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Project titleThe selective biomimetic transformations of organic compounds using the iodine regants and porphyrines

Research area 03 - CHEMISTRY AND MATERIAL SCIENCES, 03-101 - Synthesis, structure and reactivity of organic compounds

KeywordsBiomimetic transformation; hypervalent iodine compounds; L-thyroxine; porphyrines;

Annotation
The main aim of the project is continuing of investigations of biomimetic transformations of organic substrates including biologically important natural compounds utilizing high-valent iodine reagents (e.g. derivatives of L-thyronine (T2, T3, T4)) and porphyrins and its analogues. In our research within the framework of RNF-16-13-10081 grant, we for the first time explored the oxidating system H2O2 - L-thyroxine (T4) - porphyrin for studying biomimetic transformations of a wide range of organic substrates. It was shown either there is no oxidation of organic substrates or the conversion of the reaction is low in heterogeneous conditions in presence of T4. At the same time oxidation of organic compounds proceeds with higher conversion using both T4 and Fe(III)-SO3H. In addition, we established the influence of numbers of iodine atoms in the iodinated derivatives of L-thyronine (T2, T3, T4 and their acylated derivatives) on the oxidation state of an organic substrate by the oxidant-porphyrin system at homogeneous conditions. The presence of iodine atoms in the structure of aminoacids (T2, T3 and T4) impacts on the oxidation process of anthracene in a media with рН=7.0-7.6. In addition, a decreasing of the conversion of anthracene to anthraquinone and other oxidation products depends on numbers of iodine atoms in aminoacid molecule. Influence of different iron-containing porphyrins including variety hemes or cytochromes on biomimetic transformations of organic substrates was investigated that let us know the correlation between activity and nature of a porphyrin. At the same time, there are some principal unsolved questions, such as: • Does the deiodination process of hypervalent iodine derivatives of L-tyrosine and L-thyronine (T2, T3, T4) in H2O2-Heme or H2O2-cytochrome P450 systems? • If it does, which aromatic ring of T3 and T4 will be in? • Investigation of the biological activity of polyvalent derivatives of L-tyrosine and L-thyronine (T2, T3, T4) and preparation of the diagnostic drugs based on them. These questions are important from the point of view of clarifying the role of iodine-containing hormone in the appearance of human intelligence. Previously unknown biomimetic transformations of organic substrates will find. In the future, it allows to know the reasons for mental retardation and the ways of solution of this pathology [S.J. Zhou, A.J Anderson, R.A. Gibson, M. Makrides. Effect of iodine supplementation in pregnancy on child development and other clinical outcomes: a systematic review of randomized controlled trials. American Journal of Clinical Nutrition. 2013, 98, (5), 1241-1254; N. Momotani, S. Iwama, K. Momotani Neurodevelopment in children born to hypothyroid mothers restored to normal thyroxine (T4) concentration by late pregnancy in Japan: no apparent influence of maternal T4 deficiency. Journal of Clinical Endocrinology and Metabolism. 2012, 97, (4), 1104-1108]. Therefore, special attention in the project will be paid to establishing of the role of hypervalent iodine derivatives of L-thyroxine in biomimetic processes of saponifiable and unsaponifiable lipids, vitamins, aminoacids, short-chain peptides and other important biological compounds. For the first time, porphyrins that contains in their structures hypervalent iodine atom instead of metal one will be synthesized. It is possible that oxidative processes proceeds in such way with the help of T4. Equally important researches of design and studying of properties of phenol-, arylimidazolyl-, arylpyrazolyl-, aryloxazolyl-, vinyl- iodonium salts will be carried out. To this moment, we have developed a new synthetic strategy for preparation of para-iodophenol hypervalent iodine compounds, and we have shown on the example of phenylbenzimidazolyliodonium acetate and its anionic form a recordselectivity in the reacton with fluoride anione, when only fluorobenzene was as a product. Synthesis of ortho- and meta-iodophenol polyvalent iodine substances is important. These investigations let to create technologies for insertion of radioactive fluorine (18F) in L-thyrosine, DOPA and dopamine, in which structures there are hydroxyl-groups. On the third stage of this grant we first have obtained hypervalent iodine derivative of iododopamine and in case of prolongation of this project, domestic technology of 18F-dopamine (one of the most important drug for PET diagnosis of the brain) preparation will be made. The development of the chemistry of iodonium salts will lead to C-arylation and C-vinylation of organic substrates without the use of transition metal compounds, in particular, palladium, similar to the reactions of Suzuki, Heck, Sonogashira, etc. A special place will be given to the synthesis and study of the properties of arylimidazolyl, arylpyrazolilyl, aryloxazolyl, vinyl iodonium salts. We also plan to significantly expand the range of new potentially useful reagents for fine organic synthesis based on iodine compounds and its polyvalent derivatives. Within the framework of the grant of the Russian National Foundation, we have developed an affordable method for the preparation of inorganic and organic polyvalent iodine derivatives using the available OXONE (I2-Ac2O-AcOH-OXONE-CF3COOH) as an oxidant. Also using this oxidizing agent, available methods for the production of vicinal iodoamines, iodoimides, diamines, aminoamides and sulfoxides have been developed. Within the framework of this project, we plan to investigate the preparative capabilities of this oxidizing system, particularly, to design a one-pot method for the synthesis of hypervalent iodine compounds containing electron donating groups, a wide range of vicinal iodoamines, iodoimides, diamines, aminoamides. In addition to Oxone, organic oxidants (malonyl peroxides and ozonides) will also be investigated, which is important for eliminating highly acidic media. Research of the synthesis and reactivity of “green” reagents based on 2-iodobenzenesulfonic acid in combination with porphyrins will also be continued.

