Molecular innovation with iodine(III) and ynamides:

Green processes and β-lactamase inhibitors

Dr Kevin CARIOU
kevin.cariou@cnrs.fr

Institute of Chemistry for Life and Health Sciences

Chimie ParisTech, PSL University, CNRS
1
Overview
Synthesis & Methodology
Applied to Research in Therapeutics

Total Medicinal
Synthesis Chemistry

New
Reactions

Mechanism
Studies

2
 The bigger picture: bacterial resistance
Yearly Deaths Attributable to Antimicrobial Resistance by 2050

Picture from J. O’Neil et al., Wellcome Trust and HM Governement, Review on Antimicrobial Resistance,3 2014
 Antibiotics targets

Picture adapted from A. Coates, Y. Hu, R. Bax, C. Page, Nat. Rev. Drug Discov. 2002, 1, 895–910
 Modes of Resistance to Antibiotics

Picture from Chellat, M. F.; Raguž, L.; Riedl, R. Angew. Chem. Int. Ed. 2016, 55, 6600.
 Penicillin: the Age of Antibiotics
Discovered in 1928 by sir Alexander Flemming
Mode of action

Penicillin G

Penicillium notatum

Figure adapted from: 6

Chellat, M. F.; Raguž, L.; Riedl, R. Angew. Chem. Int. Ed. 2016, 55, 6600.
 β-Lactamase Resistance
Evolutionnary pressure
Mode of action

Penicillin G

Penicillium notatum

Figure adapted from: 7

Chellat, M. F.; Raguž, L.; Riedl, R. Angew. Chem. Int. Ed. 2016, 55, 6600.
 β-Lactams and β-Lactamase inhibitors
β-lactam timeline: market – resistance

Pénicillin G 1943 – 1945 Ceftazidime 1983 – 1987 Imipenem 1985 – 1998

(penicilin) (cephalosporine) (carbapenem)

β-lactamase inhibitors timeline: approval

clavulanic acid, 1985 sulbactam, 1987 avibactam, 2015 vaborbactam, 2017

(clavam) (penam) (DBO) (boronic acids)
8
 Example of a bad bug
Escherichia coli isolate Gue

“Our study was initiated by the isolation of a multidrug-resistant E. coli strain GUE that had
been community-acquired in India.

E. coli isolate GUE was resistant to most β-lactams (remaining susceptible to aztreonam),
penicillin/inhibitor combinations and broad-spectrum cephalosporins,

and showed reduced susceptibility to carbapenems, […] (imipenem, ertapenem, and

meropenem […].

It was also resistant to gentamicin, kanamycin, tobramycin, sulfonamides, tetracycline,

and fluoroquinolones,

but remained susceptible to amikacin, chloramphenicol, rifampicin, and colistin.”

R. A. Bonnin, L. Poirel, A. Carattoli, P. Nordmann Plos One 2012, 7, e34752. 9

 Role of the synthetic chemist?
Common chemical reactions in drug discovery and development

From: Brown, D. G. & Boström, J. Nature Reviews Drug Discovery 17, 709–727 (2018)
Expanding the medicinal chemistry synthetic toolbox
See also: Brown, D. G. & Boström, J. J. Med. Chem. 59, 4443–4458 (2016).
Analysis of past and present synthetic methodologies on medicinal chemistry:
10
where have all the new reactions gone?
New synthetic strategies

Iodine(III)-Mediated Halogenation Reactions:

towards Avibactam Analogues

New
Reactions

Mechanism
Studies

11
 Avibactam analogues
Analogues

ETX2514 FPI-1465 FPI-1602

Better inhibitor Better inhibitor Inhibitor + antibiotic

Standard disconnection
 Avibactam analogues
Standard disconnection

Review (Laure Peilleron)

Org. Biomol. Chem. 2020, 18, 830-844

Alternative disconnection
 Hypervalent Iodine(III) Compounds
Superior Atom/Group Transfer Agents

Willgerodt, C. J. Prakt. Chem. 1886, 33, 155

« Organo-nonmetallic Systems »

