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originaux pour la synthèse, l’évaluation biologique et
l’étude structurale de nouveaux composés
peptidomimétiques
Mathéo Berthet
To cite this version:
Délivré par l’Université de Montpellier
Préparée au sein de l’école doctorale Sciences Chimiques Balard Et de l’Institut des Biomolécules Max Mousseron-UMR5247
Spécialité : Ingénierie Moléculaire
Présentée par Mathéo BERTHET
Soutenue le 2 décembre 2016 devant le jury composé de
Dr Valérie Alezra Maître de conférences,
Université Paris-sud
Rapporteur
Dr Vincent Aucagne Chargé de recherche,
Université d’Orléans
Rapporteur
Dr Renata M. de Figueiredo Chargée de recherche,
ENSCM Montpellier
Examinateur
Dr Jean-Christophe Meillon Directeur et fondateur
Oxeltis Montpellier
Examinateur
Dr Gilles Dujardin Directeur de recherche,
Université du Maine
Examinateur
Pr Jean Martinez Professeur,
Université de Montpellier
Directeur de thèse
Dr Isabelle Parrot Maître de conférences,
Université de Montpellier
Examinateur (Co-encadrante)
Oxaprolines et oxadiazine-3,6-diones
Des motifs originaux pour la synthèse, l’évaluation
biologique et l’étude structurale de nouveaux
Délivré par l’Université de Montpellier
Préparée au sein de l’école doctorale Sciences Chimiques Balard Et de l’Institut des Biomolécules Max Mousseron-UMR5247
Spécialité : Ingénierie Moléculaire
Présentée par Mathéo BERTHET
Soutenue le 2 décembre 2016 devant le jury composé de
Dr Valérie Alezra Maître de conférences,
Université Paris-sud
Rapporteur
Dr Vincent Aucagne Chargé de recherche,
Université d’Orléans
Rapporteur
Dr Renata M. de Figueiredo Chargée de recherche,
ENSCM Montpellier
Examinateur
Dr Jean-Christophe Meillon Directeur et fondateur
Oxeltis Montpellier
Examinateur
Dr Gilles Dujardin Directeur de recherche,
Université du Maine
Examinateur
Pr Jean Martinez Professeur,
Université de Montpellier
Directeur de thèse
Dr Isabelle Parrot Maître de conférences,
Université de Montpellier
Examinateur (Co-encadrante)
Oxaprolines et oxadiazine-3,6-diones
Des motifs originaux pour la synthèse, l’évaluation
biologique et l’étude structurale de nouveaux
Any sufficiently advanced technology is indistinguishable from magic.
Arthur C. Clark
3
REMERCIEMENTS
Ce travail, effectué à l’Institut des Biomolécules Max Mousseron (IBMM – UMR 5247, UM – CNRS) au sein de la Faculté des Sciences de l’Université de Montpellier, dans l’équipe F10 synthèses stéréosélectives et acides aminés modifiés du département des acides aminés, protéines et peptides (DAPP) a été financé par l’ANR OXAPROL et le LabEx CheMISyst. Je souhaiterais donc dans un premier temps remercier ces deux organismes pour avoir permis la mise en place de mon projet de thèse.
Je souhaite remercier sincérement le Professeur Jean Martinez pour m’avoir accueilli dans son laboratoire, pour son aide précieuse lors de la rédaction de ma revue et pour avoir assurer le suivi et l’orientation de ma thèse au cours de nombreuses réunions et discussions.
Je tiens également à remercier très vivement le Docteur Isabelle Parrot-Smietana pour m’avoir offert l’opportunité de développer ces travaux de thèse. J’ai eu la chance de participer à un travail multidisciplinaire passionnant, dans un laboratoire doté des meilleurs équipements, tout en bénéficiant d’un encadrement extrémement motivant et formateur. Je tiens à la remercier pour sa confiance, son soutien et ses conseils avisés mais aussi pour m’avoir accompagné et fait progresser tout au long de ces trois années.
Je remercie le Docteur Valérie Alezra de l’Université d’Orsay-Paris sud, le Docteur Vincent Aucagne du CNRS d’Orléans, le Docteur Renata M. De Figueiredo de l’Institut Charles Gerhardt de Montpellier et le Docteur Jean-Christophe Meillon de la start-up OXELTIS de Montpellier de l’honneur qu’ils me font en acceptant de juger ce travail.
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Je tiens aussi à exprimer ma plus profonde gratitude à l’ensemble du personnel du Laboratoire de Mesures Physiques de l’IBMM de Montpellier et plus particulièrement à Monsieur Guillaume Cazals pour les analyses LC/MS, HRMS et à Monsieur Aurélien Lebrun qui nous a sauvés à plusieurs reprises grâce à l’interprétation de spectres RMN et l’élucidation de structures. Les travaux présentés ici n’auraient jamais été possibles sans son aide (Merci aussi à vous deux pour les supers moments pendant les matchs de Basket). Je remercie également Monsieur Pierre Sanchez (Faculté de pharmacie de Montpellier) pour les analyses LC/MS et Messieurs Arie Van Der Lee (Institut Européen des Membranes de Montpellier) et Monsieur Pascal Retailleau (Institut de Chimie des Substances Naturelles de Gif sur Yvette) pour la diffraction des rayons X. Je remercie également tous les stagiaires qui ont travaillé au sein de notre groupe et qui ont permis l’avancement des projets : Thomas, Sophie, Pauline, Aurélie, Florian et Maëva.
La thèse est aussi une très belle expérience humaine, à ce titre je voudrais remercier tous les membres du DAPP avec qui j’ai pu avoir des discussions scientifiques toujours intéressantes ainsi que, mes camarades et collègues qui m’ont accompagné pendant ces trois années :
- Audrey : merci pour tous les bons moments au labo mais aussi pour m’avoir aidé à persévérer et à tenir bon dans les moments difficiles. Je te remercie également pour ton aide et le temps que tu m’as accordé, autant dans le cadre de ma thèse que pour ma recherche de post doc.
- Mathieu : merci d’avoir rendu la thèse très agréable à vivre au quotidien grâce à ta bonne humeur, merci aussi pour tous tes précieux conseils, nos fameux matchs de basket, les soirées Fifa et tous les services rendus (tu me donneras la note).
- Thomas : merci pour ton aide et le travail considérable que tu as fourni, tu as été un super camarade de paillasse, merci aussi pour les cluedo géants, les matchs de Basket et tous les bons délires hors du labo.
- Elodie : merci pour ta sincérité, ton aide pour faire avancer les choses plus rapidement, le chocolat et les odeurs de parfum (plus ou moins agréables) dans le box.
- Manue, Erwann, Pierre et Maxime : merci pour les bons moments qu’on a pu partager ensemble. Merci à Manue pour sa compréhension et compassion sur les difficultés rencontrées avec des dérivés de la proline, merci à Erwann pour les discussions du vendredi soir et les soirées autour d’une bière.
