMR experiments
have been performed and carefully analyzed. 1H–1HCOSY and
1H–13CHSQC allow the correct assignment of most protons
and carbon atoms in CTP 2.(Data are included in the Support-
ing Information.) To determine the correctlinkage of b-amino
acids, HMBC experiments can provide critical information. C26
of the amidine bond (numbered in CTP 2;Figure 3) was found
at d=167.1 ppm and showedacorrelation with protons at
C25, which was separated by two bonds,asshown in Figure S1
in the Supporting Information. Furthermore, C26 also gave
acorrelation with the protononC1inthe HMBC spectrum
(Figure 3), whichsupports the structuralarrangementofCTP 2.
In the case of CTP 2’,the correlation of the amidine carbon
with corresponding methylene protons separated by four
bonds are rarely observed. Therefore, the correctstructure of
the CTP product can be determined as that of CTP 2.Ring
Table 2. Optimization of conditionsfor copper(I)-catalyzed denitrogena-
tive macrocyclization of tetrapeptides.
Entry Catalyst
[equiv]
Base SolventConcentration
[mm]
Yield
[%]
1CuI (0.2) K2CO3ACN 10 19
2CuI (0.5) K2CO3ACN 10 20
3CuI (0.2) TEA THF 10 12
4CuI (0.2) TEA ACN 10 trace
5CuI (0.2) K2CO3solvent[a] 10 trace
6[b] CuCl (0.2) K2CO3DCM 10 11
7[c] CuCl (0.2) K2CO3ACN 10 14
8CuI (0.5) K2CO3cosolvent[d] 522
9CuI (1.0) K2CO3cosolvent[d] 532
[a] THF,DCM, dioxane, DMF.[b] At reflux. [c] 508C. [d] DCM/DMF =1:1.
Scheme5.Synthesis of CTP 2.
Scheme6.Tw opossible pathways for CTP cyclization.
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strain of the reaction intermediates in the two pathways
shown in Scheme 6may explain the preference for path a, in
which nucleophilic attack mayoccur in a13-membered ring
structure. However,nucleophilic acyl substitution depictedin
path binScheme 6has to overcome larger ring strain of an
11-membered ring intermediate;this makes it aless favored
pathway.
Conclusion
We have developed anovel synthetic method for the prepara-
tion of cyclic a3b-tetrapeptides as HDAC inhibitor analogues
throughthe copper(I)-catalyzed formation of aketenimine in-
termediate, which immediately undergoes intramolecular cycli-
zationbynucleophilic attacktoform the corresponding tosyl
amidinestructure. Cyclizationaffordedtwo forms of the cyclic
b-peptide analogues with adequate yields. To the best of our
knowledge, this is the first reported method that enables the
direct formation of a3b-CTP analogues through head-to-tail
cyclization. Furthermore, various allyl group transformations
could allow the structural diversity of cyclic a3b-tetrapeptides
analogues to be explored. Owing to the stability of amidines,
the correspondingtransformations to amidesorother function-
al groups were rarelyaddressed. There has been asuccessful
example of converting amidineinto amide by using concen-
trated HCl.[33] However,the development of milderalternatives
to providenative CTPs is ongoing in our group. Furthermore,
tosyl amidineanalogues of CTPs are new and have never been
studied. Therefore, with the synthetic method developed in
this research, avariety of CTPs analogues could be synthesized
and carefullyused in screening for biological activities. We be-
lieve that this method is an attractive optionfor the construc-
tion of cyclic a3b-tetrapeptides as HDAC inhibitor analogues.
Experimental Section
General
All reactions were performed under an atmosphere of nitrogen
and workup was carried out in air.All solvents used to optimize
conditions were dried by using reported procedures.[32] In particu-
lar,DMF should be freshly prepared. Unless noted otherwise, all
materials were purchased from commercial suppliers and used as
received. TsN3was prepared in house by ausing conventional pro-
cedure. CupriSorb resin was purchased from Seachem Laboratory
and dried in high vacuum before use. 1Hand 13CNMR spectra
were recorded on aBruker Ultrashield 300 and 75 MHz spectrome-
ter and aVarian UNITY INOVA500 and 125 MHz spectrometer,re-
spectively.Residual solvent signals for calibration:for 1HNMR :
CDCl3:d=7.26 ppm, CD3OD: d=3.31 ppm;for 13CNMR:CDCl3:
d=77.2 ppm, CD3OD: d=49.2 ppm. Melting points of the products
were measured in open capillary tubes on aFargo MP-2D melting
point apparatus. IR spectra were recorded on aPerkinElmer
100 FTIR spectrometer.High-resolution mass spectra were recorded
on an electrospray ionization time-of-flight (ESI-TOF), fast atom
bombardment (FAB), and electron ionization (EI) mass spectrome-
ter.Nominal and exact m/zvalues are reported in Daltons. Flash
chromatography was performed by using silica gel (43–60 mm,
Merck).
Synthesis of 1[34]
Glycine (2000 mg, 26.66 mmol) and di-tert-butyl dicarbonate
(7.35 mL, 32 mmol) were added to astirred solution of sodium hy-
droxide (1600 mg, 40 mmol) in water (54 mL) at RT,and reacted for
16 hunder anitrogen atmosphere. After completion of the reac-
Figure 3. Partial spectrum of the HMBC experiment for CTP 2.
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tion, as monitored by TLC, the pH was adjusted to 2–3 by 1 nHCl,
and then extracted with ethyl acetate (2 V50 mL). The combined
organic layers were dried over MgSO4,filtered, and concentrated
under reduced pressure. The desired product (1)was afforded as
awhite solid (4483 mg, 96%). M.p. 87–90 8C; 1HNMR (300 MHz,
CDCl3): d=5.02 (brs, 1H), 3.96 (s, 2H), 1.46 ppm (s, 9H); 13CNMR
(75 MHz, CDCl3): d=174.9, 156.2, 80.7, 42.5, 28.5 ppm;IR(KBr): n
˜=
3354, 2980, 1729, 1714, 1251 cm@1;HRMS (ESI-TOF): m/zcalcd for
C7H13NO4Na [M+Na]+:198.0742;found:198.0737.
