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Synthesis of Alkynyl Ribofuranosides

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Synthesis of Alkynyl Ribofuranosides City University of New York (CUNY) CUNY Academic Works Dissertations and Theses City College of New York 2011 Synthesis of Alkynyl Ribofuranosides Christian Rodriguez CUNY City College How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/cc_etds_theses/25 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] SYNTHESIS OF ALKYNYL RIBOFURANOSIDES A Thesis Presented to The Faculty of the Chemistry Program The City College of New York In (Partial) Fulfillment of the Requirements for the Degree Master of Arts by Christian Rodriguez December, 2010 - 1 - Synthesis of Alkynyl Ribofuranosides By Christian Rodriguez Mentor: P. Meleties Table of Contents Chapter 1 1.1 Introduction 6 1.2 Preparation of ribonolactone template 8 1.3 Synthesis of protected ribonolactone 9 Chapter 2 2.1 Preparation of ethynyl ribofuranosides 10 2.2 Reaction with ethynylmagnesium bromide 12 2.3 Intramolecular cyclization of diyne diol 14 2.4 Reaction of ribonolactone with lithium acetylide 15 2.5 Boron trifluoride hemiacetal deoxygenation 15 2.6 Alternative deacetylation 16 Chapter 3 3.1 Selecting appropriate protecting group 19 3.2 Preparation of trimethylsilyl alkynyl 5-O-benzyl-2,3-O isopropylidene 19 ribofuranoside 3.3 Lewis acid promoted triethylsilane dehydroxylation mechanism 20 Chapter 4 4.1 Hemiacetal alkynylation 25 4.2 Hemiacetal nucleophilic addition mechanism 26 4.3 Intramolecular cyclization of alkynyl diol 30 4.4 Proposed intramolecular cyclization mechanism 32 4.5 Intramolecular Nicholas reaction 33 - 2 - 4.6 Mitsunobu intramolecular cyclization 36 4.7 Preparation of different diol substrates 38 Chapter 5 5.1 Sodium Borohydride reduction of hemiacetals 40 Chapter6 6.1 Selective deprotection of silyl moieties of 13 42 6.2 Exploring mild oxidation conditions using tempo and co-oxidants 43 Chapter 7 Conclusion 45 References 49 Experimental procedures 51 Acknowledgements 80 IR,NMR spectra 81 - 3 - Table of contents: Figures, Schemes, Tables Figure 1. D-Ribose and its derivatives 6 Figure 2. Examples of C-glycosides 7 Figure 3. NOESY coupling interaction with the proton H1 of 38 and Ex-1 24 Figure 4. Cram chelate model for 1,2 and 1,3 chelation 27 Figure 5. NOESY coupling interaction of proton H1 of 13 32 Scheme 1. Preparation of alkynyl ribofuranoside from D-Ribose 7 Scheme 2. Preparation of the protected ribonolactone 8 Scheme 3. Proposed Alkynylation and Hemiacetal Reduction 10 Scheme 4. Synthesis of protected alkynyl C-ribosyl glycoside derivatives 11 Scheme 5. Ethynylation of ribonolactone 13 Scheme 6. Synthesis of C-nucleoside 14 Scheme 7. Reported diol cyclization 15 Scheme 8. Synthesis of ribosyl nicotamide 17 Scheme 9. Reduction and desilylation of the acetylated derivative 17 Scheme 10. Preparation of protected lactone 36 and alkynyl ribofuranoside 38 19 Scheme 11. Mechanism for C-glycosylation of ribose derivatives 21 Scheme 12. Mechanism for β-Selective C-allylation 22 Scheme 13. Proposed mechanism of the Lewis acid hemiacetal deoxygenation 23 Scheme 14. Lactol hydroxy aldehyde equilibrium 25 Scheme 15. Nucleophilic addition of hemiacetal 8 25 Scheme 16. Suggested mechanism for the nucleophilic approach towards the 28 prochiral center Scheme 17. Cyclization of alkynyl diol 45R,S 30 - 4 - Scheme 18. Suggested mechanism for the tosylchloride pyridine cyclization 32 Scheme 19. Acid promoted dehydration and nucleophilic addition of propargyl 33 alcohols Scheme 20. Synthesis β-D-ribofuranosides 34 Scheme 21. Proposed synthesis of 13α/β via intramolecular Nicholas reaction 34 Scheme 22. Proposed mechanism for intramolecular Nicholas reaction 35 Scheme 23. Synthesis of β-heterocyclic C-nucleosides 36 Scheme 24. Proposed synthesis of 13α/β via intramolecular Mitsunobu 37 cyclization Scheme 25. Proposed Mitsunobu cyclization mechanism on diol 45 R,S 37 Scheme 26. Attempted alkynylation and cyclization reactions 38 Scheme 27. Nucleophilic addition on hemiacetal 12 40 Scheme 28. Proposed Sodium borohydride reduction of hemiacetal 12 41 Scheme 29. Proposed deprotection and oxidation reaction 42 Scheme 30. Proposed oxidation of primary hydroxyl group 43 Scheme 31. Synthesis of Pyridin-2-yl C-ribonucleosides 47 Scheme 32. Proposed future synthesis of alkynyl ribofuranoside 72 47 Table 1. Hemiacetal reduction conditions 22 Table 2. Reaction conditions for ring opening diol formation 26 Table 3. Alkynylation of isopropylidene hemiacetals 29 Table 4. Tosylchloride pyridine cyclization reaction conditions 31 - 5 - Chapter 1: Carbohydrate Templates 1.1 Introduction Over the years, carbohydrates have become important chiral starting materials that are commercially available and cost