Table des matières
REMERCIEMENTS ... 3
LISTE DES ABRÉVIATIONS ... 9
INTRODUCTION ... 13
I. ETAT DE L’ART SUR LES ISOXAZOLIDINES, LEURS SYNTHÈSES ET APPLICATIONS ... 19
I.1. Introduction... 22
I.2. Occurrence of the isoxazolidine moiety in natural products ... 23
I.3. Synthetic strategies to prepare the isoxazolidine ring ... 28
I.3.1. 1-3-dipolar cycloaddition ... 29
I.3.2. Cyclisations of unsaturated hydroxylamines ... 35
I.3.2.1. Electrophilic cyclisations ... 35
I.3.2.2. Electrophilic 5-exo cyclisations ... 36
I.3.2.3. Electrophilic 5-endo cyclisations ... 38
I.3.3. Palladium-mediated cyclisations ... 41
I.3.4. Radical cyclisations... 42
I.3.5. Michael additions ... 43
I.3.6. Other synthetic strategies ... 45
I.3.6.1. From isoxazolidinones ... 45
I.3.6.2. From isoxazolines ... 46
I.3.6.3. From isoxazolinium salts ... 47
I.4. Applications in organic chemistry ... 48
I.4.1. Reductive ring opening: synthesis of 1,3-aminoalcohols ... 48
I.4.1.1. Ring opening by reduction under catalytic hydrogenolysis ... 48
I.4.1.1.1. Using Pd Catalysts ... 48
I.4.1.1.2. Using Raney-Ni catalyst ... 50
I.4.1.2. Ring opening by reduction with Zn/H+ ... 51
I.4.1.3. Ring opening by reduction with molybdenum hexacarbonyl ... 54
I.4.1.4. Ring opening by reduction with trimethylsilyl chloride/KI/H2O ... 55
I.4.1.5. Ring opening by reduction with samarium iodide ... 56
I.4.1.6. Miscellaneous ... 58
I.4.2. Dismutative ring opening... 58
I.4.2.1. Synthesis of 1,3-aminocarbonyl compounds ... 58
I.4.2.2. Synthesis of N-oxide-1,3-amino alcohols ... 60
I.4.2.3. Synthesis of 1,3-hydroxylamino alcohols ... 61
I.4.2.4. Synthesis of 1,3-nitro alcohols ... 62
I.4.3. From ring opening of isoxazolidines to novel heterocycles ... 62
I.4.3.1. Synthesis of α-amino lactones ... 63
I.4.3.2. Synthesis of α-hydroxy lactams ... 63
I.4.3.3. Synthesis of benzoazepines ... 64
I.4.3.4. Synthesis of tetrahydro-1,3-oxazines ... 65
I.4.3.5. Synthesis of tetrahydro-1,3-oxazin-2-ones ... 66
I.4.3.6. Synthesis of β-lactams ... 67
I.4.4. Thermic rearrangement ... 68
I.4.4.1. Synthesis of β-lactams ... 68
I.4.4.2. Synthesis of 1,4-tetrahydropyridinones ... 69
I.4.4.3. Other thermic rearrangement of isoxazolidines ... 71
I.4.5. Application in organocatalysis ... 72
I.5. Natural building block mimetics ... 74
I.5.1. Nucleoside analogues ... 74
I.5.2. Carbohydrate analogues ... 77
I.5.3. PNA mimetics ... 79
I.5.4. Peptidomimetics ... 80
I.5.4.1. Insertion in peptides ... 80
I.5.4.2. Ligations ... 82
I.5.5. Steroid analogues ... 84
I.6. Medicinal chemistry ... 87
I.6.1. Cytotoxic activities ... 87
I.6.1.1. Using DNA intercalators ... 87
I.6.1.2. Using transcriptional activators ... 88
I.6.1.3. Using other strategies ... 89
I.6.2. Antiviral activities ... 90
I.6.3. Antifungal/antimicrobial activities ... 90
I.6.5. Advanced glycation end inhibitor activities ... 93
I.7. Other applications ... 93
I.8. Conclusion ... 94
II. SYNTHÈSE D’OXAPROLINES ET VALORISATION PAR INSERTION DANS DES PEPTIDES D’INTÉRÊT... 95
II.1. Introduction... 97
II.1.1. Le motif 5-oxaproline, un isostère de la proline ... 97
II.1.2. Contexte biologique ... 99
II.1.3. Analyses conformationnelles par dichroïsme circulaire de peptides de références ... 101
II.1.3.1. Principe du dichroïsme circulaire ... 101
II.1.3.2. Etude de DC des peptides de référence ... 101
II.1.3.3. Allure d’un spectre DC conventionnel pour une hélice PPII ... 102
II.1.3.3.1. Résultats des spectres DC des peptides de références ... 103
II.2. Synthèse diastéréosélective de 5-oxaprolines ... 104
II.3. Synthèse de mimes d’hélices PPII ... 106
II.3.1. Insertion d’oxaprolines dans le peptide d’intérêt APSYSPPPPP ... 106
II.3.1.1. Synthèse d’une penta-oxaproline par SPPS en stratégie Fmoc ... 106
II.3.1.2. Synthèse d’une penta-oxaproline par LPPS en stratégie Boc ... 108
II.3.2. Insertion d’oxaprolines dans le peptide d’intérêt HSKYPLPPLP ... 112
II.3.3. Perspectives et suite donnée pour l’accès à des mimes d’hélices PPII ... 115
II.4. Développement de mimes de PLG à base de 5-oxaproline ... 119
II.4.1. Mise en place du projet ... 119
II.4.2. Synthèse de mimes de PLG comportant le motif 5-Opr ... 121
II.4.3. Les récepteurs dopaminergiques ... 122
II.4.3.1. Rappels sur les récepteurs couplés aux protéines G ... 122
II.4.3.2. Caractéristiques et propriétés des récepteurs dopaminergiques ... 123
II.4.3.3. Voie de signalisation des récepteurs de la dopamine ... 124
II.4.4. Mises en place des tests biologiques ... 125
II.4.4.1. Mesure de la libération de Ca2+ intracellulaire par fluorescence ... 126
II.4.4.2. Mesure de libération d’AMPc ... 129
II.4.5. Stabilité enzymatique ... 130
II.4.5.1. Généralité sur les protéases ... 131
II.4.5.2. Mises en place des tests de stabilité et résultats ... 131
II.4.6. Perspective et suite données à l’accès à des mimes de PLG... 132
II.5. Conclusion ... 132
III. SYNTHÈSE ET ÉTUDE STRUCTURALE D’OXADIAZINE-3,6-DIONES ...133
III.1.1. Etat de l’art sur le motif ... 135
III.1.2. Synthèse d’une librairie d’oxa-DKPs ... 138
III.1.2.1. Etape 1 : synthèse de Btc-XAA-OH ... 138
III.1.2.2. Etape 2 : synthèse de Btc-XAA1-N(OH)-R1... 139
III.1.2.3. Etape 3 : cyclisation intramoléculaire ... 140
III.1.2.4. Analyses par diffraction des rayons X d’une 1,2,5-Oxd[XAA1] ... 141
III.1.3. Application de réarrangement de TRAL aux oxa-DKPs ... 142
III.1.4. Insertion des oxa-DKPs dans des séquences peptidomimétiques ... 143
III.1.4.1. Synthèse de 1,2,5-Oxd[PG-XAA2-XAA1] ... 144
III.1.4.2. Etude structurale des dérivés 1,2,5-Oxd[PG-XAA2-XAA1]... 145
III.1.4.2.1. Introduction sur les β-turns ... 145
III.1.4.2.2. Analyses conformationnelles d’1,2,5-Oxd[PG-XAA2-XAA1] par RMN ... 147
III.1.4.2.3. Analyses conformationnelles d’1,2,5-Oxd[PG-XAA2-XAA1] par DC ... 148
III.1.4.2.4. Etude par modélisation moléculaire ... 151
III.1.4.3. Synthèse de 1,2,5-Oxd[PG-(XAA)n] ... 152
III.1.4.3.1. Stratégie impliquant une séquence réactionnelle one pot ... 154
III.1.4.3.2. Stratégie impliquant l’utilisation de β- et γ- amino acide ... 156
III.1.5. Perspectives et conclusions sur les oxa-DKPs ... 158
III.2.LE MOTIF 1,2,4-OXADIAZINE-3,6-DIONES OU AZA-DKM ...160
III.2.1. Etat de l’art ... 160
III.2.2. Approche rétro-synthétique ... 161
III.2.5. Résultats... 163
III.2.5.1. Synthèse d’une librairie d’oxyaza-dipeptides... 163
III.2.5.2. Cyclisation intramoléculaire d’oxyaza-dipeptides ... 163
III.2.5.3. Couplage d’1,2,4-Oxd avec des acides aminés ... 165
III.2.5.4. Analyse par DC du composé M64-f ... 166
III.2.6. Conclusions sur les aza-DKMs ... 167
IV.1. Etat de l’art ... 171