Synthesis of 2[35]
EDC·HCl (4376 mg, 22.83 mmol) and HOBt (3085 mg, 22.83 mmol)
were added to astirred solution of Boc-Gly-OH (1;2000 mg,
11.42 mmol) in DMF (40 mL) at RT,and allowed to stir for 20 min
under anitrogen atmosphere. Next, propargylamine (0.8 mL,
13.7 mmol) and TEA (4.8 mL, 34.26 mmol) were added and reacted
at RT for 9hunder anitrogen atmosphere. After completion of the
reaction, as monitored by TLC, the reaction was quenched with
water (10 mL). The solvent was removed and the resulting residue
was extracted with ethyl acetate (2 V30 mL) and washed with 1 n
HCl (30 mL) and an aqueous solution of sodium bicarbonate
(30 mL). The combined organic layers were dried over MgSO4,fil-
tered, and concentrated under reduced pressure to afford the
crude product. The crude residue was purified by column chroma-
tography on silica gel by using 10 %ethyl acetate in hexane as
asolvent system to affordthe desired product (2)asawhite solid
(2263 mg, 93 %). M.p. 11 6–1188C; 1HNMR (300 MHz, MeOD): d=
3.98 (d, J=1.6 Hz, 2H), 3.70 (s, 2H), 2.56 (s, 1H), 1.45 ppm (s, 9H);
13CNMR (75 MHz, MeOD): d=172.4, 158.6, 80.9, 80.6, 72.3, 44.6,
29.5, 28.8 ppm ;IR(KBr): n
˜=3307, 2980, 2124, 1668, 1251 cm@1;
HRMS (ESI-TOF): m/zcalcd for C10H16N2O3Na [M+Na]+:235.1053 ;
found:235.1054.
Synthesis of 3[36]
TFA(5mL) was added to astirred solution of 2(2000 mg,
9.42 mmol) in DCM (31 mL), and the resultant mixture was stirred
at RT for 60 min under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, solvent was removed under re-
duced pressure and the resulting residue was washed with water
(20 mL) and extracted with DCM (20 mL). The combined aqueous
layers were concentrated under reduced pressure to afford the de-
sired product (3)asacolorless liquid (1130 mg, quantitative).
1HNMR (300 MHz, MeOD): d=4.03 (s, 2H), 3.67 (s, 2H), 2.64 ppm
(s, 1H); 13CNMR (75 MHz, MeOD): d=167.1, 80.1, 72.9,41.6,
29.7 ppm;IR(KBr): n
˜=3325, 2978, 2191, 1748, 1713, 1223 cm@1;
HRMS (ESI-TOF): m/zcalcd for C5H9N2O[M+H]+:113.0715 ;found:
113.0717.
Synthesis of 4[37]
EDC·HCl (2588 mg, 13.5 mmol) and HOBt (1824 mg, 13.5 mmol)
were added to astirred solution of 1(1577 mg, 9.0 mmol) in DMF
(20 mL) at RT,and allowed to stir for 20 min under anitrogen at-
mosphere. Next, 2-amino-N-(prop-2-yn-1-yl)acetamide (3;1211mg,
10.8 mmol) and TEA (3.10 mL, 22.5 mmol) were added and stirring
was continued at RT for 10 hunder anitrogen atmosphere. After
completion of the reaction, as monitored by TLC, the reaction was
quenched with water (5 mL) and the solvent was removed under
reduced pressure. The resulting residue was extracted with ethyl
acetate (2V30 mL) and washed with 1nHCl (30 mL) and an aque-
ous solution of sodium bicarbonate (30 mL). The combined organic
layers were dried over MgSO4,filtered, and concentrated under re-
duced pressure to afford the crude product. The crude residue was
purified by column chromatography on silica gel by using 20 %
ethyl acetate in hexane as asolvent system to afford the desired
product (4)asawhite solid (2060 mg, 85%). M.p. 147–1508C;
1HNMR (300 MHz, MeOD): d=3.98 (d, J=2.5 Hz, 2H), 3.87 (s, 2H),
3.73 (s, 2H), 2.56 (t, J=2.4 Hz, 1H), 1.46 ppm (s, 9H); 13CNMR
(75 MHz, MeOD): d=173.3, 171.4, 158.9, 81.2, 80.5, 72.4, 45.1, 43.4,
29.6, 28.9 ppm ;IR(KBr): n
˜=3307, 2980, 2121, 1680, 1245 cm@1;
HRMS (ESI-TOF): m/zcalcd for C12H19N3O4Na [M+Na]+:292.1268;
found:292.1268.
Synthesis of 5[38]
Potassium carbonate (3160 mg, 22.84 mmol) was added to astirred
solution of 1(2000 mg, 11.42 mmol) in DMF (18 mL). Asolution of
iodomethane (6480 mg, 45.69 mmol) in DMF (20 mL) was added
dropwise by means of an addition funnel. The reaction was al-
lowed to stir at RT for 12 hunder anitrogen atmosphere. After
completion of the reaction, as monitored by TLC, the solvent was
removed under reduced pressure and then washed with water
(15 mL) and extracted with ethyl acetate (2 V30 mL). The combined
organic layers were dried over MgSO4,filtered, and concentrated
under reduced pressure. The desired product (5)was afforded as
acolorless liquid (2100 mg, 97 %). 1HNMR (300 MHz, CDCl3): d=
4.99 (brs, 1H), 3.92 (d, J=5.3 Hz, 2H), 3.75 (s, 3H), 1.45 ppm (s,
9H); 13CNMR (75 MHz, CDCl3): d=171.0, 155.9, 80.2, 52.4, 42.5,
28.5 ppm;IR(KBr): n
˜=2979, 1748, 1714, 1211cm
@1;HRMS (EI): m/z
calcd for C8H15NO4Na [M+Na]+:212.0893 ;found:212.0896.
Synthesis of 6[39]
TFA(4mL) was added to astirred solution of methyl (tert-butoxy-
carbonyl)glycinate (5;2000 mg, 10.58 mmol) in DCM (26 mL), and
the resultant mixture was stirred at RT for 30 min under anitrogen
atmosphere. After completion of the reaction, as monitored by
TLC, the solvent was removed and then washed with water
(20 mL) and extracted with DCM (20 mL). The combined aqueous
layers were concentrated under reduced pressure. The desired
product (6)was afforded as awhite solid (988 mg, quantitative).
M.p. 162–1658C; 1HNMR (300 MHz, MeOD): d=3.84 (s, 3H),
3.83 ppm (s, 2H); 13CNMR (75 MHz, MeOD): d=169.1, 53.6,
41.0 ppm;IR(KBr): n
˜=3417, 2962, 1754, 1184 cm@1;HRMS (EI): m/z
calcd for C3H7NO2[M]+:89.0477;found :89.0474.
Synthesis of 7[40]
EDC·HCl (4379 mg, 22.84 mmol) and HOBt (3086 mg, 22.84 mmol)
were added to astirred solution of 1(2102 mg, 12 mmol) in DMF
(35 mL). The reaction was stirred for 20 min at RT under anitrogen
atmosphere. Next, methyl glycinate (6;892 mg, 10 mmol) and TEA
(4.20 mL, 30 mmol) were added and stirring was continued at RT
for 9hunder anitrogen atmosphere. After completion of the reac-
tion, as monitored by TLC, the reaction was quenched with water
(5 mL), solvent was removed, and the solution was extracted with
ethyl acetate (30 mL x2), and washed with 1nHCl (30 mL) and an
aqueous solution of sodium bicarbonate (30 mL). The combined
organic layers were dried over MgSO4,filtered, and concentrated
under reduced pressure to afford crude. The crude residue was pu-
rified by column chromatography on silica gel by using 10%ethyl
acetate in hexane as asolvent system to afford the desired product
(7)asacolorless liquid (2328 mg, 95 %). 1HNMR (300 MHz, MeOD):
d=3.96 (s, 2H), 3.75 (s, 2H), 3.72 (s, 3H), 1.45 ppm (s, 9H); 13CNMR
(75 MHz, MeOD): d=173.2, 171.9, 158.5, 80.9, 52.8, 44.6, 41.9,
28.8 ppm;IR(KBr): n
˜=2979, 1748, 1696, 1215 cm@1;HRMS (ESI-
Chem. Asian J. 2017,12,1326 –1337 www.chemasianj.org T2017 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim1332
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TOF): m/zcalcd for C10H18N2O5Na [M+Na]+:269.1108;found :
269.1109.
