氧鍵結之醣苷類化合物廣泛存在於天然物中。然而，這些醣體於生物體中容易被醣水解酶或酸性條件下所降解，因此利用硫、氮或碳原子取代醣苷鍵的氧原子已被報導可增加醣苷鍵的穩定性，且與天然物的生物活性相似，具發展為治療藥物的潛力，其中，碳鍵結之醣苷分子具穩定性佳、分佈於自然界中细菌、昆蟲和植物體内等特性，引起科學家廣泛的興趣。文獻中常將多酚類化合物與一個以上的醣基結合，藉此增加二苯乙烯部分的水溶性，然而從自然界純化分離之碳鍵結醣苷分子含量稀少，且目前尚未發展出簡易效率高的合成策略，故其生理作用機制仍有待釐清。
第一部分利用微波輔助之Heck反應合成碳鍵結的二苯乙烯單醣及雙醣，此方法提供高選擇性與高產率的碳鍵結反式二苯乙烯醣苷合成方法，並應用於不同官能基修飾的碘化芳烴基醣體與不同位置取代的二苯乙烯之排列組合，同時完成C2對稱的碳鍵結反式二苯乙烯雙醣，而針對建構好的化合物進行人類SGLT2抑制活性測試，結果顯示其中三個類似物在 12 至 33 µM的濃度範圍中，對hSGLT2有明顯抑制效果。
第二部分發展4-(苯基-C-醣苷基)-1,2,3三唑之改進與多樣化合成策略，其中關鍵合成步驟為利用銅催化炔-疊氮環化加成反應 (copper(I)-catalyzed azide alkyne cycloaddition, CuAAC) 結合疊氮基醣苷化合物與不同取代之碳鍵結苯乙炔醣苷，而使用鄰苯二胺為CuAAC之配體可有效縮短反應時間並簡化純化過程，此方法適用於多種官能基且產率良好。透過交叉反應後得到一個小分子庫，對於β-galactosidase 及β-Galectin的抑制活性測試正在進行中。

O-Glycosides are integral part several natural products. However, the O-glycosidic bond is prone to cleavage under acidic condition and enzymatic in vivo conditions. Therefore several O-glycoside mimics were prepared to address this problem which includes S, N and C-Glycosides. These mimics generally will show similar biological activity compared to the natural compounds and thus can be considered as potential therapeutic targets. Among these glycomimetics C-Glycosides are particularly gained much interest because of their presence in number of natural products and stability under physiological conditions. Structural modification by glycosylation offers an attractive approach to increase the water solubility of polyhydroxy stilbenes. Even though C-glycosides are part of several natural products, the biological activity of C-glycoside stilbenes is not explored particularly due to rare occurrence and lack of straight forward synthetic methods.
In Chapter-1 we have developed microwave assisted Heck-coupling for the synthesis of mono- and bis-C-glycoside stilbenes using C-aryl glycosides and styrenes. This method provides exclusively C-glycoside trans-stilbenes with good yields. The developed Pd-catalyzed Heck-coupling method is successfully applied to various functionalized C-glycosyl aryl iodides and differentially substituted styrenes to deliver several C-glycoside trans-stilbenes with high selectivity. Synthesis of C-2 symmetric bis-C-glycoside-trans-stilbene is also accomplished. The obtained C-glycosyl trans-stilbenes were examined for human SGLT-2 inhibitory activity. Three of the analogues have shown hSGLT-2 inhibition in micro molar range (12 to 33 µM).
In Chapter-2, an improved and diversified synthesis for 4-(Phenyl-C-glycosyl)-1,2,3-triazoles was developed. The key step in the synthesis involves the copper catalyzed azide alkyne click chemistry between glycosyl azide and various substituted C-glycosylated phenyl acetylenes. Use of o-Phenylene diamine as a ligand in Copper catalyzed azide-alkyne click chemistry considerably shorten the reaction the time and allows simple purification. We have generated a small library to triazoles with broad substrate scope in terms of sugars. Interestingly each triazole analogue is having two free sugar units, one attached to the triazole nitrogen and other attached to the phenyl ring at C-4. The synthesized C-glycosylated triazole analogues were assayed for β-galactosidase and β-Galectin inhibition.