IV.2. Etude méthodologique sur un modèle choisi ... 173
IV.2.1. Criblage d’acides de Lewis ... 173
IV.3. Mise au point des paramètres de la réaction ... 175
IV.3.1. Effet du solvant ... 176
IV.3.2. Effet de la température ... 176
IV.3.3. Effet de quantité et de qualité de MgI2 ... 177
IV.4. Etude de la racémisation ... 177
IV.5. Etat de l’art sur l’utilisation du MgI2 ... 178
IV.6. Extension de notre méthodologie à divers GPs ... 178
IV.6.1. Comportements des GPs d’esters ... 178
IV.6.2. Comportements des GPs d’amines ... 179
IV.6.3. Comportement d’acides aminés aux chaînes latérales variées ... 180
IV.6.4. Sélectivité en fonction du temps de réaction ... 181
IV.6.5. Comportement du GP trityle ... 182
IV.6.6. Comportement d’autres GPs ... 183
IV.7. Extension de notre méthodologie aux résines et à la SPPS ... 183
IV.7.1. Comportement de différentes résines ... 183
IV.7.2. Mise en place d’une synthèse SPPS en stratégie Cbz ... 184
IV.8. Mécanisme de la réaction de déprotection de GP en présence de MgI2 ... 185
CONCLUSION GENERALE ...187
PRODUCTION SCIENTIFIQUE ...191
PARTIE EXPERIMENTALE ...193
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LISTE DES ABRÉVIATIONS
1,3-DC 1,3-Dipolar cycloaddition 5-FU 5-Fluorouracile 5-Opr 5-OxaprolineA
Ac AC ACE ACN AcOH EtOAc ADT ADF AGE Acétyle Adenylyl cyclaseAngiotensin converting enzyme Acétonitrile Acide acétique Acétate d’éthyle 4-aza-2,3-dideoxythymidine 5-Fluorouracil isoxazolidinyl nucleoside
Advanced glycation end products
AgOTf Alk AMP AMPc aq. APTS Ar atm AZT Triflate d’argent Alkyle Adenosine monophosphate
Adenosine monophosphate cyclique Aqueux Acide paratoluènesulfonique Aryle Atmosphère Azidothymidine
B
Bmim Bn BnBr Boc 1-Butyl-3-méthylimidazolium Benzyle Bromure de benzyle Tert-butyloxycarbonyle Boc2O BOP Bz Di-tert-butyldicarbonate Hexafluorophosphate de benzotriazolyl-1-oxy-tris-(diméthylamino)-phosphonium BenzoyleC
Cbz CCR5 cHx CI50 Cod Carboxybenzyle C-C chemokine receptor Cyclohexyle/cylohexane Concentration inhibitrice médiane 1,5-cyclooctadiene COSY Cp CTAB CSA CorrelationSpectroscopy Cyclopentadiényle Bromure de cetyltrimethylammonium Acide camphosulphoniqueD
DAST Dba DBP DBU DCC DCE DCM DDQ DFT Diethylaminosulfur trifluoride Dibenzylideneacetone Dibenzoyl peroxide 1,8-Diazabicyclo[5.4.0]undéc-7-ène Dicyclohexylcarbodiimide 1,2-Dichloroéthane Dichlorométhane 2,3-Dichloro-5,6-dicyano-1,4-benzoquinoneDensity functional theory
10
E-H
E EC50 ed ee ESI ELISA Et et al. EtOH Fmoc Groupement electrophile Concentration efficace moyenne Excès diastéréoisomérique Excès énantiomérique Electrospray ionization Enzyme-linked immunosorbent assay Éthyle Et alii Ethanol 9-Fluorenylmethyloxycarbonyl FSK GCl HCTU Forskoline Chlorure de guaninidinium 2-(6-chlor-1H-benzotriazol-1-yl)- 1,1,3,3-tetramethylaminium-hexafluorophosphate Heteronuclear HMBC HPLC HRMS HSQCHeteronuclear multiple bond correlation
High-performance liquid chromatography
High-resolution mass spectrometry Heteronuclear single quantum coherence
I
IBMX IBX ID50 i-Bu IP3 3-isobutyl-1-methylxanthine Acid ortho-iodoxybenzoique Dose infectieuse médiane Isobutyle Inositol trisphosphate i-Pr i-PrOH IUPAC Isopropyle IsopropanolUnion of Pure and Applied Chemistry
K-L
KAHA Kd KHMDS LCMS Acide α-ceto-hydroxylamine Constante de dissociation Potassium hexaméthyldisilazane Liquid chromatography mass spectrometry LDA LH Ln LiHMDS Lithium diisopropylamide Liaison hydrogène Ligand L Lithium hexaméthyldisilazaneM
M MW mCPBA Me MeOH MIC Mole/litre, molarité Micro-ondes Acide métachloroperbenzoïque Méthyle Methanol Concentration minimale inhibitrice min Ms MsCl MSH MOM Morph m,p-OBn-Ph Minute Mésyle Chlorure de mésyleMelanotrope Stimulating Hormone Methoxymethylether Morpholine 3,5-Dibenzyloxyphenyle
N
NBA NBD NBS n-Bu n-BuLi NCS Nd n-hex N-bromoacétamide 7-nitro-1,2,3-benzoxadiazole N-Bromosuccinimide n-butyle n-butyllithium N-chloro-succinimide Non déterminé n-hexyle NIS NMM NMO NOE NOESY NPM N-iodosuccinimide N-Méthylmorpholine N-Méthylmorpholine N-oxide Nuclear Overhauser effect Nuclear Overhauser effect spectroscopy N-phenylmaleimideO-P
PAH p-CF3 -phenyl11 p-Cl-Ph Pd/C PG Ph Para-chlorophényle Palladium sur charbon Groupement protecteur Phényle PMB pNpp ppb PPII Pyr. p-Méthoxybenzyle p-nitrophénylphosphate Partie par milliard Polyproline II Pyridine
R-S
Rac. Rdt Refl. Racémique Rendement Reflux ROESY SH3Rotating frame nuclear Overhauser effect spectroscopy Src homology domain 3 Rf RM RMN RMN 1H RMN 13C RNA Rapport frontal Reactif organometallique
Résonance magnétique nucléaire Résonance magnétique nucléaire de l’hydrogène
Résonance magnétique nucléaire du carbone 13 Acide ribonucleique SIDA SN2 S-Phos SPPS Syndrome d’immunodéficience acquise Substitution nucléophile bimoléculaire 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl
Solid phase peptide synthesis
T
t1/2 T33T TAD t-AmOH TBAB t-Bu TBAF TEA TBME TBS TEMPO TFA THF TFAA TFE Temps de demi-vieProkaryotic ubiquitin-like protein Transcriptional activator domain Tert-amyl alchohol
Bromure de tetra-n-butylammonium Tert-butyle
Tetra-n-butylammonium fluoride Triéthylamine
Tert-butyl methyl ether Tert-Butyldiméthylsilyle 2,2,6,6-(tetramethylpiperidin-1-yl)oxyl radical Acide trifluoroacétique Tétrahydrofurane Anhydride trifluoroacétique Trifluoroéthanol TFFH Tf Thy TLC TMS TMS-I TMS-OH TMSOTf TOF Tol TRINS rt Ts Fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate Triflate Thymine
Thin layer chromatography Triméthylsilyle/Triméthylsilane Trimethylsilyl iodide Trimethylsilyl hydroxide Trifluoromethanesulfonate Time of flight Toluene
Truncated reverse isoxazolidinyl nucleoside Temps de rétention Tosyl U-Z UV VIH VEGF-A Ultraviolet Virus de l’immunodéficience humaine
Theory vascular endothelial growth factor A
15
Durant ces travaux de thèse, nous nous sommes intéressés à l’étude des 1,2-oxyazahétérocycles, plus précisemment, à la synthèse des motifs 5-oxaprolines (5-Opr), 1,2,4- et 1,2,5- oxadiazine-3,6-diones (Oxd) avec pour objectif le développement de nouveaux composés peptidomimétiques originaux à structuration ou activité biologique potentielles (Figure 1).
Figure 1. Structure des motifs isoxazolidines, 5-Opr, 1,2,4- et 1,2,5- Oxd
La 5-Opr étant très peu décrite dans la littérature, un premier chapitre a été réalisé sous la forme d’une revue reportant l’état de l’art general sur le cycle isoxazolidine incluant leurs synthèses et applications en chimie organique et médicinale. Cette revue a fait l’objet d’une soumission récente dont le graphical abstract est représenté dans la Figure 2.