Synthesis of 8[41]
TFA(5mL) was added to astirred solution of 7(2000 mg,
8.12 mmol) in DCM (27 mL), and the resultant mixture was stirred
at RT for 40 min under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, the solvent was removed and
then washed with water (20 mL) and extracted into DCM (20 mL).
The combined aqueous layers were concentrated under reduced
pressure. The desired product (8)was afforded as awhite solid
(1242 mg, quantitative). M.p. 134–1378C; 1HNMR (300 MHz,
MeOD): d=4.03 (s, 2H), 3.76–3.72 ppm (m, 5H); 13CNMR (75 MHz,
MeOD): d=171.7, 168.0, 52.9, 42.0, 41.5 ppm ;IR(KBr): n
˜=3244,
2963, 1743, 1680, 1203 cm@1;HRMS (ESI-TOF): m/zcalcd for
C5H11N2O3[M+H]+:147.0770 ;found:147.0768
Synthesis of 9
Compound 4(300 mg, 1.11mmol), potassium carbonate (308 mg,
2.23 mmol), Ts N 3(243 mg, 1.24 mmol) and copper iodide (106 mg,
0.56 mmol) were added to astirred solution of 8(200 mg,
1.37 mmol) in the cosolvent system (DMF (6 mL) and DCM (6 mL)),
and the resultant mixture was stirred at RT for 2hunder anitrogen
atmosphere. After completion of the reaction, as monitored by
TLC, the reaction mixture was treated with CupriSorb resin
(800 mg) for 30 min to remove traces of copper,filtered through
apad of Celite, washed with excess DCM (10 mL), and the com-
bined filtrate was concentrated under reduced pressure. Then fil-
trate was dissolved in ethyl acetate (50 mL);washed with water
(50 mL);and the combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure to afford the
crude product. The crude residue was purified by column chroma-
tography on silica gel by using 50 %ethyl acetate in hexane as
asolvent system to affordthe desired product (9)asayellow
liquid (315 mg, 48 %). 1HNMR (500 MHz, MeOD): d=7.75 (d, J=
8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 3.98 (s, 2H), 3.89 (s, 2H), 3.86
(s, 2H), 3.75 (s, 2H), 3.71 (s, 3H), 3.61 (t, J=6.4 Hz, 2H), 2.97 (t, J=
6.4 Hz, 2H), 2.41 (s, 3H), 1.45 ppm (s, 9H); 13CNMR (125 MHz,
MeOD): d=173.5, 172.2, 171.8, 171.4, 169.1, 158.8, 144.1, 142.2,
130.5, 127.4, 81.1, 52.8, 45.8, 45.0, 43.8, 42.0, 38.4, 34.9, 28.9,
21.6 ppm;IR(KBr): n
˜=3302, 2933, 1748, 1668, 1273 cm@1;HRMS
(ESI-TOF): m/zcalcd for C24H36N6O9SNa [M+Na]+:607.2162;found:
607.2153.
Synthesis of 10
Compound 2(720 mg, 3.39 mmol), potassium carbonate (938 mg,
6.79 mmol), TsN3(736 mg, 3.73 mmol), and copper iodide (323 mg,
1.70 mmol) were added to astirred solution of 6(302 mg,
3.39 mmol) in acosolvent system (DMF (17 mL) and DCM (17 mL)),
and the resultant mixture was stirred at RT for 1hunder anitrogen
atmosphere. After completion of the reaction, as monitored by
TLC, the reaction mixture was treated with CupriSorb resin
(2000 mg) for 30 min to remove traces of copper,filtered through
apad of Celite, washed with excess DCM (20 mL), and the com-
bined filtrate was concentrated under reduced pressure. Then the
filtrate was dissolved in ethyl acetate (80 mL) and washed with
water (80 mL). The combined organic layers were dried over
MgSO4,filtered, and concentrated under reduced pressure to
afford the crude product. The crude residue was purified by
column chromatography on silica gel by using 50 %ethyl acetate
in hexane as asolvent system to afford the desired product (10)as
ayellow solid (1357 mg, 85 %). M.p. 56–58 8C; 1HNMR (300 MHz,
MeOD): d=7.73 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 4.00 (s,
2H), 3.69 (s, 2H), 3.64 (s, 3H), 3.59 (t, J=6.7 Hz, 2H), 2.97 (t, J=
6.7 Hz, 2H), 2.41 (s, 3H), 1.45 ppm (s, 9H); 13CNMR (75 MHz,
MeOD): d=173.0, 171.2, 168.9, 158.7, 144.2, 142.1, 130.5, 127.4,
81.0, 52.9, 44.9, 44.3, 38.5, 34.6, 28.8, 21.5 ppm;IR(KBr): n
˜=3300,
2932, 1747, 1275 cm@1;HRMS (ESI): m/zcalcd for C20H30N4O7SNa
[M+Na]+:493.1733 ;found:493.1742.
Synthesis of 16[42]
EDC·HCl (2876 mg, 15 mmol) and HOBt (2027 mg, 15 mmol) were
added to astirred solution of Boc-l-Leu-OH (2313 mg, 10 mmol) in
DCM (45 mL). The reaction was stirred at RT for 20 min under ani-
trogen atmosphere. Next, N,O-dimethylhydroxylamine hydrochlo-
ride (1171 mg, 12 mmol) and TEA (4.18 mL, 30 mmol) were added
and stirring was continued at RT for 12 hunder anitrogen atmos-
phere. After completion of the reaction, as monitored by TLC, the
reaction was quenched with water (10 mL), the solvent was re-
moved, the reaction mixture was extracted into ethyl acetate
(30 mLV2), and washed with 1 nHCl (30 mL) and an aqueous solu-
tion of sodium hydrogen carbonate (30 mL). The combined organic
layers were dried over MgSO4,filtered, and concentrated under re-
duced pressure to afford the crude product. The crude residue was
purified by column chromatography on silica gel by using 50 %
ethyl acetate in hexane as asolvent system to afford the desired
product (16)asawhite solid (2632 mg, 96%). M.p. 87–908C;
1HNMR (300 MHz, CDCl3): d=5.04 (br s, 1H), 4.72 (brs, 1H), 3.78 (s,
3H), 3.20 (s, 3H), 1.78–1.65 (m, 1H), 1.52–1.32 (m, 11 H), 0.99–
0.91 ppm (m, 6H); 13CNMR (75 MHz, CDCl3): d=174.2, 155.9, 79.7,
61.8, 49.2, 42.3, 32.4, 28.6, 25.0, 23.6, 21.8 ppm;IR(KBr): n
˜=3328,
2980, 1756, 1668, 1368, 1212, 1176 cm@1;HRMS (FAB): m/zcalcd for
C13H27N2O4[M+H]+:275.1971;found:275.1977.
