Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones

Pedro Salas-Ambrosio, Antoine Tronnet, Marc Since, Sandra Bourgeade-Delmas, Jean-Luc Stigliani,

Communication

Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide

(

LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access

to Bioactive Backbones

Amelie Vax, S é bastien Lecommandoux, Bruno Dupuy, Pierre Verhaeghe,* and Colin Bonduelle*

Cite This: J. Am. Chem. Soc. 2021, 143, 3697 −3702

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sı Supporting Information

ABSTRACT: Cyclic polymers display unique physicochemical and biological properties. However, their development is often

limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-

carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the

unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against

Clostridioides diﬃcile, a bacterium responsible for nosocomial infections.

yclic polymers are unique macromolecules that have

diﬀerent physical properties than their linear counter-

parts due to the “double constraint” related to the cyclization.

(DBU) can aﬀord cyclic polypeptoids from NNCA.

Although being quite eﬃcient, these approaches remain

sensitive to solvent eﬀects, limiting the scope of the monomers

18,21

For instance, cyclic polyesters demonstrated modiﬁed

that can be used for solubility reasons.

Herein, we report

2,3

solubility,

crystallinity,

and an improved degradation

an alternative approach leading to another REP of NNCA that

can be performed in a more polar medium (DMF), using

lithium bis(trimethylsilyl)amide (LiHMDS). LiHMDS is a

strong base already known to promote the superfast ROP of

nonalkylated NCA monomers. Unexpectedly, in this work,

the use of LiHMDS allowed the synthesis of cyclic

polypeptoids when mixed with various NNCA: sarcosine-

NCA (Sar-NCA), N-benzyl-NCA (N-phe-NCA), or N-Cbz-

aminobutyl-NCA (Z-N-lys-NCA). Using those monomers, the

LiHMDS methodology allows simple access to cationic

macromolecules with interesting antibacterial activities

proﬁle against chemical hydrolysis. Theoretically, the radius

of gyration of a cyclic polymer is expected to be 1/√2 that of

the linear one in unperturbed conditions. With cyclic diblock

copolymers, the models predict a transition from the

disordered to an ordered phase in bulk at (χN) = 17.8 for a

symmetric diblock copolymer as compared to linear diblocks

for which (χN) = 10.5. In solution, cyclic polymers possess a

ring-like topology displaying smaller hydrodynamic volume

and it has been shown that cyclization concentrates spatial

distribution of the side chains to achieve unique biological

properties. For these reasons, eﬃcient syntheses of cyclic

polymers have attracted great interest in recent years.

So far, three main routes have been proposed to synthesize

(

Scheme 1).

As part of a catalytic study aiming at synthesizing

polysarcosine (poly(sar)), we ﬁrst implemented the ROP of

Sar-NCA at 0.4 M in DMF from hexylamine, with or without a

stoichiometric amount of LiHMDS (as compared to hexyl-

amine) at a monomer/LiHMDS ratio (M/B; B stands for

base) = 100, leading to poly(sar) 1 and 2 (Table 1).

Monitoring the disappearance of the NNCA peak by FTIR

Figure S3 ) revealed that the Sar-NCA stretching was

disappearing at a faster rate of k = 9.5 × 10 min in the

absence of hexylamine (poly(sar) 3). Upon puriﬁcation,

polymer 3 was characterized by H NMR and the SEC

,9,10

cyclic polymers.

Two of these routes involve a

postpolymerization grafting using tailored extremities of linear

11−13

polymers and uni- or bimolecular couplings.

In these two

options, the synthesis of polymers remains diﬃcult in marked

contrast to the third option, named ring-expansion polymer-

,14

ization (REP), that is far more eﬃcient.

REP involves the

(

insertion of cyclic monomers via the use of speciﬁc catalyst/

−3

−1

initiator systems and it has been used in metathesis

polymerization to produce cyclic oleﬁns, or in ring-opening

4,16

polymerization (ROP) to produce cyclic polyesters

and

analysis revealed a lower elution time and a narrow dispersity

polypeptides. N-Heterocyclic carbenes (NHCs) have pro-

vided spectacular results in this direction by promoting REP

with evolving growth control.