Figure 2. Résumé schématique du chapitre I
16
interactions protéine-protéine ; et (2) la synthèse de mimes du tripeptide Pro-Leu-Gly-NH2 (PLG),
un modulateur allostérique des récepteurs D2 de la dopamine (Figure 3).
Figure 3. Résumé schématique du chapitre II
Le chapitre III sera quant à lui dédié à la synthèse de composés de type 1,2,4- et 1,2,5- Oxd considérés comme des aza-dicétomorpholines (aza-DKMs) ou oxa-dicétopipérazine (oxa-DKPs), respectivement. Après avoir décrit la stratégie de synthèse permettant l’accès à chacun de ses deux motifs, nous expliciterons leur couplage avec différents acides aminés puis l’étude de leur structuration par RMN et dichroïsme circulaire, mettant ainsi potentiellement en évidence un comportement de type β-turn pour les oxa-DKPs (Figure 4).
17
Enfin, nous détaillerons lors du quatrième et dernier chapitre, une nouvelle méthodologie de clivage chimiosélectif de groupements protecteurs (GPs) en présence d’iodure de magnésium sous irradiation micro-ondes. Nous décrirons plus spécifiquement l’étude méthodologique réalisée avec différents acides de Lewis et discuterons de l’épimérisation ainsi que de l’influence du solvant, du mode de chauffage et de la température. Après avoir examiné le comportement de nombreux groupements protecteurs, de nouvelles orthogonalités ont été mises en évidence alimentant ainsi une vision plus récente et plus large sur l’emploi de GPs (Figure 5).
Figure 5. Résumé schématique du chapitre IV
Ces travaux de recherche ont été réalisés au sein de la Faculté des Sciences de l’Université Montpellier, à l’Institut des Biomolécules Max Mousseron (IBMM), dans l’équipe F10 Synthèses stéréosélectives et acides aminés modifiés du département de acides aminés, protéines et peptides (DAPP) sous la direction du Pr. Jean Martinez et l’encadrement du Dr. Isabelle Parrot. Ce projet a bénéficié de la mise en place de nombreuses collaborations scientifiques, notamment (1) le groupe du Dr. G. Dujardin, le Dr. A. Martel, le Dr. M. Laurent, F. Legros (Unité de Chimie Organique Moléculaire et Macromoléculaire du Mans, UCO2M) et le Dr. Sandrine Py (Equipe Synthèse et Réactivité en Chimie Organique de Grenoble, SERCO) pour le partenariat sur le projet OXAPROL, (2) le groupe de biologistes du Dr. Y. Collette, le Dr. X. Morelli, le Dr. S. Betzi et le Dr. P. Roche (Centre de Recherche en Cancérologie de Marseille, CRCM) pour les tests d’inhibitions protéine-protéine, mais également (3) les biologistes Pr. M. Vignes et le Dr. J. Guiramand (Equipe Stress oxydant et neuroprotection de Montpellier) pour les évaluations biologiques sur les récepteurs D2. Une collaboration avec le LMP et en particulier avec A. Lebrun, G. Cazals (Laboratoire de
18
Retailleau (Institut de Chimie des Substances Naturelles de Gif sur Yvette) pour la diffraction des rayons X a également été initiée (Figure 6). Le projet décrit ici a bénéficié d’un financement ANR sur deux années dont le coordinateur est le Dr Gilles Dujardin mais également d’un projet Labex porté par notre laboratoire.
21
Dans ce premier chapitre, nous nous intéresserons aux différentes études menées sur le motif isoxazolidine détaillant leurs différentes voies de synthèses ainsi que leurs multiples applications en chimie organiques et médicinales. C’est lors d’une étude bibliographique sur les 5-oxaprolines que nous nous sommes aperçus que le cycle isoxazolidinyle simple, dont les 5-Opr sont un cas particulier, représentait un potentiel très important en terme de synthèse et d’applications biologiques. Alors que les 5-Opr sont très peu décrites dans la littérature, les isoxazolidines semblent présenter un grand intérêt pour les chimistes organiciens au vu des nombreuses publications consacrées à ce cycle. Bien que la littérature contienne déjà de nombreuses revues sur les cycloadditions 1,3-dipolaires, voie de synthèse la plus répandue pour accéder aux isoxazolidines, aucune revue ne répertorie les autres voies d’accès ainsi que les nombreuses applications qui lui sont propre (Figure 7). Suite à ce constat, nous avons donc jugé pertinent et intéressant de réaliser ce travail bibliographique qui a fait l’objet d’une soumission dans le journal Chemical Review.
Figure 7. Voies de synthèse et applications des isoxazolidines
22
I.1. Introduction
The saturated five membered isoxazolidine, containing adjacent nitrogen and oxygen atoms, part of several natural products, showed an increasing interest this last decade. This heterocyle can be obtained through the well-known 1-3 dipolar cycloaddition providing access to a large diversity of compounds. Other efficient strategies have been proposed to enlarge the variety of isoxazolidines that could not be obtained by this classical method. Since this moiety is rarely found in natural products, it represents an important synthetic intermediate, especially due to the labile nature of the N-O bond. Accordingly, several groups of investigators have then developed mild conditions to improve the synthesis of a large variety of isoxazolidine derivatives and their use for the total syntheses of natural compounds. Alternately, isoxazolidines are important scaffolds in drug discovery mimicking a wide range of natural building blocks and being found to exhibit interesting diverse biological activities. The objective of the present review is to summarize and discuss the synthetic routes of the isoxazolidine ring, as well as the significance of this moiety in natural products, and the potential biological applications and physico-chemical properties of the “isoxazolidine” structure. This review excluded isoxazolidine-3-one, isoxazolidine-5-one, isoxazolidine-3,5-diones and isoxazolidinium salts. The numbering of the isoxazolidine ring is shown in Figure 8.
23
I.2. Occurrence of the isoxazolidine moiety in natural products
Figure 9. Occurrence of the isoxazolidine moiety in natural products
The isoxazolidine moiety is a particularly useful intermediate in organic synthesis being occasionally reported in natural products (Figure 9). This heterocycle always found as a fused bicyclic ring system has been highlighted in nine types of alkaloids extracted from marine sponges, plants or fungal metabolites. Only Zetekitoxin AB, the first isolated isoxazolidine-containing alkaloid extracted from the skin of the Panamanian golden frog (Atelopus Zetecki), comes from an animal source. Discovered in 1969, its structure and relative stereochemistry was determined only in 2004 by Daly et al. through NMR and mass spectral analyses.1 The group of
24
Scheme 1. Synthesis of a structural model of Zetekitoxin AB
Zetekitoxin AB was found to be a potent voltage-dependent sodium channel’s blocker, more potent than its analogue Saxitoxin for which no synthesis seems to have been developed (Figure 10).
