合成新穎芳香碳醣苷衍生物並評估其生物活性

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研究生：	卡力亞納 ponnapalli, kalyana kumar
論文名稱：	合成新穎芳香碳醣苷衍生物並評估其生物活性 synthesis of novel c-aryl glycoside analogues and evaluation of their bioactivities
指導教授：	林俊成 Lin, Chun-Cheng
口試委員:	陳建添 Chen, Chien-Tien 汪炳鈞 Uang, Biing-Jiun 梁健夫 Liang, Chien-Fu 蒙國光 Mong, Kowk-Kong Tony
學位類別：	博士 Doctor
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	426
中文關鍵詞：	芳香碳醣苷衍生物
外文關鍵詞：	C-aryl glycoside
相關次數：	點閱：66 下載：0
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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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