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Short literature review on approaches to the total synthesis of gliocladride-DKP alkaloids
As the only known example of hydroxamic DKP, the total synthesis of mycelianamide I-43 (double oxidative form of gliocladride-DKP) has attracted lots of attention since 1963. Brantley attempted three different approaches to synthesize the 1,4-dihydroxy-2,5- diketopiperazine core, yet without success (Scheme II-3):130
a) direct oxidation of 2,5-DKP I-38.
b) condensation methods utilizing hydroxylamine II-8 and α-halo acid halides II-9.
c) reduction of nitroesters II-10 to α-hydroxylamino esters II-11 and subsequent bimolecular condensation of these compounds. None of these approaches was successful to provide II-7.
Literature review on approaches to the 2,3-disubstituted quinazolinone motif and some examples of total syntheses of quinazolino-DKP alkaloids
A number of synthetic approaches have been developed to construct the 2,3-disubstituted quinazolinone core, such as condensations (a, b, e), radical cyclization (c135, d) and transitionmetal- catalyzed C-N bond formation (f-h) (Scheme II-8).65 These methods were further developed to make quinazolinones fused with a DKP core and applied to total syntheses with varying degrees of success.
alkaloids. The total synthesis of the simplest members, such as glyantrypine, (-)- fumiquinazoline G and (-)-fiscalin B, resulting from double cyclodehydration of linear tripeptides, have been largely studied for decades (Scheme II-9). 136 As the majority of synthetic methods developed are substrate-dependent, the most universal and straightforward route to synthesize these 2,3-disubstituted quinazolinones is still to use the intramolecular dehydrative cyclization of suitably substituted diamides. The direct double condensation attempts of diamides were achieved by exploring the peptide assembly on Sasrin® resin, which afforded anacine, verrucine A and verrucine B with a low yield.
Snider’s synthesized (-)-fumiquinazoline G by using an intramolecular aza-Wittig annulation developed by Eguchi138. The transformation of quinazoline-4-one II-39 to an amide was initiated by the deprotection of the dimethoxybenzyl group (Scheme II-9a).139 As requiring many judicious manipulations of protecting groups, the application of this method was not expanded to other quinazolinone-DKPs.
The cyclodehydration of N-acylanthranilamides II-42 to iminobenzoxazines II-43 has also been a frequent approach for the synthesis of quinazolino-DKPs by employing Ph3P/Br2/Et3N conditions developed by Mazurkiewicz, 140 or HMDS/I2 developed by Argade 141 through dehydration of β-keto amides to oxazine (Scheme II-9b). After removal of Fmoc group with piperidine, the oxazine-quinazoline rearrangement was mediated by silica or refluxing conditions and ended with an intramolecular cyclization to get the DKP core. This approach was then successfully applied to the synthesis of (-)-fumiquinazoline G and (-)-fiscalin B,142 but failed for fumiquinazoline F and ent-alantrypinone.143 This work demonstrates that this method is sensitive to steric hindrance and not applicable to highly functionalized quinazolinones.
Biomimetic synthesis of the quinazolino-DKP scaffold
From a structural perspective, the first design of our quinazolino-DKP intermediate was based on a linear assemblage of three amino acids: anthranilic acid I-114, valine and phenylalanine, which allowed getting biomimetic precursors (II-51 and II-54) of varioxepine A. The 3,6,8- trioxabicyclo[3.2.1]octane motif contained in the varioxepine A is indeed more attractive and challenging for late-stage functionalization studies.
Two different assemblages of tripeptides Isa-Val-Phe or Phe-Isa-Val were initially prepared from isatoic anhydride II-52 (Isa) by standard methods, as shown in Scheme II-10.
Oxidation attempts of DKPs and gliocladride-type DKP scaffolds
Most of the hydroxamic acid derivatives isolated from nature show potential therapeutic uses as inhibitors of siderophores.153 Acting as powerful metal ion chelators, cyclic hydroxamic acids can scavenge iron and interact with iron-containing metalloproteinases,154 thus being useful for the treatment and prevention of cancer metastasis, inflammation and immune diseases.155 The development of a general method to get rapidly N-substituted hydroxamic acids would thus be useful for drug discovery.
Linear terminal hydroxamic acid derivatives are easily accessible by generating amide bonds from hydroxylamine and carboxylic acids. Cyclic hydroxamic acids are N-hydroxy lactams, which are difficult to synthesize directly from amide groups. Very few successful examples are found in the literature. DMDO and TFDO could be used to oxidize the CBoc-N bond of linear N-Boc protected peptides I-138 (Scheme II-15a). 156 Peroxo-molybdenum complex MoO5 DMF is reported to oxidize the aromatic lactam II-77 to cyclic hydroxamic acid II-78 in the presence of DMF (Scheme II-15b). 157 Diperoxo-oxo(hexamethylphosphoramido) molybdenum(VI) pyridine complex (MoO5 PyHMPA or MoOPH) was developed to oxidize N-trimethylsilylamides to furnish the corresponding hydroxamic acids, which was also applied to the synthesis of (±)-tenellin (Scheme II-15c).158 However, in most cases, yields are usually low, showing the difficulties of this oxidation.
Oxidation attempts of the quinazolino-DKP scaffold
Much work has been reported in the literature on the reactivity of 2,3-disubstituted quinazolinone.164 The position C1 can be deprotonated by strong bases, and the generated anions II-84 could undergo stereoselective alkylations, acylations and Michael reactions (Scheme II-17a).165 The tertiary acyliminium species II-86 could also be generated at position C1 by using Koser’s reagent or free-radical bromination, leading to hydroxyl, alkoxy, acyloxy and aryl derivatives.166 The oxidation with PCC could also generate a tertiary acyliminium cation in order to give 1-oxo derivatives II-87.167 Regarding position C4, only nucleophilic reactions have been developed after deprotonation with LiHMDS in the presence of R1 substituent at position C1 (Scheme II-17b). 168 During the synthesis of (±)-lapatin B, the imidate-protected diketoperazine core could be aromatized by DDQ, affording II-91 as intermediate, which involved in fact a C1 oxidation.
Microbial oxidations for gliocladride-type DKPs
Introduced in the first chapter, all gliocladride DKPs are natural products isolated from marine strains.60 Thus, it was logical to screen a selection of marine fungal species from the collection of the MCAM unit of the National Natural History Museum and some known bacteria and fungi species for oxidoreductions, as potential biotransformation strains (Table II-13).
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