Figure 10. Chemical structure of Saxitoxin
Isolated from the Chinese medicinal plant Dactylicapnos torulosa, Dactylicapnosinine and Dactylicapnosine were the first alkaloids with an isoxazolidine skeleton to be described. Since the structure of Dactylicapnosine was elucidated by a single crystal X-ray analysis by C. Steinbeck et al.,4 the structure of its less complex analogue, Dactylicapnosinine, was ascertained by NMR
experiments. To the best of our knowledge, neither their biological activity, nor their total syntheses have been reported. However, we can mention the recent development of a visible light photo redox catalytic strategy to reach dactylicapnosinine analogues.5
25
Scheme 2. Biosynthetic route for Alsmaphorazine A and B
Another hypothetic biogenetic pathway suggesting an 1,3-DC to obtain the isoxazolidine ring followed by oxidation steps was proposed by Vanderwal et al. Thus, inspired by these proposed biosynthetic pathways, they performed the first total synthesis of Alsmaphorazine B in 15 steps (Scheme 3).7
Scheme 3. Total synthesis of Alsmaphorazine B
26
biosynthesis of the different isoxazolidine architectures has been recently investigated, essentially by density functional theory calculations, resulting in speculative discussions on the spontaneity of the reaction, with a possible role of an enzyme-catalysed system.8
Dipolar cycloaddition in a biological environment was in fact widely used as a biomimetic transformation to synthesize isoxazolidine alkaloids. Especially, Pyrinodemin A total synthesis has undergone considerable interest. Isolated by Kobayashi et al. in 1999 from the Okinawan marine sponge Amphimedon sp, (±)-Pyrinodemin A displays a characteristic cis-cyclopent[c]isoxazolidine core.9 The structure originally proposed was afterward subjected to
revision concerning the position of the double bond on the side chain. Kobayashi et al.10 finally
corroborated in 2005 the Snider’s group proposal,11 validating that Pyrinodemin A naturally
exists as a racemic mixture, the double bond being positioned at C15’-C16’. Among the various
synthetic strategies initiated to reach the Pyrinodemin skeleton or Pyrinodemin A,12 the first
enantioselective and probably the most interesting access to the real structure was developed by Kouklovsky and co-workers (Figure 11).13 The 14-steps route relies on an asymmetric
intramolecular dipolar cycloaddition to build the bicyclic fragment of the natural compound. Pyrinodemin A, such as other Pyrinodemins B, C and D later discovered, exhibit potent cytotoxicity in vitro against murine leukaemia L1210 and KB epidermoid carcinoma cells, as well as slight antimicrobial or antifungal activities.14
Figure 11. Enantioselective strategy for (-)-Pyrinodemin A synthesis
Biomimetic approaches have been also undertaken to develop a synthetic route to (-)-Flueggine A,15,16 (-)-Virosaine A or (+)-Virosaine B,17 all three being isolated by Ye and co-workers
from the same plant Flueggea virosa. About one year after the discovery of these novel Securinega alkaloids, the groups of Li18 and Gademann19 reported the total enantioselective synthesis of
27
Figure 12. Enantioselective strategy for (-)-Flueggine A synthesis
The syntheses of (-)-Flueggine A (Figure 12), and (+)-Virosaine B (Figure 13) have been achieved in 11 and 10 steps with good overall yields of 5.92% and 6.68%, respectively, whereas (-)-Virosaine A (Figure 13) was synthesized in 18 steps with an overall yield of 7.78%.18 While
Virosaines do not inhibit the proliferation of several cancer cells, Flueggine A shows weak inhibitory activity against the growth of three different breast cancer lines.
Figure 13. Enantioselective strategy for (-)-Virosaine A and (+)-Virosaine B syntheses
Pyridomacrolidin was isolated in 1998 from fungus Beauveria bassiana metabolites by Nakagawa et al.20 We can only mention a succinct biological study, the macrocyclic structure weakly
inhibiting protein tyrosine kinase activity. The biogenetic pathway to Pyridomacrolidin has already been proposed, and various investigations to build the principal core of this natural compound by stereospecific 1,3-dipolar cycloaddition of a nitrone and a 2-cylodecenone have already been published (Scheme 4).21–25 However, the total synthesis of the isoxazolidine
28
Scheme 4. Access to the principal core of Pyridomacrolidin
Concerning Lycojaponicumins A and B, a biogenic route involving an intramolecular cycloaddition between a nitrone and an alkene for the construction of the bicyclic isoxazolidine skeleton has been postulated.8,26 To the best of our knowledge no total synthesis has been reported so far.
Finally, Setigerumine I, isolated from Papaver Setigerum, containing an isoxazolidine moiety, was the most recent natural product discovered. 27 However, only rare studies are currently available.
I.3. Synthetic strategies to prepare the isoxazolidine ring
The 1,3 dipolar cycloaddition (1,3-DC) of nitrones and alkenes is one of the most developed reactions to prepare isoxazolidine compounds. Previous reviews covered the advances in the synthesis of isoxazolidines through 1,3-DC in solution 28–35 and in solid phase.36 Although this
section will give a brief survey of the 1,3-DC principle and will outline key synthetic advances, particularly in “green chemistry”, we will mainly focus on the synthesis of isoxazolidines through other synthetic pathways. Indeed, there are two logical disconnections in an isoxazolidine ring: the C3-C4 and the O1-C5 bonds (A) or/and the O1−C5 and the N2-C3 bonds (B).
Scheme 5. Retrosynthetic study of the isoxazolidine ring
As previously mentioned, the pathway A is routinely followed, while the use of disconnection B has only been recently reported thanks to the four different cyclisations of unsaturated hydroxylamines: (i) electrophilic cyclisation, (ii) palladium-catalysed cyclisation, (iii) radical cyclisation, and (iv) Michael addition.
29 I.3.1. 1-3-dipolar cycloaddition
According to the literature, the principal synthetic route to access to isoxazolidines is the 1-3 dipolar cycloaddition of nitrones and ethylenic dipolarophiles, which was proposed by Morita et al. in 1967.37 This versatile pericyclic reaction, which can involved a range of electron-poor,
neutral and electron-rich dipolarophiles, offers the possibility of generating isoxazolidines with up to three new contiguous stereocenters. Such 1,3-DC reactions and relevant (3+2) processes have been reviewed in a general manner 29,38 or more focused on some specific reactants, such as
heterosubstituted dienophiles.34,35 Despite the numerous methodologic improvements brought to
this major class of cycloaddition, regio- and stereoselectivity of this reaction still represent a challenge for chemists. Considering that these selectivity features of 1,3-DC realized between nitrones and alkenes has been deeply reviewed,31,39–41 we will briefly remind here the principle of
the reaction, we will draw the current scope of the isoxazolidines that can be reached in a selective manner and we will highlight a few original syntheses, principally the works dealing with “green protocols”.
The isoxazolidine synthesis through 1,3-DC involves a nitrone 1 as a 1-3 dipolar molecule, and an alkene 2 as a dipolarophile, by analogy with the dienophile of the Diels Alder cycloaddition. Sterically demanding reactants are well tolerated in a number of 1,3-DC reactions. From monosubstituted dipolarophiles, both regioisomers 3 and 4 (3-4 and 3-5) could be obtained, in which the regioselectivity principally depends on the R3 group (Scheme 6). In contrast with the
Diels Alder cycloaddition, in the case of 1,3-DC, steric and electronic effects were both important to induce regioselectivity. With electron-rich dipolarophiles, both effects favour 3,5-regiocontrol, meanwhile steric effects can counterbalance electronic effects in the case of some electron-poor dipolarophiles, which sometimes makes prediction difficult.
1 2 3
3-4 regioisomer
4 3-5 regioisomer
Scheme 6. Formation of 3-4 and 3-5 isoxazolidines through 1,3-DC
30
represented in Scheme 7. When the nitrone exists through a Z/E equilibrium, like for some functional acyclic aldonitrones (R2 = ester),42 high levels of overall stereocontrol are even more
difficult to reach, since each of the 4 stereomers can be produced by both an exo and a endo approach (Scheme 7). Indeed, the cis 1 isomer for instance can be produced by an exo approach of the dipolarophile to the bottom face of the Z nitrone, and also by an endo approach to the top face of the E nitrone.
Scheme 7. 3,5-Diastereomers possibilities from 1,3-DC
At last, when the dipolarophile is β-substituted, the number of possible stereoisomers is generally preserved, thanks to the stereospecificity of the concerted pericyclic process. However, this number can increase in some cases, due either to the in situ loss of the stereochemical integrity of the dipolarophile under the reaction conditions, or to a catalyst-induced stepwise mechanism. Thus, it appears clearly that several conditions are necessary to ensure the regio- and stereocontrol that is required to optimize the cycloaddition result. In this aim, the broad use of chiral auxiliaries (typically used under simple thermal conditions), or of chiral catalysts (Lewis acid or organocatalysts) have been developed as mentioned in several reviews.29–31,38,39,41
31
compounds 9-10 from neutral ones (allylic alcohols)48,49 and compounds 11-25from electron
poor ones (enals, enmides, enones, nitro olefines, methylene malonates)).39,50–63 Only a limited
number of exemples concern nitrones bearing protecting groups at the nitrogen atom, mainly using a benzyl group. In other cases, N-substituents are an aryl or a methyl group.