Expected results
In the course of this project, the following world-level scientific results of fundamental and practical importance will be obtained: • The synthesis of polyvalent iodine derivatives of L-tyrosine and L-thyroxine and establishing their role as an oxidant in combination with porphyrins in biomimetic transformations of biologically important substances. These results will lead to breakthrough in world science and will let to answer to the question about L-thyroxine role in human life. The idea of the synthesis of new porphyrins, that contains hypervalent iodine instead of metal atoms, is revolutionary in hypervalent iodine chemistry and porphyrins as well. Research of biological activity of hypervalent iodine derivatives of L-tyrosine and L-thyroxine will let to get new knowledges about these aminoacids in human body and to create diagnostic drugs for nuclear medicine. • The synthesis of new porphyrins containing hypervalent iodine instead of metal atom and investigation of their preparative capabilities in biomimetic transformations of organic substrates, in particular, physiology active ones. The research will open a new page in porphyrin chemistry and chemistry of polyvalent iodine as bio-oxidative system. • The synthesis and studying of properties of phenol-, arylimidazolyl-, arylpyrazolyl-, aryloxazolyl-, vinyl- iodonium salts. Synthesis of ortho- and meta-iodophenol hypervalent iodine compounds is important. These investigations will let to design the technology of insertion of radioactive fluorine (18F) in L-tyrosine, DOPA and dopamine, in which structures there are hydroxyl groups. • The design of novel reagents based on hypervalent iodine for fine organic synthesis and synthesis of new substances with useful properties. The explorations will expand the range of reagents, which are correspond to the “green” chemistry, particularly, reagents using for C-C-, C-O-, C-N- and C-S-coupling instead of transition metals. • Enlargement of preparative scope of organic and inorganic high-valent iodine derivatives that is prepared with the use of available OXONE (I2-Ac2O-AcOH-OXONE-CF3COOH), organic peroxides and ozonides as oxidants. The examinations will allow to develop methodology of the one-pot synthesis of hypervalent iodine compounds containing electron-donating groups, wide range of vicinal iodoamines, iodoimides, diamines, aminoamides.

