Straightforward Functionalization of Sulfur-Containing Peptides via 5- And 6- endo - Dig Cyclization Reactions

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2021, 53, 1805–1820

paper

1805

en

S. Lapcinska, P. Arsenyan

Paper

Synthesis

Straightforward Functionalization of Sulfur-Containing Peptides

via 5- and 6-endo-dig Cyclization Reactions

Sindija Lapcinska

Pavel Arsenyan*

Latvian Institute of Organic Synthesis, Aizkraukles 21,

LV-1006, Riga, Latvia

pavel@osi.lv

R'

O

Ph

S

O

N⁺

R"

R''''

S

OH

S

R

S

R'''

Ph

N

PLeaMtvvaeiClalAonprraIrsnveeessntlp@yitoauonntsdeii.lnovgf OArugtahnoirc Synthesis, Aizkraukles 21, LV-1006, Riga, Latvia

X

R = H or

S

X = O, N

>30 examples

Yields up to 91%

Fluorescent dye for visualization of lipid droplets

O

Received: 23.11.2020

Accepted after revision: 28.12.2020

Published online: 28.12.2020

protocol requires high tolerance of different functional

groups, compatibility with various solvents, including wa-

ter, and the reaction should provide products in short reac-

tion times and in high yields.

DOI: 10.1055/a-1343-5607; Art ID: ss-2020-z0601-op

Abstract We present a simple and convenient method for the gener-

ation of sulfenyl electrophiles from peptides containing S–S or S–H

bonds by employing N-chlorosuccinimide. The corresponding sulfenyl

electrophiles are further utilized in 5- and 6-endo-dig cyclization reac-

tions yielding indolizinium salts, indoles, benzo[b]furans, polyaromatic

hydrocarbons (PAHs) and isocoumarins, as well as quinolinones bearing

a glutathione moiety. PAH derivatives can be used as selective fluores-

cent dyes for the visualization of lipid droplets in living cells.

A list of methods exist for the modification of cysteine

motifs in proteins.^13,14The sulfhydryl group in cysteine can

be easily alkylated,¹⁴arylated^15,16and used in Michael addi-

tion reactions.¹³Methods for cysteine stapling with differ-

ent aryl linkers have been demonstrated^17–21as well as thiol-

ene/yne reactions that are usually radical-mediated.^22–24

Another widespread modification of sulfhydryl groups is

oxidation reactions forming a disulfide bond.^13,14Respec-

tively, two thiol groups within a peptide can form an intra-

molecular disulfide bridge.¹³However, the above-men-

tioned methods mostly rely on the high nucleophilicity of

the sulfhydryl group, although a sulfur atom can be con-

verted into an electrophilic species as well. Very often

sulfenyl halides serve as electrophilic sulfenyl species that

can be easily prepared from thiols or disulfides using halo-

gens,^25,26SOCl₂,²⁷SO₂Cl₂²⁸or N-halosuccinimides.^29–31Metal

salts can also be used to generate sulfenyl electrophiles:

FeCl₃has been used to induce electrophile formation from

thiols³²or disulfides;^33,34another iron salt, FeF₃,³⁵has been

employed in the presence of a catalytic amount of iodine;

Key words benzofurans, cysteine, 5-endo-dig, 6-endo-dig, indoles, lip-

id droplets, peptides, polyaromatic hydrocarbons

Short peptides^1–3are a unique class of molecules that

have promising properties for drug discovery; furthermore,

a significant number of marketed drugs are already pep-

tide-based compounds.^4–6As intrinsic signaling molecules

for many physiological functions, peptides present an op-

portunity for therapeutic intervention that closely mimics

natural pathways.^7,8Peptides containing sulfur atoms ex-

hibit unique properties,⁹whilst the existence of a disulfide

bond in peptides can improve their pharmacological prop-

erties, stability, activity and selectivity.^9,10With the aim of

overcoming some problems associated with peptides, e.g.,

low solubility, oral bioavailability and membrane permea-

bility,¹⁰peptide and small molecule conjugates have been

designed.^6,11,12Conjugation is an attractive mechanism for

enhancing the properties of peptides.⁸Notably, 30% of pep-

tides that have entered clinical development in the last de-

cade are conjugates, and the search for novel peptide-based

pharmaceuticals continues.⁸Essentially, the conjugation

36

37

CuBr₂and AlCl₃can be used as well. Furthermore, phe-

nyl iododiacetate induces the formation of electrophilic sul-

fur species in the presence of KI.³⁸Pre-made N-thioalkyl or

aryl phthalimides³⁹or N-thiosuccinimides⁴⁰can also serve

as effective electrophiles. Recently we have reported meth-

ods^41,42for the generation of selenium electrophiles from

selenocystine-containing peptides by employing a mild

Lewis acid and an inorganic oxidant. Herein, we report a

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1806

S. Lapcinska, P. Arsenyan

Paper

Synthesis

method for the generation of sulfenyl electrophiles from

analogous sulfur-containing peptides.

succinimide (NIS) led to the formation of the corresponding

halo-indolizinium salts 3a and 3b in high yields (88 and

90%, respectively) in a short reaction time (1 h). In contrast,

the utilization of N-chlorosuccinimide (NCS) resulted in the

desired Cys-containing indolizinium salt 4a (65% yield) as a

mixture of diastereomers (1:1) (Scheme 1). The results

clearly showed that the electrophilic center in cysteinyl

chloride is the sulfur atom, unlike in cysteinyl bromide and

iodide where the electrophilic centers are halogen atoms

due to the smaller difference in the relative electronegativi-

ties (RENs) (S = 2.58, Cl = 3.16, Br = 2.96, I = 2.66). Accord-

ingly, the triple bond coordinates with the electrophilic sul-

fur atom forming a thiirenium cation, which upon nitrogen

atom attack forms a 5-membered ring.

Control reactions of alkyne 2a with N-halosuccinimides

revealed that NCS does not react with alkyne 2a, whereas

NBS and NIS provided the respective halo-indolizinium

salts in 3 days, together with unidentified side products

confirming that a sulfenyl halide indeed is formed and rap-

idly reacts with propargyl pyridines providing indolizinium

salts via 5-endo-dig cyclization. Notably, cyanuric chloride

was less convenient than NCS. A reaction with 0.33 equiva-

Due to the presence of a heterocyclic moiety in a vast

array of biologically active compounds, an important part

of research in heterocyclic chemistry is devoted towards

developing novel strategies for ring formation.⁴³Many natu-

rally occurring alkaloids such as swainsonine, monomorine,

gephyrotoxin and lamellarins contain indolizine as the core

structure.⁴⁴Indolizine-ring-containing molecules have

drawn attention because of their pharmacological proper-

ties, e.g., antibacterial, anti-inflammatory, antiviral, anti-

tumor and antioxidant.⁴⁵

Due to the necessity of mild reaction conditions while

working with peptides, we decided to prepare electrophilic

sulfenyl species in situ using N-halosuccinimides. N-Cbz-

cysteine ethyl ester 1 was chosen as a model compound. A

slight excess (1.2 equiv) of the N-halosuccinimide was add-

ed to a solution of 1 (1 equiv) in dichloromethane at 0 °C.

After stirring the reaction mixture for 1 hour, 4-phenyl-2-

(pyridin-2-yl)but-3-yn-2-ol (2a) (0.5 equiv) was added. Ex-

amination of the reaction mixture led us to conclude that

the employment of N-bromosuccinimide (NBS) and N-iodo-

H₃C

OH

O

CH₃

OH

X

N

X

X = Br, I

NHR¹

N

R²

O

N

NHR¹

Cl

Ph

CH₂Cl₂, 0 °C

R²

X

HS

1,7,8

3a X = Br, 88%

3b X = I, 90%

S

X

Ph

R³

O

R³

OH

NHR¹

N

R²

X = Cl

OH

S

NHR¹

R²

2

S

N

O

R²

N

S

5,6a,6b

R⁴

NHR¹

2

Cl

O

4

R⁴

NHCbz

OEt

OH

NHCbz

OEt

NHCbz

OEt

Ph

OH

S

OH

H₃C

Ph

S

OEt

H₃C

S

N

S

O

N

O

N

Ph

C₅H₁₁

Ph

4d, 69%

Ph

Cl

4e, 73%

Cl

4c, 30%

4b, 54%

Cl

4a, 65%

Cl

OH

CH₃

OH

Ph

OH

CH₃

N

CH₃

OAc

CH₃

OAc

Ph

S

Ph

OAc

OBn

S

F₃CCOO

H₃N

S

O

H

AA

H

BocHN

N

OBn

N

OBn

N

OBn

N

OBn

BocHN

H

O

BocHN

O

9d, 67%

9b, 52%

9c, 75%

9e-g, 0%

AA: Boc-His

Boc-Trp

Boc-Arg

9a, 78%

14% (from 7)

CO₂tBu

CO₂H

NHCbz

O

NHBoc

OtBu

O

NHCbz

H

N

Starting materials:

H

BnO

NHBoc

BnO

N

H

O

N

NHBoc

H

O

NHCbz

EtO

O

S

R

S

R

S

6b

7 R=H

5 R=

8 R=H

HS

S

H

OtBu

O

6a R=

O

1

BocHN

N

H

N

OBn

N

H

O

N

H

OBn

BocHN

OBn

CbzHN

O

NHBoc

O

Scheme 1 Synthesis of indolizinium-type salts. Reagents and conditions: Cbz-Cys-OEt or S–S peptide (1 equiv), NCS (1.2 equiv), alkyne 2 (0.5 equiv for

Cbz-Cys-OEt, 1 equiv for S–S peptides), CH₂Cl₂, 0 °C to rt. 2a, R³= Me, R⁴= Ph; 2b, R³,R⁴= Ph; 2c, R³= Me, R⁴= C₅H₁₁; 2d, R³= Me, R⁴= Ph; 2e, R³,R⁴= Ph.

1807

S. Lapcinska, P. Arsenyan

Paper

Synthesis

lents of cyanuric chloride with 1 in the presence of 2a did

not lead to full conversion of the starting material in 16

hours, whereas the employment of 1 equivalent of cyanuric

chloride led to a non-selective reaction with many side

products. Since the initially chosen reaction conditions

proved to be suitable for 5-endo-dig cyclization, we moved

on to examine the substrate scope of the cyclization reac-

tion. The introduction of a phenyl group at position R³re-

sulted in a slightly lower yield (4b, 54%), whereas changing

R²from an aryl to an alkyl group resulted in a significantly

lower yield (4c, 30%).

Notably, not only were propargyl pyridines 2a–c suit-

able substrates, propargyl thiazole 2d and N-methylimidaz-

ole 2e also effectively trapped the in situ prepared cysteinyl

chloride and provided indolizinium-type systems 4d,e in

higher yields (69–73%). However, in the case of imidazole

derivative 2e, the reaction was slower: 24 hours were re-

quired for full conversion of the starting materials (the re-

action time for propargyl pyridines and thiazole was 3 h).

Next, we moved on to the preparation of cysteine-con-

taining peptides 7 and 8 by employing conventional meth-

odology⁴⁶used in peptide chemistry. Unfortunately, previ-

ously used conditions were not appropriate for the synthe-

sis of 9a. Even after 48 hours, starting materials (7 and 2a)

were observed in the reaction mixture with only traces of

the desired product. Changing the solvent to acetonitrile re-

sulted in isolation of the desired product in only 14% yield,

which encouraged us to seek another route to prepare the

sulfenyl chloride. Lei et al. recently demonstrated that NCS

can be used in reactions with disulfides in the presence of

TEMPO, thus obtaining a sulfenyl chloride and N-sulfenyl

succinimide in situ.⁴⁷

Encouraged by these results, we tested the reaction be-

tween peptide dimer 5, alkyne 2a and NCS in dichloro-

methane, both with and without TEMPO. Luckily, the reac-

tion without TEMPO resulted in the isolation of product 9a

in 76% yield, whereas the addition of TEMPO did not im-

prove the yield, thereby indicating that the reaction did not

proceed through a radical pathway. Electrophilic sulfenyl

chloride is formed that reacts with the alkyne. The employ-

ment of dipeptide 5 and glutathione 6a provided the corre-

sponding indolizinium salts 9a–c in moderate to good

yields. Next, we were interested in determining the toler-

ance of different amino acids under the chosen reaction

conditions. Unfortunately, the desired product was ob-

tained only with protected lysine-containing tripeptide di-

mer 6b, whereas histidine (His)-, tryptophan (Trp)- and ar-

ginine (Arg)-containing peptides were not suitable for this

reaction.

The indole ring is one of the most important heterocy-

cles and is widely found in biologically active natural prod-

ucts.⁴⁸One of the proteinogenic -amino acids contains an

indole ring, i.e., tryptophan, which is also the biogenetic

precursor for all indole alkaloids.⁴⁹Notably, a significant

O

R²-HN

S

O

R²-HN

O

R²-HN

R¹

Ph

R¹

S

Ph

R = Ph

X

H

R

Ph

R'

Cl

X

Cl

X-R'

1, 7 or 8

NCS

R'

CO₂Et

11

CO₂Et

CbzHN

X

CH₂Cl₂

CO₂Et

Bu

S

NHCbz

Bu

R'

10

S

R = Bu

Bu

Cl

12a R' = Ns, 44%

12b R' = 2-NO₂-Ns, 42%

NH

NH-R'

O

OH

R'

O

OtBu

O

S

O

S

NH₂

EtO₂C

O

S

NHBoc

H

N

NHCbz

Ph

NHCbz

H

N

BnO

NHBoc

BnO

NHBoc

BnO

N

H

N

H

N

H

N

H

O

S

O

S

·TFA

Ph

N

O

N

O

N

O

R'

11i R' = Ts, 53%

11j R' = Ns, 27%

11k R' = Boc, 25%

11a R' = Ts, 85%

11b R' = Boc 68%

11c R' = Ns, 77%

11h, 44% (from 10j)

80% (from 10k)

11l, 66% (from 10k)

11m R' = Ts, 60%

11n R' = Ns, 20%

11o, 33% (from 10k)

11d R' = 2-NO₂-Ns, 80%

11e R' = Me, 0%

11f R' = Bn, 0%

11g R' = H, 0%

Scheme 2 Synthesis of Cys-indoles and benzo[b]furans. Reagents and conditions: Cbz-Cys-OEt or S–H peptide (1 equiv), NCS (1.2 equiv), alkyne 2

(0.5 equiv for Cbz-Cys-OEt, 1 equiv for S–H peptides), CH₂Cl₂, 0 °C to rt. 10a, X = NTs, R′ = H, R = Ph; 10b, X = NBoc, R′ = H, R = Ph; 10c, X = NNs, R′ = H,

R = Ph; 10d, X = NNs, R′ = H, R = Bu; 10e, X = N-(2,4-dinitrophenylsulfonyl), R′ = H, R = Ph; 10f, X = N-(2,4-dinitrophenylsulfonyl), R′ = H, R = Bu; 10g,

X = NMe, R′ = Me, R = Ph; 10h, X = NBn, R′ = Bn, R = Ph; 10i, X = NBn, R′ = H, R = Ph; 10j, X = O, R′ = H, R = Ph; 10k, X = O, R′ = Me, R = Ph.

