Sulphonamides, N-oxides and phosphonamides – unexplored directing groups in HIE reactions

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Hydrogen isotope exchange acid-mediated labelling

Acid or base-catalyzed HIE methods are in principle the easiest protocols to perform as long as there is no issue with stability, solubility or selectivity. At temperatures above 100°C generally a very efficient but unselective hydrogen deuterium exchange takes place. Most of these examples are of older provenance, with no new application having been reported in the last ten years, most probably due to the development of more effective alternative methods. While simple Brönsted acids such as DCl43 or D2SO444 are mostly used to introduce deuterium into activated aromatic compounds, bases like NaOD/D2O,45 DMAP/D2O,46 Na2CO3/D2O47 or even near-critical D2O48 are convenient reagents for introducing the hydrogen isotope into aliphatic CH-positions. Due to the fact that the isotope source is used in high excess there are only a few acid/base-catalyzed protocols known to introduce tritium.6
As peptides have become more and more important in pharmaceutical research, a significant increase of reported methods to prepare deuterium-labeled amino acids or peptides has been observed. For example, Hashimoto et al. reported the deuteration of α-amino acids derivatives by triflic acid (trifluoromethanesulfonic acid) with high deuterium content (scheme I.6, 12,13 =>14,15 ).49 In one example, a pentapeptide was deuterated at room temperature in 9 hours with up to 8 deuterium atoms introduced at the aromatic positions.50
Chen and Yin et. al. demonstrated, by Brønsted acid-catalyzed deuteration at the methyl group of N-heteroarylmethanes, the deuteration of complex molecules like tropicamide 17 or papaverine 19, under mild reaction conditions (scheme I.7).51 Quinolines, pyridines, benzo[d]thiazoles, indoles and imines were all deuterated at the methyl groups with high (>90%D) deuterium incorporation.

Hydrogen isotope exchange with heterogeneous metal catalysis

One of the technical advantages of heterogeneous catalysis is the possibility to remove the catalyst by simple filtration on reaction completion. Moreover, in exchange processes that occur without side reactions or decomposition, no further purification step is necessary. Catalysts are also often more stable and much less expensive than homogeneous catalysts. However, due to the generally low levels of selectivity there is always the possibility of unwanted dehalogenation, hydrogenation, hydrolysis, or, under more harsh conditions, racemization. High catalytic activity for H/D exchange by heterogeneous approaches has been found with palladium, platinum, rhodium, nickel, cobalt, and, more recently, ruthenium catalysts. On the other hand, no particular exchange activity has been observed in heterogeneous reaction procedures with either iridium or iron, which are used with success in homogeneous catalysis (see next section). Regarding the isotope source, gaseous deuterium or tritium, deuterium- or tritium-oxide, and deuterated protic solvents that transfer their labile deuterium to the substrate have all been used as isotopic hydrogen sources.Error! Bookmark not defined.,Error! Bookmark not defined. A selection of the most recent method developments and trends of heterogeneously catalyzed HIE reactions is described below.

a) Transition metal-catalyzed HIE reactions

Palladium is amongst the most common transition metals applied in C–H functionalization, and there are many recent applications of such heterogeneously catalyzed HIE reactions reported.8e,54,55,56,57,58,59,60 In principle, Pd/C is one of the most widely used heterogeneous catalyst in organic synthesis, as typically applied in hydrogenation reactions. Many different catalyst variations are commercially available, generating a complex portfolio of hydrogenation reactivity measured in turn-over-numbers of different model reactions. Pd/C has also proven its usefulness in HIE reactions.
Pd/C has been widely applied to introduce tritium into molecules.15,58,59 In addition to palladium, platinum also plays an appreciable role in heterogeneous catalyzed HIE reactions. Platinum has especially proven to be very efficient for aromatic C–H positions, with much higher deuterium incorporation compared to aliphatic C–H positions. Recently, a method for deuteration of several arenes under Pt/C-iPrOH-D2O conditions was reported (scheme I.10). Remarkably, the activation of the metal surface was performed by in situ generated hydrogen/deuterium through transfer hydrogenation from iso-propanol. This developed external hydrogen gas-free method could, therefore, be used on process scale or for substrates where undesired Pt/H2-reductions were otherwise likely.

c) HIE reactions with nanoparticles

Another cutting-edge catalyst application is the use of nanoparticles.65 These heterogeneous particles are fully dispersed in an aqueous or organic solvent and invisible to the human eye, and may be considered homogeneous in contrast with heterogeneous catalysts which are made of metal nanoparticles supported on an inorganic matrix. Therefore, the critical reaction parameter continues to be the surface of the activated catalyst with an exceptionally huge surface/volume ratio.