Synthesis of 18[42]
Astirred solution of tert-butyl (S)-{1-[methoxy(methyl)amino]-4-
methyl-1-oxopentan-2-yl}carbamate (16;1200 mg, 4.37 mmol) in
THF (15 mL) was cooled to 08Conanice bath. LAH (61 mg V3,
4.81 mmol) was added and stirring was continued for 20 min at
08Cunder anitrogen atmosphere. After completion of the reac-
tion, as monitored by TLC, water (6 mL) and 1nHCl (12 mL) were
added to quench the reaction and then it was extracted with ethyl
acetate (2V20 mL). The combined organic layers were dried over
MgSO4,filtered, and concentrated under reduced pressure. The
crude residue of tert-butyl (S)-(4-methyl-1-oxopentan-2-yl)carba-
mate (17)was afforded (flask A). Compound 17 was directly used
without further purification. Next, TsN3(1294 mg, 6.56 mmol) and
potassium carbonate (1209 mg, 8.75 mmol) were added to another
flask (flask B) containing astirred solution of dimethyl-2-oxopropyl-
phosponate (1090 mg, 6.56 mmol) in ACN (11mL). The reaction
was stirred at RT for 2hunder anitrogen atmosphere, until com-
pletion of the reaction was observed by TLC. Then the crude resi-
due (17)inflask Awas dissolved with methanol (5 mL). The com-
pleted reaction mixture in flask Bwas added to flask Abymeans
of an addition funnel at 0 8Conice bath. Next, the reaction was al-
lowed to proceed at RT for 12 hunder anitrogen atmosphere.
After completion of the reaction, as monitored by TLC, the reaction
was quenched with water (10 mL), concentrated under reduced
pressure to remove solvent, extracted with ethyl acetate (2 V
20 mL), and washed with water (20 mL). The combined organic
layers were dried over MgSO4,filtered, and concentrated under re-
duced pressure to afford the crude product. The crude residue was
purified by column chromatography on silica gel by using 10 %
Chem. Asian J. 2017,12,1326 –1337 www.chemasianj.org T2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim1333
Full Paper

ethyl acetate in hexane as asolvent system to afford the desired
product (18 as acolorless liquid) (553 mg, 60 %). 1HNMR (300 MHz,
CDCl3): d=4.62 (brs, 1H), 4.43 (br s, 1H), 2.25 (s, 1H), 1.89–1.73 (m,
1H), 1.57–1.48 (m, 2H), 1.45 (s, 9H), 0.97–0.89 ppm (m, 6H);
13CNMR (75 MHz, CDCl3): d=155.0, 84.1, 80.1, 70.9, 45.4, 41.5, 28.6,
25.2, 22.9, 22.1 ppm;IR(KBr): n
˜=3314, 2934, 2872, 2117, 1705,
1699, 1368, 1249, 1171 cm@1;HRMS (ESI-TOF): m/zcalcd for
C12H21NO2Na [M+Na]+:234.1470 ;found:234.1467.
Synthesis of 19[43]
TFA(3mL) was added to astirred solution of 18 (800 mg,
3.79 mmol) in DCM (15 mL), and the resultant mixture was stirred
at RT for 30 min under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, the solvent was removed under
reduced pressure, the solution was washed with water (20 mL),
and the product was extracted into DCM (20 mL). The combined
aqueouslayers were concentrated under reduced pressure. The de-
sired product (19)was afforded as acolorless liquid (445 mg, quan-
titative). 1HNMR (300 MHz, CDCl3): d=4.02–3.92 (m, 1H), 2.53 (d,
J=1.8 Hz, 1H), 1.95–1.82 (m, 1H), 1.82–1.69 (m, 1H), 1.67–1.54 (m,
1H), 1.02–0.85 ppm (m, 6H); 13CNMR (75 MHz, CDCl3): d=78.0,
76.4, 42.2, 42.2, 25.1, 23.0, 21.1 ppm;IR(KBr): n
˜=3312, 3257, 2964,
2127, 1672, 1530, 1378, 1203, 1142 cm@1;HRMS (ESI-TOF): m/z
calcd for C7H14N[M+H] +:112.1126;found:112.1124.
Synthesis of 20
HBTU (1900 mg, 5.01 mmol) was added to astirred solution of
Boc-l-Trp-OH (1016 mg, 3.34 mmol) in DMF (11mL). The reaction
was stirred for 20 min at RT.Then asolution of (S)-5-methylhex-1-
yn-3-amine (300 mg, 2.7 mmol) in DMF (8 mL) and TEA (0.94 mL,
2.70 mmol) was added and stirring was continued at RT for 9h
under anitrogen atmosphere. After completion of the reaction, as
monitored by TLC, water (5 mL) was added to quench the reaction
and solvent was removed. The resulting residue was dissolved in
ethyl acetate (30 mL) and washed with 1nHCl (30 mL) and brine
(30 mL x2). The combined organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure to afford the
crude product. The crude residue was purified by column chroma-
tography on silica gel by using 10 %ethyl acetate in hexane as
asolvent system to afford the desired product (20)asayellow
liquid (1073 mg, quantitative). 1HNMR (300 MHz, CDCl3): d=8.11
(brs, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28–7.10
(m, 3H), 7.07 (br s, 1H), 5.88 (brs, 1H), 4.70 (dd, J=15.0, 7.5 Hz,
1H), 4.46–4.39 (m, 1H), 3.36–3.10 (m, 2H), 2.16 (d, J=1.7 Hz, 1H),
1.75–1.60 (m, 1H), 1.43 (s, 9H), 1.41–1.32 (m 2H), 0.92–0.82 ppm
(m 6H); 13CNMR (75 MHz, CDCl3): d=170.8, 155.7, 136.5, 127.6,
123.6, 122.6, 120.1, 119.2, 111.4, 11 0.8, 83.3, 80.4, 71.1 55.3, 44.8,
39.9, 28.5, 25.1, 22.8, 22.1 ppm;IR(KBr): n
˜=3308, 2959, 2872, 1695,
1661, 1506 1368, 1248, 1168 cm@1;HRMS (ESI-TOF): m/zcalcd for
C23H31N3O3Na [M+Na]+:420.2263 ;found:420.2256.