effective. Examples of carbohydrates range from simple molecules such as D-glucose, D-mannose, and D-ribose 1 to complex compounds such as disaccharides, oligosaccharides, and polysaccharides.1 These molecules are just a few of the many carbohydrates commonly found in living systems. Deoxy-D-ribose is a carbohydrate component which closely resembles D-ribose. It is commonly found in DNA nucleosides such as adenosine 2. D-ribose is the carbohydrate component found in the RNA nucleoside uridine 3. Figure 1. D-ribose and some derivatives D-ribose has been used as a chiral template for the preparation of various C-glycosides, such as the naturally occurring molecules pyrazomycin 4, formycin2 5, and the synthetic enediyne compound oxabicycloenediyne3 6 (Figure 2). D-ribofuranosyl derivatives like pyrazomycin 4 and formycin 5 are C-glycosides that are composed of a carbohydrate unit that is linked by a C-C bond at the C-1 position within the heterocyclic unit instead of the C-N bond found in DNA and RNA. The diverse biological activity of these C-nucleosides includes antibiotic, antitumor, antiviral, and carcinogenic activity.2,4 - 6 - Figure 2. Examples of C-glycosides and enediyne 6 Alkynyl-glycosides are key intermediates in the synthesis of a wide variety of C-glycoside derivatives. The alkynyl functional group can serve as a site for 1,3-dipolar cycloaddition reactions,2,5 and coupling reactions.4 Many reports described the nucleophilic addition, and alkynylation of benzylated ribose,2,5 benzylated arabinose lactone6, and isopropylidene ribonolactone5 derivatives with lithium acetylide, and other alkynyl Grignard reagents. The resulting alkynyl derivatives were reduced to yield the corresponding alkynyl C-glycosides. These alkynyl ribofuranosides (scheme 1) can be a suitable starting material for the synthesis of a novel enediyne class of compounds similar to 6 bearing the alkyne bond at the C-1 and C-5 position instead of the C-2 and C-5 position found in 6. Scheme 1. Preparation of alkynyl ribofuranoside from D-ribose The aim of this project is the preparation of 1-ethynyl derivatives of ribose that may be suitable starting molecules for the synthesis of enediyne heterocyclic compounds that may have potential biological activity. For this purpose D-ribose 1 should be protected appropriately to - 7 - avoid interference of the hydroxyl groups during the reaction steps to prepare the enediyne moiety. This project is divided in three parts. 1) Preparation of Protected D-ribonolactone template. 2) Nucleophilic alkynylation followed by anomeric deoxygenation. 3) Intramolecular cyclization of prepared diols. The first part of the project is the protection of the hydroxyl groups at the C-2, C-3 and C-5 positions. After the protected ribofuranoside is prepared, the anomeric center at the C-1 position will be oxidized to yield the corresponding protected ribonolactone (scheme 2). The second part will be the nucleophilic addition of the alkynyl group followed by the reduction of the anomeric hydroxyl group6 (Scheme 3). The third part includes the pursuit of a different synthetic route incorporating different intramolecular cyclization reactions. Scheme 2. Preparation of the protected ribonolactone7 1.2 Preparation of the protected ribonolactone template Even though there are many D-ribose and D-ribonolactone derivatives which have different protecting groups, our preferred method was the transformation of D-ribose into 5-O-(tert- butyldimethylsilyl)-2,3-O-isopropylidene-D-ribonolactone 9. The silyl ether lactone derivative 9 was preferred because of the ease in preparation, isolation, and purification.7 It also provides an advantage for the selective removal of the tert-butyldimethylsilyl protecting group of the ribofuranose core using fluorinated reagents such as tetra-n-butyl ammonium fluoride (TBAF). - 8 - 1.3 Synthesis of 5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-D-ribonolactone7 (9) The ribonolactone derivative 9 is prepared from D-ribose 1 in three steps (Scheme 3). D- ribose 1 is treated with a catalytic amount of concentrated sulfuric acid in acetone giving the 5- hydroxy- 2,3-O-isopropylidene-D-ribofuranose 7 in 99% yield. The primary hydroxyl group at the fifth position is selectively protected as a silyl ether by treating the 5-hydroxy lactol 7 with imidazole and tert-butyl dimethyl silyl chloride in dimethylformamide (DMF) yielding the lactol 5-O-(tert-butyldimethylsilyl)- 2,3-O-isopropylidene-D-ribofuranose 8. This reaction is followed by the oxidation of the lactol 8 at the anomeric center yielding the protected ribonolactone 9. The oxidation was successful with potassium permanganate in acetone. Oxidation of the lactol 8 with bromine, sodium bicarbonate, tertiary butanol,
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