1808

S. Lapcinska, P. Arsenyan

Paper

Synthesis

number of marketed drugs contain an indole scaffold, e.g.,

indomethacin (an anti-inflammatory drug), vinblastine and

vincristine (anticancer agents) and delavirdine (an anti-HIV

drug).^50,51Furthermore, indole and benzo[b]furan are con-

sidered as ‘privileged structures’.⁵²Benzofuran derivatives

are present in both natural product structures and synthet-

ic drugs.⁵³

We decided to use the same method for the generation

of sulfenyl electrophiles and to perform the 5-endo-dig cy-

clization with 2-(phenylethynyl)anilines, phenol and

anisole that could result in the formation of 3-Cys-contain-

ing indoles and benzo[b]furans. The reaction of 1 with pro-

tected 2-(phenylethynyl)anilines in the presence of NCS

provided 3-Cys indoles 11a–d in high yields (Scheme 2).

Neither dimethyl and dibenzyl amino, nor unprotected

(phenylethynyl)aniline were suitable substrates. Obviously,

the properties of the methyl and benzyl substituents as

leaving groups are too weak to facilitate ring closure under

the given conditions. Tosyl, nosyl, 2,4-dinitrophenylsulfonyl

and Boc protecting groups were well tolerated under the

current reaction conditions.

Polycyclic aromatic hydrocarbons (PAHs) are com-

pounds employed not only as starting materials in organic

synthesis, but also as fluorescent markers in bio-imaging,

for example, naphthalene,⁵⁴pyrene,⁵⁵carbazole⁵⁶and

rhodamine⁵⁷derivatives have been commonly used for this

purpose. We therefore turned our attention to exploring

whether it was possible to generate sulfenyl electrophiles

using the same methodology and to perform 6-endo-dig

cyclizations with 2-(phenylethynyl)biaryls.^58,59

Gratifyingly, the reaction between 5 and alkyne 13a in

the presence of NCS provided 6-endo-dig cyclization prod-

uct 14a in 72% yield (Scheme 3). We preferred to use sub-

strates containing S–S (not S–H) bonds due to the improved

yields and diminished formation of side products. The triple

bond coordinates with the electrophilic sulfur atom form-

ing a thiirenium ring, which is attacked by the closest aro-

matic ring to produce a 6-membered cycle. Aromaticity is

restored after deprotonation with a chloride anion, provid-

ing the final product. Furthermore, benzo[c]phenanthrene

system 14b was easily constructed in almost quantitative

yield by applying our methodology. The use of glutathione 7

resulted in the isolation of glutathione-containing polyaro-

matic systems 14c,d in good yields as well. Benzo[g]chry-

sene and benzo[pqr]picene systems with a glutathione

moiety, 14e and 14f, were successfully synthesized, howev-

er, the isolated yields were moderate due to difficulties in

the purification process.

Unfortunately, 2-hexynylanilines, under the same reac-

tion conditions, provided only triple bond addition prod-

ucts 12a,b due to formation of an aryl-group-stabilized vi-

nyl cation that prevents 5-endo-dig cyclization. Similarly, 3-

Cys-benzo[b]furan 11h was easily prepared using 2-

(phenylethynyl)phenol 10j. Notably, the reaction yield was

significantly

improved

by

employing

2-(phenyl-

The development of selective fluorescent dyes for imag-

ing of living cells is a very popular research direction due to

the beneficial visualization of organelles and in vitro process-

es in different cells. Polyaromatic hydrocarbons are known

for their fluorescent properties; however, bioavailability was

ethynyl)anisole 10k. Next, peptides 7 and 8 were used as

substrates; however, the reaction yields were inconsistent.

Products 11i–o were obtained in 20–66% yield.

O

RHN

OBn

RHN

S

OBn

N

H

N

H

BnO

NHR

Ph

N

H

O

S

Ph

O

Ph

S

5 or 6a

NCS

Ph

H

Cl

CH₂Cl₂

Ar

13

14

O

OH

O

OH

O

OH

O

OH

RO

O

BnO

O

BnO

O

BnO

O

BnO

O

BnO

O

S

NH₂

O

S

NH₂

·TFA

O

S

O

S

O

S

NH₂

O

NH₂

H

N

H

N

H

N

NH₂

·TFA

Ph

NHBoc

N

H

N

H

N

H

N

H

N

H

N

H

·AcOH

·TFA

O

·TFA

O

S

Ph

14c, 65%

14a, 72%

14d, 81%

14b, 91%

14e, 40%

H₂, Pd/C

MeOH

14f R = Bn, 35%

15 R = H, 60%

Scheme 3 Synthesis of S-peptide-containing PAHs. Reagents and conditions: S–S peptide (1 equiv), NCS (2.2 equiv), alkyne (1 equiv), CH₂Cl₂, 0 °C to rt.

1809

S. Lapcinska, P. Arsenyan

Paper

Synthesis

always under question because of low solubility. Luckily,

the functionalization of PAHs with peptide moieties in-

creases their solubility in physiological media, thereby al-

lowing the utilization of such derivatives as fluorescent

dyes. Derivative 15 was characterized by UV/Vis and fluo-

rescence spectroscopy; the excitation and emission spectra

in 20 mM HEPES buffer solution (pH 7.4) are presented in

Figure 1. The absorption and emission maxima were deter-

mined at 322 nm and 489 nm (CIE coordinates: X:

0.050031497, Y: 0.274001803, turquoise, sky blue), respec-

tively (PLQY: 3.8%). To evaluate cell permeability and the

fluorescent properties, peptide derivative 15 was incubated

for 17 hours with rat embryo myoblast cell line H9C2 (2-1)

and internalization was visualized using fluorescence mi-

croscopy (Figure 2). According to the obtained data, deriva-

tive 15 crosses the cell membrane and accumulates in or-

ganelles (Figure 2A); notably, extracellular media does not

have an emission, confirming full accumulation into the

cell.

Figure 2 A: Visualization of LDs with 15. B: Visualization of LDs with

Nile Red. C: Overlap of Figures 2A and 2B.

dig cyclization of methyl 2-(phenylethynyl)benzoate (16) in

the presence of electrophilic species.⁷¹For the synthesis of

4-sulfenyl isocoumarins, sulfenyl chloride, which can be

prepared in situ from a disulfide and PhICl₂, was used as the

source of electrophilic sulfur.⁷²A recent report on the syn-

thesis of 4-(methylthio)isocoumarins demonstrated that

methyl sulfenyl chloride can be formed in situ by employ-

ing DMSO and SOCl₂.⁷³Such cyclization has also been per-

formed using diorganyl disulfide and FeCl₃.³⁴For the intro-

duction of -SCF₃or -SCF₂-moieties, bismuth(III) chloride can

be employed alone⁷⁴or in combination with BF₃·Et₂O.⁷⁵

An evaluation of the NCS method was applied for syn-

thesis of isocoumarins with a glutathione moiety. Luckily,

the desired products 17a,b were obtained in moderate

yields by employing peptides with S–H bonds (7 and 8)

(Scheme 4), whereas peptides with S–S bonds (5 and 6)

were not able to provide the products.

Figure 1 Absorption (black line) and emission (blue line) spectra of 15

in 20 mM HEPES buffer solution (pH 7.4)

With the purpose of specifying the nature of the organ-

elle, the same cells were treated with Nile Red, which is a

well-known and selective fluorescent dye for the determi-

nation of lipid droplets (Figure 2, B). Lipid droplets (LDs) are

cytoplasmic lipid-enriched organelles and are of extremely

high interest due to the correlation of the amount of LDs in

cells with cardio diseases and cancer.^60–65The overlap of

both Figures 2A and 2B (Figure 2C) allowed us to unambigu-

ously conclude that derivative 15 selectively accumulated in

cell lipid droplets and emitted in the blue region. In other

words, this type of PAH-substituted glutathione 15 can

serve as a blue fluorescent dye in in vitro cell media, howev-

er, further improvement of the dye structure in terms of in-

creasing the quantum yield will be necessary.

CO₂tBu

H₂N

·TFA

O

BnO

NH

S

BnO

NH₂

S

N

Ph

N

·TFA

Ph

H

O

Ph

CO₂Me

O

16

O

NCS,

CH₂Cl₂;

then TFA

RHN

OBn

7 or 8

17b, 40%

N

17a, 53%

H

O

R

S

Ph

O

The isocoumarin scaffold is present in many biologically

active natural products.^66,67Notably, compounds containing

an isocoumarin moiety exhibit antimicrobial,⁶⁸antifun-

gal,⁶⁹cytotoxic⁷⁰and anti-inflammatory⁷⁰activities. An at-

tractive way to construct an isocoumarin ring is via 6-endo-

Cl

O

Scheme 4 Synthesis of S-peptide-containing isocoumarins. Reagents

and conditions: peptide (1 equiv), NCS (1.2 equiv), alkyne (1 equiv),

CH₂Cl₂, 0 °C to rt.

1810

S. Lapcinska, P. Arsenyan

Paper

Synthesis

We next moved on to another 6-endo-dig cyclization

with the aim to prepare coumarins and quinolinones. Un-

fortunately, attempts to prepare coumarins, an important

class of heterocycle, failed.

corded on a Waters Synapt GII Q-ToF UPLC/MS system. Infrared (IR)

spectra were recorded with a Prestige-21 FTIR spectrophotometer

(Shimadzu, Kyoto, Japan). N-Cbz-cysteine ethyl ester 1,⁷⁹propargyl

pyridines 2a⁸⁰and 2b,⁸¹thiazole 2d,⁴¹imidazole 2e,⁸²phenyl ethynyl

anilines 10a,⁸³10b,⁸⁴10c,⁸⁵10d,e,⁴²10g,h,⁸⁶and 10i,⁸⁷phenol 10j,⁸⁸

arene-alkynes 13a–c⁴¹and alkynes 16,⁸⁹18⁹⁰and 20⁹¹were prepared

according to literature procedures.

Peptides containing S–H or S–S bonds were unable to

provide the desired compounds. However, the reaction of

glutathione 8 with NCS and aryl propiolamide 20 resulted

in the formation of 1-methyl-3-sulfenyl-quinolinone 21

(Scheme 5). It is noteworthy that quinolinones are the core

structures of many drugs, including some of the most wide-

ly used antibiotics (e.g., ciprofloxacin and levofloxacin).^76–78

Furthermore, a literature search for methods for the prepa-

ration of 3-sulfenyl quinolinones indicated that there is

clearly room for novel methods.

2-(Pyridin-2-yl)non-3-yn-2-ol (2c)

To a solution of 1-heptyne (0.72 mL, 5.46 mmol, 2 equiv) in THF (20

mL) was added BuLi (1.90 mL, 2.3 M in cyclohexane, 4.37 mmol, 1.6

equiv) at –20 °C. The reaction mixture was stirred for 20 min, cooled

to –78 °C and a solution of benzoyl pyridine (0.5 g, 2.73 mmol, 1

equiv) in THF (20 mL) was added. The mixture was stirred for 1 h,

then it was warmed to rt and stirred for 16 h. Saturated aqueous NH₄-

Cl was added and the mixture was extracted with EtOAc. The com-

bined extracts were dried, filtered and evaporated. The residue was

purified by flash chromatography (PE/EtOAc) to give the title com-

pound as a dark oil (0.46 g, 77%).

¹H NMR (400 MHz, CDCl₃):  = 8.49 (ddd, J = 4.9, 1.8, 1.0 Hz, 1 H), 7.72

(td, J = 7.9, 7.4, 1.7 Hz, 1 H), 7.60 (dt, J = 8.0, 1.1 Hz, 1 H), 7.22 (ddd, J =

7.4, 4.9, 1.1 Hz, 1 H), 5.38 (s, 1 H), 2.20 (t, J = 7.2 Hz, 2 H), 1.73 (s, 3 H),

1.50 (quin, J = 7.2 Hz, 2 H), 1.40–1.22 (m, 4 H), 0.87 (t, J = 7.1 Hz, 3 H).

O

NH₂

CO₂H

·TFA

H

N

BnO

N

H

O

X

Ph

S

Ph

O

19 X = O, 0%

X

O

21 X = NCH₃, 44%

18 X = O

20 X = NCH₃

¹³C NMR (101 MHz, CDCl₃):  = 162.7, 147.4, 137.3, 122.7, 120.1, 84.8,

83.4, 68.8, 32.7, 31.2, 28.4, 22.3, 18.9, 14.1.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₁₄H₂₀NO]⁺: 218.1539;

found: 218.1547.

OBn

O

HN

O

1. 8, NCS

CH₂Cl₂

O

Ph

Cl

Ph

H

S

2. TFA

NH

O

Indolizinium Salts 3a,b and 4a–e; General Procedure

X

O

X

O

To a solution of N-halosuccinimide (1.2 equiv) in CH₂Cl₂(3 mL) was

added a solution of N-Cbz-cysteine ethyl ester (1 equiv) in CH₂Cl₂(4

mL) at 0 °C. The mixture was stirred for 1 h, then a solution of alkyne

(0.5 equiv) in CH₂Cl₂(3 mL) was added. The reaction mixture was

stirred until the starting material had disappeared and was then

evaporated and the residue purified by reverse-phase chromatogra-

phy (MeCN/H₂O + HCl, 10–85%) to afford the indolizinium salts.

NHBoc

tBuO₂C

Scheme 5 Synthesis of S-peptide-containing quinolinones. Reagents

and conditions: peptide (1 equiv), NCS (1.2 equiv), alkyne (1 equiv),

CH₂Cl₂, 0 °C to rt.

In conclusion, a simple method has been demonstrated

for the in situ preparation of cysteinyl chloride using N-

chlorosuccinimide. As a result, series of indolizinium salts,

indoles and benzo[b]furans have been obtained by a 5-

endo-dig mechanism. The yields of the products depend on

the nature of the substituent and on the source of sulfenyl

chloride. Notably, the developed methodology was also

suitable for 6-endo-dig cyclization, providing glutathione-

containing polyaromatic systems, isocoumarins and quino-

linones in good yields. Importantly, a glutathione-contain-

ing PAH was found to selectively accumulate in cell lipid

droplets, thus serving as a blue fluorescent dye.

2-Bromo-1-hydroxy-1-methyl-3-phenyl-1H-indolizin-4-iumChlo-

ride (3a)

Prepared from 1 (100 mg, 0.35 mmol), NBS (75 mg, 0.43 mmol) and

2a (39 mg, 0.18 mmol).

Yield: 53 mg (88%); yellow solid.

