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Synthesis of polyfunctionalized terpenic derivatives via radical and cationic reactions


Author: Gîrbu Vladilena
Degree:doctor of chemistry
Speciality: 02.00.10 - Bioorganic chemistry; chemistry of natural and physiological active compounds
Year:2020
Scientific adviser: Veaceslav Kulciţki
doctor, professor, Institute of Chemistry of the ASM
Scientific consultant: Nicon Ungur
doctor habilitat, associate professor (docent), Institute of Chemistry of the ASM
Institution: Institute of Chemistry of the ASM

Status

Term of presenting of the thesis 16 June, 2020

Abstract

Adobe PDF document1.71 Mb / in romanian
Adobe PDF document1.68 Mb / in english

Thesis

CZU 547.596/.597:577.1 (043.2)

Adobe PDF document 4.52 Mb / in english
154 pages


Keywords

terpenoids, radical chemistry, carboazidation, carbohydrogenation, hydroazidation, skeletal rearrangements, biologically active compounds

Summary

ANNOTATION Gîrbu Vladilena, "Synthesis of polyfunctionalized terpenic derivatives via radical and cationic reactions", PhD thesis in chemical science, Chișinău 2019. Structure of the thesis: Introduction, 4 chapters, general conclusions and recommendations, bibliography of 203 references, 111 basic text pages, 65 figures, 6 tables, 1 annex. The results of the research have published in 20 scientific papers. Key-words: terpenoids, radical chemistry, carboazidation, carbohydrogenation, hydroazidation, skeletal rearrangements, biologically active compounds. The aim of the thesis: is functionalization of terpenoids with nitrogen, oxygen and halogen heteroatoms through radical reactions thus obtaining compounds with high potential biological activity; modification of readily available terpenoids via skeletal rearrangements and generation of compounds with rearranged skeletons. Research objectives: the use of hydroazidation, carboazidation and carbohydrogenation radical reactions for the functionalization of natural and synthetic diterpenoids; modification of the carbonic skeleton in isocopalic and homodrimanic derivatives through cationic migrations to obtain the terpenic derivatives, the analogues of which are found in nature in a small amount; characterization of the compounds using modern methods of analysis. Scientific novelty and the originality: For the first time, the usefulness of radical addition with atom transfer has been demonstrated for the functionalization of diterpenic compounds, such as ent-kaurane, labdane and isocopal derivatives. Ninety new compounds have been synthesized, some showing pronounced biological activity. For the first time, due to cationic transpositions, compounds with halimane, ent-verrucosin and hyrtiosane skeleton have been synthesized. The results which can contribute to the solution of an important scientific problem in the thesis consist in the simultaneous introduction of functional groups via radical reactions and obtaining labdanic, ent-kauranic and isocopalic compounds functionalized with nitrogen, oxygen or halogen heteroatoms, some demonstrating biological activity; a series of sesquiterpenoids with halimane, hyrtiosane and ent-verrucosin skeleton, compounds with theoretical and applicative value have been obtained. The theoretical value: consists in the successful application of radical transformations for broadening the structural diversity of terpenic compounds with complex structure, demonstrating the influence of stereoelectronic effects on the selectivity of the processes approached and developing efficient ways of functionalization of the selected substrates based on radical and cationic reactions. The applicative value of the research is the viability of radical chemistry on complex terpenic substrates; demonstration of the click reaction on diterpenic substrates and their use in biological activity studies. The implementation of scientific results: a number of compounds synthesized throughout the research demonstrated selective cytotoxic activity. Based on these results, four patent applications have been filed.

Summary


1. FUNCTIONALIZATION AND REARRANGEMENT OF NATURAL COMPOUNDS VIA FREE RADICAL AND CATIONIC INDUCED REACTIONS
  • 1.1 The radical C-H functionalization of natural compounds
  • 1.2 The C-C and C-X bonds formation via atom transfer radical addition methodology
  • 1.3 Recent examples of natural compounds synthesized via cationic reactions
  • .4 Conclusions to chapter 1

2. RADICAL TRANSFORMATIONS OF ENT-KAURANE DITERPENOIDS
  • 2.1 Hydroazidation of methyl ent-kaur-16-en-19-oate
  • 2.2 Carboazidation and carboiodination of ent-kaurane derivatives
  • 2.3 Carbohydrogenation of ent-kaurane derivatives
  • 2.4 Conclusions to chapter 2
  • 2.5 Experimental part

3. RADICAL TRANSFORMATIONS OF LABDANIC AND ISOCOPALIC DITERPENOIDS
  • 3.1 Hydroazidation of epi-manoyl oxide 81
  • 3.2 Carboazidation and carboiodination of manoyl oxides 82
  • 3.3 Carboazidation of natural compound Forskolin
  • 3.4 Carbohydrogenation of manoyl oxides 3.5 Carboazidation of isocopalic related diterpenoids 3.6 Conclusions to chapter 3 3.7 Experimental part 94

4. SYNTHESIS OF SOME TERPENOIDS VIA CATIONIC REARRANGEMENTS
  • 4.1 Synthesis of ent-verrucosin and hyrtiosane skeleton
  • 4.2 The acid-induced rearrangement of homodrimanic epoxide
  • 4.3 Conclusions to chapter 4
  • 4.4 Experimental part 4.
OVERALL CONCLUSIONS AND RECOMMENDATIONS

REFERENCES