14,17,18

Received: December 22, 2020

Published: March 2, 2021

This work is focused on the synthesis of cyclic poly(α-

peptoid)s using the ROP of glycine-based N-alkylated-N-

carboxyanhydrides (NNCA). Zhang and her collaborators

carried out pioneer works about such cyclic structures: they

have shown that NHC and 1,8-diazabicycloundec-7-ene

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 3697−3702

697

Journal of the American Chemical Society

Communication

Scheme 1. LiHMDS-Mediated REP of NNCA

Cyclic and bioactive species are produced in a controlled fashion.

Table 1. LiHMDS-Mediated REP of Sar-NCA (B =

LiHMDS)

theo M

DP from

M/B

(g/mol)

SEC

⟨G⟩

poly(sar) 1 100

7100

2500

4200

5300

14200

28400

7100

6100

2300

3500

1800

2100

2600

5000

8200

3200

115

1.06

1.29

1.06

1.03

1.04

1.08

1.06

1.04

1.10

poly(sar) 2 100

poly(sar) 3 100

poly(sar) 4 35

poly(sar) 5 60

poly(sar) 6 75

poly(sar) 7 200

poly(sar) 8 400

poly(sar) 9 50 + 50

0.88

0.81

0.88

0.89

0.83

Mass relation ⟨G⟩ (M_w_c_y_c_l_i_c/M_w_a_f_t_e_r_p_r_o_p_y_l_a_t_i_o_n) provides a clue

regarding the radius gyration. Molar masses were determined by

SEC using MALS detection in DMF (LiBr 1%). Theoretical M

−1

taking B as initiator. Polymerization degree (DP = M /71 g mol ).

B stands for hexylamine.

(

Figure 1A, Figure S4, and Table 1). MALDI analyses were

then carried out to clarify the structure of 3: it revealed the

presence of three sets of ions matching Δ ≈ 71 g/mol with an

initiation attributable to previously observed spirocyclic

structures (Figure 1B). So far, the existence of cyclic

poly(α-peptoid)s in solvents with high dielectric constants

such as DMF was never reported. In this work, ESI-MS and

FTIR spectra run during the early stages of the polymerization

Figure 1. Macromolecular characterizations: (A) SEC character-

ization in DMF (1% LiBr) of poly(sar) 1 and poly(sar) 3. (B) Full

MALDI-ToF spectra with assignment of the individual peaks from

poly(sar) 1.

molecule. H and ¹³C NMR spectra of this new polymer

Figures S6 and S7) highlight most of the key intermediates of

corroborated the proposed Mu

and S13 ), and FTIR analyses showed both the carbonyl

stretching of the zwitterionic structure and the Munchnone

initiation species at 1568 and 1759 cm as well as the polymer

nchnone species (Figures S10

a possible REP mechanism starting from Sar-NCA deproto-

nation ((Scheme 2) and Scheme S4.4). Moreover, DFT

calculations carried out on a model zwitterionic intermediate

−

(

5 monomer unit) show that the cyclic form is energetically

backbone at 1639 cm (Figure S11). It should be noted that

the mesoionic oxazole moiety is known to ring-open, in acidic

more favorable than the linear one (ΔG = −18.6 kJ/mol,

Figure S8 ). As depicted in Figure 2, the chemical structure of

this intermediate includes LiHMDS and involves three

stabilizing interactions between the polymer and the Li⁺

cation, allowing spatial proximity between the anionic

carbamoyl extremity and the positive charge of the

conditions (Scheme S4.5 ). Thus, the reactivity of the 5-OH-

DHE ring from the cyclic structures was ﬁrst evaluated by

exposing polymer 4 to HBr (2 equiv) in TFA. After this

treatment, MALDI-TOF and C NMR spectra indeed

revealed possible ring-opening into an iminium acid derivative

(Figures S12 −S14 ) without modiﬁcation of the overall

macrocyclic topology, as attested by NMR, MALDI-TOF

and SEC analyses (Figure S15). On the other hand, cyclic

poly(α-peptoid) were reported to react with acyl chlorides to

5-OH-DHE in Figure 2).