IR (film): 3060, 1627, 1488, 1448, 1126 cm^–1

.

¹H NMR (400 MHz, CD₃OD):  = 8.74–8.63 (m, 2 H), 8.45 (d, J = 7.5 Hz,

1 H), 8.05 (t, J = 6.6 Hz, 1 H), 7.78–7.64 (m, 5 H), 1.83 (s, 3 H).

¹³C NMR (101 MHz, CD₃OD):  = 160.7, 146.9, 140.6, 137.6, 133.1,

132.9, 131.7, 131.0, 128.9, 125.1, 124.5, 81.8, 23.5.

HRMS (ESI/Q-TOF): m/z [M – Cl]⁺calcd for [C₁₅H₁₃NOBr]⁺: 302.0175;

found: 302.0194.

1-Hydroxy-2-iodo-1-methyl-3-phenyl-1H-indolizin-4-ium Chlo-

Unless otherwise stated, all reagents were purchased from commer-

cial suppliers and were used without further purification. Thin-layer

chromatography (TLC) was performed using MERCK Silica gel 60 F254

plates, which were visualized by UV (254 nm) fluorescence. ZEO-

CHEM silica gel (ZEOprep 60/35–70 microns, SI23501) was used for

column chromatography. ¹H and ¹³C NMR spectra were recorded on a

Bruker Avance Neo spectrometer at 400 or 300 MHz (product 3b) and

101 MHz, respectively, at 298 K in CD₃OD or CDCl₃. HRMS were re-

ride (3b)⁹²

Prepared from 1 (100 mg, 0.35 mmol), NIS (96 mg, 0.43 mmol) and 2a

(39 mg, 0.18 mmol).

Yield: 61 mg (90%); yellow solid.

¹H NMR (300 MHz, CD₃OD):  = 8.67–8.56 (m, 2 H), 8.48–8.41 (m, 1

H), 7.99 (ddd, J = 7.7, 6.2, 1.4 Hz, 1 H), 7.76–7.59 (m, 5 H), 1.75 (s, 3 H).

1811

S. Lapcinska, P. Arsenyan

Paper

Synthesis

2-(((R)-2-(((Benzyloxy)carbonyl)amino)-3-ethoxy-3-oxopropyl)-

thio)-1-hydroxy-1-methyl-3-phenyl-1H-indolizin-4-ium Chloride

(4a)

H), 2.93–2.81 (m, 2 H), 1.78 and 1.77 (2 s, 6 H), 1.73–1.57 (m, 2 H),

1.62–1.47 (m, 2 H), 1.48–1.30 (m, 8 H), 1.33–1.17 (m, 6 H), 0.99–0.87

(m, 6 H).

¹³C NMR (101 MHz, CD₃OD):  = 171.9, 171.7, 162.0, 161.9, 158.7,

158.3, 146.2, 146.1, 144.5, 144.2, 139.8, 139.1, 138.2, 136.6, 136.5,

129.5, 129.1, 128.8, 128.73, 128.67, 128.6, 123.6, 83.3, 83.2, 67.8, 67.7,

62.9, 62.8, 56.4, 55.5, 34.2, 34.0, 32.4, 27.4, 25.12, 25.05, 24.8, 23.3,

14.5, 14.4, 14.3.

HRMS (ESI/Q-TOF): m/z [M – Cl]⁺calcd for [C₂₇H₃₅N₂O₅S]⁺: 499.2261;

found: 499.2281.

Prepared from 1 (381 mg, 1.34 mmol), NCS (215 mg, 1.61 mmol) and

2a (150 mg, 0.67 mmol).

Yield: 0.237 g (65%); yellow solid.

IR (film): 3054, 2471, 1742, 1635, 1520, 1455, 1245, 1046, 760 cm^–1

.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.63–

8.54 (m, 2 H), 8.51 (dd, J = 11.6, 6.2 Hz, 2 H), 8.35 (d, J = 7.8 Hz, 2 H),

8.03–7.94 (m, 2 H), 7.71–7.60 (m, 10 H), 7.37–7.24 (m, 10 H), 5.11–

5.01 (m, 4 H), 4.38–4.25 (m, 2 H), 4.17–4.02 (m, 4 H), 3.68 (dd, J =

13.9, 4.1 Hz, 1 H), 3.29–3.16 (m, 2 H), 2.95–2.85 (m, 1 H), 1.88 (s, 3 H),

1.85 (s, 3 H), 1.25–1.09 (m, 6 H).

¹³C NMR (101 MHz, CD₃OD):  = 171.6, 171.4, 161.3, 161.2, 158.6,

158.2, 145.8, 145.7, 143.6, 143.0, 138.7, 138.6, 138.1, 138.0, 136.0,

135.9, 132.9, 132.8, 132.1, 131.00, 130.98, 129.5, 129.12, 129.09,

128.85, 128.80, 128.60, 128.56, 125.9, 123.73, 123.70, 83.5, 83.4,

67.83, 67.78, 62.80, 62.77, 55.5, 55.0, 33.5, 33.2, 25.2, 25.1, 14.4.

6-(((R)-2-(((Benzyloxy)carbonyl)amino)-3-ethoxy-3-oxopropyl)-

thio)-7-hydroxy-7-methyl-5-phenyl-7H-pyrrolo[2,1-b]thiazol-4-

ium Chloride (4d)

Prepared from 1 (371 mg, 1.31 mmol), NCS (210 mg, 1.57 mmol) and

2d (150 mg, 0.66 mmol).

Yield: 0.247 g (69%); yellow solid.

IR (film): 3086, 2804, 1718, 1529, 1261, 1213, 1049, 748 cm^–1

.

HRMS (ESI/Q-TOF): m/z [M – Cl]⁺calcd for [C₂₈H₂₉N₂O₅S]⁺: 505.1792;

found: 505.1800.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.35

(t, J = 3.8 Hz, 2 H), 8.20 (dd, J = 9.8, 3.7 Hz, 2 H), 7.74–7.65 (m, 4 H),

7.65–7.54 (m, 6 H), 7.40–7.25 (m, 10 H), 5.13–4.98 (m, 4 H), 4.39 (t, J =

7.1 Hz, 1 H), 4.29 (dd, J = 10.8, 3.9 Hz, 1 H), 4.16–4.04 (m, 4 H), 3.73

(dd, J = 13.9, 4.0 Hz, 1 H), 3.30–3.20 (m, 2 H), 2.90 (dd, J = 13.9, 10.8

Hz, 1 H), 1.94 and 1.92 (2 s, 6 H), 1.25–1.11 (m, 6 H).

¹³C NMR (101 MHz, CD₃OD):  = 178.0, 177.9, 171.7, 171.5, 158.5,

158.2, 141.6, 140.9, 139.3, 139.2, 138.04, 137.99, 132.7, 132.6, 131.1,

130.60, 130.55, 129.96, 129.90, 129.5, 129.1, 128.83, 128.81, 128.77,

128.72, 126.7, 84.0, 83.8, 67.8, 67.8, 62.8, 62.7, 55.7, 55.0, 34.5, 33.8,

26.2, 26.0, 14.42, 14.41.

2-(((R)-2-(((Benzyloxy)carbonyl)amino)-3-ethoxy-3-oxopropyl)-

thio)-1-hydroxy-1,3-diphenyl-1H-indolizin-4-ium Chloride (4b)

Prepared from 1 (398 mg, 1.05 mmol), NCS (169 mg, 1.26 mmol) and

2b (150 mg, 0.53 mmol).

Yield: 0.170 g (54%); yellow solid.

IR (film): 3064, 2958, 2778, 1734, 1512, 1455, 1319, 1272, 1217,

1057, 748 cm^–1

.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.58

(d, J = 6.0 Hz, 2 H), 8.52–8.41 (m, 2 H), 8.05–7.93 (m, 4 H), 7.81–7.64

(m, 14 H), 7.55–7.39 (m, 6 H), 7.39–7.23 (m, 10 H), 5.11–4.99 (m, 4 H),

4.32 (dd, J = 9.2, 4.5 Hz, 1 H), 4.11 (q, J = 7.0 Hz, 2 H), 4.04 (q, J = 7.0 Hz,

2 H), 3.93 (dd, J = 9.2, 5.3 Hz, 1 H), 3.60 (dd, J = 13.7, 4.5 Hz, 1 H), 3.25

(dd, J = 13.7, 5.3 Hz, 1 H), 3.07 (dd, J = 13.7, 9.2 Hz, 1 H), 2.72–2.61 (m,

1 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.16 (t, J = 7.1 Hz, 3 H).

HRMS (ESI/Q-TOF): m/z [M – Cl]⁺calcd for [C₂₆H₂₇N₂O₅S₂]⁺: 511.1356;

found: 511.1370.

6-(((R)-2-(((Benzyloxy)carbonyl)amino)-3-ethoxy-3-oxopropyl)-

thio)-7-hydroxy-1-methyl-5,7-diphenyl-1,7-dihydropyrrolo[1,2-

a]imidazol-4-ium Chloride (4e)

Prepared from 1 (590 mg, 2.08 mmol), NCS (334 mg, 2.5 mmol) and 2f

(150 mg, 0.52 mmol).

¹³C NMR (101 MHz, CD₃OD):  = 171.4, 171.2, 160.9, 145.9, 145.8,

138.0, 137.2, 137.1, 136.2, 132.9, 132.0, 131.12, 131.07, 130.81,

130.77, 130.7, 130.6, 129.5, 129.0, 128.8, 128.73, 128.71, 126.42,

126.36, 125.79, 125.75, 124.6, 86.8, 86.7, 67.7, 62.74, 62.68, 55.5, 55.2,

32.6, 32.3, 17.7, 14.44, 14.42.

HRMS (ESI/Q-TOF): m/z [M – Cl]⁺calcd for [C₃₃H₃₁N₂O₅S]⁺: 567.1948;

found: 567.1957.

Yield: 0.23 g (73%); yellow solid.

IR (film): 2974, 2496, 1733, 1616, 1587, 1515, 1302, 1265, 1214,

1049, 756 cm^–1

.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 7.75–

7.71 (m, 4 H), 7.66–7.54 (m, 12 H), 7.49–7.26 (m, 18 H), 5.08–4.99 (m,

4 H), 4.09 (s, 3 H), 4.06 (s, 3 H), 4.05–3.91 (m, 5 H), 3.88 (dd, J = 8.7, 4.7

Hz, 1 H), 2.91–2.78 (m, 2 H), 2.68–2.57 (m, 2 H), 1.20–1.08 (m, 6 H).

¹³C NMR (101 MHz, CD₃OD):  = 171.5, 171.4, 158.1, 158.0, 149.22,

149.15, 140.4, 140.3, 138.6, 138.5, 138.43, 138.35, 138.02, 137.97,

137.0, 136.9, 131.5, 131.4, 130.8, 130.7, 129.93, 129.90, 129.8, 129.5,

129.1, 128.89, 128.86, 128.5, 128.4, 126.8, 119.5, 79.2, 79.1, 67.7, 62.7,

62.6, 54.9, 54.8, 38.7, 38.4, 37.2, 14.42, 14.39.

2-(((R)-2-(((Benzyloxy)carbonyl)amino)-3-ethoxy-3-oxopropyl)-

thio)-1-hydroxy-1-methyl-3-pentyl-1H-indolizin-4-ium Chloride

(4c)

Prepared from 1 (782 mg, 2.76 mmol), NCS (442 mg, 3.31 mmol) and

2c (300 mg, 1.38 mmol).

Yield: 0.217 g (30%); yellow oil.

HRMS (ESI/Q-TOF): m/z [M – Cl]⁺calcd for [C₃₂H₃₂N₃O₅S]⁺: 570.2057;

found: 570.2049.

IR (film): 3091, 2956, 2930, 2872, 1718, 1716, 1534, 1327, 1215,

1052, 748 cm^–1

.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 9.12–

9.02 (m, 2 H), 8.65–8.54 (m, 2 H), 8.29 (d, J = 7.8 Hz, 2 H), 8.15–8.03

(m, 2 H), 7.43–7.23 (m, 10 H), 5.22–5.01 (m, 4 H), 4.57–4.49 (m, 1 H),

4.36 (dd, J = 10.9, 3.7 Hz, 1 H), 4.26–4.13 (m, 3 H), 4.06 (dd, J = 13.8,

3.7 Hz, 1 H), 3.58–3.48 (m, 2 H), 3.08–3.00 (m, 1 H), 2.99–2.91 (m, 3

Benzyl (6R,11R)-6-((2-(Benzyloxy)-2-oxoethyl)carbamoyl)-11-

((tert-butoxycarbonyl)amino)-2,2-dimethyl-4,12-dioxo-3-oxa-8,9-

dithia-5,13-diazapentadecan-15-oate (5)

To a solution of glycine benzyl ester hydrochloride (1.37 g, 6.81 mmol,

3 equiv) in DMF (5 mL) was added NMM (1 mL, 9.08 mmol, 4 equiv) at

0 °C and the mixture was stirred for 5 min. Next, a solution of Boc-L-

1812

S. Lapcinska, P. Arsenyan

Paper

Synthesis

cystine (1 g, 2.27 mmol, 1 equiv) in DMF (5 mL) was added to the re-

action mixture followed by the addition of HOBt (0.697 g, 4.54 mmol,

2 equiv) and EDC·HCl (1.74 g, 9.08 mmol, 4 equiv). The reaction mix-

ture was stirred at 0 °C for 10 min and then at rt for 1 h. The reaction

mixture was evaporated and the residue was purified by reverse-

phase chromatography (MeCN/H₂O, 10–85%) to give the product as

white solid in 95% yield.

¹H NMR (400 MHz, CD₃OD):  = 7.41–7.26 (m, 10 H), 5.16 (s, 4 H), 4.49

(d, J = 18.0 Hz, 2 H), 4.08–3.92 (ABm, 4 H), 3.23–3.09 (m, 2 H), 2.86

(dd, J = 13.8, 9.5 Hz, 2 H), 1.44 (s, 18 H).

¹³C NMR (101 MHz, CD₃OD):  = 175.4, 172.8, 170.9, 158.9, 158.2,

138.4, 137.1, 129.6, 129.5, 129.36, 129.35, 128.9, 128.8, 116.1, 80.9,

68.0, 67.3, 56.4, 53.6, 42.3, 41.6, 41.4, 32.8, 30.5, 28.8, 24.0.

HRMS (ESI/Q-TOF): m/z [M + Na]⁺calcd for [C₆₂H₈₂N₈O₁₆S₂Na]⁺:

1281.5188; found: 1281.5208.

Dibenzyl 9,9′-(Disulfanediylbis(methylene))(6S,6′S,9R,9′R)-bis(6-

((1H-indol-3-yl)methyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-

triazatridecan-13-oate) (6c)

Prepared from 5 (150 mg, 0.2 mmol), Boc-Trp (186 mg, 0.61 mmol),

NMM (0.07 mL, 0.61 mmol), HOBt (30 mg, 0.2 mmol) and EDC·HCl

(117 mg, 0.61 mmol).

