Microbial oxidations for gliocladride-type DKPs

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Table of contents

ACKNOWLEDGEMENTS
LIST OF ABBREVIATIONS
FOREWORD
Chapter I. General Introduction
1. New era of natural product total synthesis
1.1. From natural products to drug candidates
1.2. From target-oriented strategies to collective strategies in natural product synthesis .
1.3. Biomimetic synthesis
1.4. Challenges and new perspectives for biomimetic collective natural product synthesis
2. Diversity and biosynthesis origins of 2,5-diketopiperazines (DKPs)
2.1. Simple DKPs: structure and biosynthesis
2.2. Gliocladride DKPs and their biosynthesis
2.3. Quinazolino-DKPs and their biosynthesis
2.4. Oxepino-DKP natural products and their biosynthesis
3. Late-stage functionalization strategies in organic and bio-organic chemistry
3.1. Late-stage C-C bond formation
3.2. Late-stage C-O bond formation
3.3. Biocatalytic functionalization
4. Objectives of the doctoral research
Chapter II. Installation Biomimetic Gliocladride and Quinazolino-DKP Scaffolds and their Functionalization
1. Synthetic works on gliocladride and quinazolino-DKP scaffolds
1.1. Gliocladride DKPs
1.1.1. Short literature review on approaches to the DKP motif
1.1.2. Short literature review on approaches to the total synthesis of gliocladride-DKP alkaloids
1.1.3. Synthesis of the gliocladride DKP scaffold
1.2. Synthesis of quinazolino-DKP intermediates
1.2.1. Literature review on approaches to the 2,3-disubstituted quinazolinone motif and some examples of total syntheses of quinazolino-DKP alkaloids
1.2.2. Biomimetic synthesis of the quinazolino-DKP scaffold
2. Post-functionalization attempts of biomimetic DKP scaffolds
2.1. Chemical oxidations
2.1.1. Oxidation attempts of DKPs and gliocladride-type DKP scaffolds
2.1.2. Oxidation attempts of the quinazolino-DKP scaffold
2.2. Biotransformation attempts
2.2.1. A short state of the art on biotransformations
2.2.2. Microbial oxidations for gliocladride-type DKPs
2.2.3. Microbial oxidation of quinazolino-DKP substrates
3. Conclusion and perspectives
Chapter III. From Tandem Cyclopropanation/ Oxa-Cope Rearrangement Studies to the Total Synthesis of Oxepin-Based Natural Products
1. Literature review
1.1. Synthetic methods towards oxepins
1.2. [3,3]-Sigmatropic rearrangements for the formation of carbocycles
1.2.1. Definitions
1.2.2. Cope rearrangements
1.2.3. Rearrangements of vinylcyclopropanes and divinylcyclopropanes into cyclopentenes and cycloheptadienes
1.3. Hetero-Cope-type rearrangements for the synthesis of heterocycles, especially 2,5- dihydro-1-heterocycloheptenes
1.3.1. Oxa-Cope rearrangements (= retro-Claisen rearrangements)
1.3.2. The Cloke-Wilson rearrangements to heterocyclopentenes
1.3.3. A few words on 1-aza-Cope rearrangements (aza-retro-Claisen rearrangements) 90
2. Experimental studies for the synthesis of 2,5-dihydrooxepines through one-pot tandem cyclopropanation/oxa-Cope rearrangement
2.1. Attempts of Knoevenagel condensation followed by cyclopropanation
2.2. Attempts of cyclopropanation followed by Wittig reaction
2.2.1. Cyclopropanation with α-bromodicarbonyl componds
2.2.2. Cyclopropanation by using diazo-derived carbenoids
2.3. Tandem cyclopropanation/oxa-Cope rearrangement by using 1,4-dibromobut-2-ene substrate as a conjunctive reagent
2.3.1. First encouraging results
2.3.2. Optimization of reaction conditions by NMR studies
2.3.3. Reaction attempts with cyclic substrates
2.3.4. Reaction attempts with linear substrates
2.3.5. Comments on the associated Cloke-Wilson rearrangement dring these experiments
2.4. Conclusions
3. DFT calculations on the transformations of acylvinylcyclopropanes to dihydroxepines and dihydroxyfurans
3.1. General background introduction
3.1.1. Computational chemistry and associated methods
3.1.2. Literature review on [1,3] and [3,3] rearrangement calculations for 2- vinylcyclopropyl aldehyde
3.2. Modelisation results of [1,3] and [3,3] rearrangements for cyclohexadione and acetylacetone vinylcyclopropane derivatives
3.2.1. Calculations results for cyclohexadione derivative III-133c
3.2.2. Calculation results for acetylacetone vinylcyclopropane II-164
3.2.3. Electronic and steric effects for acyclic substrate
3.3. Conclusions
Chapter IV. Total Synthesis of Benzoxepines and Oxepino-Diketopiperazines by using Oxa-Cope Rearrangements
1. Total synthesis of radulanin natural products
1.1. Introduction: isolation and biological activities of radulanins
1.2. Literature reviews on radulanin synthesis
1.3. New synthetic strategy and results
1.4. Bioactivity tests of radulanins
1.5. Conclusion and perspectives
2. Total synthesis of janoxepin and cinereain by using the oxa-Cope rearrangement
2.1. Taylor’s total synthesis of janoxepin
2.2. Total synthesis of janoxepin and cinereain
2.3. Conclusions and perspectives
Chapter V. General Conclusion
Experimental Section