Synthesis of 11
TFA(4mL) was added to astirred solution of 20 (1600 mg,
4.02 mmol) in DCM (20 mL) and the resultant mixture was stirred
for 60 min at RT under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, solvent was removed and the
pH was adjusted to 8–9 by 1 nNaOH. Following extraction with
ethyl acetate (20 mL), the combined organic layers were dried over
MgSO4,filtered, and concentrated under reduced pressure to
afford the crude product. The crude residue was purified by
column chromatography on silica gel by using 10 %methanol in
DCM as asolvent system to afford the desired product (11)as
ayellow liquid (1220 mg, quantitative). 1HNMR (300 MHz, MeOD):
d=7.68 (d, J=7.7 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.22–7.04 (m,
3H), 4.69 (td, J=7.8, 1.8 Hz, 1H), 3.99 (t, J=6.6 Hz, 1H), 3.38–3.16
(m, 2H), 2.68 (d, J=2.2 Hz, 1H), 1.84–1.71 (m, 1H), 1.63–1.42 (m,
2H), 0.93 ppm (d, J=6.6 Hz, 6H); 13CNMR (75 MHz, MeOD): d=
170.6, 138.4, 128.6 125.8, 122.9, 120.4, 119.4, 11 2.6, 108.3, 83.8,
72.7, 55.3, 45.5, 41.0, 29.4, 26.2, 23.0, 22.4 ppm;IR(KBr): n
˜=3404,
3395, 2876, 2109, 1705, 1685, 1528, 1207, 1139 cm@1;HRMS (EI): m/
zcalcd for C18H22N3O[M@H] +:296.1763;found :296.1769.
Synthesis of 21[44–46]
TEA (1.67 mL, 12.0 mmol) was added to astirred solution of l-
serine methyl ester hydrochloride (1560 mg, 10.0 mmol) in DCM
(13.3 mL) at 08Conanice bath. When the stirred solution became
clear,asolution of trityl chloride (3070 mg, 11.0 mmol) in DCM
(20 mL) was added dropwise by means of an addition funnel, and
the reaction was allowed to proceed for 2h under anitrogen at-
mosphere. After completion of the reaction, as monitored by TLC,
the solvent was removed partially.Following direct wet loading,
the crude residue was purified by column chromatography on
silica gel by using 3% methanol in DCM as asolvent system to
afford the desired product (S)-methyl 3-hydroxy-2-(tritylamino)pro-
panoate (21-1)asawhite solid (2890 mg, 80 %). M.p. 148–1518C;
1HNMR (300 MHz, CDCl3): d=7.52–7.43 (m 6H), 7.31–7.24 (m, 6H),
7.24–7.15 (m, 3H), 3.77–3.64 (m, 1H), 3.62–3.51 (m, 2H), 3.30 (s,
3H), 2.98 (br s, 1H), 2.27 ppm (br s, 1H); 13CNMR (75 MHz, CDCl3):
d=174.1, 145.8, 129.0, 128.1 126.8, 71.2, 65.2, 58.0, 52.2 ppm ;IR
(KBr): n
˜=3445, 3958, 2951, 1773, 1596, 1490, 1205 cm@1;HRMS
(ESI-TOF): m/zcalcd for C23H23NO3Na [M+Na]+:384.1576;found:
384.1575.
Allyl bromide (1.5 mL, 17.36 mmol) was added To astirred solution
of sodium hydride (284 mg, 11.83 mmol) in DMF (15 mL) at 0 8C
(ice bath). Then the solution of 21-1 (2850 mg, 7.89 mmol) in DMF
(10 mL) was added dropwise by means of an addition funnel. The
reaction was allowed to proceed for 1h under anitrogen atmos-
phere. After completion of the reaction, as monitored by TLC, an
aqueous solution of sodium bicarbonate (10 mL) was added to
quench the reaction. Following extraction with brine (30 mL) and
ether (2V30 mL), the combined organic layers were dried over
MgSO4,filtered, and concentrated under reduced pressure. The de-
sired product, (S)-methyl 3-(allyloxy)-2-(tritylamino)propanoate (21-
2), was afforded as acolorless liquid (2910 mg, 92 %). 1HNMR
(300 MHz, CDCl3): d=7.55–7.46 (m 6H), 7.31–7.23 (m, 6H), 7.23–
7.13 (m 3H), 5.95–5.77 (m, 1H), 5.32–5.12 (m, 2H), 4.04–3.90
(m,2H), 3.81–3.72 (m 1H), 3.61–3.43 (m, 2H), 3.22 (s, 3H), 2.77 ppm
(brs, 1H); 13CNMR (75 MHz, CDCl3): d=174.5, 146.1, 134.6, 129.0,
128.0, 126.6, 117.1, 72.9, 72.2, 71.1, 56.6, 51.9 ppm;IR(KBr): n
˜=
3321, 3058, 2949, 2924, 1737, 1646, 1596, 1491, 1328, 1205 cm@1;
HRMS (ESI-TOF): m/zcalcd for C26H28NO3[M+H]+:402.2069;
found:402.2072.
TFA(4mL) was added to astirred solution of 21-2 (2900 mg,
7.22 mmol) in DCM (20 mL) and the resultant mixture was stirred
for 30 min at RT under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, the reaction was concentrated
under reduced pressure to remove the solvent, washed with water
(10 mL), and the product was extracted into DCM (20 mL). The
combined aqueous layers were concentrated under reduced pres-
sure. The desired product (21)was afforded as acolorless liquid
(1165 mg, quantitative). 1HNMR (300 MHz, CDCl3): d=5.90–5.73 (m,
1H), 5.30–5.16 (m, 2H), 4.28–4.22 (m, 1H), 4.08–3.92 (m, 2H), 3.92–
3.85 (m, 2H), 3.83 ppm (s, 3H); 13CNMR (75 MHz, CDCl3): d=168.1,
133.3, 118.8, 72.6, 66.5, 53.8, 53.7 ppm;IR(KBr): n
˜=3398, 2923,
Chem. Asian J. 2017,12,1326 –1337 www.chemasianj.org T2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim1334
Full Paper

2855, 1755, 1679, 1532 1442, 1245, 1203, 1135 cm@1;HRMS (ESI-
TOF): m/zcalcd for C7H14NO3[M+H]+:160.0974 ;found:160.0973.
Synthesis of 22[47]
HBTU (5010 mg, 13.21 mmol) was added to astirred solution of
(tert-butoxycarbonyl)-l-alanine (1667 mg, 8.81 mmol) in DMF
(35 mL) and reacted for 20 min at RT under anitrogen atmosphere.
Then asolution of 6(941 mg, 10.57 mmol) in DMF (8 mL) and DIEA
(3.1 mL, 17.62 mmol) were added and stirring was continued for
9hat RT under anitrogen atmosphere. After completion of the re-
action, as monitored by TLC, water (5 mL) was added to quench
the reaction and it was concentrated under reduced pressure. The
resulting residue was dissolved in ethyl acetate (30 mL) and
washed with 1nHCl (30 mL) and brine (2V30 mL). The combined
organic layers were dried over MgSO4,filtered, and concentrated
under reduced pressure to affordthe crude product. The crude res-
idue was purified by column chromatography on silica gel by
using 10%ethyl acetate in hexane as asolvent system to afford
the desired product (22)asacolorless liquid (2275 mg, 99 %).