¹³C NMR (101 MHz, CD₃OD):  = 173.8, 170.8, 157.8, 137.1, 129.6,

129.3, 80.9, 67.9, 55.2, 42.3, 42.2, 28.7.

HRMS (ESI/Q-TOF): m/z [M + Na]⁺calcd for [C₃₄H₄₆N₄O₁₀S₂Na]⁺:

Yield: 150 mg (73%); white solid.

757.2553; found: 757.2548.

¹H NMR (400 MHz, CD₃OD):  = 7.58 (d, J = 7.9 Hz, 2 H), 7.36–7.25 (m,

12 H), 7.11 (s, 2 H), 7.06 (t, J = 7.2 Hz, 2 H), 6.98 (t, J = 7.3 Hz, 2 H), 5.11

(s, 4 H), 4.84–4.79 (m, 2 H), 4.43 (dd, J = 7.7, 6.0 Hz, 2 H), 3.97–3.76

(m, 4 H), 3.27 (dd, J = 14.1, 6.1 Hz, 2 H), 3.14–2.96 (m, 4 H), 2.86 (dd,

J = 14.1, 8.8 Hz, 2 H), 1.34 (s, 18 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.9, 172.5, 170.7, 157.9, 137.9,

137.0, 129.6, 129.37, 129.35, 128.8, 124.9, 122.5, 119.9, 119.5, 112.3,

110.8, 80.9, 68.0, 57.2, 53.8, 42.2, 41.6, 29.1, 28.7.

Peptides 6a–d; General Procedure

To a solution of 5 (1 equiv) in CH₂Cl₂(4 mL) was added TFA (2 mL) at 0

°C and the reaction mixture was stirred at rt for 1 h and then evapo-

rated. The residue was dissolved in DMF (5 mL), NMM (3 equiv) was

added at 0 °C and the mixture was stirred for 5 min. Next, a solution

of protected amino acid (3 equiv) in DMF (5 mL) was added followed

by HOBt (1 equiv) and EDC·HCl (3 equiv). The resulting mixture was

stirred at 0 °C for 10 min and then at rt for 2 h. The mixture was evap-

orated and the residue was purified by reverse-phase chromatogra-

phy (MeCN/H₂O, 5–85%) to provide the product.

HRMS (ESI/Q-TOF): m/z [M + Na]⁺calcd for [C₅₆H₆₆N₈O₁₂S₂Na]⁺:

1129.4139; found: 1129.4172.

Dibenzyl 9,9′-(Disulfanediylbis(methylene))(6S,6′S,9R,9′R)-bis(6-

((1H-imidazol-4-yl)methyl)-2,2-dimethyl-4,7,10-trioxo-3-oxa-

5,8,11-triazatridecan-13-oate) (6d)

Dibenzyl 11,11′-(Disulfanediylbis(methylene))(6S,6′S,11R,11′R)-

bis(6-(tert-butoxycarbonyl)-2,2-dimethyl-4,9,12-trioxo-3-oxa-

5,10,13-triazapentadecan-15-oate) (6a)

Prepared from 5 (1.5 g, 2 mmol), Boc-Glu-O^tBu (1.97 g, 6.12 mmol),

NMM (0.67 mL, 6.12 mmol), HOBt (0.306 g, 2 mmol) and EDC·HCl

(1.18 g, 6.12 mmol).

Prepared from 5 (150 mg, 0.2 mmol), Boc-His (156 mg, 0.61 mmol),

NMM (0.07 mL, 0.61 mmol), HOBt (30 mg, 0.2 mmol) and EDC·HCl

(117 mg, 0.61 mmol).

Yield: 130 mg (65%); white solid.

¹H NMR (400 MHz, CD₃OD):  = 7.60 (s, 2 H), 7.39–7.26 (m, 10 H), 6.89

(s, 2 H), 5.16 (s, 4 H), 4.85–4.77 (m, 2 H), 4.37–4.29 (m, 2 H), 4.08–

3.96 (ABm, 4 H), 3.19 (dd, J = 14.0, 4.7 Hz, 2 H), 3.07 (dd, J = 14.8, 5.6

Hz, 2 H), 2.94 (dd, J = 14.1, 9.1 Hz, 4 H), 1.39 (s, 18 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.4, 172.9, 170.9, 157.8, 137.1,

136.3, 134.4, 129.6, 129.4, 118.4, 81.0, 68.0, 56.3, 53.8, 42.3, 41.4,

30.6, 28.7.

Yield: 1.8 g (80%); white solid.

¹H NMR (400 MHz, CD₃OD):  = 7.39–7.27 (m, 10 H), 5.16 (s, 4 H),

4.84–4.81 (m, 2 H), 4.07–3.96 (m, 6 H), 3.17 (dd, J = 14.0, 4.9 Hz, 2 H),

2.91 (dd, J = 14.0, 9.5 Hz, 2 H), 2.36 (t, J = 7.6 Hz, 4 H), 2.18–2.05 (m, 2

H), 1.95–1.83 (m, 2 H), 1.46 (s, 18 H), 1.44 (s, 18 H).

¹³C NMR (101 MHz, CD₃OD):  = 175.0, 173.3, 173.1, 170.9, 158.1,

137.1, 129.6, 129.36, 129.35, 82.8, 80.5, 68.0, 55.4, 53.8, 42.3, 41.9,

33.0, 28.9, 28.3.

HRMS (ESI/Q-TOF): m/z [M

+

H]⁺calcd for [C₄₆H₆₁N₁₀O₁₂S₂]⁺:

1009.3912; found: 1009.3925.

HRMS (ESI/Q-TOF): m/z [M

+

H]⁺calcd for [C₅₂H₇₇N₆O₁₆S₂]⁺:

1105.4837; found: 1105.4818.

Peptides 7 and 8

To a solution of S–S-bond-containing peptide (1 equiv) in MeOH (5

mL) and H₂O (0.5 mL) was added nBu₃P (1.3 equiv), and after stirring

for 30 min, the reaction mixture was evaporated and purified by flash

chromatography (EtOAc/PE, 2:1 to 5:0)

Benzyl ((9S,12R,17R)-12-((2-(Benzyloxy)-2-oxoethyl)carbamoyl)-

17-((S)-6-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)-

amino)hexanamido)-9-((tert-butoxycarbonyl)amino)-3,10-dioxo-

1-phenyl-2-oxa-14,15-dithia-4,11-diazaoctadecan-18-oyl)glyci-

nate (6b)

Benzyl (tert-Butoxycarbonyl)-L-cysteinylglycinate (7)

Prepared from 5 (150 mg, 0.2 mmol), Boc-Lys(Cbz) (233 mg, 0.61

mmol), NMM (0.07 mL, 0.61 mmol), HOBt (30 mg, 0.2 mmol) and

EDC·HCl (117 mg, 0.61 mmol).

Prepared from 5 (200 mg, 0.27 mmol, 1 equiv) and nBu₃P (0.088 mL,

0.37 mmol).

Yield: 190 mg (73%); white solid.

Yield: 144 mg (72%); white solid.

¹H NMR (400 MHz, CD₃OD):  = 7.37–7.25 (m, 20 H), 5.14 (s, 4 H), 5.04

(s, 4 H), 4.07–3.94 (m, 6 H), 3.18 (dd, J = 14.0, 4.7 Hz, 2 H), 3.10 (t, J =

6.7 Hz, 4 H), 2.95 (dd, J = 14.0, 9.4 Hz, 2 H), 1.83–1.70 (m, 2 H), 1.70–

1.58 (m, 2 H), 1.55–1.41 (m, 8 H), 1.41 (s, 18 H), 1.40–1.35 (m, 2 H).

¹H NMR (400 MHz, CD₃OD):  = 7.45–7.22 (m, 5 H), 5.17 (s, 2 H), 4.29–

4.19 (m, 1 H), 4.09–3.92 (ABm, 2 H), 2.88–2.73 (m, 2 H), 1.45 (s, 9 H).

¹³C NMR (101 MHz, CD₃OD):  = 173.6, 170.9, 157.7, 137.1, 129.6,

129.4, 81.0, 68.0, 58.0, 42.2, 28.7, 27.5.

HRMS (ESI/Q-TOF): m/z [M

+

Na]⁺calcd for [C₁₇H₂₄N₂O₅SNa]⁺:

391.1304; found: 391.1299.

1813

S. Lapcinska, P. Arsenyan

Paper

Synthesis

tert-Butyl N⁵-((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-3-mer-

4.59–4.49 (m, 2 H), 3.96 (s, 3 H), 3.93 (s, 3 H), 3.77 (dd, J = 14.0, 4.5 Hz,

1 H), 3.39–3.32 (m, 1 H), 3.36–3.20 (m, 2 H), 2.90 (dd, J = 14.0, 10.3 Hz,

1 H), 2.36–2.14 (m, 4 H), 2.13–1.95 (m, 2 H), 1.91–1.78 (m, 8 H), 1.50–

1.42 (m, 36 H).

capto-1-oxopropan-2-yl)-N²-(tert-butoxycarbonyl)-L-glutaminate

(8)

Prepared from 6a (200 mg, 0.18 mmol, 1 equiv) and nBu₃P (0.059 mL,

¹³C NMR (101 MHz, CD₃OD):  = 175.0, 173.3, 172.7, 172.4, 170.83,

170.80, 161.4, 161.3, 158.1, 145.9, 145.8, 143.3, 142.5, 139.9, 138.8,

137.17, 137.16, 136.0, 135.9, 132.7, 132.2, 130.91, 130.86, 129.6,

129.4, 129.33, 129.28, 129.22, 129.17, 128.5, 128.4, 126.0, 125.9,

123.88, 123.86, 83.6, 83.4, 82.72, 82.65, 80.51, 80.47, 67.81, 67.78,

55.5, 54.5, 54.3, 42.23, 42.19, 33.6, 33.2, 33.0, 28.8, 28.3, 28.2, 25.3.

0.23 mmol).

Yield: 0.59 mg (75%); white solid.

¹H NMR (400 MHz, CD₃OD):  = 7.40–7.25 (m, 5 H), 5.16 (s, 2 H), 4.84–

4.80 (m, 1 H), 4.08–3.95 (m, 3 H), 3.17 (dd, J = 14.0, 4.9 Hz, 1 H), 2.91

(dd, J = 14.0, 9.4 Hz, 1 H), 2.36 (t, J = 7.6 Hz, 2 H), 2.18–2.05 (m, 1 H),

1.94–1.82 (m, 1 H), 1.46 (s, 9 H), 1.44 (s, 9 H).

¹³C NMR (101 MHz, CD₃OD):  = 175.0, 173.3, 173.1, 170.9, 158.1,

137.1, 129.6, 129.36, 129.35, 82.8, 80.5, 68.0, 55.4, 53.8, 42.3, 41.9,

33.0, 28.8, 28.3.

HRMS (ESI/Q-TOF): m/z [M

–

OAc]⁺calcd for [C₄₁H₅₁N₄O₉S]⁺:

775.3371; found: 775.3395.

2-(((R)-2-((S)-4-Ammonio-4-carboxybutanamido)-3-((2-(benzyl-

oxy)-2-oxoethyl)amino)-3-oxopropyl)thio)-1-hydroxy-1,3-diphe-

nyl-1H-indolizin-4-ium 2,2,2-Trifluoroacetate (9c)

HRMS (ESI/Q-TOF): m/z [M

576.2356; found: 576.2346.

+

Na]⁺calcd for [C₂₆H₃₉N₃O₈SNa]⁺:

Prepared from 6a (100 mg, 0.09 mmol), NCS (27 mg, 0.20 mmol) and

alkyne 2b (40 mg, 0.14 mmol). The product was isolated after treat-

ment with TFA.

Indolizinium Salts 9a–f; General Procedure

To a solution of N-halosuccinimide (2.2 equiv) in CH₂Cl₂(3 mL) was

added a solution of S–S-bond-containing peptide (1 equiv) in CH₂Cl₂

(4 mL) at 0 °C. The mixture was stirred for 1 h, then a solution of the

corresponding alkyne (1 equiv) in CH₂Cl₂(3 mL) was added. The re-

sulting mixture was stirred until the starting material had disap-

peared and was then evaporated. The residue was purified by reverse-

phase chromatography (MeCN/H₂O + AcOH, 10–85%) to afford the in-

dolizinium salt.

Yield: 61 mg (75%); colorless oil.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.60–

8.53 (m, 2 H), 8.51–8.40 (m, 2 H), 8.04–7.93 (m, 4 H), 7.81–7.63 (m, 14

H), 7.52–7.41 (m, 6 H), 7.39–7.26 (m, 10 H), 5.20–5.11 (m, 4 H), 4.51

(dd, J = 9.3, 4.9 Hz, 1 H), 4.36 (dd, J = 8.2, 5.8 Hz, 1 H), 4.05–3.97 (m, 2

H), 3.97–3.86 (m, 6 H), 3.61 (dd, J = 13.8, 4.9 Hz, 1 H), 3.25–3.15 (m, 1

H), 3.16–3.07 (m, 1 H), 2.74–2.65 (m, 1 H), 2.55–2.35 (m, 4 H), 2.25–

2.08 (m, 4 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.2, 172.6, 172.3, 172.0, 171.4,

170.80, 170.77, 160.9, 146.0, 145.9, 144.6, 144.0, 142.7, 139.3, 138.4,

137.18, 137.13, 137.12, 136.4, 136.3, 132.9, 131.11, 131.05, 130.78,

130.73, 130.65, 130.60, 129.6, 129.4, 129.34, 129.30, 129.23, 129.21,

128.7, 128.3, 128.0, 126.5, 126.4, 125.8, 125.74, 124.66, 86.9, 86.7,

67.92, 67.90, 65.2, 54.6, 54.1, 53.5, 42.3, 42.12, 42.05, 41.8, 32.7, 32.4,

32.3, 27.0.

2-(((R)-3-((2-(Benzyloxy)-2-oxoethyl)amino)-2-((tert-butoxycar-

bonyl)amino)-3-oxopropyl)thio)-1-hydroxy-1-methyl-3-phenyl-

1H-indolizin-4-ium Acetate (9a)

Prepared from 5 (100 mg, 0.14 mmol), NCS (41 mg, 0.31 mmol) and

alkyne 2a (46 mg, 0.20 mmol).

Yield: 69 mg (78%); white solid.

