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Universita' Degli Studi Di Parma UNIVERSITA’ DEGLI STUDI DI PARMA Dottorato di ricerca in Scienze degli Alimenti Ciclo XXIX Development of new synthetic and analytical methods for the investigation of specific polyphenolic human metabolites Coordinatore: Chiar.mo Prof. Furio Brighenti Tutor: Chiar.mo Prof. Daniele Del Rio Dottorando: Nicoletta Brindani Tutor: Daniele Del Rio Laboratory of Phytochemicals in Physiology of the Department of Food Science (University of Parma) Cotutor: Prof. Claudio Curti Bio-Organic Synthesis Group of the Department of Pharmacy (University of Parma) PhD student: Nicoletta Brindani Parma - December 2016 TABLE OF CONTENTS GENERAL INTRODUCTION…………………………………………………………………………………1 INTRODUZIONE GENERALE……………………………………………………………………………….2 CHAPTER 1 Chiral valerolactone metabolites: when challenging synthetic targets meet relevant food science 1.1. Classifications of polyphenols: flavonoid and non-flavonoid compounds…………………………………………………………………………………………………3 1.1.1. A focus on Flavan-3-ol subclass………………………………………………………….6 1.2. Polyphenols fate in human………………………………………………………………………10 1.2.1. The stereochemical effect of flavan-3-ol on their bioavailability………13 1.2.2. Microbiota catabolism of flavan-3-ols………………………………………………14 1.2.3. Focusing on -valerolactone metabolites: past identifications and open questions………………………………………………………………………………………….18 1.3. Bioactive valerolactone metabolites………………………………………………………..22 1.4. Conclusion and perspectives……………………………………………………………………24 1.5. References……………………………………………………………………………………………….26 CHAPTER 2 The catalytic, enantioselective, vinylogous aldol reaction (VMAR) with heterocyclic donor systems 2.1. Introduction: the pillars of organic synthesis……………………………………………30 I 2.2. The origin of the vinylogous Mukaiyama aldol reactions (VMAR)…………….35 2.3. Denmark’s bisphosphoramide-SiCl4 chiral complex in enantioselective VMAR………………………………………………………………………………………………………36 2.4. Summary and conclusion………………………………………………….........................40 2.5. References……………………………………………………………………………………………….41 CHAPTER 3 Catalytic, Enantioselective Vinylogous Mukaiyama Aldol Reaction of Furan- Based Dienoxy Silanes: A Chemodivergent Approach to -Valerolactone Flavan-3-ol Metabolites and -Lactone Analogues………………………………………..43 3.1. Introduction…………………………………………………………………………………………….44 3.2. Results and discussion……………………………………………………………………………..48 3.2.1. Synthesis of -valerolactones…………………………………………………………48 3.2.2. Unexpected Reductive Ring Expansion: Synthesis of - Valerolactones………………………………………………………………………………………..57 3.3. Stereochemical assessment……………………………………………………………………..64 3.4. Conclusion……………………………………………………………………………………………….67 3.5. Experimental section……………………………………………………………………………….68 3.6. References……………………………………………………………………………………………….91 CHAPTER 4 Synthetic and analytical strategies for the quantification of phenyl-γ- valerolactone conjugated metabolites in human urine…………………………………95 II 4.1. Introduction…………………………………………………………………………………………….96 4.2. Results and discussion……………………………………………………………………………..98 4.2.1. Synthesis of conjugated phenyl-γ-valerolactones………………………….98 4.2.2. Development and optimization of the UHPLC-ESI-MS/MS method…………………………………………………………………………………….101 4.2.3. Method validation……………………………………………………………………….103 4.2.4. Method application: urinary excretion of phenyl-γ-valerolactones after consumption of green tea…………………………………………………..105 4.3. Conclusions……………………………………………………………………………………………106 4.4. Experimental section……………………………………………………………………………..110 4.4.1 Urine collection and processing …………………………………………………..110 4.4.2 UHPLC-ESI-QqQ-MS/MS ……………………………………………………….........111 4.4.3. Method validation ……………………………………………………………………...112 4.4.4. Data and statistical analysis ………………………………………………………..113 4.4.5. Chemicals ……………………………………………………………………………………113 4.5. References……………………………………………………………………………………………..134 CHAPTER 5 5-(3',4'-dihydroxyphenyl)-γ-valerolactone and its sulfate conjugates: representative circulating metabolites of flavan-3-ols, exhibiting anti- adhesive activity against uropathogenic Escherichia coli in bladder epithelial cells………………………………………………………………………………………………………………137 5.1. Introduction…………………………………………………………………………………………..138 5.2. Results and discussion……………………………………………………………………………140 III 5.2.1. Anti-adhesive effects of dihydroxyphenyl-γ-valerolactone derivatives on the adherence of E. coli to bladder epithelial cells………………….140 5.2.2. Metabolism of γ-valerolactone derivatives in bladder epithelial cells…………………………………………………………………………………………….141 5.3. Discussion……………………………………………………………………………………………..143 5.4. Conclusions……………………………………………………………………………………………146 5.5. Experimental section…………………………………………………………………………….147 5.5.1. Chemicals ……………………………………………………………………………………147 5.5.2. Bladder epithelial cells and cytotoxicity