Annotation of the results obtained in 2020
At the current stage, studies on the synthesis of polyvalent iodine derivatives, primarily iodo-L-tyrosines, were continued. Systematic studies of the oxidative processes of the iodine atom not only in iodine-containing amino acids but also in their close model analogues were conducted. Various peracids, cyclic organic peroxides, and potassium iodate were used as oxidizing agents. Particular attention was paid to the oxidation of 2-iodo-L-tyrosine by malonic acid peroxides, as the mildest oxidant similar to biological systems. Analysis of the reaction mixture by 1H NMR showed that besides the oxidation product I (+3), the reaction mixture contained products of hydroxylation of the aromatic ring. At the previous stage, we established this fact in the case of iodonium salts. In this case, the oxygenation process also occurs through the polyvalent iodine compound, especially the process is simplified in the presence of porphyrins. To next intense the study, we synthesized an analogue of L-thyronine - 4-methoxy-4/-methyldiphenyl ether and its monoiodinated derivative 4-methoxy-3-iodo-4/-methyldiphenyl ether. As in the case of iodine derivatives of L-tyrosine, the action of oxidants led not only to a hypervalent iodine derivative but also to the formation of products of deiodination, re-iodination, and oxygenation. In addition to research of the transformations of biological iodides, the synthetic applicability of reagents based on polyvalent iodine was significantly expanded during the implementation of the project. The method of synthesis of aryliodoxoles has been developed and their reactivity in the radiofluorination reaction has been shown. The synthesis of [18F] -labelled benzoic acids with the highest, previously unachievable, radiochemical yields (up to 85%) was shown based on nitroaryliodoxole in "hot-cells" conditions. Systematic studies on the synthesis of the corresponding ω-[18F]-fluoroaliphatic carboxylic acids and succinimide-1-yl-6-[18F]-fluorohexanoate as promising prosthetic groups were carried out on the example of ω-iodoaliphatic carboxylic acids under the same conditions. We have also developed a method of the synthesis of cyclic iodonium salts based on pyrazoles applying an earlier founded oxidizing system based on Oxone. Oxone in combination with I2 in trifluoroacetic acid media resulted in I (3+) - I (OCOCF3)3 - which was isolated as yellow crystals. These studies open the way to the widespread use of previously difficult to prepare inorganic polyvalent iodine reagent. Within the framework of the stated investigations, an easy [2,3]-sigmatropic rearrangement of allyl sulfides through N-sulfilimine intermediates in the absence of metal derivatives was developed. Optimization of conditions was carried out and a plausible mechanism of this rearrangement was proposed. Within the framework of this stage, studies of intramolecular catalytic cyclization of aromatic aldoximes in the presence of polyvalent iodine compounds into the corresponding benzopyranoisoxazolines and benzopyranoisoxazoles were carried out. The research demonstrates the huge synthetic importance of hypervalent iodine compounds in the preparation of annulated heterocyclic compounds. The next direction of our research was the synthesis of new quaternary phosphonium salts with the participation of an iodonium salt in the presence of water. At the early stages of this project, we have discovered the process of generating benzyne from aryliodoboroxoles in the presence of water. At the moment, we have developed a simple and convenient method for the preparation of new phosphonium salts as a result of the reaction of benzyne and different triphenylphosphines.

Publications

1. Akira Yoshimura, Scott M. Larson, Gunnar B. Frahm, Christopher D. Huss, Gregory T. Rohde, Victor N. Nemykin, Mekhman S. Yusubov, Akio Saito, Viktor V. Zhdankin Synthesis of arylbenziodoxoles using pseudocyclic benziodoxole triflate and arenes Arkivoc, iv, 35-49 (year - 2020) https://doi.org/10.24820/ark.5550190.p011.324

2. Cody L. Makitalo, Akira Yoshimura, Gregory T. Rohde, Irina A. Mironova, Rosa Y. Yusubova, Mekhman S. Yusubov, Viktor V. Zhdankin, Akio Saito Imino-λ3-iodane and Catalytic Amount of I2-Mediated Synthesis of N-Allylsulfenamides via [2,3]-Sigmatropic Rearrangement Eur. J. Org. Chem., 6433-6439 (year - 2020) https://doi.org/10.1002/ejoc.202000961

3. Mariia S. Larkina, Anastasia V. Ozerskaya, Ekaterina V. Podrezova, Mikhail V. Belousov, Vladimir Tolmachev, Viktor V. Zhdankin, Mekhman S. Yusubov Efficient Synthesis of ω-[18F]Fluoroaliphatic Carboxylic Esters and Acids for Positron Emission Tomography European Journal of Organic Chemistry, 6375–6381 (year - 2020) https://doi.org/10.1002/ejoc.202000934

4. Akira Yoshimura, Akio Saito, Mekhman S. Yusubov, Viktor V. Zhdankin Synthesis of Oxazoline and Oxazole Derivatives by Hypervalent- Iodine-Mediated Oxidative Cycloaddition Reactions Synthesis, 52, 2299–2310 (year - 2020) https://doi.org/10.1055/s-0040-1707122