IR (film): 3290, 2980, 1682, 1534, 1188 cm^–1

.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.62–

8.53 (m, 2 H), 8.52 (d, J = 6.1 Hz, 2 H), 8.36 (d, J = 7.9 Hz, 2 H), 8.02–

7.94 (m, 2 H), 7.72–7.60 (m, 10 H), 7.40–7.28 (m, 10 H), 5.17–5.09 (m,

4 H), 4.34–4.28 (m, 1 H), 4.22 (dd, J = 9.9, 4.5 Hz, 1 H), 3.98–3.92 (m, 4

H), 3.63 (dd, J = 13.8, 4.5 Hz, 1 H), 3.31–3.24 (m, 2 H), 2.88 (dd, J =

13.8, 9.9 Hz, 1 H), 1.89 (s, 6 H), 1.46–1.36 (m, 18 H).

¹³C NMR (101 MHz, CD₃OD):  = 173.1, 172.8, 170.9, 170.8, 161.5,

157.8, 157.6, 145.7, 145.6, 143.3, 137.2, 135.9, 132.80, 132.78, 132.0,

131.0, 129.6, 129.3, 129.24, 129.19, 128.50, 128.47, 128.0, 125.91,

125.89, 123.72, 123.69, 83.5, 81.2, 81.1, 67.90, 67.88, 65.2, 55.7, 55.6,

42.2, 33.8, 28.71, 28.65, 25.2, 23.9.

HRMS (ESI/Q-TOF): m/z [M – CF₃COO]⁺calcd for [C₃₇H₃₇N₄O₇S]⁺:

681.2377; found: 681.2376.

2-(((R)-3-((2-(Benzyloxy)-2-oxoethyl)amino)-2-((S)-6-(((benzyl-

oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)hexanami-

do)-3-oxopropyl)thio)-1-hydroxy-1-methyl-3-phenyl-1H-indolizin-

4-ium Acetate (9d)

Prepared from 6b (120 mg, 0.092 mmol), NCS (27 mg, 0.20 mmol) and

alkyne 2a (31 mg, 0.139 mmol).

Yield: 59 mg (67%); colorless oil.

IR (film): 3305, 2935, 1704, 1533, 1249, 1176 cm^–1

.

HRMS (ESI/Q-TOF): m/z [M

–

OAc]⁺calcd for [C₃₂H₃₆N₃O₆S]⁺:

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.59–

8.50 (m, 2 H), 8.48 (dd, J = 6.2, 2.8 Hz, 2 H), 8.34 (d, J = 7.8 Hz, 2 H),

7.99–7.92 (m, 2 H), 7.69–7.56 (m, 10 H), 7.38–7.25 (m, 20 H), 5.14–

5.10 (m, 4 H), 5.05 (s, 4 H), 4.67–4.51 (m, 2 H), 4.02–3.88 (m, 5 H),

3.89–3.79 (m, 2 H), 3.39 (dd, J = 13.8, 7.9 Hz, 1 H), 3.30–3.24 (m, 1 H),

3.13–3.04 (m, 4 H), 2.98 (dd, J = 13.9, 9.9 Hz, 1 H), 1.91–1.86 (m, 6 H),

1.75–1.60 (m, 2 H), 1.60–1.50 (m, 2 H), 1.47–1.29 (m, 28 H).

¹³C NMR (101 MHz, CD₃OD):  = 175.4, 172.1, 171.9, 170.8, 170.7,

161.4, 161.2, 158.9, 158.2, 157.9, 145.73, 145.65, 143.1, 142.9, 139.1,

138.4, 137.2, 137.1, 136.2, 135.9, 132.7, 132.1, 132.0, 131.00, 130.96,

129.6, 129.5, 129.33, 129.25, 129.2, 129.0, 128.8, 128.5, 128.4, 125.9,

125.8, 123.7, 83.6, 83.5, 80.9, 80.6, 67.9, 67.3, 56.5, 56.1, 54.6, 54.1,

42.2, 42.1, 41.4, 33.1, 32.7, 30.5, 30.4, 28.8, 25.3, 25.2, 23.9, 22.5.

590.2319; found: 590.2325.

2-(((R)-3-((2-(Benzyloxy)-2-oxoethyl)amino)-2-((S)-5-(tert-bu-

toxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanamido)-3-oxo-

propyl)thio)-1-hydroxy-1-methyl-3-phenyl-1H-indolizin-4-ium

Acetate (9b)

Prepared from 6a (100 mg, 0.09 mmol), NCS (27 mg, 0.20 mmol) and

alkyne 2a (30 mg, 0.13 mmol).

Yield: 40 mg (52%); colorless oil.

IR (film): 3246, 2978, 1670, 1518, 1246, 1153 cm^–1

.

¹H NMR (400 MHz, CD₃OD) (1:1 mixture of diastereomers): δ = 8.62–

8.52 (m, 2 H), 8.48 (t, J = 7.1 Hz, 2 H), 8.38 (t, J = 8.4 Hz, 2 H), 8.03–7.93

(m, 2 H), 7.69–7.60 (m, 10 H), 7.39–7.27 (m, 10 H), 5.14–5.08 (m, 4 H),

1814

S. Lapcinska, P. Arsenyan

Paper

Synthesis

HRMS (ESI/Q-TOF): m/z [M

852.3637; found: 852.3687.

–

OAc]⁺calcd for [C₄₆H₅₄N₅O₉S]⁺:

¹H NMR (400 MHz, CDCl₃):  = 8.24 (d, J = 7.5 Hz, 1 H), 7.76–7.69 (m, 1

H), 7.47–7.27 (m, 12 H), 5.12–5.06 (m, 1 H), 5.00 (d, J = 12.2 Hz, 1 H),

4.93 (d, J = 12.2 Hz, 1 H), 4.37–4.28 (m, 1 H), 3.88–3.79 (m, 1 H), 3.58–

3.44 (m, 1 H), 3.27 (dd, J = 13.9, 4.5 Hz, 1 H), 3.01 (dd, J = 13.9, 5.0 Hz,

1 H), 1.21 (s, 9 H), 1.00 (t, J = 7.1 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 170.0, 155.5, 149.7, 143.2, 136.6,

133.2, 130.2, 130.1, 128.6, 128.4, 128.2, 128.1, 127.9, 125.4, 123.6,

119.6, 115.5, 110.5, 84.0, 66.9, 61.6, 53.4, 36.1, 27.5, 13.9.

N-(2-(Hex-1-yn-1-yl)phenyl)-2,4-dinitrobenzenesulfonamide (10f)

To a solution of 2-(hex-1-yn-1-yl)aniline (0.3 g, 1.73 mmol, 1 equiv)

in CH₂Cl₂(7 mL) were added pyridine (0.28 mL, 3.46 mmol, 2 equiv)

and 2,4-dinitrobenzenesulfonyl chloride (0.57 g, 2.08 mmol, 1.2

equiv) at 0 °C. The reaction mixture was stirred for 16 h at room tem-

perature and then poured into ice water and extracted with CH₂Cl₂.

The combined organic layer was washed with 2 M HCl and brine and

then dried over Na₂SO₄. After filtration and evaporation, the residue

was purified by flash chromatography (PE/EtOAc, 10:1 to 3:1) to give

the title compound (0.42 g, 61%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃):  = 8.68 (d, J = 2.2 Hz, 1 H), 8.42 (dd, J = 8.6,

2.2 Hz, 1 H), 8.17–8.12 (m, 2 H), 7.70 (dd, J = 8.6, 1.2 Hz, 1 H), 7.34–

7.26 (m, 2 H), 7.09 (td, J = 7.6, 1.2 Hz, 1 H), 2.38 (t, J = 7.1 Hz, 2 H),

1.57–1.49 (m, 2 H), 1.48–1.34 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 150.2, 148.3, 138.4, 136.0, 133.0,

132.7, 129.1, 127.0, 125.8, 120.9, 120.7, 116.3, 99.2, 74.8, 30.6, 22.2,

19.4, 13.7.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₁₈H₁₈N₃O₆S]⁺: 404.0916;

found: 404.0906.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₂H₃₅N₂O₆S ]⁺: 575.2216;

found: 575.2219.

Ethyl N-((Benzyloxy)carbonyl)-R-(1-((4-nitrophenyl)sulfonyl)-2-

phenyl-1H-indol-3-yl)-L-cysteinate (11c)

Prepared from 1 (225 mg, 0.79 mmol), NCS (127 mg, 0.95 mmol),

alkyne 10c (150 mg, 0.40 mmol) and CH₂Cl₂(10 mL).

Yield: 203 mg (77%); yellow solid; []_D²⁰+49.1 (c 1.0, CHCl₃).

IR (film): 3406, 2983, 1729, 1533, 1348, 1185 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 8.28 (d, J = 8.2 Hz, 1 H), 8.11–8.03 (m, 2

H), 7.63 (d, J = 8.0 Hz, 1 H), 7.55–7.47 (m, 2 H), 7.47–7.22 (m, 11 H),

5.01 (d, J = 7.8 Hz, 1 H), 4.94 (d, J = 12.2 Hz, 1 H), 4.84 (d, J = 12.2 Hz, 1

H), 4.30–4.19 (m, 1 H), 3.85–3.73 (m, 1 H), 3.59–3.43 (m, 1 H), 3.13

(dd, J = 14.0, 4.3 Hz, 1 H), 2.97 (dd, J = 14.0, 4.9 Hz, 1 H), 0.96 (t, J = 7.1

Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 169.7, 155.3, 150.7, 143.3, 142.9,

136.8, 136.2, 131.9, 131.2, 129.8, 129.6, 128.6, 128.30, 128.25, 128.1,

127.7, 126.4, 125.4, 124.1, 120.4, 116.2, 115.7, 77.5, 77.2, 76.8, 67.0,

61.7, 53.5, 35.6, 13.9.

Indoles and Benzo[b]furans 11a–h; General Procedure

To a solution of NCS (1.2 equiv) in CH₂Cl₂was added a solution of N-

Cbz-cysteine ethyl ester 1 in CH₂Cl₂at 0 °C. The mixture was stirred

for 1 h, then a solution of the corresponding alkyne (0.5 equiv) in

CH₂Cl₂(4 mL) was added. The reaction mixture was stirred until the

starting material had disappeared and was then evaporated. The resi-

due was purified by flash chromatography (PE/EtOAc, 10–100%) to

give the product.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₃H₃₀N₃O₈S₂]⁺: 660.1474;

found: 660.1455.

Ethyl N-((Benzyloxy)carbonyl)-R-(1-((2,4-dinitrophenyl)sulfonyl)-

2-phenyl-1H-indol-3-yl)-L-cysteinate (11d)

Ethyl N-((Benzyloxy)carbonyl)-R-(2-phenyl-1-tosyl-1H-indol-3-

yl)-L-cysteinate (11a)

Prepared from 1 (200 mg, 0.71 mmol), NCS (114 mg, 0.85 mmol),

alkyne 10e (150 mg, 0.35 mmol) and CH₂Cl₂(10 mL).

Yield: 200 mg (80%); yellow solid; []_D²⁰+35.5 (c 1.0, CHCl₃).

Prepared from 1 (245 mg, 0.86 mmol), NCS (138 mg, 1.04 mmol),

alkyne 10a (150 mg, 0.43 mmol) and CH₂Cl₂(10 mL).

Yield: 230 mg (85%); yellow oil; []_D²⁰+46.5 (c 1.0, CHCl₃).

IR (film): 3404, 2928, 1723, 1554, 1347, 1181 cm^–1

.

IR (film): 3405, 3032, 1746, 1511, 1377, 1178 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 8.45 (d, J = 2.3 Hz, 1 H), 8.11–8.04 (m, 2

H), 7.76 (dd, J = 6.1, 3.0 Hz, 1 H), 7.46–7.41 (m, 2 H), 7.39–7.30 (m, 5

H), 7.28–7.20 (m, 6 H), 5.15 (d, J = 7.8 Hz, 1 H), 4.98 (d, J = 12.2 Hz, 1

H), 4.88 (d, J = 12.2 Hz, 1 H), 4.39–4.30 (m, 1 H), 3.91–3.79 (m, 1 H),

3.60–3.47 (m, 1 H), 3.25 (dd, J = 14.0, 4.2 Hz, 1 H), 3.03 (dd, J = 14.0,

5.2 Hz, 1 H), 1.00 (t, J = 7.1 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 169.9, 155.4, 150.1, 147.8, 141.9,

137.6, 137.3, 136.2, 132.6, 132.3, 130.04 129.96, 129.0, 128.6, 128.3,

128.1, 128.0, 126.6, 126.2, 125.2, 120.4, 120.3, 116.0, 115.1, 77.5, 77.2,

76.8, 67.1, 61.9, 53.5, 35.9, 13.9.

¹H NMR (400 MHz, CDCl₃):  = 8.34 (d, J = 8.2 Hz, 1 H), 7.65 (d, J = 7.2

Hz, 1 H), 7.45–7.24 (m, 14 H), 7.06 (d, J = 8.1 Hz, 2 H), 5.05 (d, J = 7.8

Hz, 1 H), 4.99 (d, J = 12.2 Hz, 1 H), 4.89 (d, J = 12.2 Hz, 1 H), 4.35–4.23

(m, 1 H), 3.88–3.73 (m, 1 H), 3.55–3.42 (m, 1 H), 3.18 (dd, J = 14.0, 4.3

Hz, 1 H), 2.97 (dd, J = 14.0, 4.9 Hz, 1 H), 2.30 (s, 3 H), 0.97 (t, J = 7.0 Hz,

3 H).

¹³C NMR (101 MHz, CDCl₃):  = 169.8, 155.4, 145.1, 143.9, 137.0,

136.3, 135.1, 132.0, 131.1, 130.2, 129.6, 129.4, 128.6, 128.3, 128.1,

127.5, 127.0, 125.8, 124.6, 119.9, 116.3, 114.0, 67.0, 61.7, 53.5, 35.8,

21.7, 13.9.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₃H₂₉N₄O₁₀S₂]⁺: 705.1325;

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₄H₃₃N₂O₆S₂]⁺: 629.1780;

found: 705.1318.

found: 629.1766.

Ethyl N-((Benzyloxy)carbonyl)-R-(2-phenylbenzofuran-3-yl)-L-

cysteinate (11h)

tert-Butyl (R)-3-((2-(((Benzyloxy)carbonyl)amino)-3-ethoxy-3-

oxopropyl)thio)-2-phenyl-1H-indole-1-carboxylate (11b)

Prepared from 1 (438 mg, 1.55 mmol), NCS (248 mg, 1.85 mmol),

alkyne 10j (150 mg, 0.77 mmol) and CH₂Cl₂(10 mL).

Yield: 160 mg (44%); white solid; []_D²⁰+42.8 (c 1.0, CHCl₃).

Prepared from 1 (289 mg, 1.02 mmol), NCS (164 mg, 1.23 mmol),

alkyne 10b (150 mg, 0.51 mmol) and CH₂Cl₂(10 mL).

Yield: 199 mg (68%); light yellow oil; []_D²⁰+33.8 (c 1.0, CHCl₃).