By decreasing the M/B ratio to 35 (an increase in dispersity

was observed for lower ratios), polymer 4 was synthesized to

conﬁrm the presence of a Munchnone ring on the macro-

nchnone moiety (5-hydroxy-2,3-dihydrooxazolium enolate

aﬀord the linear counterparts. Accordingly, MALDI-TOF

698

J. Am. Chem. Soc. 2021, 143, 3697−3702

Journal of the American Chemical Society

same molar masses (Figure 3 A and Figure S15 ).

Communication

Scheme 2. Postulated Basic Mechanism for LiHMDS-

Mediated REP of NNCA

with polymer 3, and in agreement with previous reports, the

more compacted structure of the cyclic polymer (before

propylation) was reﬂected by a larger elution volume at the

Figure 3. LiHMDS-mediated REP of Sar-NCA. (A) Diﬀerence of

elution proﬁles of polymer 3 before or after propylation versus the

log M (g/mol). The diﬀerence in slope is hypothetically explained by

a slight contamination of 3′ with cyclic structures. (B) Evolution of

M and Đ (M /M ) with M/LiHMDS ratio (determined by SEC in

DMF using a dn/dc = 0.0978).

To further study the LiHMDS-induced polymerization,

several REP of Sar-NCA were carried out in DMF by varying

the M/B ratio from 60 to 400 (yield: 89%−97%, Table S5).

SEC characterizations were performed and all polymers

presented increasing M_wvalues with controlled dispersities

(

Đ = 1.03−1.08, Table 1 and Figure 3B). The lower the

Figure 2. Most stable zwitterionic intermediate upon DFT calculation

amount of LiHMDS added, the higher the weighted-average

molecular weight (M ), and an unexplained deviation was

observed, especially for the higher ratios. For all polymers, the

M_w_c_y_c_l_i_c/M_w_a_f_t_e_r_p_r_o_p_y_l_a_t_i_o_nfrom SEC analysis were close to 0.8,

the value established with cyclic polypeptoids when formed

from NHCs promoted REP (⟨G⟩, Table 1 and the Supporting

(

basis M062X/6-31+G(d,p)) in DMF: (A) front view and (B) top

view. The polymer backbone is colored black. Red lines show

stabilizing interactions between Li , the polymer chain, the carbamoyl

extremity, and the Munchnone moiety (5-OH-DHE).

analyses revealed that the treatment of cyclic polymer 4 with

propionic anhydride (2 equiv) aﬀorded a linear analogue of the

polymer for which the SEC analysis revealed a higher molar

mass (Figures S15 −S18). Similar propylation was repeated

25,26

Information ).

Ultimately, the living nature of the REP was

evaluated. Synthesis of poly(sar) at M/B = 50 was ﬁrst

performed and, at full conversion, another feed of Sar-NCA

699

J. Am. Chem. Soc. 2021, 143, 3697−3702

Journal of the American Chemical Society

M/B = 50) was added to the reaction until it was also

https://pubs.acs.org/doi/10.1021/jacs.0c13231.

Communication

(

pathogenic Gram-positive bacterium responsible for severe

34,35

consumed (FTIR monitoring). The resulting poly(sar) 9

hospital acquired intestinal infections: C. diﬃcile

and

−

presented a M of 3200 g·mol close to the M of polymer 3

copolymers 11−21 were evaluated in vitro against this

pathogen (Table 2). In this study, the bacteria were incubated

for 24 h with increasing concentrations of cyclic polypeptoids,

to determine the minimum inhibitory concentrations (MICs).

In parallel, the in vitro cytotoxicity of the best polymers (15,

19−21) was tested on a human intestinal epithelial cell line

(Caco-2), allowing us to measure the 50% cytotoxic

concentrations (CC ) and to calculate the selectivity indices

and associated with a low dispersity of Đ = 1.1 (Table 1). This

result indicated that diblocks could be designed using

LiHMDS.

