Copper catalyzed C-O cross-coupling synthesis of structurally complex vinylic ethers: enabling technology for the non-traditional synthesis of various glycosides Restricted; Files Only
Kim, Taehee (Spring 2025)
Abstract
Carbohydrates are the most abundant macromolecules that participate in various biological activities and have shown therapeutic effects, such as antibacterial vaccines, tumor-associated carbohydrate antigens, and diabetes treatment. Accessing a large quantity of structurally defined glycosides is critical in a comprehensive understanding of this macromolecule. Due to the heterogeneous nature of carbohydrates, it is often impractical to extract them from natural sources. The chemical synthesis of glycosides is an alternative to provide structurally defined glycosides. Although traditional glycosylation is well developed, the field of glycosylation still suffers from a lack of uniform methodology to form a glycosidic bond due to its complicated mechanism that varies from SN2 and SN1 mechanism. An alternative approach is an electrophile-promoted intramolecular oxacyclization of carbohydrate-derived acyclic vinylic ethers. However, we discovered a gap in knowledge regarding an efficient synthetic method for vinylic ethers with structural complexity on both sides of the ether linkages.
Addressing the lack of efficient synthesis of structurally complex vinylic ethers, we developed an efficient synthesis of vinylic ethers via the C-O cross-coupling catalyzed by Cu(I) and cyclic (±)-N,N’-dimethylethylenediamine (CyDMEDA) as a ligand. The substrate scope of this cross-coupling included polyhydroxy alcohols, unsaturated alcohols, tertiary amine containing alcohol, and reducible anomeric alcohol,
Our C-O cross coupling method enabled the synthesis of acyclic vinylic ethers from monosaccharide building blocks, namely from D-lyxose, D-ribose, and D-arabinose. This was the first example of synthesizing 1,2-disubstituted vinylic ethers with structural and stereochemical complexity on both sides of the ether linkage via cross-coupling. The cross-coupling method provided stereospecific 1,2-disubstituted vinylic ethers, unlike previously used Horner-Wittig olefination or Julia-Kocienski olefination. Upon epoxidation / in-situ oxacyclization of each acyclic vinylic ether product, we have synthesized disaccharides with α-D-talo-, β-D-allo-, and α-D-altropyranoside stereochemistry.
Subsequently, we began expanding the electrophile-promoted oxacyclization of acyclic vinylic ether intermediates toward the synthesis of 6-deoxy- and 2,6-dideoxyglycosides. The preliminary investigation with D-ribo stereoisomer showed that the acid-catalyzed intramolecular oxacyclization can form 2,6-dideoxyglycosides directly from acyclic vinylic ether intermediates. Further investigation of this transformation is warranted, with other diastereomers and protective group patterns.
Table of Contents
Chapter 1 Introduction 1
1.1 Carbohydrates 1
1.1.1 Background 1
1.1.2 Traditional glycosylation 2
1.1.3 Controlling stereoselectivity in traditional glycosylation 4
1.1.4 Intramolecular Glycosylation 7
1.1.4.1 Electrophile-promoted oxacyclization and the synthesis of carbohydrate-derived acyclic vinyl ethers 8
1.2 Vinylic Ethers 13
1.2.1 Background 13
1.2.2 Previous methods to synthesize vinylic ethers 15
1.2.3 Copper-catalyzed C(sp2)-O cross coupling 16
1.3 Motivation 21
1.3.2 Acid-catalyzed glycosylation 23
1.3.3 This project 24
Chapter 2 Cu(I)-catalyzed cross-coupling synthesis of vinylic ethers 27
2.1 Introduction 27
2.2 Results and discussion 27
2.2.1 Optimization 27
2.2.1.1 Proposed mechanism 30
2.2.2 Substrate scope 31
2.3 Concurrent methods of vinylic ether synthesis 35
2.4 Conclusion 36
Chapter 3 Non-traditional approach toward disaccharides via acyclic vinylic ether intermediates 38
3.1 Background 38
3.2 Results and Discussion 39
3.2.1. Synthesis of vinylic iodides from monosaccharide building blocks 39
3.2.2 Vinylic ethers via Cu(I) catalyzed cross-coupling 43
3.2.3. Electrophile promoted oxacyclization of carbohydrate-derived vinylic ethers 45
3.2.3.1. Proposed mechanism 45
3.2.3.2 Results 46
3.2.4 Structural determination of disaccharides 54
3.3 Conclusion 57
Chapter 4 Synthesis of 6-deoxy and 2,6-dideoxy glycosides via acyclic vinylic ether intermediates 59
4.1 Background 59
4.2 Results and Discussion 60
4.2.1 Synthesis of E-vinylic iodides from D-ribo-alkynes 60
4.2.2. Synthesis of hydroxy vinylic ether intermediates via Cu-catayzed cross-coupling followed by debenzoylation 61
4.2.2.1. Synthesis of vinylic ethers via Cu(I)-catalyzed cross-coupling 61
4.2.2.2 Attempt at the synthesis of vinylic boronate and Cu(II)-catalyzed cross-coupling 63
4.2.3. Electrophile-promoted oxacyclization of acyclic vinylic ether intermediates 65
4.2.3.1 Synthesis of 6-deoxyglycosides via m-CPBA promoted oxacyclization 65
4.2.3.2 Synthesis of 2,6-dideoxyglycosides via acid-catalyzed oxacyclization 68
4.3 Conclusion and future works 73
References 75
Experimental Sections 90
General Considerations 90
Experimental for Chapter 2 92
NMR Spectra of E-vinylic ethers 114
Experimental for Chapter 3 153
Experimental for vinylic iodides 153
Experimental for the vinylic ethers 165
Experimental for disaccharides 177
NMR Spectra for Chapter 3 187
Experimental for Chapter 4 264
Experimental for vinylic iodides 264
Experimental for the vinylic ethers 268
Experimental for the 6-deoxy- and 2,6-dideoxy glycosides 273
NMR spectra for Chapter 4 277
References 282
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