IR (film): 3337, 2981, 1736, 1501, 1202, 1067 cm^–1

.

IR (film): 3404, 2981, 1733, 1516, 1318, 1058 cm^–1

.

1815

S. Lapcinska, P. Arsenyan

Paper

Synthesis

¹H NMR (400 MHz, CDCl₃):  = 8.24 (d, J = 7.1 Hz, 2 H), 7.73–7.64 (m, 1

H), 7.54–7.29 (m, 11 H), 5.42 (d, J = 7.7 Hz, 1 H), 5.00 (d, J = 12.2 Hz, 1

H), 4.91 (d, J = 12.2 Hz, 1 H), 4.55–4.45 (m, 1 H), 3.99–3.86 (m, 1 H),

3.77–3.63 (m, 1 H), 3.44–3.32 (m, 2 H), 1.02 (t, J = 7.1 Hz, 3 H).

¹³C NMR (101 MHz, CDCl₃):  = 170.0, 156.4, 155.5, 153.7, 136.3,

131.0, 129.9, 129.4, 128.7, 128.6, 128.3, 128.1, 127.5, 125.4, 123.6,

120.1, 111.5, 106.3, 67.0, 61.9, 53.9, 36.8, 13.9.

tert-Butyl (R)-3-((3-((2-(Benzyloxy)-2-oxoethyl)amino)-2-((tert-

butoxycarbonyl)amino)-3-oxopropyl)thio)-2-phenyl-1H-indole-1-

carboxylate (11k)

Prepared from 7 (200 mg, 0.54 mmol), NCS (87 mg, 0.65 mmol),

alkyne 10b (158 mg, 0.54 mmol) and CH₂Cl₂(10 mL).

Yield: 89 mg (25%); colorless oil; []_D²⁰+9.3 (c 1.0, CHCl₃).

IR (film): 3331, 2979, 2481, 1733, 1456, 1340, 1178 cm^–1

.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₂₇H₂₆NO₅S]⁺: 476.1532;

found: 476.1536.

¹H NMR (400 MHz, CD₃OD):  = 8.21 (d, J = 8.2 Hz, 1 H), 7.75–7.72 (m,

1 H), 7.48–7.26 (m, 12 H), 5.12 (s, 2 H), 3.99–3.93 (m, 1 H), 3.83–3.75

(ABm, 2 H), 2.95 (dd, J = 13.6, 4.7 Hz, 1 H), 2.77 (dd, J = 13.6, 8.3 Hz, 1

H), 1.38 (s, 9 H), 1.21 (s, 9 H).

Indoles and Benzo[b]furans 11i–o; General Procedure

To a solution of NCS (1.2 equiv) in CH₂Cl₂was added a solution of S–

H-bond-containing peptide (1 equiv) in CH₂Cl₂at 0 °C. The mixture

was stirred for 1 h, then a solution of the corresponding alkyne (1

equiv) in CH₂Cl₂(4 mL) was added. The reaction mixture was stirred

until the starting material had disappeared and was then evaporated.

The residue was purified by reverse-flash chromatography

(MeCN/H₂O, 30–85%) to give the product.

¹³C NMR (101 MHz, CD₃OD):  = 173.5, 170.7, 157.3, 150.9, 144.4,

137.8, 137.1, 134.9, 131.9, 131.4, 129.5, 129.31, 129.25, 129.0, 126.2,

124.5, 120.6, 116.2, 112.5, 84.9, 80.9, 67.9, 55.8, 42.1, 38.0, 28.7, 27.7.

HRMS (ESI/Q-TOF): m/z [M

+

Na]⁺calcd for [C₃₆H₄₁N₃O₇SNa]⁺:

682.2563; found: 682.2556.

Benzyl N-(tert-Butoxycarbonyl)-R-(2-phenylbenzofuran-3-yl)-L-

cysteinylglycinate (11l)

Benzyl N-(tert-Butoxycarbonyl)-R-(2-phenyl-1-tosyl-1H-indol-3-

Prepared from 7 (200 mg, 0.54 mmol), NCS (87 mg, 0.65 mmol),

alkyne 10k (113 mg, 0.54 mmol) and CH₂Cl₂(10 mL).

Yield: 200 mg (66%); white solid; []_D²⁰–2.4 (c 1.0, CHCl₃).

yl)-L-cysteinylglycinate (11i)

Prepared from 7 (100 mg, 0.27 mmol), NCS (43 mg, 0.33 mmol),

alkyne 10a (94 mg, 0.27 mmol) and CH₂Cl₂(10 mL).

Yield: 103 mg (53%); white solid; []_D²⁰+23.0 (c 1.0, CHCl₃).

IR (film): 3315, 2977, 1749, 1684, 1528, 1169 cm^–1

.

IR (film): 3340, 2978, 1747, 1680, 1522, 1449, 1178 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 8.31–8.19 (m, 2 H), 7.74–7.64 (m, 1 H),

7.61–7.43 (m, 3 H), 7.45–7.28 (m, 8 H), 5.15 (s, 2 H), 4.19 (s, 1 H),

3.94–3.71 (m, 2 H), 3.35–3.20 (m, 1 H), 3.18 (dd, J = 13.7, 5.7 Hz, 1 H),

1.33 (s, 9 H).

¹³C NMR (101 MHz, CDCl₃):  = 170.34, 170.28, 169.27, 169.24, 153.8,

135.2, 131.0, 130.0, 129.4, 128.8, 128.7, 128.5, 127.6, 125.5, 123.7,

120.0, 111.6, 106.6, 80.7, 67.3, 54.4, 41.5, 41.3, 28.2.

¹H NMR (400 MHz, CD₃OD):  = 8.29 (d, J = 8.3 Hz, 1 H), 7.68 (ddd, J =

7.7, 1.3, 0.8 Hz, 1 H), 7.49–7.25 (m, 14 H), 7.17 (d, J = 7.9 Hz, 2 H), 5.11

(s, 2 H), 3.89 (dd, J = 8.2, 5.0 Hz, 1 H), 3.76 (s, 2 H), 2.87 (dd, J = 13.5,

5.0 Hz, 1 H), 2.71 (dd, J = 13.5, 8.2 Hz, 1 H), 2.30 (s, 3 H), 1.38 (s, 9 H).

¹³C NMR (101 MHz, CD₃OD):  = 173.2, 170.6, 157.2, 146.9, 145.3,

138.3, 137.1, 136.3, 133.1, 132.7, 131.9, 130.7, 130.1, 129.5, 129.3,

128.4, 127.9, 126.7, 125.7, 121.1, 117.1, 116.2, 80.9, 67.9, 55.6, 42.1,

37.5, 28.7, 21.5.

HRMS (ESI/Q-TOF): m/z [M

+

Na]⁺calcd for [C₃₁H₃₂N₂O₆SNa]⁺:

583.1879; found: 583.1876.

HRMS (ESI/Q-TOF): m/z [M + Na]⁺calcd for [C₃₈H₃₉N₃O₇S₂Na]⁺:

736.2127; found: 736.2094.

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((2-phe-

nyl-1-tosyl-1H-indol-3-yl)thio)propan-2-yl)amino)-1-carboxy-4-

oxobutan-1-aminium 2,2,2-Trifluoroacetate (11m)

Benzyl N-(tert-Butoxycarbonyl)-R-(1-((4-nitrophenyl)sulfonyl)-2-

phenyl-1H-indol-3-yl)-L-cysteinylglycinate (11j)

Prepared from 8 (150 mg, 0.27 mmol), NCS (43 mg, 0.33 mmol),

alkyne 10a (94 mg, 0.27 mmol) and CH₂Cl₂(10 mL). The product was

isolated after treatment with TFA.

Prepared from 7 (100 mg, 0.27 mmol), NCS (44 mg, 0.33 mmol),

alkyne 10c (103 mg, 0.27 mmol) and CH₂Cl₂(10 mL).

Yield: 120 mg (60%); colorless oil.

IR (film): 3063, 1740, 1653, 1375, 1178 cm^–1

Yield: 54 mg (27%); yellow solid; []_D²⁰+17.4 (c 1.0, CHCl₃).

.

IR (film): 3335, 2927, 1695, 1533, 1183, 758 cm^–1

.

¹H NMR (400 MHz, CD₃OD):  = 8.29 (d, J = 8.2 Hz, 1 H), 7.67–7.63 (m,

1 H), 7.48–7.26 (m, 13 H), 7.15 (d, J = 8.8 Hz, 2 H), 5.14–5.05 (m, 2 H),

3.98 (dd, J = 9.9, 4.5 Hz, 1 H), 3.76 (s, 2 H), 3.54 (t, J = 6.5 Hz, 1 H), 3.02

(dd, J = 13.8, 4.5 Hz, 1 H), 2.64 (dd, J = 13.8, 9.9 Hz, 1 H), 2.39–2.30 (m,

1 H), 2.28 (s, 3 H), 2.25 (s, 1 H), 2.15–1.99 (m, 1 H), 2.01–1.86 (m, 1 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.8, 173.1, 170.8, 146.8, 145.7,

138.4, 137.0, 136.1, 133.2, 132.6, 131.7, 130.7, 130.2, 129.5, 129.34,

129.29, 128.4, 127.9, 126.8, 125.8, 121.1, 117.2, 115.6, 67.9, 55.2, 54.6,

42.0, 36.8, 32.6, 27.6, 21.5.

¹H NMR (400 MHz, CD₃OD):  = 8.33 (d, J = 8.3 Hz, 1 H), 8.31–8.20 (m,

2 H), 7.76–7.64 (m, 3 H), 7.55–7.38 (m, 7 H), 7.38–7.27 (m, 5 H), 5.14

(s, 2 H), 3.88 (dd, J = 8.2, 4.9 Hz, 1 H), 3.78 (s, 2 H), 2.94 (dd, J = 13.7,

4.9 Hz, 1 H), 2.74 (dd, J = 13.7, 8.2 Hz, 1 H), 1.40 (s, 9 H).

¹³C NMR (101 MHz, CDCl₃):  = 170.0, 169.9, 169.1, 150.8, 143.3,

142.9, 136.9, 135.3, 132.0, 131.3, 130.5, 129.9, 129.8, 128.80, 128.76,

128.6, 128.2, 127.9, 126.5, 125.5, 124.3, 120.4, 116.4, 116.2, 80.7, 77.5,

77.2, 76.8, 67.4, 41.4, 41.3, 28.3.

HRMS (ESI/Q-TOF): m/z [M + Na]⁺calcd for [C₃₇H₃₆N₄O₉S₂Na]⁺:

767.1816; found: 767.1827.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₈H₃₉N₄O₈S₂]⁺: 743.2204;

found: 743.2214.

1816

S. Lapcinska, P. Arsenyan

Paper

Synthesis

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-3-((1-((4-nitro-

phenyl)sulfonyl)-2-phenyl-1H-indol-3-yl)thio)-1-oxopropan-2-

yl)amino)-1-carboxy-4-oxobutan-1-aminium 2,2,2-Trifluoroace-

tate (11n)

HRMS (ESI/Q-TOF): m/z [M

676.1549; found: 676.1575.

+

H]⁺calcd for [C₃₁H₃₅N₃O₈S₂Cl]⁺:

Ethyl N-((Benzyloxy)carbonyl)-R-(1-chloro-1-(2-((2,4-dinitrophe-

Prepared from 8 (140 mg, 0.25 mmol), NCS (41 mg, 0.3 mmol), alkyne

10c (95 mg, 0.25 mmol) and CH₂Cl₂(10 mL). The product was isolated

after treatment with TFA.

nyl)sulfonamido)phenyl)hex-1-en-2-yl)-L-cysteinate (12b)

To a solution of NCS (75 mg, 0.57 mmol, 1.2 equiv) in CH₂Cl₂(3 mL)

was added a solution of N-Cbz-cysteine ethyl ester 1 (134 mg, 0.47

mmol, 1 equiv) in CH₂Cl₂(4 mL) at 0 °C. The mixture was stirred for 1

h, then a solution of alkyne 10f (100 mg, 0.24 mmol, 0.5 equiv) in

CH₂Cl₂(4 mL) was added. The reaction mixture was stirred until the

starting material had disappeared and was then evaporated. The resi-

due was purified by flash chromatography (PE/EtOAc, 10–70%) to give

the product as a yellow oil (71 mg, 42%).

¹H NMR (400 MHz, CDCl₃):  = 8.66–8.62 (m, 1 H), 8.35 (dd, J = 8.6, 2.3

Hz, 1 H), 8.03 (dd, J = 8.6, 3.7 Hz, 1 H), 7.67–7.62 (m, 1 H), 7.40–7.32

(m, 6 H), 7.26–7.19 (m, 1 H), 7.16–7.10 (m, 1 H), 5.17–5.07 (m, 2 H),

4.53–4.42 (m, 1 H), 4.30–4.12 (m, 2 H), 3.20–3.06 (m, 2 H), 2.89 (dd,

J = 13.7, 6.0 Hz, 1 H), 2.61–2.49 (m, 1 H), 2.40–2.27 (m, 1 H), 1.54–1.46

(m, 2 H), 1.41–1.33 (m, 2 H), 1.29–1.20 (m, 3 H), 0.94 (t, J = 7.2 Hz, 3

H).

Yield: 53 mg (20%); yellow solid.

IR (film): 3283, 1743, 1653, 1533, 1183, 752 cm^–1

.

¹H NMR (400 MHz, CD₃OD):  = 8.30 (d, J = 8.3 Hz, 1 H), 8.24–8.16 (m,

2 H), 7.70–7.58 (m, 3 H), 7.53–7.35 (m, 7 H), 7.33–7.25 (m, 5 H), 5.12–

5.08 (ABm, 2 H), 3.95 (dd, J = 10.0, 4.4 Hz, 1 H), 3.76 (s, 2 H), 3.54 (dd,

J = 7.3, 6.0 Hz, 1 H), 3.06 (dd, J = 13.8, 4.4 Hz, 1 H), 2.67 (dd, J = 13.8,

10.0 Hz, 1 H), 2.42–2.30 (m, 1 H), 2.29–2.20 (m, 1 H), 2.14–2.01 (m, 1

H), 1.97–1.86 (m, 1 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.9, 173.9, 173.0, 170.8, 152.3,

145.5, 143.7, 138.3, 137.1, 133.1, 132.8, 131.3, 130.5, 129.5, 129.34,

129.31, 128.6, 127.3, 126.4, 125.5, 121.4, 117.2, 117.0, 67.9, 55.2, 54.6,

42.0, 36.7, 32.6, 27.6.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₇H₃₆N₅O₁₀S₂]⁺: 774.1898;

found: 774.1904.