5 (A), dr>99:1 cis: up to 74% ee 6 (A), dr>95:5 cis: up to 94% ee 7 (B), dr up to 97:3 trans: up to 90% ee 8 (A), dr 84:16 cis: 89% ee 9 (A), dr not given
92% ee
10 (A), dr not given
98% ee 11 (B), dr up to 99:1 3,4-trans: up to 99% ee 12 (B), dr up to 97:3 3,4-cis up to 92% ee 13 (A), dr up to 97:3 3,4-trans: 92% ee 14 (A), dr>95:5 trans: up to 90% ee 15 (A), dr>95:5 trans: up to 97% ee 16 (A), dr 91:9 3,4-trans: 90% ee 17 (A), dr up to >99:1 3,4-trans: up to>99% ee 18 (A), dr up to >99:1 3,4-cis up to 95% ee 19 (A), dr up to 90:1 3,4-cis: up to 99% ee 20 (A), dr up to 97:3 trans: up to 99% ee 21 (A), dr up to 97:3 trans: up to 99% ee 22 (A), dr>99:1 trans/CHO: up to 99% ee 23 (A), dr up to 99:1 3,4-cis: up to 88% ee 24 (A), dr 99:1 3,5-trans: up to 99% ee 25 (A), dr up to 99:1 trans/CHO: up to 99% ee
Figure 14. Isoxazolidines produced by metal-based (A) and organo (B) catalytic asymmetric 1,3-DC of acyclic aldonitrones
32
thermal conditions(Figure 15).64–82 Enantioselective access to such kind of adducts from achiral
cyclic nitrones by catalytic asymmetric pathways has not yet been reported.
26
X=OEt, CH2OR, H/Alk, Ar, NPht
ds up to single isomer 27 X= CH2OH, CO2R’ ds up to single isomer 28 R = Ph, Alk dr > 20:1 29 single isomer 30 R = CH2-glycosyl, CHMeR, CH2Br ds up to single isomer 31 X = OH, Cl ds up to single isomer 32 R = Ar, Alk dr up to 20:1 33 R = Ar, Alk ds up to single isomer 34 EWG = CHO, CO2Me ds up to single isomer Figure 15. Isoxazolidines produced by asymmetric dipolar 1,3-DC reactions of chiral cyclic nitrones Interestingly, acyclic carboxy ketonitrones are found to display a pure and stable E-geometry. Accordingly, high levels of stereocontrol were reported by our group in chiral auxiliary-controlled thermal 1,3-DC reactions involving aspartic nitrones and vinyl ethers, 83 as well as in
enantioselective catalyzed cycloadditions involving alanine-containing nitrones and enals(Figure 16).84–86 35 (B), dr 96:4 3,4-trans: 95% ee 36 (A), dr 97:3 3,5-cis: 91% ee 37 (thermal), dr (exo) up to 94:6 (facial) up to 98:2
Figure 16. Isoxazolidines produced by asymmetric dipolar 1,3-DC reactions of carboxy ketonitrones (A) metal-based and (B) organo catalysis
Recently, original studies about 1,3-DC performed through a “green protocol” have been reported such as the efficient synthesis of N-benzyl-fluoro-isoxazolidines 38 in ionic liquids described by Chakraborty et al.87 (Scheme 8). Indeed, the corresponding endo isoxazolidines were exclusively
33
mixture was recovered in moderate yields (57-62%). Moreover, ionic liquids present the advantage to be recycled several times without loss of activity and selectivity.
38
Scheme 8. Synthesis of isoxazolidines involving 1,3-DC in ionic liquids R = 2,6 difluoro, 2-fluoro, 3,4-difluoro, 4-fluoro, 2-hydroxy, 4-hydroxy benzene/phenyl
With the aim to promote green chemistry conditions, Bhattacharya et al.88 performed one-pot the
combinaison of the nitrone formation and the 1,3-DC, in a water medium, in the presence of cetyl trimethylammonium bromide (CTAB) as a surfactant catalyst. In this eco-friendly system, they obtained several substituted isoxazolidines with a high level of regio- and enantio- control. In the same reaction conditions, the authors a lso reported an unprecedented stereoselective intramolecular nitrone cycloaddition (Scheme 9).89
Scheme 9. Synthesis of isoxazolidines by 1,3-DC in water
Often, microwave-assisted synthesis revealed to be a valuable alternative to conventional heating to accomplish more efficient reaction, due to its unique advantages, such as shorter reaction times, cleaner reactions, higher yields and better selectivity. Since 1,3-DC was often realized under thermic conditions, chemists have naturally envisioned the reaction under microwave (MW) irradiation. Indeed, several 1,3-DC lead to the formation of isoxazolidine compounds when thermic heating did not produce any product.90,91 Furthermore, MW conditions can also lead to a
different selectivity compared to thermic conditions. For example, Muthusubramanian et al.92
34 39 40 41 42 43
Scheme 10. Synthesis of isoxazolidines by 1,3-DC under microwave irradiation
1,3-DC is a powerful reaction to prepare N-benzyl or N-aryl isoxazolidines but these nitrogen-protecting groups are difficult to remove without a concomitant ring opening. As a valuable exception, the use of appropriate hydrogen transfer conditions proved its efficiency to achieve N-debenzylation in respect of the isoxazolidine ring of adducts produced from N-benzyl carboxy ketonitrones.73,86,98 Glycosylnitrones and tetrahydropyranosyl substituted nitrones lead to
N-protected isoxazolidines, which may be deN-protected by hydrolysis while leaving the N-O bond intact.99–102 N-benzyhydryl nitrones were also reported to yield cycloadducts, which could be
removed by NBS oxidation,58 either in acidic conditions (HCl in MeOH)62 or via a reductive
cleavage with Et3SiH.103 However, the synthesis of isoxazolidines bearing an easily removable
electron-withdrawing group at nitrogen (crucial for performing further synthesis) was poorly exploited. Using phase-transfer catalysis (PTC), Ricci et al.104 reported an original asymmetric
1,3-DC from N-Boc or N-Cbz hydroxyl-α-amido sulfones 44 and gluconates 45 (Scheme 11) leading to isoxazolidines 46. Depending on the N-protecting group (Boc or Cbz), 46 could produce to the isoxazolidine 47 in the presence of TFA or the substituted δ-lactam 48 after hydrogenation.
44 45 46 47 70%, ee>99% 48 75%, ee 99%
Scheme 11. Synthesis of N-Boc or N-Cbz isoxazolidines through 1,3-DC PG = Boc, Cbz
35
stability. The access to acyl protected isoxazolidines can proceed efficiently after selective N-deprotection, but this 2-step method has been only described from C-carboxyketonitrone-derived adducts.73,86,98,102 Consequently, several groups developed new strategies to obtain this interesting
intermediate for further synthetic applications. Among them is the cyclisation of unsaturated hydroxylamines.
I.3.2. Cyclisations of unsaturated hydroxylamines
Unsaturated hydroxylamines, through intramolecular cyclisation, offer an alternative method to efficiently produce original isoxazolidine derivatives. This strategy allowed to access to novel isoxazolidines that could not be obtained by 1,3-DC. Depending on the intramolecular cyclisation conditions that are applied, the reaction mechanism is different. Thus we decided to divide this section in four subparts: (i) electrophilic cyclisations; (ii) palladium-catalysed cyclisations; (iii) radical cyclisations; and (iv) Michael additions.
I.3.2.1. Electrophilic cyclisations
Among the cyclisation of unsaturated hydroxylamines, an interesting route to access to the isoxazolidine skeleton concerned electrophilic cyclisation, which was highlighted by Trombini et al.105 Initially described to build other heterocyclic ring-systems such as oxazolines106 or
pyrrolidines,107–109 this chemical strategy requires alkenes bearing N- or O-nucleophilic
36
Scheme 12. Possible combinations for the electrophilic cyclisation
I.3.2.2. Electrophilic 5-exo cyclisations
Starting from N-homoallyl-hydroxylamine derivatives 49, electrophilic 5-exo cyclisation to reach 5-iodomethyl isoxazolidines 50 has been investigated by Trombini et al.110,111 (Scheme 13).