Title i
Acknowledgements ii
Abstract iv
Table of contents viii
List of figures xi
List of schemes xii
List of tables xiii
Abbreviation xv
Chapter 1: Trans-Stilbene C-Glycosides: Synthesis by a Microwave-Assisted
Heck Reaction and Evaluation of the SGLT-2 Inhibitory Activity 1
1 Introduction 2
1.1 C-glycosides 2
1.2 General synthetic strategies for C-aryl glycosides 4
1.2.1 Friedel-Craft’s reaction using trichloroacetimidate donor 4
1.2.2 Friedel-Craft’s reaction using trifluoro acetate donor 5
1.2.3 Friedel-Craft’s reaction using anomeric acetate donors 6
1.2.4 Fries type O→C rearrangement 8
1.2.4.1 Controlling the ratio of O- and C-glycosides 9
1.2.5 C-glycosylation using organometallic reagents 12
1.2.5.1 C-glycosylation using organolithium reagents 12
1.2.5.2 C-glycosylation using Negishi coupling 13
1.2.5.3 Substrate controlled C-glycosylation using organozinc reagents 14
1.2.5.4 C-glycosylation using anomeric stannanes 17
viii

1.3 Objectives 20
1.4 Diabetes-SGLT-2 inhibitors 21
1.4.1 Phlorizin and analogues as non selective SGLT-2 inhibitors 21
1.4.2 C-aryl glycoside analogues as potential SGLT-2 inhibitors 23
1.4.3 C-aryl glycoside analogues as potential SGLT-1 inhibitors 24
1.5 Polyhydroxy stilbenes and their O-and C-glycosides 25
1.5.1 Synthesis of polyhydroxy stilbenes and their O-and C-glycosides 26
1.6 Results and Discussion 30
1.7 Synthesis of bis C-glycoside stilbenes using microwave assisted heck coupling 42
1.8 SGLT-2 inhibition of Stilbene C-glycosides 43
1.9 Conclusion 44
1.10 Experimental section 45
1.10.1 General information 45
1.10.2 Characterization of compounds 45
1.10.3 General Pd/C mediated debenzylation 49
1.10.4 general peracetylation procedure 52
1.10.5 Standard iodination procedure 60
1.10.6 General procedure for Heck coupling 63
1.10.7 General experimental procedure for deacetylation 73
1.11 Establishment of SGLT-2 stable cell line 85
1.12 Radioactive SGLT-2 assay 86
1.13 References 87

ix
Chapter 2: Improved synthesis of 4-(Phenyl-C-glycosyl)-1,2,3-triazole derivatives 100
2.1 Introduction 101
2.1.1 Click chemistry : Overview 101
2.1.2 Copper catalyzed azide alkyne click chemistry (CuAAC) 102
2.1.3 Mechanism of CuAAC 104
2.1.4 1,2,3-triazoles as isosters of amide 107
2.2 Applications of Click chemistry in carbohydrate research 108
2.2.1 Applications of Click chemistry in Drug discovery 109
2.2.2 Protein tyrosine phosphate inhibitors 110
2.2.3 Protein kinase inhibitors 111
2.2.4 Glycogen Phosphorylase inhibitors 111
2.2.5 Glycosidase inhibitors 112
2.2.6 Neuraminidase inhibitors 113
2.2.7 Triazole analogues for lectin binding 114
2.2.7.1 Triazole analogues for galectin (S-lectin) inhibitory activity 114
2.3 Objective 116
2.4 Design and synthesis of triazole analogues 117
2.4.1 Results and discussion 118
2.4.2 Galactosidase and Galectin inhibition assay 124
2.5 Conclusion 126
2.6 Experimental section 127
2.7 References 148

x

Chapter 3: Total synthesis of trans-resveratrol 4-C-β-glucopyranoside and 158
trans-resveratrol 2-C-β-glucopyranoside
3.1 Introduction 159
3.2 Results and discussion 161
3.3 Prospective 163
3.4 References 164