1HNMR (300 MHz, MeOD): d=4.11(br s, 1H), 3.94 (dd, J=25.7,
17.6 Hz, 2H), 3.72 (s, 3H), 1.45 (s, 9H), 1.33 ppm (d, J=7.2 Hz, 3H);
13CNMR (75 MHz, MeOD): d=176.6, 171.8, 157.8, 80.8, 52.7, 51.7,
42.0 28.8, 18.5 ppm;IR(KBr): n
˜=3323, 2981, 1755, 1696, 1369,
1250, 1168 cm@1;HRMS (ESI-TOF): m/zcalcd for C11 H25N2O5Na [M+
Na]+:283.1270 ;found:283.1263.
Synthesis of 23
HBTU (4511mg, 11.90 mmol) was added to astirred solution of
(tert-butoxycarbonyl)-l-alanine (1500 mg, 7.93 mmol) in DMF
(16 mL). The reaction was allowed to proceed for 20 min at RT
under anitrogen atmosphere. Then asolution of 6(1147 mg,
7.21 mmol) in DMF (8 mL) and DIEA (2.5 mL, 14.41 mmol) were
added and stirring was continued for 9hat RT under anitrogen at-
mosphere. After completion of the reaction, as monitored by TLC,
water (5 mL) was added to quench the reaction and the solution
was concentrated under reduced pressure. The resultant residue
was dissolved with ethyl acetate (30 mL), and washed with 1nHCl
(30 mL) and brine (2V30 mL). The combined organic layers were
dried over MgSO4,filtered, and concentrated under reduced pres-
sure to afford the crude product. The crude residue was purified
by column chromatography on silica gel by using 10%ethyl ace-
tate in hexane as asolvent system to affordthe desired product
(23)asacolorless liquid (2005 mg, 84 %). 1HNMR (300 MHz, CDCl3):
d=6.79 (brs, 1H), 5.91–5.74 (m, 1H), 5.29–5.14 (m 2H), 5.04 (brs,
1H), 4.76–4.65 (m, 1H), 4.21 (br s, 1H), 4.04–3.91 (m, 2H), 3.91–3.84
(m, 1H), 3.76 (s, 3H), 3.68–3.61 (m, 1H), 1.45 (s, 9H), 1.38 ppm (d,
J=7.1 Hz, 3H); 13CNMR (75 MHz, CDCl3): d=172.8, 170.6, 155.4,
134.1, 117.6, 80.1, 72.3, 69.6, 52.7, 52.7, 50.2, 28.4, 18.7 ppm;IR
(KBr): n
˜=3319, 2980, 1748, 1668, 1516, 1368, 1248, 1168 cm@1;
HRMS (ESI-TOF): m/zcalcd for C15H26N2O6Na [M+Na]+:353.1689 ;
found:353.1691.
Synthesis of 12[48]
A1nsolution of NaOH (10 mL) was added to astirred solution of
22 (1500 mg, 5.76 mmol) in methanol (20 mL), and the resultant
mixture was stirred for 8h at RT under anitrogen atmosphere.
After completion of the reaction, as monitored by TLC, the reaction
was concentrated under reduced pressure to remove methanol,
and then extracted with DCM (30 mL). The aqueous layers were
collected and the pH was adjusted to 2–3 by 2 nHCl. Following ex-
traction with DCM (2 V20 mL), the combined organic layers were
dried over MgSO4,filtered, and concentrated under reduced pres-
sure. The desired product (12)was afforded as acolorless liquid
(1280 mg, 90 %). 1HNMR (300 MHz, MeOD): d=4.11(brs, 1H),
3.98–3.84 (m, 2H), 1.44 (s, 9H), 1.33 ppm (d, J=7.2 Hz, 3H),
13CNMR (75 MHz, MeOD): d=176.4, 172.9, 157.8, 80.8, 51.7, 41.9,
28.8, 18.6 ppm;IR(KBr): n
˜=3324, 2981, 1667, 1257, 1369, 1251,
1176 cm@1;HRMS (ESI-TOF): m/zcalcd for C10H18N2O5Na [M+Na]+:
269.1113; found:269.1117.
Synthesis of 13
A1nsolution of NaOH (8 mL) was added to astirred solution of
23 (1900 mg, 5.75 mmol) in methanol (20 mL) and the resultant
mixture was stirred for 8h at RT under anitrogen atmosphere.
After completion of the reaction, as monitored by TLC, the reaction
was concentrated under reduced pressure to remove methanol,
and then extracted with DCM (30 mL). The aqueous layers were
collected and the pH was adjusted to 2–3 by 2 nHCl. Following ex-
traction with DCM (20 mL V2), the combined organic layers were
dried over MgSO4,filtered and concentrated under reduced pres-
sure. The desired product (13)was afforded as acolorless liquid
(1676 mg, 92 %). 1HNMR (300 MHz, CDCl3): d=7.06 (br s, 1H), 5.91–
5.74 (m, 1H), 5.29–5.14 (m, 2H), 4.78–4.65 (m, 1H), 4.27 (brs, 1H),
3.99 (d, J=5.7 Hz, 2H), 3.95–3.87 (m, 1H), 3.73–3.63 (m, 1H), 1.43
(s, 9H), 1.37 ppm (d, J=7.1 Hz, 3H); 13CNMR (75 MHz, CDCl3): d=
173.5, 172.6, 155.9, 134.0, 118.2, 80.8, 72.6, 69.3, 52.8, 50.5, 28.5,
18.6 ppm;IR(KBr): n
˜=3320, 2980, 1751, 1669, 1520, 1367, 1248,
1210 cm@1;HRMS (ESI-TOF): m/zcalcd for C14H24N2O6Na [M+Na]+:
339.1532;found :339.1533.
Synthesis of 24
HBTU (2215 mg, 5.84 mmol) was added to astirred solution of 12
(1200 mg, 4.87 mmol) in DMF (10 mL) and reacted for 20 min at RT.