Formation of the heterocyclic moiety always takes place regioselectively after O-trialkylsilylation of the acyclic substrate. Despite the fact the O-tButyldimethylsilyl group increased selectivity in some examples, its use resulted in lower yields. Thus, the O-trimethylsilyl group was generally preferred. Among the electrophilic species tested, N-iodosuccinimide (NIS) was considered to be the most suitable electrophilic source.
49 50
Scheme 13. 5-Exo iodocyclisation with substituted hydroxylamines R1 = Me, Bn, t-Bu, L-gul, R2 = Ph, n-C5H11, i-Pr, CH2OBn, n-hex, i-Bu, cHx
R3 = H, Me, AcO, R4 = H, Me
The configuration of the 3-4 position on the substrate (syn/anti) was conserved in the reaction product. When R3 is an acetoxy group, in this particular case, a 4-5-cis selectivity is induced since
37
51 52
58% 17% 53
Azetidine N-oxide Scheme 14. Formation of azetidine N-oxide
Hence, Trombini et al. applied their methodology to the synthesis of isoxazolidine that could not be synthesized through 1,3-dipolar cycloaddition using alkenes, which contain either an enolether or an enolester functionality along with a nucleofuge, is not a good substrate for 1,3-dipolar cycloaddition (Scheme 15). 110
Scheme 15. Unsuccessful synthesis of isoxazolidines by 1,3-DC vs successful synthesis of isoxazolidine through electrophilic cyclisation
Similarly, Studer et al.112 have investigated 5-exo cyclisation of O-homoallyl-hydroxylamine 54 in
the presence of diverse electrophilic sources (E+ = NaOCl, PhSeBr, NBS, NIS, I2), to obtain various
substituted isoxazolidines 55 (Scheme 16). Subsequently, Togo et al.113 developed a green version
forming bromonium species from KBr and oxone, in situ. This strategy required the use of N-protected hydroxylamines (R1 = PhSO2, Ac, or Tos) to avoid a concomitant oxidation of the
isoxazolidine into isoxazoline. Both research teams reported enantio- and 3-5-cis regio-selectivity in good to excellent yields (d.r. up to 11.3:1).
54 55
Scheme 16. 5-exo cyclisation using substituted O-homoallyl-hydroxylamines R2 = Ph, Me, C6H11, H, p-MeO-Phe, p-CF3-Ph, p-Cl-Ph, thiophene, n-Bu,
R3= R4 = H, Me
38
studies of Bates et al.114–118 and of Toste et al.119 the more suitable catalysts were based on silver
and gold transition metals. Consequently, the synthesis of numerous natural products such as Porantheridine or (-)-Sedinine has been accomplished. Shi et al.120 also reported excellent yields
of 5-exo-cyclisations using Yb(OTf)3.
56 57
Scheme 17. Electrophilic 5-exo-cyclisations of allenic hydroxylamines mediated by a Lewis acid At last, Cossy et al.121 realized a unique Fe(III) complex-catalyzed intramolecular reaction from
N-Protected δ-hydroxylamino allylic acetates 58 (Scheme 18). Mechanistic studies revealed that cyclisation proceeded via an allylic carbocation intermediate. The cis product was then favoured by kinetic control when R2=H (minimization of steric interactions) and by thermodynamic control
when R2=Ph (cis-isomers were the more stable). However, starting from β-hydroxylamino allylic
acetates, the trans product was preferentially formed, probably due to an SN2-type mechanism
instead of a carbocationic pathway.
58 59
Scheme 18. Intramolecular electrophilic 5-exo cyclisation of O-homoallyl-hydroxylamines
I.3.2.3. Electrophilic 5-endo cyclisations
To the best of our knowledge, 5-endo cyclisations could only be realized from O-allylhydroxylamines. Seleno-cyclisations were reported by Tiecco et al.33,122,123 as well as Li et al.124
whereas Egart et al.125 tested various halogeno-cyclisations. As for the 5-exo cyclisation of
O-homoallyl-hydroxylamines, the 5-endo cyclisation required to use of N-protected hydroxylamines 60. However, contrary to 5-exo-cyclisation, the 5-endo-cyclisation leads preferentially or exclusively to a 3-4-trans selectivity, which was explained through a SN2 pathway (Scheme 19).
60 61 62
39
Tiecco et al. used phenylselenenyl sulphate produced in situ from diphenyl diselenide, ammonium persulfate and trifluoromethanesulfonic acid in acetonitrile to perform seleno-cyclisation of O-allyl-hydroxylamines. In a first study, they observed that formation of 1,4,2-dioxazines 65 depends both on reaction temperature and on R1 substituent. However, 65 could be converted
into the isoxazolidine 64 starting the reaction at -50°C, and leaving then the reaction mixture at room temperature (Scheme 20).
63
64 65
1,4,2-dioxazine Scheme 20. Formation of isoxazolidines and 1,2,4-dioxazines
More recently, the research team of Tiecco et al. reported an extension of the methodology using optically active diselenides 68 to increase the diastereoselectivity during the isoxazolidines synthesis.33 In contrast with previous works, hydroxylamine 67 was N-protected with an O-allyl
40 66 67 68 69 70
Scheme 21. Synthesis of isoxazolidines from chiral diselenide
In 2013, Egart et al.125 reported the 5-endo bromocyclisation from O-allyl-N-tosyl-hydroxylamine
71. After performing experimental studies, better conditions were attempted with N-bromoacetamide (NBA) in dichloromethane at room temperature (Scheme 22). In these optimal conditions, they evaluated the substituent effect on the cyclisation selectivity, their results being summarized in Table 1. The 3-4 trans selectivity was observed by 1H NMR studies, which
confirmed the formation of a bromonium bridge that was opened through a nucleophilic substitution with inversion of the configuration (SN2).
71 72
Scheme 22. 5-Endo bromocyclisation with NBA
41 I.3.3. Palladium-mediated cyclisations
Palladium-catalysed diastereoselective cascade reaction is a suitable method for the synthesis of heterocyclic compounds. Accordingly, several groups have naturally extended this method for carbo-etherification of unsaturated hydroxylamine substrates, providing a new stereoselective method for the construction of substituted isoxazolidines. In many cases the stereo-chemical outcome of these transformations is complementary to that of nitrone cycloadditions. The power of this cyclisation was deeply studied to get suitable N-protected isoxazolidines. Thus, Dongol et al.126 synthesized isoxazolidine derivatives 75 from N-Boc-O-homoallyl-hydroxylamine 74 with a
ratio cis/trans up to 10:1. However, moderate to good yields were obtained, due to the isolation of a Heck coupling adduct 76. Changing either the catalyst loading or the ligand, did not result in any improvement. This methodology was improved by Rosen et al.127 who performed the efficient
cyclisation of the same hydroxylamine derivatives 74 using different experimental conditions, affording only the expected ring 73 in excellent yield and d.r (Scheme 23).
73 81% d.r 20 : 1 74 75 8-79% d.r up to 10:1 76
Scheme 23. Palladium-catalyzed cyclisation of N-Boc-O-homoallyl-hydroxylamine R1 = R2 = Ph
Using two equivalents of aryl bromide, Dongol et al.52, Peng et al.54,55 accomplished an efficient
sequential N-arylation/cyclisation/C-arylation of 77 in excellent yield and diastereoselectivity. After a methodological study on the catalyst structure and on the ligand, the best results were obtained with Pd2(dba)3/Xantphos, NaOtBu in toluene at 90°C. Formation of the undesired
N,N-bisarylation and the Heck type side products was also totally suppressed. They extended the reaction on various substituted substrates 77 conserving a total diastereoselectivity for the cis product 78 (Scheme 24).
77 78
Scheme 24. Sequential N-arylation/cyclisation/C-arylation of O-homoallyl-hydroxylamines
42
79 were described (Scheme 25).130 When R2 = H or Boc, the formation of the Heck product was
observed whereas with R2 = Bn, Me, tBu or with cyclic hydroxylamine, the desired N-protected
isoxazolidines 80 was obtained in 56-94% yield with a d.r up to 20:1.
79 80
Scheme 25. Palladium-catalyzed cyclisation of N-homoallyl-hydroxylamine
To target 5-vinyl substituted isoxazolidines not accessible through 1,3-DC, Merino et al.131
performed an original intramolecular cyclisation of 81 (Scheme 26). By the action of Pd(0) or Pd(II) catalysts, the authors observed a different diastereoselectivity (cis or trans) that was explained by two alternative mechanisms.