14
Moriarty, R. M. J. Org. Chem. 2005, 70, 2895
 Diazabicyclooctanes
Retrosynthesis of the key intermediate

Laure Peilleron (& Aurélien Brion)

Unpublished results

Model cyclization using hypervalent iodine(III)

15
 Study of the key cyclization step
Bromocyclization optimization
 Study of the key cyclization step
Bromocyclization optimization

« Br ⁻ » source
LiBr Et4NBr Pr4NBr NH4Br
Additive
ZnBr2 nBu4NBr PyrMe·Br
MgO MS 3Å
CuBr2 NEt3·HBr Pyridine·HBr
I(III) source
Temperature PIDA PhI(OH)OTs
Solvent
DCM EtOH MeCN 0 °C 20 °C PhI(OPiv)2 PIFA
-40 °C -78 °C
MeCN/HFIP (1:1) Toluene
 Study of the key cyclization step
Bromocyclization optimization: O-cyclization

78% isolated yield

« Br ⁻ » source
LiBr Et4NBr Pr4NBr NH4Br
Additive
ZnBr2 nBu4NBr PyrMe·Br
MgO MS 3Å
CuBr2 NEt3·HBr Pyridine·HBr
I(III) source
Temperature PIDA PhI(OH)OTs
Solvent
DCM EtOH MeCN 0 °C 20 °C PhI(OPiv)2 PIFA
-40 °C -78 °C
MeCN/HFIP (1:1) Toluene
 Study of the key cyclization step
Bromocyclization optimization: N-cyclization

« Br ⁻ » source
LiBr Et4NBr Pr4NBr NH4Br 38% isolated yield
Additive
ZnBr2 nBu4NBr PyrMe·Br
MgO MS 3Å
CuBr2 NEt3·HBr Pyridine·HBr
I(III) source
Temperature PIDA PhI(OH)OTs
Solvent
DCM EtOH MeCN 0 °C 20 °C PhI(OPiv)2 PIFA
-40 °C -78 °C
MeCN/HFIP (1:1) Toluene
 Model reaction study
Chemoselective iodine(III)-mediated cyclizations

Laure Peilleron
20
Adv. Synth. Cat. 2019; 361, 1753–1769
 Iodoarene catalysis
Context and green chemistry strategies

Review:
21
Yoshimura, Y.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328.
 Iodoarene catalysis
Spirocyclization of N-oxyamides as a benchmark reaction

HETEROCYCLES 2003, 59, 149 Chem. Commun. 2007, 1224

Chem. Commun. 2010, 46, 7697

Nat. Chem. 2018, 10, 200

22
 Iodoarene catalysis
Crazy idea: dual aerobic catalysis

23
 State of the art
Iodine(III) and photoredox catalysis

Seminal paper: J. Lalevée et al. Polym. Chem. 2011, 2, 1986

Review: Wang, L.; Liu, J. Eur. J. Org. Chem. 2016, 1813

For a catalyst free activation of iodine(III) with blue light:

T. Chidley, I. Jameel, S. Rizwan, P. A. Peixoto, L. Pouysegu, S. Quideau, W. S. Williams, G. K. Murphy, 24

Angew. Chem. Int. Ed. 2019, 58, 16959
 Strategy
Choice of the photoredox catalyst

25
Potential values: Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Synlett 2016, 27, 714.
 Strategy
Choice of the iodoarene catalyst

26
 Optimization

Iodoarene Temperature Photocatalyst

E*red vs. SCE
50°C RT 0°C Acridinium

Time
24 h 48 h 72 h

Light source Solvent Pyrylium

Led stripes (3 W) Lamps (2x 12 W) DCM DCE

MeCN TFE

HFIP HFIP/DCE 27
 Optimization
58%

Iodoarene Temperature Photocatalyst

E*red vs. SCE
50°C RT 0°C Acridinium

Time
24 h 48 h 72 h
2 x 2.5 mol%
20 mol% Pyrylium
Light source Solvent
Led stripes (3 W) Lamps (2x 12 W) DCM DCE