Then asolution of (S)-2-amino-3-(1H-indol-3-yl)-N-[(S)-5-methylhex-
1-yn-3-yl]propenamide (11;1310 mg, 4.43 mmol) in DMF (6 mL)
and DIEA (1.5 mL, 8.86 mmol) were added and stirring was contin-
ued for 5h at RT under anitrogen atmosphere. After completion
of the reaction, as monitored by TLC, water (5 mL) was added to
quench the reaction and the reaction was concentrated under re-
duced pressure. The resulting residue was dissolved in ethyl ace-
tate (30 mL) and washed with 1 nHCl (30 mL) and brine (30 mLV
2). The combined organic layers were dried over MgSO4,filtered,
and concentrated under reduced pressure to afford the crude
product. The crude residue was purified by column chromatogra-
phy on silica gel by using 20 %ethyl acetate in hexane as asolvent
system to afford the desired product (24)asayellow solid
(1750 mg, 75%). M.p. 203–2068C; 1HNMR (300 MHz, MeOD): d=
7.59 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.12–6.97 (m, 3H),
4.69–4.59 (m, 2H), 4.02 (dd, J=14.4, 7.1 Hz, 1H), 3.89–3.73 (m, 2H),
3.31–3.30 (m, 2H), 2.57 (d, J=2.2 Hz, 1H), 1.80–1.63 (m, 1H), 1.54–
1.42 (m, 1H), 1.42 (s, 9H), 1.27 (d, J=7.1 Hz, 3H), 0.93–0.85 ppm
(m, 6H); 13CNMR (75 MHz, MeOD): d=176.7, 172.9, 171.4, 158.0,
138.2, 129.0, 124.8, 122.5, 120.0, 119.5, 112.4, 110.8, 84.1, 81.0, 72.1,
55.5, 52.1, 45.4, 43.9, 40.8, 28.9, 26.1 23.0, 22.5, 18.2 ppm;IR(KBr):
n
˜=3286, 2957 2108, 1655, 1509, 1247, 1164 cm@1;HRMS (ESI-TOF):
m/zcalcd for C28H39N5O5Na [M+Na]+:548.2849;found:548.2854.
Synthesis of 25
HBTU (2410 mg, 6.07 mmol) was added to astirred solution of 13
(1600 mg, 5.06 mmol) in DMF (10 mL) and reacted for 20 min at RT
under anitrogen atmosphere. Then asolution of 11 (1360 mg,
4.60 mmol) in DMF (6 mL) and DIEA (1.6 mL, 9.21 mmol) were
Chem. Asian J. 2017,12,1326 –1337 www.chemasianj.org T2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim1335
Full Paper

added and allowed to stir for afurther 4h at RT under anitrogen
atmosphere. After completion of the reaction, as monitored by
TLC, water (5 mL) was added to quench the reaction and the reac-
tion was concentrated under reduced pressure. The resulting resi-
due was dissolved in ethyl acetate (30 mL) and washed with 1n
HCl (30 mL) and brine (30 mLV2). The combined organic layers
were dried over MgSO4,filtered, and concentrated under reduced
pressure to afford the crude product. The crude residue was puri-
fied by column chromatography on silica gel by using 20 %ethyl
acetate in hexane as asolvent system to afford the desired product
(25)asayellow liquid (2055 mg, 75 %). 1HNMR (300 MHz, MeOD):
d=7.58 (d, J=7.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.15–6.90 (m,
3H), 5.92–5.74 (m, 1H), 5.29–5.10 (m, 2H), 4.72–4.60 (m, 2H), 4.58–
4.48 (m, 1H), 4.46–4.34 (m, 1H), 3.99–3.93 (m, 2H), 3.76–3.57 (m,
2H), 3.29–3.16 (m, 2H), 2.59 (d, J=2.3 Hz, 1H), 1.75–1.63 (m, 1H),
1.51–1.43 (m 2H), 1.38 (s, 9H), 1.19 (d, J=7.2 Hz, 3H), 0.89 ppm
(dd, J=6.6, 1.9 Hz, 6H); 13CNMR (75 MHz, MeOD): d=176.4, 172.6,
172.0, 138.2, 135.7, 129.0, 125.0, 124.7, 122.6, 120.0, 119.6, 11 8.0,
112.4, 11 0.7, 84.1, 81.1, 73.4, 72.2, 70.1, 55.4, 52.1, 45.5, 40.8, 30.8,
28.8, 28.7, 26.1, 22.9, 22.5, 17.9 ppm;IR(KBr): n
˜=3286, 2957, 2108,
1655, 1509, 1247, 1164 cm@1;HRMS (ESI-TOF): m/zcalcd for
C33H45N5O6Na [M+Na]+:618.3268 ;found:618.3275.
Synthesis of 14
TFA(5mL) was added to astirred solution of 24 (1587 mg,
3.02 mmol) in DCM (15 mL) and the resultant mixture was stirred
at RT for 60 min under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, the reaction was concentrated
under reduced pressure, then the pH was adjusted to 8–9 by 1 n
NaOH, and the solution was concentrated under reduced pressure
to afford the crude product. The crude residue was purified by
column chromatography on silica gel by using 10 %methanol in
DCM as asolvent system to affordthe desired product (14)as
ayellow solid (1295 mg, quantitative). M.p. 131–133 8C; 1HNMR
(300 MHz, MeOD): d=7.61 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.1 Hz,
1H), 7.14–6.97 (m, 3H), 4.71–4.59 (m, 2H), 3.92–3.76 (m, 2H), 3.52
(dd, J=13.7, 6.9 Hz, 1H), 3.30–3.10 (m, 2H), 2.60 (d, J=2.3 Hz, 1H),
1.80–1.62 (m, 1H), 1.57–1.40 (m, 1H), 1.27 (d, J=7.0 Hz, 3H), 0.94–
0.85 ppm (m, 6H); 13CNMR (75 MHz, MeOD): d=178.6, 172.8,
171.3, 138.1, 129.0, 125.0, 122.6, 120.1, 119.5, 112.4, 110.5, 84.2,
72.2, 55.5, 51.4, 45.4, 43.7, 40.8, 29.0, 26.1, 23.0, 22.5, 20.9 ppm;IR
(KBr): n
˜=3402, 2962, 2117, 1680, 1532 1440, 1206 cm@1;HRMS (ESI-
TOF): m/zcalcd for C23H32N5O3[M+H]+:426.2505;found:
426.2515.
Synthesis of 15
TFA(4mL) was added to astirred solution of 25 (1200 mg,
2.01 mmol) in DCM (10 mL) and the resultant mixture was stirred
at RT for 60 min under anitrogen atmosphere. After completion of
the reaction, as monitored by TLC, the reaction was concentrated
under reduced pressure, the pH was adjusted to 8–9 by 1 nNaOH,
and the solution was concentrated under reduced pressure to
afford the crude product. The crude residue was purified by
column chromatography on silica gel by using 10 %methanol in
DCM as asolvent system to affordthe desired product (15)as
awhite solid (1007 mg, quantitative). M.p. 214–217 8C; 1HNMR
(300 MHz, MeOD): d=7.60 (d, J=7.7 Hz, 1H), 7.32 (d, J=8.1 Hz,
1H), 7.13–6.98 (m, 3H), 5.83–5.65 (m, 1H), 5.30–5.14 (m, 2H), 4.69–
4.60 (m, 2H), 4.43 (t, J=5.2 Hz, 1H), 4.05–3.91 (m, 2H), 3.72–3.64
(m, 1H), 3.64–3.56 (m, 1H), 3.34 (q, J=6.9 Hz, 1H), 3.30–3.15 (m,
2H), 2.61 (d, J=2.3 Hz, 1H), 1.78–1.58 (m, 1H), 1.55–1.35 (m, 2H),
1.11(d, J=6.9 Hz, 3H), 0.88 ppm (d, J=6.5 Hz, 6H); 13CNMR
(75 MHz, MeOD): d=178.7, 172.5, 171.8, 138.1, 135.7, 129.0, 125.1,
122.6, 120.1, 119.6, 11 8.0, 112.5, 110.2, 84.1, 73.4, 72.3, 70.3, 55.4,
55.2, 51.3, 45.4, 40.8, 28.7, 26.1, 23.0, 22.5, 21.1 ppm;IR(KBr): n
˜=
3286, 3056, 2961, 2917, 1509, 1247, 1164 cm@1;HRMS (ESI-TOF): m/
zcalcd for C27H38N5O4[M+H]+:496.2924;found:496.2919.