List of Figures
Chapter-1
Figure 1.1 Structures of biologically active C-glycoside natural products 3
Figure 1.2 The O→C rearrangement mechanism 8
Figure 1.3 Substrate controlled transition metal free C-glycosylation 16
Figure 1.4 Structures of Phlorizin (42), its O-glycoside (43-45) and C-glycoside 22
analogues (46)
Figure 1.5 Structures of approved SGLT-2 inhibitors in the market (2016) 23
Figure 1.6 Structures of SGLT-1 inhibitors 24
Figure 1.7 Structures of polyhydroxy stilbenes and their O- and C-glycoside analogues 26
Figure 1.8 Outline of the synthetic approach for the construction of C-glyccoside 30
trans-Stilbenes
Figure 1.9 H-H cosy spectrum of 65 31
Figure 1.10 H-H cosy spectrum of 82a 38
Chapter-2
Figure 2.1 click reaction types 102
Figure 2.2 Structures of some useful ligands in click chemistry 104
xi
Figure 2.3 Proposed catalytic cycle of stepwise CuAAC 106
Figure 2.4 Isosteric similarities between amide and triazoles 108
Figure 2.5 Structures of PTP inhibitors 110
Fugure 2.6 Structures of protein kinase inhibitors 111
Figure 2.7 Structures of glycogen phosphorylase inhibitors 112
Figure 2.8 Structures of glycosidase inhibitors 112
Figure 2.9 Structures of Neuraminidase inhibitors and their triazole analogues 114
Figure 2.10 Structures of Lectin inhibitors 115
Figure 2.11 Comparision of synthetic approaches 118
Figure 2.12 Galactosidase inhibition assay 124
Chapter-3
Figure 3.1 Structures of resveratrol C-glycoside analogues 159
List of Schemes
Chapter-1
Scheme 1.1 C-glycosylation of phenolic ethers using trichloroacetimidate donor 5
Scheme 1.2 C-glycosylation of phenolic ethers using trifluoroacetate donor 6
Scheme 1.3 C-glycosylation of 1,4-dimethoxy benzene using AgOTfa/SnCl4 8
Scheme 1.4 The O→C rearrangement using Sc(OTf)3 10
Scheme 1.5 Mono and bis C-glycosylation of resorcinol derivatives using Sc(OTf)3 11
Scheme 1.6 C-aryl glycosylation using aryl lithium reagent 12
Scheme 1.7 C-glycosylation using Negishi coupling 14
Scheme 1.8 Substrate controlled transition metal free C-glycosylation 15
Scheme 1.9 Synthesis of SGLT-2 inhibitors using substrate controlled transition metal 17
free C-glycosylation
xii
Scheme 1.10 Stereospecific synthesis of C-aryl glycosides using anomeric stannanes 18
Scheme 1.11 Stereospecific synthesis of C-aryl glycosides using anomeric stannanes 19
Scheme 1.12 Chemical synthesis of resveratrol O-glycosides 27
Scheme 1.13 Chemical synthesis of resveratrol O-glycosides 28
Scheme 1.14 Enzymatic synthesis of resveratrol O-glycosides 28
Scheme 1.15 Synthesis of fully protected C-glucosyl trans-stilbene 32
Scheme 1.16 Debenzylation of aryl C-glycosides 33
Scheme 1.17 MW-assisted synthesis of non natural bis C-glucosyl stilbenes derivative 42
Chapter 2.
Scheme 2.1 Synthesis of alkyne derivative (39a) 119
Scheme 2.2 Synthesis of azide derivatives (42a-d) 121
Scheme 2.3 Synthesis of galactose based highly water soluble triazole derivatives (40q-r) 125
Chapter 3.
Scheme 3.1 Stille coupling approach for synthesis of resveratrol C-glycoside analogues 160
(1 and 2a)
Scheme 3.2 Synthesis of 4-iodo resveratrol (3) 161
Scheme 3.3 Synthesis of stannane (5) 162
Scheme 3.4 Stille coupling of 4-iodo resveratrol (3) using anomeric stannane (5) 162
Scheme 3.5 Synthesis of resveratrol 4-C-β-glucopyranoside using Heck coupling 163
List of tables
Chapter-1
Table 1.1 C-glycosylation of p-Methoxy toluene using AgOTfa/SnCl4 7
Table 1.2 Halogenation conditions screening 34
Table 1.3 MW-mediated Pd (II) catalyzed heck reaction: Optimization of reaction 36
xiii
-conditions
Table 1.4 MW-mediated synthesis of trans-stilbene C-glucosides:variation of styrene 37
Table 1.5 Stereoselective C-glycosylation: Synthesis of glycosyl C-aryl iodides (85-88) 40
Table 1.6 MW-assisted formation of Stilbene C-glycosides: variation of the sugar and 41
aromatic ring
Table 1.7 SGLT-2 inhibitory activity of trans-stilbene C-glycosides 44
Chapter-2:
Table 2.1 Synthesis of alkyne derivativs (39b-d) 120
Table 2.2 Synthesis of triazole derivatives (40a-p) 123