HRMS (ESI/Q-TOF): m/z [M

+

H]⁺calcd for [C₃₁H₃₄N₄O₁₀S₂Cl]⁺:

721.1399; found: 721.1407.

tert-butyl N⁵-((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-1-oxo-3-

((2-phenylbenzofuran-3-yl)thio)propan-2-yl)-N²-(tert-butoxycar-

bonyl)-L-glutaminate (11o)

1-(2-(Phenylethynyl)phenyl)pyrene (13d)

1-Bromo-2-(phenylethynyl)benzene (0.6 g, 2.33 mmol, 1 equiv), 1-

pyrenylboronic acid (0.86 g, 3.5 mmol, 1.5 equiv), Pd(PPh₃)₄(0.135 g,

0.167 mmol, 0.05 equiv), Na₂CO₃(0.49 g, 4.67 mmol, 2 equiv) and a

mixture of solvents [EtOH (6 mL), H₂O (6 mL), toluene (12 mL)] were

added sequentially into a high-pressure vial. The resulting mixture

was stirred at 70 °C for 8 h. Next, the mixture was cooled to rt and

extracted with EtOAc (3 × 10 mL). The combined organic layers were

dried over Na₂SO₄, filtered and the volatiles were evaporated under

reduced pressure. The residue was purified by flash column chroma-

tography on silica gel (PE/EtOAc, 2–20%) to afford the product as a yel-

low solid (0.64 g, 72%).

¹H NMR (400 MHz, CDCl₃):  = 8.28 (d, J = 7.8 Hz, 1 H), 8.23 (dd, J = 7.8,

1.2 Hz, 1 H), 8.18 (dd, J = 7.8, 1.2 Hz, 1 H), 8.14 (d, J = 1.8 Hz, 2 H), 8.11

(d, J = 7.8 Hz, 1 H), 8.07–7.97 (m, 3 H), 7.84–7.76 (m, 1 H), 7.63–7.56

(m, 1 H), 7.59–7.45 (m, 2 H), 7.11–7.02 (m, 1 H), 7.01–6.91 (m, 2 H),

6.79–6.71 (m, 2 H).

Prepared from 8 (140 mg, 0.25 mmol), NCS (41 mg, 0.3 mmol), alkyne

10k (53 mg, 0.25 mmol) and CH₂Cl₂(10 mL).

Yield: 62 mg (33%); white solid.

IR (film): 3289, 2977, 1719, 1700, 1653, 1507, 1155, 748 cm^–1

.

¹H NMR (400 MHz, CD₃OD):  = 8.32–8.22 (m, 2 H), 7.77–7.66 (m, 1

H), 7.62–7.23 (m, 11 H), 5.10 (s, 2 H), 4.34 (dd, J = 9.4, 4.8 Hz, 1 H),

3.96–3.87 (m, 1 H), 3.86–3.76 (ABm, 2 H), 3.38–3.32 (m, 1 H), 3.01

(dd, J = 13.7, 9.4 Hz, 1 H), 2.25–2.09 (m, 1 H), 2.05–1.82 (m, 2 H), 1.82–

1.60 (m, 1 H), 1.46 (s, 9 H), 1.44 (s, 9 H).

¹³C NMR (101 MHz, CDCl₃):  = 172.4, 171.5, 170.1, 169.3, 156.4,

155.9, 153.8, 135.3, 131.0, 130.0, 129.5, 128.8, 128.7, 128.6, 128.5,

127.7, 125.5, 123.7, 120.1, 111.6, 106.7, 82.4, 80.1, 67.2, 53.4, 53.0,

41.4, 41.3, 36.0, 32.0, 28.4, 28.1.

HRMS (ESI/Q-TOF): m/z [M

+

Na]⁺calcd for [C₄₀H₄₇N₃O₉SNa]⁺:

¹³C NMR (101 MHz, CDCl₃):  = 143.5, 136.4, 132.3, 131.4, 131.3,

131.1, 131.0, 130.9, 129.1, 128.18, 128.15, 127.93, 127.87, 127.52,

127.49, 127.3, 126.0, 125.8, 125.1, 125.0, 124.9, 124.8, 124.3, 123.9,

123.0, 93.0, 89.2.

768.2925; found: 768.2933.

Ethyl N-((Benzyloxy)carbonyl)-R-(1-chloro-1-(2-((4-nitrophe-

nyl)sulfonamido)phenyl)hex-1-en-2-yl)-L-cysteinate (12a)

HRMS (ESI/Q-TOF): m/z [M]⁺calcd for [C₃₀H₁₈]: 378.1409; found:

To a solution of NCS (85 mg, 0.63 mmol, 1.2 equiv) in CH₂Cl₂(3 mL)

was added a solution of N-Cbz-cysteine ethyl ester 1 (150 mg, 0.53

mmol, 1 equiv) in CH₂Cl₂(4 mL) at 0 °C. The mixture was stirred for 1

h, then a solution of alkyne 10d (100 mg, 0.26 mmol, 0.5 equiv) in

CH₂Cl₂(4 mL) was added. The reaction mixture was stirred until the

starting material had disappeared and was then evaporated. The resi-

due was purified by flash chromatography (PE/EtOAc, 10–70%) to give

the product as a yellow solid (78 mg, 44%).

¹H NMR (400 MHz, CDCl₃):  = 8.25–8.13 (m, 2 H), 8.00–7.86 (m, 2 H),

7.67–7.60 (m, 1 H), 7.41–7.28 (m, 6 H), 7.20–7.04 (m, 2 H), 5.22–5.09

(m, 2 H), 4.51–4.39 (m, 1 H), 4.32–4.09 (m, 2 H), 3.23–3.08 (m, 1 H),

3.00–2.82 (m, 1 H), 2.68–2.53 (m, 1 H), 2.49–2.27 (m, 1 H), 1.62–1.46

(m, 2 H), 1.45–1.34 (m, 2 H), 1.32–1.20 (m, 3 H), 1.03–0.92 (m, 3 H).

378.1403.

S-Peptide-Containing Polyaromatic Hydrocarbons 14a–f; General

Procedure

To a solution of N-chlorosuccinimide (2.2 equiv) in CH₂Cl₂(3 mL) was

added a solution of S–S- bond-containing peptide (1 equiv) in CH₂Cl₂

(4 mL) at 0 °C. The mixture was stirred for 1 h, then a solution of the

corresponding alkyne (1 equiv) in CH₂Cl₂(3 mL) was added. The reac-

tion mixture was stirred until the starting material had disappeared

and was then evaporated. The residue was purified by flash chroma-

tography (PE/EtOAc, 10–85%) (14b and 14d). Products 14a, 14c and

14e,f were isolated after treatment with TFA and purified by reverse-

phase chromatography (MeOH/H₂O, 10–85%).

1817

S. Lapcinska, P. Arsenyan

Paper

Synthesis

(R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-3-((2-methyl-10-phen-

ylphenanthren-9-yl)thio)-1-oxopropan-2-aminium 2,2,2-Trifluo-

roacetate (14a)

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((6-

phenylbenzo[c]phenanthren-5-yl)thio)propan-2-yl)amino)-1-car-

boxy-4-oxobutan-1-aminium 2,2,2-Trifluoroacetate (14d)

Prepared from 5 (200 mg, 0.27 mmol), NCS (79 mg, 0.59 mmol) and

alkyne 13a (73 mg, 0.33 mmol).

Prepared from 6a (200 mg, 0.18 mmol), NCS (53 mg, 0.40 mmol) and

alkyne 13b (55 mg, 0.18 mmol).

Yield: 127 mg (72%); colorless oil; []_D²⁰+41.2 (c 1.0, MeOH).

Yield: 102 mg (81%); light yellow solid.

¹H NMR (400 MHz, CD₃OD):  = 8.87–8.80 (m, 1 H), 8.82–8.75 (m, 1

H), 8.74 (d, J = 8.5 Hz, 1 H), 7.79–7.70 (m, 2 H), 7.61–7.47 (m, 4 H),

7.42–7.22 (m, 7 H), 7.20–7.15 (m, 1 H), 5.17–5.05 (ABm, 2 H), 3.86–

3.73 (m, 3 H), 3.10 (dd, J = 13.8, 5.8 Hz, 1 H), 3.00 (dd, J = 13.8, 7.3 Hz,

1 H), 2.37 (s, 3 H).

¹H NMR (400 MHz, CD₃OD):  = 9.12–8.99 (m, 2 H), 8.99–8.89 (m, 1

H), 8.01 (d, J = 7.4 Hz, 1 H), 7.83–7.62 (m, 5 H), 7.59–7.45 (m, 3 H),

7.44–7.20 (m, 8 H), 5.08 (s, 2 H), 4.16 (dd, J = 9.3, 4.6 Hz, 1 H), 3.93 (t,

J = 6.4 Hz, 1 H), 3.84–3.68 (m, 2 H), 3.09 (dd, J = 13.8, 4.6 Hz, 1 H), 2.86

(dd, J = 13.8, 9.3 Hz, 1 H), 2.48–2.27 (m, 2 H), 2.14–1.97 (m, 2 H).

¹³C NMR (101 MHz, CD₃OD):  = 170.4, 168.6, 147.5, 141.6, 138.1,

136.9, 133.3, 132.7, 132.4, 131.7, 131.6, 130.7, 130.3, 129.58, 129.55,

129.43, 129.39, 128.93, 128.85, 128.81, 128.50, 128.48, 128.3, 124.2,

123.9, 68.1, 53.9, 42.1, 38.4, 21.6.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₃H₃₁N₂O₃S]⁺: 535.2050;

found: 535.2071.

¹³C NMR (101 MHz, CD₃OD):  = 174.1, 173.0, 171.4, 170.7, 146.6,

141.6, 137.0, 135.0, 134.7, 132.0, 131.9, 131.8, 131.4, 130.7, 130.2,

129.84, 129.82, 129.6, 129.5, 129.4, 129.33, 129.26, 128.6, 128.3,

128.24, 128.18, 128.0, 127.8, 127.51, 127.48, 126.1, 67.9, 65.2, 54.8,

53.4, 42.0, 41.7, 38.6, 32.4, 26.9.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₄₁H₃₈N₃O₆S]⁺: 700.2476;

found: 700.2479.

Benzyl N-(tert-Butoxycarbonyl)-S-(6-phenylbenzo[c]phenanthren-

5-yl)-L-cysteinylglycinate (14b)

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((5-

phenylbenzo[g]chrysen-6-yl)thio)propan-2-yl)amino)-1-carboxy-

4-oxobutan-1-aminium 2,2,2-Trifluoroacetate (14e)

Prepared from 5 (241 mg, 0.33 mmol), NCS (96 mg, 0.72 mmol) and

alkyne 13b (120 mg, 0.33 mmol).

Prepared from 6a (105 mg, 0.095 mmol), NCS (28 mg, 0.21 mmol) and

alkyne 13c (34 mg, 0.095 mmol).

Yield: 200 mg (91%); light yellow solid; []_D²⁰+26.7 (c 1.0, CHCl₃).

¹H NMR (400 MHz, CD₃OD):  = 9.01 (t, J = 8.8 Hz, 2 H), 8.95–8.89 (m,

1 H), 8.00–7.93 (m, 1 H), 7.77–7.58 (m, 5 H), 7.55–7.43 (m, 3 H), 7.38–

7.17 (m, 8 H), 5.06 (s, 2 H), 4.03–3.95 (m, 1 H), 3.82–3.70 (ABm, 2 H),

2.99 (dd, J = 13.6, 4.6 Hz, 1 H), 2.88 (dd, J = 13.6, 8.4 Hz, 1 H), 1.27 (s, 9

H).

¹³C NMR (101 MHz, CD₃OD):  = 173.5, 170.6, 157.2, 146.3, 141.6,

137.0, 134.9, 134.8, 131.9, 131.8, 131.7, 131.4, 130.7, 129.72, 129.66,

129.5, 129.4, 129.33, 129.26, 128.6, 128.3, 128.1, 127.7, 127.41,

127.37, 126.1, 80.8, 67.8, 55.9, 42.1, 39.2, 28.6.

Yield: 33 mg (40%); light yellow oil.

¹H NMR (400 MHz, CD₃OD):  = 8.80 (dd, J = 8.4, 1.4 Hz, 1 H), 8.78–

8.68 (m, 3 H), 8.60 (d, J = 8.2 Hz, 1 H), 7.78–7.59 (m, 4 H), 7.49–7.34

(m, 6 H), 7.34–7.21 (m, 6 H), 7.03–6.94 (m, 1 H), 5.10–4.96 (ABm, 2 H),

3.74 (dd, J = 9.5, 4.5 Hz, 1 H), 3.65 (s, 2 H), 3.42 (t, J = 6.6 Hz, 1 H), 2.99

(dd, J = 13.9, 4.5 Hz, 1 H), 2.74 (dd, J = 13.9, 9.5 Hz, 1 H), 2.28–2.16 (m,

1 H), 2.16–2.05 (m, 1 H), 1.99–1.88 (m, 1 H), 1.86–1.76 (m, 1 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.6, 173.1, 170.7, 144.1, 137.1,

134.3, 133.7, 133.4, 132.8, 132.1, 132.0, 131.3, 131.2, 131.04, 130.96,

130.4, 130.17, 130.13, 129.5, 129.4, 129.3, 129.3, 129.0, 128.7, 128.6,

128.4, 128.3, 127.8, 127.4, 126.5, 124.7, 124.2, 67.8, 55.2, 54.7, 49.6,

49.4, 49.2, 49.0, 48.8, 48.6, 48.4, 41.9, 38.2, 32.7, 27.5.

HRMS (ESI/Q-TOF): m/z [M

+

Na]⁺calcd for [C₄₁H₃₈N₂O₅SNa]⁺:

693.2399; found: 693.2397.

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-3-((2-methyl-10-

phenylphenanthren-9-yl)thio)-1-oxopropan-2-yl)amino)-1-car-

boxy-4-oxobutan-1-aminium 2,2,2-Trifluoroacetate (14c)

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₄₅H₄₀N₃O₆S]⁺: 750.2632;

found: 750.2643.

Prepared from 6a (200 mg, 0.18 mmol), NCS (53 mg, 0.40 mmol) and

alkyne 13a (48 mg, 0.18 mmol).

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((12-

phenylbenzo[pqr]picen-11-yl)thio)propan-2-yl)amino)-1-car-

boxy-4-oxobutan-1-aminium Acetate (14f)

Yield: 91 mg (65%); colorless oil.

¹H NMR (400 MHz, CD₃OD/CDCl₃):  = 8.82–8.71 (m, 2 H), 8.66 (d, J =

8.5 Hz, 1 H), 7.74–7.62 (m, 2 H), 7.55–7.41 (m, 4 H), 7.38–7.20 (m, 7

H), 7.15 (s, 1 H), 5.13–5.02 (ABm, 2 H), 4.14 (dd, J = 9.6, 4.5 Hz, 1 H),

3.80 (s, 2 H), 3.52 (t, J = 6.5 Hz, 1 H), 3.05 (dd, J = 13.5, 4.5 Hz, 1 H),

2.80 (dd, J = 13.5, 9.6 Hz, 1 H), 2.42–2.33 (m, 4 H), 2.35–2.21 (m, 2 H),

2.11–1.98 (m, 1 H), 2.00–1.87 (m, 1 H).