Synthesis of CTP 1
Potassium carbonate (32 mg, 0.24 mmol), Ts N 3(35 mg, 0.18 mmol),
and copper iodide (23 mg, 0.12 mmol) were added to astirred so-
lution of 14 (50 mg, 0.12 mmol) in acosolvent system (DMF
(12 mL) and DCM (12 mL)) under anitrogen atmosphere, and the
resultant mixture was stirred at RT for 1.5 h. After completion of
the reaction, as monitored by TLC, the reaction mixture was treat-
ed with CupriSorb resin (80 mg) for 30 min to remove traces of
copper,filtered through apad of Celite, washed with excess DCM
(10 mL), and the combined filtrate was concentrated under re-
duced pressure. Then the filtrate was dissolved in ethyl acetate
(20 mL) and washed with water (20 mL). The combined organic
layers were dried over MgSO4,filtered, and concentrated under re-
duced pressure to afford the crude product. The crude residue was
purified by column chromatography on silica gel by using 5%
methanol in DCM as asolvent system to afford the desired product
CTP 1as ayellow liquid (22 mg, 32 %). 1HNMR (500 MHz, MeOD):
d=7.71 (d, J=8.2 Hz, 2H), 7.60 (d, J=7.9 Hz, 1H), 7.35–7.29 (m,
3H), 7.12–6.98(m, 3H), 4.76–4.68 (m, 2H), 4.36(d, J=14.2 Hz, 1H),
4.12–4.04 (m, 1H), 3.38–3.32 (m, 1H), 3.28 (d, J=14.2 Hz, 1H),
3.19–3.12 (m, 1H), 3.09–3.03 (m 1H), 2.56(t, J=12.9 Hz, 1H), 2.40 (s,
3H), 1.45–1.38 (m, 1H), 1.30 (d, J=6.9 Hz, 3H), 1.03–0.96 (m, 1H),
0.94–0.85 (m, 1H), 0.71–0.65 ppm (m, 6H); 13CNMR (125 MHz,
MeOD): d=174.5, 173.7, 172.0, 167.1, 144.2, 142.0, 138.2, 130.7,
128.7, 127.2, 124.4, 122.6, 120.0, 119.5, 112.4, 110.6, 56.8, 51.9, 49.7,
45.6, 45.3, 40.0, 28.6, 25.7, 23.1 22.7, 21.6, 16.3 ppm;IR(KBr): n
˜=
3333, 3083, 2980, 2936, 1747, 1683, 1680, 1540, 1436 cm@1;HRMS
(ESI-TOF): m/zcalcd for C30H38N6O5SNa [M+Na]+:617.2522;found:
617.2524.
Synthesis of CTP 2
Potassium carbonate (50 mg, 0.36 mmol), Ts N 3(53 mg, 0.27 mmol),
and copper iodide (34 mg, 0.18 mmol) were added to astirred so-
lution of 15 (89 mg, 0.18 mmol) in acosolvent system (DMF
(18 mL) and DCM (18 mL)) under anitrogen atmosphere, and the
resultant mixture was stirred at RT for 1.5 h. After completion of
the reaction, as monitored by TLC, the reaction mixture was treat-
ed with CupriSorb resin (100 mg) for 30 min to remove traces of
copper,filtered through apad of Celite, washed with excess DCM
(10 mL), and the combined filtrate was concentrated under re-
duced pressure. Then the filtrate was dissolved in ethyl acetate
(30 mL) and washed with water (30 mL). The combined organic
layers were dried over MgSO4,filtered, and concentrated under re-
duced pressure to afford the crude product. The crude residue was
purified by column chromatography on silica gel by using 5%
methanol in DCM as asolvent system to afford the desired product
CTP 2as ayellow liquid (41 mg, 35 %). 1HNMR (500 MHz, MeOD):
d=7.72 (d, J=8.2 Hz, 2H), 7.59 (d, J=7.8 Hz, 1H), 7.36–7.29 (m,
3H), 7.11–6.97 (m, 3H), 5.97–5.85 (m, 1H), 5.32–5.13 (m, 2H), 4.75–
4.66 (m, 3H), 4.05–3.94 (m, 3H), 3.83–3.78 (m, 1H), 3.64–3.58 (m,
1H), 3.36–3.32 (m, 1H), 3.22–3.15 (m, 1H), 3.07–3.01 (m, 1H), 2.61
(t, J=12.9 Hz, 1H), 2.40 (s, 3H), 1.43–1.35 (m, 1H), 1.28 (d, J=
6.7 Hz, 3H), 1.03–0.85 (m, 2H), 0.69–0.62 ppm (m, 6H); 13CNMR
(125 MHz, MeOD): d=174.3, 173.8, 171.7, 167.1, 144.2, 142.0, 138.2,
136.0, 130.7, 128.7, 127.2, 124.5, 122.6, 120.0, 119.5, 117.8, 112.4,
110.7, 73.5, 68.1, 56.5, 53.5, 51.8, 49.9, 45.3, 39.9, 28.5, 25.7, 23.1,
Chem. Asian J. 2017,12,1326 –1337 www.chemasianj.org T2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim1336
Full Paper

22.6, 21.6, 16.3 ppm;IR(KBr): n
˜=3296, 3061, 2955, 2929, 1652,
1548, 1457 cm@1;HRMS (ESI-TOF): m/zcalcd for C34H44N6O6SNa
[M+Na]+:687.2941;found :687.2939.
Acknowledgements
This work is supported by grants from the MinistryofScience
and Technology (MOST104-2738-M-110-001, MOST104-2113-M-
110-001, and MOST104-2627-M-007-003)and National Sun Yat-
sen University (04B39131 and 04B39132).
Keywords: copper ·inhibitors ·macrocycles ·peptides ·
synthesis design
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Manuscript received:March 6, 2017
Revised manuscript received:March 23, 2017
Accepted manuscript online:April 25, 2017
Version of record online :May 23, 2017
Chem. Asian J. 2017,12,1326 –1337 www.chemasianj.org T2017 Wiley-VCH Ve rlag GmbH &Co. KGaA, Weinheim1337
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