81 82
Scheme 26. Palladium-mediated synthesis of 5-vinyl substituted isoxazolidines
Instead of Ar-X as the electrophilic source, Bates and Sa-Ei132, Dongol et al.133, and Malkov et al.130
used carbon monoxide in methanol to directly afford the corresponding isoxazolidine methyl ester 84 (Scheme 27).
83 84
Scheme 27. Palladium-mediated cyclisation in the presence of CO in methanol
I.3.4. Radical cyclisations
Among the cyclisation of unsaturated hydroxylamines, there are only a few reports about radical cyclisation. The first study was described by Janza and Studer134 in 2005. They described
43
85 86 87 88
Scheme 28. Radical cyclisation of O-homoallyl-hydroxylamines using IBX
Using copper complexes and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical (TEMPO) as mild oxidant on N-sulfonyl hydroxylamines, Karyakarte et al.135 observed the selective formation of
3-5-cis-isoxazolidines with excellent yields and d.r (up to 20:1), except with the β-phenyl substrate, which yielded the 3,4-trans product. They proposed a mechanism, which is described in Figure 17.
Figure 17. Catalytic cycle with copper complexes
I.3.5. Michael additions
The hetero-Michael addition reaction emerged as a powerful synthetic strategy to create C-N or C-O bonds. By means of bisnucleophiles such as hydroxylamines, this method provided a novel access to N-protected isoxazolidines. After first reports in 1978 136 and then in the nineties137,138,
the reaction was deeply developed in 2006 by Chen et al.139 After removal of the silyl group from
N-Boc-unsaturated hydroxylamines 89, an intramolecular oxy-Michael addition was observed, leading to Boc-isoxazolidines 90 in excellent yields (99%) and d.r (10:1) (Scheme 29).
89 90
Scheme 29. Synthesis of N-Boc isoxazolidine via an intramolecular oxy-Michael addition
44
hydroxylamine is followed by a Wittig homologation, affording the unsaturated hydroxylamines 92. Then, treatment of 92 with TBAF implied removal of the silyl group and the intramolecular oxy-Michael addition, leading to the desired Boc-isoxazolidine 90 in 99% yield and d.r 10:1 (Scheme 30).
91 92 90
Scheme 30. Synthesis of N-Boc isoxazolidine via a double Michael addition
From this tandem reaction and inspired by Edward and Davis works140, Yin et al.141 synthesized
isoxazolidines 94 through a double hetero Michael addition of N-substituted hydroxylamines from quinone monoketals 93 (Scheme 31). Good to excellent yields of the corresponding isoxazolidines bearing a variety of substituents on the hydroxylamine function (R = Boc, Bn, Me, Ac) were obtained as well as several substituted or not quinone monoketals. However, 2-chloro-quinone monoketals led to lower yields (17-32%). Isolation of the mono-Michael addition intermediate showed that the first conjugate addition was the N-addition. Furthermore, the first addition took place on the more electrophilic double bond when it was not substituted, and on the sterically less hindered site when it was substituted. Depending on electronic and steric effects governed the regio-control, the obtained products depended only on the steric hindrance induced by the substituent on the double bond.
93 94
Scheme 31. Double hetero Michael addition of N-substituted hydroxylamines using quinone monoketals At last, starting from α,β-unsaturated aldehydes 96, the synthesis of several 5-hydroxyisoxazolidines has been accomplished with a chemo- and stereo- selective control. Aza-Michael addition of an hydroxylamine either catalysed by a chiral amine142 or by a Lewis acid
(Yb(OTf)3)143, followed by an aldol condensation, yielded either N-Boc or N-Cbz cycloadducts 95
45
95 96 97
PG = Boc, Cbz
R1 = p-NO2-Ph, 2-naphtyl, CO2Et, n-Bu, n-Pr
R2 = H
R1 = i-Pr, i-Bu, cHx, Ph, R2 = CO2Et
Scheme 32. Aza –Michael addition and aldol condensation-mediated synthesis of 5-hydroxyisoxazolidines Catalysed by trimethylsilyl triflate, condensation of 2-trimethylsilyloxyfuran 98 with an aldonitrone 99 led to the unsaturated hydroxylamine 100. After removal of the silyl group, an intramolecular oxy-Michael addition led to the bicyclic isoxazolidines 101. The first step displayed a complete facial selectivity affording two diastereomers 100 in a 82/18 ratio. The desired cycle 101 was obtained in quantitative yield through a silica gel induced ring-closure (Scheme 33).144–146
98 99 100 101
Scheme 33. Synthesis of bicyclic isoxazolidines by an intramolecular oxa-Michael addition
I.3.6. Other synthetic strategies
I.3.6.1. From isoxazolidinones
Also synthesized via an aza-Michael addition followed by a cyclisation step, isoxazolidine-3-ones 104 have been efficiently converted into the corresponding 5-hydroxyisoxazolidines 105 in the presence of DIBAH, thanks to a chemo-selective reduction (Scheme 34).147
102 103
104 (rac)-105
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I.3.6.2. From isoxazolines
Isoxazoline is an unsaturated five-member ring, which can be prepared by 1,3-DC of nitrile oxides and olefins. This substrate is easily transformed into the corresponding saturated cycle through various methods. For example, using different organometallics in the presence of etherate borane, Buhrlage et al.148 performed a nucleophilic addition on isoxazolines 106 to obtain original
isoxazolidines 107 in 73-80% yield with a d.r between 7:1 and 20:1 (Scheme 35, R = Bn, Ph, allyl, Me, thienyl, 2-methylallyl). Thus, they proposed an efficient method to prepare suitable N-unprotected isoxazolidines.
106
107
Scheme 35. Synthesis of isoxazolidines by nucleophilic addition on isoxazolines
Thanks to the use of borane/1,2-amino alcohol complex as chiral source, a racemic mixture of isoxazolines could be efficiently reduced into diastereomeric pure isoxazolidines. By changing the chiral source and the substrate, Tokizane et al.149 succeeded to orientate the reaction to the
privileged formation of one product. Using (-)-norephedrine as chiral source and 2,4-diphenyl-isoxazoline as substrate, only isoxazolidines in 84% with a 6:4 cis/trans ratio were obtained. In contrast, using (-)-ephedrine as chiral source, only the starting isoxazoline was recovered (Scheme 36).
108 108 109
84%
cis/trans 6:4
Scheme 36. Synthesis of isoxazolidines by reduction of isoxazolines with borane/1,2-amino alcohol complexes
By applying a similar method, cis- 3-5-substituted isoxazolidines 112 were obtained in 8:2 d.r by reduction with NaBH4 in acetic acid without using any chiral source. A second step of reduction
47
110 111 112 113
Scheme 37. Synthesis of isoxazolidines by reduction of isoxazolines with NaBH4
At last, 3-substituted 2,3-dihydroisoxazoles 115 were efficiently converted into 2,3,4-trisubstituted isoxazolidines by an oxidative process. The 2,3-dihydroxy cycle 116 was obtained in the presence of K2OsO4.2H2O and NMO in acetone-water, whereas 2-hydroxy-3-bromo
isoxazolidines 114 were synthetized thanks to NBS in H2O/THF (Scheme 38).151
114 115 116
Scheme 38. Synthesis of isoxazolidines by isoxazolin’s oxydation
I.3.6.3. From isoxazolinium salts
Hydrogenation of isoxazolinium salts 117 in the presence of iridium catalyst lead to a fully saturated cis isoxazolidine 118 in excellent yields and e. r (up to 89:11).152
117 118
Scheme 39. Synthesis of isoxazolidines by isoxazolinium salts reduction
t-AmOH: tert-amyl alchohol, cod : 1,5-cyclooctadiene, R1 = Ph, Me, R2 = Me, n-Bu, CH2CH2Ph, H
Interestingly, when the reaction was performed in the presence of a double amount of catalysts, in THF at 70°C for 4h, a mixture of saturated and unsaturated rings 120, 121 and 122 was obtained.
