Stereoselective synthesis of enantiomericallypure cis-2,5-disubstituted-2,5-dihydropyrrolesystem from glycals

UNIVERSITÀ DI PISA

DIPARTIMENTO DI FARMACIA

CORSO DI LAUREA SPECIALISTICA IN

CHIMICA E TECNOLOGIA FARMACEUTICHE

Stereoselective synthesis of enantiomerically

pure cis-2,5-disubstituted-2,5-dihydropyrrole

system from glycals

Relatore Candidata

Prof. Paolo Crotti Stefania Francesca Musolino

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Multisubstituted 2,5-dihydropyrroles are recognized as valuable heterocycles systems because they could be advantageously used as starting materials for the preparation of many pharmaceutically relevant compounds. The possibility of the construction of an enantiomerically pure cis-2,5-disubstituted-2,5-dihydropyrrole system starting from D-allal and D-galactal-derived vinyl N-mesyl aziridines, when subjected to

appropriate reaction conditions, was examined.

The reaction of N-mesyl aziridines with metal enolates derived from active methylene compounds, as dimethyl malonate and dibenzoyl methane, afforded, through a rearrangement process implying an opening-closing process with contemporary ring contraction of the initially obtained 1,4-addition product (primary reaction product), the corresponding cis-2,5-disubstituted-2,5-dihydropyrrole (the secondary reaction product) in a completely regio- and stereoselective fashion.

Subsequently, the possibility of substituting the N-mesyl group of aziridine with an easily removable protecting-activating-group was checked in the same rearrangement process.

In this framework N-nosyl group turned out to be sufficiently efficient for the rearrangement process to 2,5-dihydropyrroles and easy to be removed by the simple PhSH/K2CO3 protocol to give corresponding 2,5-dihydropyrroles bearing the free NH

group.

Preliminary studies were also carried out on the new N-Cbz and N-TFA substituted aziridines in order to check the possibility of using these alternative N-protections in glycosylation reactions of alcohols taken as a simple and appropriate model reaction.

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Abstract... iii

Contents...iv

Abbreviations...vi

1. Chapter I. Synthetic approaches for the preparation of 2,5-dihydropyrroles 1.1. Introduction...1

1.2. State of Research...2

2. Chapter II. 2,3-Unsaturated-O-glycosides from glycal-derived vinyl epoxides and N-mesyl and N-nosyl aziridines 2.1. D-Galactal- and D-allal-derived vinyl epoxides and vinyl aziridines...11

2.2. Synthesis and regio- and stereoselectivity of the addition of O-, C-, and S-nucleophiles to D-galactal-derived vinyl epoxides 2.1 …...14

2.2.1. O-Nucleophiles...14

2.2.2. C-Nucleophiles...17

2.2.3. S-Nucleophiles...18

2.3. Synthesis and regio- and stereoselectivity of the addition of O-, C-, and S- nucleophiles to D-allal derived vinyl epoxide 2.1...19

2.3.1. O-Nucleophiles...20

2.3.2. C-Nucleophiles...21

2.3.3. S-Nucleophiles...22

unsaturated-b-O-glycosides via the new D-galactal-derived

N-(mesyl)-aziridine 2.2b...28

2.5.4. Comparison of the results obtained with vinyl N-mesyl aziridines 2.2 and 2.2...32

2.6. D-Galactal- and D-allal-derived vinyl N-(nosyl)-aziridines 2.3 and 2.3...32

3. Chapter III. Synthesis of enantiomerically pure cis-2,5-disubstituted-2,5- dihydropyrroles 3.1. Introduction...36

3.2. Reactions of vinyl aziridines 2.2a-Ms and 2.2b-Ms with metal enolates of methylene active compounds...36

3.3. Preliminary study on the use of other N-protective-activating groups than mesyl group in aziridine 2.2...46

3.3.1. Vinyl N-Cbz and N-TFA aziridines 3.31a and 3.33a in methanolysis reactions...48

3.3.2. N-Nosyl aziridine 2.3a in reactions with metal enolates derived from dibenzoylmethane... 53

3.3.3. Deprotection of N-nosyl anti-1,2-glycal derivatives 3.42, 3.45 and 2,5-dihydropyrrole 3.47...56

4. Chapter IV. Experimental Section 4.1. General Procedures...59 4.2. Materials...59 4.3. Instrumentation...59 4.4. Experimental...60 Appendix...89 References...100 v

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13_{C Carbon 13} 1_{H Proton}

AcOEt Ethyl Acetate

Boc2O Di-tert-butyl dicarbonate

CDCl3 Chloroform-d

CH2Cl2 Dichloromethane

DMF N,N-dimethylformamide

DOS Diversity-Oriented Synthesis DPP Diphenylphosphine

DYKAT Dynamic Kinetic Asymmetric Transformation

e.e. Enantiomeric Excess ETFA Ethyl Trifluoroacetate Et2O Diethyl Ether

FTIR Fourier Transform Infrared Spectroscopy

LHMDS Lithium bis(trimethylsilyl)amide / Lithium hexamethyldisilazide MeCN Methyl Cyanide / Acetonitrile

MeMgBr Methylmagnesium Bromide MgSO4 Magnesium Sulfate

RCM Ring-Closing Methathesis

t-BuOK Potassium tert-Butoxide

TBAF Tetra-n-butylammonium Fluoride TBAOAc Tetrabutylammonium Acetate TBAOH Tetrabutylammonium Hydroxide TBAOMe Tetrabutylammonium Methoxide

TBAOSiMe3 Tetrabutylammonium trimethylsilanolate

TBDMSCl tert-Butyldimethylsilyl Chloride

THF Tetrahydrofuran

TLC Thin Layer Chromatography TMGA Tetramethylguanidinium Azide