xiv
Abberiviation
AlCl3 Aluminium trichloride
Ac2O Acetic anhydride
ACN Acetonitrile
AIEC Adherent invasive E-coli
AgOTFA Silver trifluoroacetate
AgClO4 Silver perchlorate
BF3.Et2O Borontrifluoride diethyletherate
Bn Benzyl
tBu tert-Butyl
BBr3 Borontribromide
tBuOH tert-Butanol
n-BuLi n-Butyl lithium
s-BuLi Secondary butyl lithium
CCl3CN Trichloro acetonitrile
Cp2HfCl2 Dichlorobis(cyclopentadienyl)hafnium
CAN Ceric ammonium nitrate
CuCl Copper (I) chloride
CuBr Copper (I) bromide
CuI Copper (I) iodide
CuSO4 .5H2O Copper (II) sulpahte pentahydrate
Cu (OAc)2 Copper (II) acetate
CaCl2 Calcium (II) chloride
CHCl3 Chloroform
xv
Cs2CO3 Cesium carbonate
CD Crohn’s disease
CRD Carbohydrate recognition domain
CuNP Copper nanoparticle
DBU 1,8-Diaza bicyclo [5.4.0] undec 7-ene
DCM Dichloromethane
DBE Dibutyl ether
DMI N, N'- dimethyl imidazolidinone
DM Diabetes mellitus
DMF N, N-dimethyl formamide
DMAP 4-dimethyl amino pyridine
DMSO Dimethyl sulphoxide
Dave-Phos 2-Dicyclohexylphosphino 2'-(N,N-dimethyl amino)
biphenyl
DIPEA N, N-diisopropyl ethyl amine
EtOAc Ethylacetate
Et3SiH Triethylsilane
EMA European medical association
Et3N Triethyl amine
EtSNa Sodium thioethoxide
Et3(PhCH2)N+Br - Benzyl triethyl ammonium bromide
FeCl3 Ferric chloride
GaCl3 Gallium (III) chloride
GPs Glycogen phosphorylase
xvi
H2 Hydrogen
HCl Hydrochloric acid
H2O Water
Hg(OAc)2 Mercuric acetate
Hg (OTfa)2 Mercuric trifluoroacetate
IDF International diabetic federation
IBD Inflammatory bowel disease
Jackie Phos 2-{Bis[3,5-bis(trifluoromethyl)phenyl] phosphino}-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, Bis(3,5-bis(trifluoromethyl)phenyl)(2′,4′,6′- triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine
KF Potassium fluoride
KCl Potassium chloride
LG leaving group
MeOH Methanol
MS 4Å Molecular sieves
MgCl2 Magnessium (II) chloride
MW Microwave
NaBH4 Sodium borohydride
NiCl2 Nickel (II) chloride
NMR Nuclear magnetic resonance
NBS N-Bromo succinimide
NIS N-iodo succinimide
Na Sodium
NH3 Ammonia
NaOH Sodium hydroxide
xvii
NaOMe Sodium methoxide
NaHCO3 Sodium bicarbonate
Pd/C Palladium on charcoal
Pd(PPh3)4 Tetrakis(triphenyl phosphine) palladium (0)
Pd(dba)2 Bis dibenzylidineacetone palladium (0)
Pd2(dba)3 Tris dibenzylidineacetone di palladium (0)
P(n-Bu)3 Tri n-butyl phosphine
P(t-Bu)3 Tri t-butyl phosphine
Pd(OAc)2 Palladium (II) acetate
Py Pyridine
PTP Protein tyrosine phosphate
PK Protein kinase
PyBOX Pyridine bis(oxazoline)
S-Phos 2-Dicyclohexylphosphino-2'-6'-dimethoxy biphenyl
SGLT Sodium dependent glucose co transporter protein
Sc(OTf)3 Scandium Triflate
SnCl4 Tin tetrachloride
TFA Trifluoro acetic acid
TFAA Trifluoro acetic anhydride
TMSOTf Trimethylsilyl trifluoro methane sulphonate
TMDMSCl t-Butyl dimethyl chloro silane
TBAF tetra-n-butyl ammonium fluoride
THF Tetrahydro furan
TLC Thin layer chromatography
xviii
TMS Trimethyl silyl
TMSN3 Azido trimethyl silane
TMEDA N, N, N', N'- tetramethyl ethylene diamine
TBTA Tris [(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine
THPTA Tris (3-hydroxypropyltriazolylmethyl) amine
TBAE Tetra-n-Butyl ammonium acetate
TCEP Tris 2-(carboxy ethyl) phosphine
USFDA United States foods and drug administration
ZnBr2 Zinc bromide
ZnCl2 Zinc chloride
ZnCl2.Et2O Zinc chloride diethyl etherate
ZnBr2.LiBr Zinc bromide lithum bromide complex












xix

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