MeCN TFE
Alfonzo, E. et al.
Org. Lett. 2017, 19, 2989.
HFIP HFIP/DCE 28
 Optimization
55%

Iodoarene Temperature Photocatalyst

E*red vs. SCE
50°C RT 0°C Acridinium

Time
24 h 48 h 72 h
2 x 2.5 mol%
2.5 mol% Pyrylium
Light source Solvent
Led stripes (3 W) Lamps (2x 12 W) DCM DCE

MeCN TFE

HFIP HFIP/DCE 29
Scope

30
Limitations

31
 Controls

Deviation from the reaction conditions:

without iodoarene, no reaction

without photocatalyst, no reaction
without O2 (Ar), no reaction
under air, 12%
without light, no reaction
+ 20 mol% BHT, no reaction
+ 20 mol% TEMPO, no reaction
with AcOH as the solvent, no reaction

32
 Mechanism
Proposal:

B, C, D, and E could be the actual oxidant

33
 Conclusions

It works…

… so much more to explore!

Loïc Habert
Habert, L.; Cariou, K. Angew. Chem. Int. Ed. 2021, 60, 171–175 Funding: Emergence@INC2019
34
Preprint: DOI: 10.26434/chemrxiv.12562355.v1 2020
New synthetic strategies

Ynamides as Ketenimines Precursors

Medicinal
Chemistry
New
Reactions

35
 Ynamides
Trachycladindoles

Capon, R. J. et al. Org. Biomol. Chem. 2008, 6, 2765.

Planned Retrosynthesis
 Ynamides
Failed (?) Attempt

No precedent

Zhang, Y. Tetrahedron Lett. 2005, 46, 6483.

 β–Addition
Heterocycles Addition

Alexandre Hentz
Angew. Chem. Int. Ed. 2014, 53, 8333
Mechanism

DFT calculations : Pr Vincent Gandon (U.-PSud)

 Mechanism

DFT calculations : Pr Vincent Gandon (U.-PSud)

• However: α-addition occurs in some cases, why ?

Mechanism
 Ynamides as ketenimines precursors
In situ generation of ketenimines

Concept Review: Chem. Eur. J. 2018 24, 2997

42
 Azetidinimines
Staudinger vs. Imino-Staudinger Synthesis

Staudinger H. Justus Liebigs Ann. Chem. 1907, 356, 51

Antibiotic activity ?

antibiotic inhibitor ?

43
 From Azetidinimines to Imidazolines
[2+2]
 From Azetidinimines to Imidazolines
[2+2]

[3+2]
 Cycloadditions with imines
Imino-Staudinger synthesis

20 examples
Chem. Eur. J. 2017 up to 64% yield
Hot Paper, Inside Cover,
functionnal modifications
highlighted in SYNFACTS

Homologous [3+2] reaction

20 examples
up to 74% yield
Adv. Synth. Cat. 2021, 363, 2903–2908 46
functionnal modifications
 Carbapenemase Inhibitors
Structure-Activity Relationships

