Parahydrogen-induced Polarization (PHIP)

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Table of contents

GENERAL INTRODUCTION
A. BIBLIOGRAPHIC STUDY
I. The Hyperpolarized 129Xe MRI and Its Encapsulating Cages
1. General presentation of MRI
a. Principles of NMR
b. Principles of MRI
c. Advantages and Disadvantages of MRI
2. How to improve the sensibility of MRI
a. The MRI contrast agents
b. Hyperpolarization
i. Parahydrogen
i. Hyperpolarized 3He
ii. Hyperpolarized 13C
3. Hyperpolarized 129Xe
a. General presentation of xenon
b. Hyperpolarization with optical pumping
c. Encapsulating structures of xenon
i. The selection criteria
ii. Cyclodextrins
iii. Calixarenes
iv. Hemicarcerands
v. Cucurbiturils
vi. Cryptophanes
II. Cryptophanes: Structure, Synthesis and Applications
1. Structures – stereochemistry, symmetry and conformers
a. Stereochemistry and symmetry
b. Conformers
2. Synthesis
a. The “direct method”
b. The “template method”
c. Coupling of CTVs
3. Strategies for the hydrosolubilization of cryptophanes
4. Strategies of mono-functionalization of cryptophanes
5. Cryptophane-based biosensors for 129Xe MRI
III. Objectives
B. CONCEPTION AND SYNTHESIS OF WATER-SOLUBLE AND MONO-FUNCTIONALIZABLE CRYPTOPHANES
I．Water-Soluble and Mono-Functionalizable Cryptophanes – Why and How
1. Background and objective
2. Different strategies to synthesize asymmetric cryptophanes
3. Polyethylene glycol – our choice for hydrosolubilization
II. Desymmetrization of Cryptophanes
1. Context
2. Optimization and scale-up
a. Optimization of the cyclotrimerization and the demethylation
b. Optimization of the alkylation of CTV
c. Conclusion of the optimization and scale-up
3. Demethylation of symmetric cryptophane
a. Demethylation of the PEGylated cryptophane with TMSI
b. Demethylation of the PEGylated cryptophane by LiPPh2
c. Scan of other reagents to perform the demethylation of cryptophane
4. Conclusion and perspective
III. Desymmetrization of CTVs
1. Cryptophanes based on the functionalization of CTVs with different benzyl alcohol derivatives
a. Conception and retrosynthetic analysis
b. Synthesis towards a mono-allyl PEGylated cryptophane
i. Synthesis of the allylic benzyl alcohol derivative 37
ii. Synthesis of the PEGylated benzyl alcohol derivative 58
iii. Synthesis towards the mono-allylated PEGylated cryptophane
iv. Functionalization of the mono-allylated PEGylated cryptophane
v. Attempts to synthesize PEGylated cryptophanol
vi. Conclusion
c. Synthesis towards a mono-benzylated PEGylated cryptophane
i. Synthesis to the mono-benzyl PEGylated cryptophane
ii. Attempts to synthesize the PEGylated cryptophanol
d. Synthesis towards a mono-acid PEGylated cryptophane
i. The synthesis of the benzyl alcohol derivative with methyl acetate
ii. Synthesis to the mono-acid PEGylated cryptophane
iii. Encapsulation of xenon inside cryptophane
iv. Hyperpolarized 129Xe NMR analysis of cryptophane
v. Conclusions and perspectives
2. Cryptophanes based on mono-halogenation of CTVs
a. Synthesis of mono-halogenated CTV
i. Synthesis of the symmetric CTV 97
ii. Mono-halogenation of CTV 97
b. Synthesis of a PEGylated mono-iodinated cryptophane
i. The analysis of cryptophane 106 by 129Xe NMR
ii. Study of anti-/syn- isomers
c. Synthesis towards a mono-ester PEGylated cryptophane
d. Conclusion and perspectives
3. Cryptophanes based on mono-protected CTVs
IV Synthesis of Asymmetric CTVs
1. Design and retrosynthetic analyse
2. Synthesis of the benzyl alcohol derivatives
3. Synthesis of asymmetric CTVs by cyclotrimerization with different monomers
4. Synthesis of a mono-acid PEGylated cryptophane
GENERAL CONCLUSIONS AND PERSPECTIVES
REFERENCES
EXPERIMENTAL PART