assays …………………………..147 5.5.3. UPEC adherence assays ………………………………………………………………148 5.5.4 UHPLC-MS/MS analysis of cell media …………………………………………..149 5.5.5 Statistical analysis ………………………………………………………………………..149 5.6. References……………………………………………………………………………………………..150 CHAPTER 6 Biomimetic total synthesis of members of the C-glucosidic subclass of ellagitannins…………………………………………………………………………………………………152 6.1. Introduction…………………………………………………………………………………………..153 6.1.1. Stereochemical consideration …………………………………………………….156 6.1.2. Synthetic challenges…………………………………………………………………….157 6.2. Synthetic planning of open-chain ellagitannins………………………………………159 6.3. Results and Discussion……………………………………………………………………………162 6.4. Conclusion and perspectives………………………………………………………………….166 IV 6.5. Experimental Section……………………………………………………………………………..167 6.6. References……………………………………………………………………………………………..177 CHAPTER 7 Synthesis of regioisomeric variants of mono glucuronide urolithin A…………179 7.1. Introduction…………………………………………………………………………………………..180 7.2. Results and discussion……………………………………………………………………………185 7.3. Preliminary structural determination…………………………………………………….189 7.4. Conclusion and perspectives………………………………………………………………….192 7.5. Experimental section……………………………………………………………………………..194 7.6. References……………………………………………………………………………………………..200 FINAL REMARKS……………………………………………………………………………………………202 ACKNOWLEDGEMENTS…………………………………………………………………………………204 V GENERAL INTRODUCTION Science is a privileged interpreter of Nature. Nature is always offering continuing transformation of the physical world and the scientific interpretation of these transformations in the wide domain of polyphenol natural products along with the desire of facing new horizons propelled the research during my three-years-long PhD studies. I tried to face this domain from a double perspective, the nutrition world and the organic synthesis world, as two curious observers are looking toward the same horizon. The intense transformation of polyphenol molecules in human body brings about many types of metabolites, whose structural complexity have stimulated modern organic chemistry toward the creation of new strategies and methods to access them by synthesis. In particular, the invention and exploitation of new methodologies to selectively drive chemical transformations of specific substrates is of paramount interest in modern synthesis. On these grounds, the development of chemical strategies including the asymmetric vinylogous Mukaiyama aldol reaction, the intra- and intermolecular biaryl coupling, and conjugation reactions of phenol substrates allowed access to specific polyphenol metabolites, in particular -valerolactones and urolithins. The synthetic obtainment of these targets gave us the possibility to study their molecular structure and investigate their metabolic profiles, thus offering new "interpretations” of Nature. 1 INTRODUZIONE GENERALE La scienza è una pregevole interprete della Natura. Quello che la Natura continua a offrire è una perpetua trasformazione. L’interpretazione di questa trasformazione all’interno del popolare mondo dei polifenoli col desiderio di affrontarne nuovi orizzonti ha generato il lavoro di ricerca che ho seguito durante i tre anni del mio dottorato, in cui due osservatori hanno cercato lo stesso orizzonte: il mondo della nutrizione e quello della chimica organica. L’intensa trasformazione dei polifenoli nel corpo umano genera diversi tipi di metaboliti, le cui strutture hanno fornito l’occasione alle moderne metodologie chimiche di esprimere la loro potenzialità sintetica. La chimica organica è appunto lo studio delle trasformazioni subite e innescate dalle entità molecolari. Come sfruttare e governare queste trasformazioni chimiche in funzione della natura del substrato e per l’ottenimento di determinati motivi strutturali è lo scopo dell’indagine metodologica. Su questa linea di ricerca l’indispensabile studio di nuove strategie, fra cui la reazione asimmetrica viniloga di Mukaiyama, gli accoppiamenti biarilici intra- ed intermolecolari e le reazioni di coniugazione di substrati fenolici hanno permesso l’accesso a specifici metaboliti polifenolici, in particolare i metaboliti valerolattonici e le urolitine. L’ottenimento sintetico di questo tipo di strutture ha fornito quindi la possibilità di analizzarne rigorosamente la struttura molecolare e di indagarne il profilo metabolico aprendo la strada a nuove “interpretazioni”. 2 CHAPTER 1 Chiral valerolactone metabolites: when challenging synthetic targets meet relevant food science 1.1. Classifications of polyphenols: flavonoid and non-flavonoid compounds The plant kingdom produces an overwhelming array of structurally diverse secondary metabolites, among which flavonoids and related phenolic and (poly)phenolic compounds
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