¹³C NMR (101 MHz, CD₃OD/CDCl₃):  = 174.5, 172.8, 170.4, 146.8,

141.3, 137.4, 136.4, 133.0, 132.8, 131.8, 131.31, 131.25, 130.0, 129.6,

129.4, 129.2, 129.1, 129.0, 128.9, 128.6, 128.3, 128.1, 127.83, 127.81,

123.6, 123.4, 67.7, 54.8, 54.6, 41.8, 38.4, 32.5, 27.1, 21.7.

Prepared from 6a (200 mg, 0.18 mmol), NCS (53 mg, 0.40 mmol) and

alkyne 13d (110 mg, 0.18 mmol).

Yield: 50 mg (36%); yellow oil.

¹H NMR (400 MHz, CD₃OD):  = 9.15 (d, J = 9.3 Hz, 1 H), 8.97 (d, J = 8.1

Hz, 1 H), 8.91 (d, J = 8.1 Hz, 1 H), 8.22 (d, J = 8.7 Hz, 2 H), 8.11 (d, J = 7.5

Hz, 1 H), 8.00 (t, J = 7.6 Hz, 1 H), 7.93–7.80 (m, 2 H), 7.82–7.62 (m, 3

H), 7.62–7.50 (m, 3 H), 7.42–7.26 (m, 2 H), 7.28–7.15 (m, 5 H), 5.03 (s,

2 H), 4.17 (dd, J = 9.3, 4.5 Hz, 1 H), 3.91 (t, J = 6.3 Hz, 1 H), 3.80–3.67

(ABm, 2 H), 3.12 (dd, J = 13.8, 4.5 Hz, 1 H), 2.90 (dd, J = 13.8, 9.3 Hz, 1

H), 2.47–2.27 (m, 2 H), 2.12–1.97 (m, 2 H).

¹³C NMR (101 MHz, CD₃OD):  = 174.1, 172.9, 171.5, 170.6, 146.8,

141.6, 137.0, 133.9, 132.9, 132.3, 132.2, 132.1, 131.7, 131.0, 130.8,

130.7, 130.2, 129.5, 129.40, 129.35, 129.3, 129.2, 129.1, 128.8, 128.7,

128.4, 128.2, 128.0, 127.72, 127.66, 127.4, 126.9, 126.4, 126.2, 125.7,

124.7, 67.9, 54.8, 53.5, 42.0, 38.5, 32.4, 26.9, 22.1.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₈H₃₈N₃O₆S]⁺: 664.2476;

found: 664.2502.

1818

S. Lapcinska, P. Arsenyan

Paper

Synthesis

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₄₇H₄₀N₃O₆S]⁺: 774.2632;

found: 774.2645.

5.0 Hz, 1 H), 3.87 (t, J = 6.4 Hz, 1 H), 3.78 (s, 2 H), 2.95 (dd, J = 13.8, 5.0

Hz, 1 H), 2.71 (dd, J = 13.8, 9.3 Hz, 1 H), 2.39–2.25 (m, 1 H), 2.23–2.13

(m, 1 H), 2.09–1.98 (m, 2 H), 1.52 (s, 9 H).

¹³C NMR (101 MHz, CD₃OD):  = 173.8, 172.8, 170.6, 169.3, 163.1,

160.5, 139.4, 137.0, 136.7, 134.4, 131.5, 131.2, 130.7, 130.0, 129.6,

129.4, 129.3, 129.1, 126.9, 122.0, 109.7, 85.5, 67.9, 53.99, 53.95, 42.0,

37.5, 31.9, 28.2, 26.9.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₆H₄₀N₃O₈S]⁺: 674.2531;

found: 674.2543.

(S)-1-Carboxy-4-(((R)-1-((carboxymethyl)amino)-1-oxo-3-((7-

phenyldibenzo[m,pqr]tetraphen-8-yl)thio)propan-2-yl)amino)-4-

oxobutan-1-aminium Acetate (15)

To a solution of 14f (30 mg) in MeOH (2 mL) and THF (1 mL) was add-

ed Pd/C and then H₂was bubbled through the reaction mixture for 1

h. After filtration and evaporation, product 15 was obtained as a yel-

low solid (16 mg, 60%).

¹H NMR (400 MHz, CD₃OD/CDCl₃):  = 9.19 (d, J = 9.3 Hz, 1 H), 9.09–

9.02 (m, 1 H), 8.91–8.82 (m, 1 H), 8.20 (dd, J = 12.7, 8.5 Hz, 2 H), 8.08

(d, J = 7.0 Hz, 1 H), 8.02–7.93 (m, 2 H), 7.90 (d, J = 9.0 Hz, 1 H), 7.79 (d,

J = 9.0 Hz, 1 H), 7.75–7.66 (m, 2 H), 7.56–7.47 (m, 3 H), 7.42–7.36 (m,

1 H), 7.34–7.28 (m, 1 H), 4.17–4.09 (m, 2 H), 3.78–3.62 (m, 2 H), 3.11

(dd, J = 13.5, 5.1 Hz, 1 H), 2.92 (dd, J = 13.5, 8.8 Hz, 1 H), 2.41–2.17 (m,

2 H), 2.09–1.99 (m, 2 H).

¹³C NMR (101 MHz, CD₃OD/CDCl₃):  = 173.3, 172.0, 171.3, 145.7,

140.5, 132.7, 131.8, 131.09, 131.05, 130.8, 129.9, 129.8, 129.7, 129.0,

128.4, 128.1, 127.8, 127.39, 127.36, 127.2, 127.1, 126.8, 126.6, 126.4,

126.0, 125.4, 125.2, 124.9, 124.8, 124.0, 53.8, 37.2, 31.7, 25.6, 1.6.

(S)-4-(((R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-3-((1-methyl-2-

oxo-4-phenyl-1,2-dihydroquinolin-3-yl)thio)-1-oxopropan-2-

yl)amino)-1-carboxy-4-oxobutan-1-aminium 2,2,2-Trifluoroace-

tate (21)

To a solution of NCS (29 mg, 0.22 mmol, 1.2 equiv) in CH₂Cl₂(3 mL) at

0 °C was added a solution of 8 (100 mg, 0.18 mmol, 1 equiv) in CH₂Cl₂

(4 mL). The mixture was stirred for 30 min, then a solution of alkyne

20 (42 mg, 0.18 mmol, 1 equiv) in CH₂Cl₂(3 mL) was added and the

mixture was stirred for 1 h. TFA (1 mL) was added and the mixture

was stirred for 1 h. After evaporation, the mixture was purified by re-

verse-phase chromatography (C-18, MeCN/H₂O, 15–85%) to provide

the product as a colorless oil (45 mg, 44%).

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₄₀H₃₄N₃O₆S]⁺: 684.2163;

found: 684.2170.

¹H NMR (400 MHz, CD₃OD):  = 7.69–7.63 (m, 2 H), 7.54–7.47 (m, 3

H), 7.36–7.29 (m, 4 H), 7.26–7.22 (m, 2 H), 7.21–7.17 (m, 2 H), 7.13–

7.09 (m, 1 H), 5.11 (s, 2 H), 4.30 (dd, J = 9.2, 4.5 Hz, 1 H), 4.04 (t, J = 6.4

Hz, 1 H), 3.92–3.89 (m, 2 H), 3.87 (s, 3 H), 3.30–3.25 (m, 1 H), 2.97 (dd,

J = 13.8, 9.2 Hz, 1 H), 2.58–2.46 (m, 2 H), 2.27–2.10 (m, 2 H).

(R)-1-((2-(Benzyloxy)-2-oxoethyl)amino)-1-oxo-3-((1-oxo-3-phe-

nyl-1H-isochromen-4-yl)thio)propan-2-aminium 2,2,2-Trifluoro-

acetate (17a)

¹³C NMR (101 MHz, CD₃OD):  = 174.3, 173.2, 171.5, 170.7, 162.7,

157.1, 140.7, 138.3, 137.1, 132.6, 130.3, 129.8, 129.7, 129.52, 129.50,

129.4, 129.3, 126.1, 123.8, 122.7, 116.1, 67.9, 54.9, 53.5, 42.1, 36.1,

32.5, 31.4, 27.0.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₃₃H₃₅N₄O₇S]⁺: 631.2221;

found: 631.2242.

To a solution of NCS (43 mg, 0.33 mmol, 1.2 equiv) in CH₂Cl₂(3 mL) at

0 °C was added a solution of 7 (100 mg, 0.27 mmol, 1 equiv) in CH₂Cl₂

(4 mL). The mixture was stirred for 30 min, then a solution of alkyne

16 (64 mg, 0.27 mmol, 1 equiv) in CH₂Cl₂(3 mL) was added and the

mixture was stirred for 1 h. TFA (1 mL) was added and the mixture

was stirred for 1 h. After evaporation, the mixture was purified by re-

verse-phase chromatography (C-18, MeCN/H₂O, 15–85%) to provide

the product as a colorless oil (84 mg, 53%).

¹H NMR (400 MHz, CD₃OD):  = 8.33–8.25 (m, 2 H), 8.00–7.92 (m, 1

H), 7.85–7.78 (m, 2 H), 7.71–7.62 (m, 1 H), 7.57–7.48 (m, 3 H), 7.38–

7.24 (m, 5 H), 5.19–5.07 (ABm, 2 H), 3.84 (t, J = 6.3 Hz, 1 H), 3.78 (s, 2

H), 3.06–2.95 (m, 2 H).

¹³C NMR (101 MHz, CD₃OD):  = 170.3, 168.3, 162.8, 160.6, 139.0,

137.0, 136.9, 134.2, 131.6, 131.3, 130.7, 130.2, 129.6, 129.5, 129.44,

129.42, 126.8, 122.0, 109.4, 68.1, 53.5, 42.0, 37.4.

HRMS (ESI/Q-TOF): m/z [M + H]⁺calcd for [C₂₇H₂₅N₂O₅S]⁺: 489.1479;

found: 489.1494.

Evaluation of Cell Permeability and Fluorescence

Rat embryo myoblast cells lines H9C2 (2-1) were purchased from

ATCC (ATCC^®CRL-1446™, Rockville, MD) and maintained in DMEM

supplemented with 10% FBS at 37 °C in humidified air containing 5%

CO₂. All the media and serums were purchased from Sigma-Aldrich.

During log-phase growth, the cells were collected and transferred to a

4 well on lumox^®slide (Sarstedt) at a concentration of 50000 cells/mL

and incubated for 72 h at 37 °C in humidified air containing 5% CO₂.

The medium was then exchanged with a medium containing com-

pound 15 at a concentration of 10 M and incubated for 17 h. The me-

dium was removed and washed once with fresh medium. Aspirate

culture media and an equal volume of 10 M Nile Red Staining Solu-

tion were added followed by incubation at 37 °C/5% CO₂for 30 min.

The Nile Red Staining Solution was removed and the wells were

washed with PBS. Cells were photographed using a Nikon Eclipse

TE300 inverted fluorescence microscope with a Nikon G-2A filter (EX

510-560, DM 575, BA 590) for Nile Red and a Nikon UV-2A filter (EX

330-380, DM 400, BA 420) for 15 (magnification: ×100).

(7R,12S)-15,15-Dimethyl-3,6,9,13-tetraoxo-7-(((1-oxo-3-phenyl-

1H-isochromen-4-yl)thio)methyl)-1-phenyl-2,14-dioxa-5,8-diaza-

hexadecan-12-aminium 2,2,2-Trifluoroacetate (17b)

To a solution of NCS (29 mg, 0.22 mmol, 1.2 equiv) in CH₂Cl₂(3 mL) at

0 °C was added a solution of 8 (100 mg, 0.18 mmol, 1 equiv) in CH₂Cl₂

(4 mL). The mixture was stirred for 30 min, then a solution of alkyne

16 (42 mg, 0.18 mmol, 1 equiv) in CH₂Cl₂(3 mL) was added and the

mixture was stirred for 1 h. TFA (1 mL) was added and the mixture

was stirred for 1 h. After evaporation, the mixture was purified by re-

verse-phase chromatography (C-18, MeCN/H₂O, 15–85%) to provide

the product as a colorless oil (57 mg, 40%).

¹H NMR (400 MHz, CD₃OD):  = 8.32–8.28 (m, 1 H), 8.25 (d, J = 8.0 Hz,

1 H), 7.95–7.89 (m, 1 H), 7.80–7.75 (m, 2 H), 7.67–7.61 (m, 1 H), 7.52–

7.42 (m, 3 H), 7.36–7.26 (m, 5 H), 5.15–5.04 (m, 2 H), 4.15 (dd, J = 9.3,

Funding Information

Financial support from the Latvijas Organiskās sintēzes institūts (Lat-

vian Institute of Organic Synthesis) is gratefully acknowledged (inter-

nal grant: IG-2020-07). LatvijasOrg

a

n

iskāssi

n

tēzesinsit

ū

ts(IG-2

0

2

0-07)

1819

S. Lapcinska, P. Arsenyan

Paper

Synthesis

Acknowledgment

(27) Wismach, C.; Jones, P. G.; du Mont, W.-. W.; Mugesh, G.; Papke,

U.; Linden, H. B.; Arca, M.; Lippolis, V. Eur. J. Inorg. Chem. 2014,

8, 1399.

(28) Li, Z.-S.; Wang, W.-M.; Lu, W.; Niu, C.-W.; Li, Y.-H.; Li, Z.-M.;

Wang, J.-G. Bioorg. Med. Chem. Lett. 2013, 23, 3723.

(29) Yukimoto, M.; Nishino, R.; Suzuki, F.; Ishihara, M.; Sugamata, K.;

Minoura, M. Chem. Lett. 2018, 47, 425.

The authors would like to thank I. Domracheva for in vitro studies and

K. Leduskrasts for photo-physical experiments.

Supporting Information

(30) Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed, J. E.;

Sexton, K. Org. Lett. 2004, 6, 819.

(31) Huang, D.; Chen, J.; Dan, W.; Ding, J.; Liu, M.; Wu, H. Adv. Synth.

Catal. 2012, 354, 2123.

Supporting information for this article is available online at

https://doi.org/10.1055/a-1343-5607.

S

u

p

ortingI

n

formati

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nS

u

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o

n

(32) Yadav, J. S.; Reddy, B. V. S.; Reddy, Y. J.; Praneeth, K. Synthesis

2009, 1520.

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Article Doi

Straightforward Functionalization of Sulfur-Containing Peptides via 5- And 6- endo - Dig Cyclization Reactions

DOI: 10.1055/a-1343-5607

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Full text of DOI:10.1055/a-1343-5607

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