Cyclic structures are used by living systems to achieve

speciﬁc bioactivities. This encompasses cyclic antimicrobial

peptides (cAMP) that are cationic and broad-spectrum anti-

infective backbones. The use of a simple REP methodology,

working in DMF, opens up interesting prospects to design

simpliﬁed analogues of such cAMPs. Up to now, only a few

monomers have been used in REP because of some limitations

related to the solvents used (in which, for example,

(SI = CC /MIC). Optimizing the cationic content of

copolymers was a key design to optimize the antibacterial

activity and copolymer 15 showed a good proﬁle, similar to the

ones of LL37 (linear AMP, Table 2) or antibiotic controls

(Table S7). Interestingly, this statistical copolymer 15 was

signiﬁcantly less toxic than copolymer diblock counterparts

(19 and 20) or than the linear counterpart 21, (linearization of

15 by propylation, Figure S26). We also observed that

compound 15 preserved its activity after trypsin digestion, in

marked contrast to LL37 (Figure S28). This resistance to

proteolysis and the ability to destabilize phospholipid

membranes were further conﬁrmed by in vitro assays involving

liposomes (Figure S29). Overall, this proof-of-concept

demonstration shows that LiHMDS-mediated REP enables

quick and simple access to libraries of copolymers to design

anti-infective backbones.

29,30

poly(sarcosine) was not soluble).

Considering that both

the hydrophobic and cationic characters are key structural

features to design antimicrobial polymers, we consequently

prepared copolymers by mixing N-protected-lysine-like NNCA

(

Z-N-lys-NCA) and phenylalanine-like NNCA (N-phe-NCA).

Monomers were prepared through an optimized three-step

synthesis method (Supporting Information ). The LiHMDS-

mediated REP of Z-N-lys-NCA was carried out in DMF at M/

LiHMDS = 50, by itself (polymer 10 Table 2 and Supporting

Table 2. In Vitro Antibacterial Activity against C. diﬃcile and

Cytotoxicity over Caco-2 Cell Line

In summary, the use of a LiHMDS-mediated REP of NNCA

in DMF was a versatile and facile route to cyclic polypeptoids

allowing ﬁne-tuning over their chemical composition. This new

methodology permits us to design cationic macrocycles

showing good activity against C. diﬃcile, the main causative

agent of nosocomial diarrheas of adults in developed countries.

Overall, the use of LiHMDS is a simple way to design original

protease-resistant backbones with proper bioactivity.

cationic

content

C. diﬀ. MIC Caco-2 CC₅₀

polymer (M/B = 50)

(%)

(μg/mL)

P(N-lys) 10

100

>100

P(N-lys-r-N-phe) 11

P(N-lys-r-N-phe) 12

P(N-lys-r-N-phe) 13

P(N-lys-r-N-phe) 14

P(N-lys-r-N-phe) 15

93 (90)

85 (80)

69 (70)

61 (60)

50 (50)

95 (90)

79 (80)

68 (70)

59 (60)

49 (50)

52 (50)

12.5

>100

12.5

>100

208 ± 9

5 post-trypsin

ASSOCIATED CONTENT

sı Supporting Information

■

P(N-lys-b-N-phe) 16

P(N-lys-b-N-phe) 17

P(N-lys-b-N-phe) 18

P(N-lys-b-N-phe) 19

P(N-lys-b-N-phe) 20

P(N-lys-r-N-phe) 21

The Supporting Information is available free of charge at

12.5

100

213 ± 7

77 ± 6

105 ± 8

47 ± 1

Synthetic procedures, macromolecular characterizations

(NMR, ESI-MS, FTIR, SEC, MALDI-ToF), sample

preparations, spectroscopic analyses, molecular model-

ing and biological assays, Cartesian coordinates, plot of

cell viability and enzymatic resistance, liposome leakage

bar graph (PDF)

LL37

LL37 post-trypsin

doxorubicin

>200

8.1 ± 0.1

r = random copolymers and b = block copolymers. From H NMR

(

in bracket, targeted). Selectivity index = CC /MIC. The MIC

value was not reached at the highest tested concentration. LL37 was

AUTHOR INFORMATION

used as AMP reference. Doxorubicin was used as a cytotoxic drug

■

control.

Corresponding Authors

Pierre Verhaeghe − LCC-CNRS, UPR8241, Université de

Toulouse, CNRS, UPS, 31400 Toulouse, France;

Email: pierre.verhaeghe@univ-tlse3.fr

Colin Bonduelle − Université Bordeaux, CNRS, Bordeaux

INP, LCPO, UMR 5629, F-33600 Pessac, France;

orcid.org/0000-0002-7213-7861;

Information ) or in copolymerization with N-phe-NCA, either

as a one-pot synthesis (leading to statistical copolymers 11−

5, Table 2) or in sequence (leading to block copolymers 16−

0, Table 2). For all copolymers, acidic deprotection of the

Cbz group (HBr 2 equiv in TFA) aﬀorded side-chain

deprotection, allowing producing cationic macrocycles show-

ing molar masses and chemical compositions, in agreement

with the feed ratios (Table S6 and Figure S25 ).