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Table of contents :

Part I
I.1. Drug Discovery and Development
I.2. Limitations of Drug Discovery and Development
I.3. Isotopically labelled compounds in DDD
I.4. Hydrogen isotopes in DDD and life sciences
I.4.1. Applications of deuterium in DDD
I.4.1.a) Deuterium labelled internal MS standards
I.4.1.b) Kinetic Isotope Effect and deuterated drugs
I.4.1.c) Deuterium PET tracers
I.4.2. Applications of tritium in DDD
I.4.2.a) Tritium in Quantitative Whole Body Audioradiography
I.4.2.b) Tritium in scintillation proximity assay
I.4.2.c) Tritium in plasma protein binding
I.5. Hydrogen isotopes labelling methods
I.5.1. Hydrogen isotope exchange acid-mediated labelling
I.5.2. Hydrogen isotope exchange base-mediated labelling
I.5.3. Hydrogen isotope exchange with heterogeneous metal catalysis
I.5.3.a) Transition metal-catalyzed HIE reactions
I.5.3.b) HIE reactions with catalyst mixtures
I.5.3.c) HIE reactions with nanoparticles
I.5.4. Hydrogen isotope exchange with homogeneous metal catalysis
I.6. Directed iridium-catalyzed HIE reactions
I.7. CH functionalization
I.8. Objectives of the thesis
Part II – Chapter 1
II.1. 1. Sulphonamides, N-oxides and phosphonamides – unexplored directing groups in HIE reactions
II.1. 2. Explanation of the HIE reaction process at Sanofi laboratories
II.1. 3. Optimization of the HIE conditions on the model sulphonamide compound
II.1. 4. Application of the optimized conditions on aryl-sulphonamides, N-oxides and arylphosphonamides
Part II – Chapter 2
II.2. 1. Introduction
II.2. 1.1. The phenylacetic acid derivatives moiety in life sciences
II.2. 1.2. Literature background of HIE reactions on phenylacetic acid derivatives
II.2. 1.3. What makes phenylacetic acid derivatives such a challenge
II.2. 2. Optimization of the model compound
II.2. 2.1. Catalyst screening
II.2. 2.2. Time screening
II.2. 2.3. Solvent and temperature screening
II.2. 2.4. Catalyst loading screening
II.2. 3. Scope and limitation of catalyst F in HIE of phenylacetic acid derivatives
II.2. 3.1. HIE reactions with catalyst F on phenylacetic ester derivatives
II.2. 3.2. HIE reactions with catalyst F on phenylacetic amide derivatives
II.2. 3.3. Application on phenylacetic acid derivatives drug molecules
II.2. 3.3.a) HIE reactions on drugs with excess of deuterium gas
II.2. 3.3.b) Transfer of the procedure to the deuterium manifold
II.2. 3.3.c) Transfer of the procedure to the tritium manifold
II.2. 4. Insights in the mechanism
II.2. 5. Conclusion
Part III – Chapter 1
III.1. 1. Introduction
III.1. 2. Comparison study of the catalysts A-G in the HIE of 8
III.1.2.1. Comparison study at low temperatures
III.1.2.2. Comparison study at high temperatures
III.1. 3. Application on complex drug-like compounds
III.1. 4. Conclusions
Part III – Chapter 2
III.2. 1. Introduction
III.2. 2. Competition HIE reactions study
III.2. 3. DFT calculations and energy profiles for insights into the competition study
III.2. 4. Prediction and experimental prove in HIE of disubstituted molecules
III.2. 5. Prediction and experimental prove in HIE of complex molecules and drugs
III.2. 6. Conclusion
Part IV
IV.1. Isotopic labeling of the drug payload of antibody-drug conjugates used for cancer treatment
IV.1.1. Application of ADC for treatment in oncology
IV.1.2. The Maytansine derivatives as ADCs
IV.1.3. Former approach for the synthesis of 3H-DM4
IV.2. Iridium-catalyzed hydrogen isotope exchange on L-DM4
IV.3. Methodology development of Hydrogen isotope Exchange on sp3-carbon centers
IV.3.1. Methodology development on the sulfur side chain
IV.3.1.a) Conditions screening of [H]-10 in HIE reaction
IV.3.1.b) Application of the developed methodology on DM4 side chain precursors
IV.3.2. Investigation of the small amino acids reactivity in HIE
IV.3.2.a) Influence of the N-terminal protecting group
IV.3.2.b) Analysis of the stereocontrol in HIE reaction of alanine
IV.3.2.c) Application of the HIE method on sterically more demanding amino acids
IV.3.3. Application of the optimized method in larger peptides
IV.3.4. Insights in the mechanism
IV.4. Conclusion
Part V
V.1. Heterogeneous iridium catalysis with nanoparticles
V.1.1. Nanoparticles: From homogeneous to heterogeneous catalysis
V.1.2. Development and synthesis of new iridium nanoparticles
V.1.3. Identification of the new directing group of interest
V.2. Literature background – HIE reactions of anilines in the past
V.3. Evaluation of the iridium nanoparticles
V.4. Application of IrNPts in HIE of small aniline molecules
V.5. The role of D2O in IrNPts catalyzed HIE reactions
V.6. Applications of IrNPts in HIE reactions of complex molecules and drugs
V.7. Conclusion
Part VI
Conclusion and future perspectives


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