CM700 CM740 CM741 CM744 CM749 CM750 MBG53.1 MBG60.1 MBG85-86 MBG87 MBG74.1

CM760 CM766 CM770 CM774 CM777 CM778 MBG89.1 MBG92.1 MBG111.1 MBG123 ROM6

CM813 CM818 SV-124-1 SV-124-2 SV-130-1

ROM111 ROM106 ROM113 ROM122 ROM129

MBG-26-1 MBG-28-1 MBG-29-1 MBG30.1 MBG31.1

ROM130 ROM131 ROM132 ROM135 ROM139

MBG32.1 MBG33.1 MBG35.1 MBG4243 MBG50.3B

ROM142 ROM157 ROM166 ROM163 ROM149

ROM160 ROM136 ROM168 ROM150 ROM143

ROM324 ROM380 ROM384 ROM385 ROM386

ROM169 ROM192 ROM193 ROM196 ROM197

KV131 KV181PP2 KV211 KV222 ADH17

ROM198 ROM199 ROM203 ROM207 ROM213

ADH26 KV242-PP1 V245 PP1 KV248 PP1 KV255PP2

ROM214 ROM215 ROM216 ROM217 ROM236

47
 Carbapenemase Inhibitors
Structure-Activity Relationships

CM700 CM740 CM741 CM744 CM749 CM750 MBG53.1 MBG60.1 MBG85-86 MBG87 MBG74.1

CM760 CM766 CM770 CM774 CM777 CM778 MBG89.1 MBG92.1 MBG111.1 MBG123 ROM6

CM813 CM818 SV-124-1 SV-124-2 SV-130-1

ROM111 ROM106 ROM113 ROM122 ROM129

MBG-26-1 MBG-28-1 MBG-29-1 MBG30.1

Dr C. Minard MBG31.1

Dr S. Ventre ROM130 ROM131 ROM132 ROM135 ROM139

MBG32.1 MBG33.1 MBG35.1 MBG4243 Dr E. Romero MBG50.3B

Dr M. Benchekroun ROM142 ROM157 ROM166 ROM163 ROM149

ROM160 ROM136 ROM168 ROM150 K. Vijayakumar ROM143

Dr A. D’Hollander ROM324 ROM380 ROM384 ROM385 ROM386

ROM169 ROM192 ROM193 ROM196 ROM197

KV131 KV181PP2 KV211 KV222 ADH17

ROM198 ROM199 ROM203 ROM207 ROM213

ADH26 KV242-PP1 V245 PP1 KV248 PP1 KV255PP2

ROM214 ROM215 ROM216 ROM217 ROM236

48
 Carbapenemase Inhibitors
Structure-Activity Relationships

ROM87 ROM110 ROM114 ROM116 ROM140

ADH221 ADH231 ADH235 ADH255 ADH218

KV93-5 KV95-3 KV83-3 KV97-2 KV84-4 KV96-1

ADH258 ADH260 ADH262 ADH268 ADH262

KV102-3 KV100-3 KV105-1 ROM344dis4 ROM345P2

ADH258 ADH292-bis ADH293-bis ADH301

ROM346P1 ROM246-1 ROM246-2 KV72-1 ADH323

ADH283 ADH258 ADH253-2 ADH253-2

KV85-1 KV75-1 KV74-PP2 KV97-1 KV83-1

Dr E. Romero
K. Vijayakumar ADH323
49
KV102-2 KV98-1 ADH220 ADH221
Dr A. D’Hollander
 Carbapenemase Inhibitors
Sub-micromolar activity of different classes of enzymes

In-vitro and MIC :

T. Naas (CHU Bicêtre)
MBLs and class A & D SBLs
CLint (µL/min/mg souris) : 13,92 Modelling and Cristallography :
IC50 HCT116 = 32.3 µM B. Iorga (ICSN)
IC50 MRC5 = 19.9 µM
Metabolism & PK :
WO2017042233 A. Pruvost (CEA)
Eur J. Med. Chem. 2021; 219, 113418

MBLs and class A & D SBLs

100% stable in plasma

WO2018162670

50
 Acknowledgments
SMART (Gif):

Laure Peilleron
Dr Robert H. Dodd (Em.)

ICB (Paris):

Capucine Mahe
Dr Loïc Habert

Former members:

Таня Grayfer Alexandre Hentz

Corinne Minard Dr Sandrine Ventre
Sophie Nocquet-Thibault Dr Mohamed Benchekroun
Dr Marion Daniel Dr Eugénie Roméro
Dr Agathe D’Hollander
Kamsana Vijayakumar
52
Role of the synthetic chemist?

53
Molecular innovation with iodine(III) and ynamides:
Green processes and β-lactamase inhibitors

Dr Kevin CARIOU
kevin.cariou@cnrs.fr

Institute of Chemistry for Life and Health Sciences

Chimie ParisTech, PSL University, CNRS
54