Email: colin.bonduelle@enscbp.fr

Authors

The bioactivity of the copolymers was then assessed. Cyclic

peptoids are promising scaﬀolds to design anti-infective

Pedro Salas-Ambrosio − Université Bordeaux, CNRS,

Bordeaux INP, LCPO, UMR 5629, F-33600 Pessac, France

Antoine Tronnet − LCC-CNRS, UPR8241, Université de

Toulouse, CNRS, UPS, 31400 Toulouse, France; LPBA,

2,33

agents,

but antibacterial copolymers have never been

developed on the basis of this chemical design. We targeted a

700

J. Am. Chem. Soc. 2021, 143, 3697−3702

Journal of the American Chemical Society

(10) Kricheldorf, H. R. Cyclic Polymers: Synthetic Strategies and

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Institut Pasteur, UMR-CNRS 2001, Université de Paris, F-

Physical Properties. J. Polym. Sci., Part A: Polym. Chem. 2010, 48 (2),

5724 Paris, France

Marc Since − Normandie Université, UNICAEN, CERMN,

4000 Caen, France

(

51−284.

11) Iatrou, H.; Hadjichristidis, N.; Meier, G.; Frielinghaus, H.;

Monkenbusch, M. Synthesis and Characterization of Model Cyclic

Block Copolymers of Styrene and Butadiene. Comparison of the

Aggregation Phenomena in Selective Solvents with Linear Diblock

and Triblock Analogues. Macromolecules 2002 , 35 (14), 5426 −5437.

Sandra Bourgeade-Delmas − UMR 152 PHARMA-DEV,

Université de Toulouse, IRD, UPS, 31400 Toulouse, France

Jean-Luc Stigliani − LCC-CNRS, UPR8241, Université de

Toulouse, CNRS, UPS, 31400 Toulouse, France

Amelie Vax − Université Bordeaux, CNRS, Bordeaux INP,

LCPO, UMR 5629, F-33600 Pessac, France

Sébastien Lecommandoux − Université Bordeaux, CNRS,

Bordeaux INP, LCPO, UMR 5629, F-33600 Pessac, France

Bruno Dupuy − LPBA, Institut Pasteur, UMR-CNRS 2001,

Université de Paris, F-75724 Paris, France

(12) Schappacher, M.; Deffieux, A. α -Acetal-ω -Bis(Hydroxymethyl)

Heterodifunctional Polystyrene: Synthesis, Characterization, and

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(13) Schappacher, M.; Deffieux, A. Synthesis, Characterization, and

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Initiators for the Ring-Expansion Polymerization of β -Lactones. J. Am.

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Funding

15) Bielawski, C. W.; Benitez, D.; Grubbs, R. H. An “Endless ”

P.S.A. received support from CONACYT (scholarship holder

No. 548662). This work was supported by the French national

agency for research (ANR): grant No. ANR-17-CE07-0039-01.

Route to Cyclic Polymers. Science 2002, 297 (5589), 2041−2044.

16) Piedra-Arroni, E.; Ladaviere, C.; Amgoune, A.; Bourissou, D.

Ring-Opening Polymerization with Zn(C 6 F 5) 2 -Based Lewis Pairs:

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Notes

The authors declare no competing ﬁnancial interest.

(17) Zhang, Y.; Liu, R.; Jin, H.; Song, W.; Augustine, R.; Kim, I.

Straightforward Access to Linear and Cyclic Polypeptides. Commun.

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ACKNOWLEDGMENTS

■

The authors acknowledge Sylvain Bourasseau for assistance

with size-exclusion chromatography, Anne-Laure Wirotious for

NMR analysis, Joan Vignolle for helpful discussions, and

Christelle Absalon for MALDI TOF analysis. This work has

beneﬁted from the facilities and expertise of the CESAMO

platform (Bordeaux University). This work was also granted

access to the HPC resources of CALMIP supercomputing

center under the allocation 2020 - P19021.

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