Annotation of the results obtained in 2019
In the 4th stage of project implementation, we continued the systematic evaluation of the oxidation process for the preparation of hypervalent iodine compounds from the appropriate amino acids and their structural analogs. Thus, we optimized the procedure for the preparation of hypervalent iodine derivatives using DMDO as an oxidant and found extremely mild conditions. We demonstrated that hypervalent derivatives of L-iodotyrosine, L-diiodotyrosine, and iodothyronines were unstable and easily decomposed with the formation of a wide range of products via the reductive process. As an example, we observed the formation of T2 and, probably, T4 in the product of T3-Hyper decomposition. Similar behavior was found for the iodonium salts derived from L-iodotyrosine and L-thyronine. The freshly prepared iodonium salts readily decomposed via reductive elimination and nucleophilic substitution. We suggested that the observed processes can play a pivotal role in the biosynthesis of key metabolites like L-dioxyphenylalanine, L-DOPA, and L-adrenalin. Particular interest that such chemical transformations can be catalyzed by porphyrin-containing biomolecules (Hem and cytochrome P350). Also, this part of the research was finalized by the development of a facile approach to the preparation of m- and o- hydroxy-substituted iodonium salts. During the project implementation, we sufficiently improved the synthetic applicability of hypervalent iodine reagents in organic synthesis and proposed the novel reagents. Thus, we developed the versatile method for the preparation of pyrazole-containing cyclic iodonium salts using Oxone as an oxidant in the presence of sulfonic acid and one-pot procedure for the preparation of iodosotrifluoroacetates via oxidation of molecular iodine by Oxone-Ac2O-AcOH-CF3COOH. Moreover, for the first time, we prepared a unique oxidant - 2-iodoxybenzoic acid ditriflate – via the simple treatment of IBX by triflic acid in DCM with the addition of CF3COOH. Nowadays, the prepared reagent demonstrates the leader oxidative ability, which was demonstrated in the oxidation of perfluorinated alcohols. Last, but not least, we developed a range of synthetic procedures for the preparation of merit products and building-blocks. We proposed the novel method for the preparation of isoxazoles via heterocyclization of aldoximes and enaminones mediated by the available Kozer reagent. Moreover, we demonstrated the high efficiency of iodonium ylides in the reaction of sulfonylimino group transfer in the mild conditions and the absence of metal catalysts.

Publications

1. Akira Yoshimura, Cody L. Makitalo, Melissa E. Jarvi, Michael T. Shea, Pavel S. Postnikov, Gregory T. Rohde , Viktor V. Zhdankin , Akio Saito, Mekhman S. Yusubov Sulfonylimino Group Transfer Reaction Using Imino-3-iodanes with I2 as Catalyst Under Metal-free Conditions Molecules, 24, 979 (year - 2019) https://doi.org/10.3390/molecules24050979

2. Akira Yoshimura, Melissa E. Jarvi, Michael T. Shea, Cody L. Makitalo, Gregory T. Rohde, Mekhman S. Yusubov, Akio Saito, and Viktor V. Zhdankin Hypervalent Iodine(III) Reagent Mediated Regioselective Cycloaddition of Aldoximes with Enaminones European Journal of Organic Chemistry, 6682–6689 (year - 2019) https://doi.org/10.1002/ejoc.201901258

3. Mekhman S. Yusubov, Natalia S. Soldatova, Pavel S. Postnikov, Rashid R. Valiev, Akira Yoshimura, Thomas Wirth, Victor N. Nemykin and Viktor V. Zhdankin 2-Iodoxybenzoic acid ditriflate: the most powerful hypervalent iodine(V) oxidant Chemical Communications, 55, 7760--7763 (year - 2019) https://doi.org/10.1039/C9CC04203B

4. Mekhman S. Yusubov, Pavel Postnikov, Akira Yoshimuraa, Viktor V. Zhdankin Benziodoxole-Derived Organosulfonates: The Strongest Hypervalent Iodine Electrophiles and Oxidants Synlett, 30, A–L (year - 2019) https://doi.org/10.1055/s-0039-1690761 ; Art ID: st-2019-a0596-a

5. Akira Yoshimura, Mekhman S. Yusubov, and Viktor V. Zhdankin Iodonium imides in organic synthesis Arkivoc, part i, 228-255 (year - 2019) https://doi.org/10.24820/ark.5550190.p010.975

6. - Самый мощный и самый мягкий реагенты на основе экологичного йода создали в Томском политехе Новости ТПУ, - (year - )

7. - New hypervalent iodine compound is most powerful oxidant in series ChemistryWorld, - (year - )