SYNTHESIS OF ALKALOID STRUCTURE ppt _ HÓA HỮU CƠ

SYNTHESIS OF ALKALOID STRUCTURE Bài giảng pptx môn ngành Y dược hay có “tài liệu ngành dược hay nhất”; https://123doc.net/users/home/user_home.php? use_id=7046916 CONTENT INTRODUCTION SYNTHESIS OF 5-SUBSTITUTED AND 5-UNSUBSTITUTED PYRIDOCARBAZOLONES, TETRAHYDROPYRIDOCARBAZOLONES ELECTROPHILIC SUBSTITUTION REACTIONS AT C-5 POSITION NUCLEOPHILIC SUBSTITUTION REACTIONS AT C-4 POSITION RINGCLOSURE REACTION OF AZIDES AND AMINE RING CONTRACTION OF 5-HYDROXYPYRIDOCARBAZOLONES CONCLUSION Pyridocarbazoles in Bioactive Structures N R R N O O Strychnine (R = H) Brucine (R = OMe) Seeds of Strychnos nux-vomica Tonic in tincture Powerful peristaltic action Stimulate the spinal cord Strychnos nux vomica tree Pyridocarbazoles in Bioactive Structures OAc R R O R R R OH N O N O N R O R Quinolones Gram stain of p aeruginosa cells Alkaloids: e.g Swietidine A, Daurine, Folidine, Glycolone A, Glycocitridine, Flindersine, Almein Bioactivity: antiallergic, herbicidic, antiinflammatoric, antiosteoporotic, tranquilizer 3-hydroxy quinolinediones P aeruginosa Scanning electron micrograph CDC Alkaloids from several plants(e.g Haplophytin) Contents from bacteria (Pseudomonas aeruginosa) antibiotic Retrosynthesis of Pyridocarbazoles Carbazole N H N HO O O RO O OR Malonate Synthetic Approach and Reactivity N HO N O O R R H O C-H acidic Electrophilic attack Nucleophilic attack SO2Cl2 POCl3 N Cl N O R N3, TosO, Amines O R Cl O N3, OH, NO2, Amines Literature Known Reaction of Carbazoles with Reactive Malonates C6H2Cl3 C6H2Cl3 O O O O R Cl N HO O R 260 °C N H + Cl Cl OH O R1 : H, i.Pr, Bn, Ph good yield Cl2 OH Cl N C6H3Cl2 C6H3Cl2 O O R O O HO O (Dioxin) + Cl O R Ziegler E., Junek H., Rossmann U., Monatsh.Chem 92 (1961) 809-13 Cl2 Reaction of Carbazoles with Diethyl Malonates R1 R2 a b c d e f g Me Et Bu Heptyl Nonyl Bn Ph Et Me Et Me Me Me Et N H O R O O R O R 6a-g 240-260 °C 6-12 h Ph2O 60-80% N HO R1 a b c d e f g Me Et Bu Heptyl Nonyl Bn Ph N O R 3a-g (A) O R H O 3a-g (B) Reaction of Tetrahydrocarbazoles with Diethyl Malonates O O Et O O R G N H G : H, CH3, Cl J : H, CH3 Tetrahydrocarbazoles J Et J G 250 - 270 °C 60 - 80% - EtOH N O O R R2 : Alkyl, Aryl G J N HO O R Tetrahydro Pyridocarbazoles Synthesis of Tetrahydrocarbazoles with Substituents in Benzene and Cyclohexene Ring O G N H NH2 HCl G : H, CH3, Cl J J : H, CH3 120 °C 40 - 85% CH3COONa/ CH3COOH G N H J Amination with Secondary Amines at the Hydroxy Position Y H N N 180 °C, reflux X = Cl Y = O, CH2 R : Ph Y N O N X O R R = Alkyl, Aryl Y H N 230 °C, sealed X = OH, Cl Y = O, CH2 N H O R Amination with Primary Amines at the Hydroxy Position Ph-CH2NH2.HCl N HO R R2-NH O N O Ph-CH2NH2.HCl 180 °C 300 °C N 240 °C R1 = alkyl, aryl R2 = Ph, CH2Ph A: H2 / Pd, 50 °C or NH3+ HCOOB: N R N H R N O reflux R2 = CH2Ph H2N R O Chlorination and Tosylation at the Hydroxy Position POCl3 reflux N O Cl MeTHPC R N HO O R MeTHPC TosCl Acetonitril R = alkyl, aryl, NO2, Cl, acetyl N Tos O O R Azidation at the Hydroxy Position N X X = Cl, Tos-O NaN3 O 20-50 °C Me-THPC R R = Aryl, Acetyl POCl3 or TosCl Mixture of SM and NaN3 POCl3 added 80-90 °C N HO O R R = Alkyl N N3 O R R = Alkyl, Aryl, Acetyl Reduction of Azides PPh3 O N3 N 80 °C N P N - N2 R R A: H2 / Pd, 50 °C or B H+ NH3+ HCOOreflux N H2 N O R O Synthesis of Heterocylic Malonates and Acetates N Cl POCl3 O NO2 K2CO3 , DMF O H 2C O N O R H C O R O NO2 O R O R HO O NO2 R : Me, Et C6H4Cl2 , H2O O O Et3N N N O - CO2 - MeOH Me O C H2 O NO2 Cyclization of Azides DSC diagram HeatFlow [mW] Peak: 173.68 °C Heat: 180 J/g 150 °C N N3 O N HN O Temp [°C] Cyclization of Azides DSC diagram HeatFlow [mW] Peak: 84.96 °C Heat: J/g 110 °C N N3 O O CH3 N O N O mp: 223.6 °C CH3 mp: 227.9 °C Temp [°C] Azido compound After refluxing in toluene Cyclization of Azides DSC diagram Peak: 164.7 °C Heat: 114 J/g N3 Azido compound After refluxing in DMF 153 °C N O NO2 N N O N + O O - Hydroxylation of the CH-acidic Position H2O2/ NaOH or MeCO3H or CPBA N HO N O O R R N O R O NO2 MeTHPC R : Alkyl, Aryl N 120 °C H2O O OH O R O OH analogs of contents of Pseudomonas aeruginosa Kitamura S et al., J Antibiot 39 (1986) 1160-66 Hydroxylation of the CH-acidic Position aq KOH, PhMe N O Me O OH r.t, h 80% N Me O OH aq KOH, PhMe N O Me O OH 60-80 °C, h 55% Kitamura S et al., J Antibiot 39 (1986) 1160-66 N HO OH O Hydroxylation of the CH-acidic Position aq KOH, PhMe N O R O OH 60-80 °C, 2-4 h 65-80% N R OH O aq KOH, PhMe N O O OH 60-80 °C, h 62% Kitamura S et al., J Antibiot 39 (1986) 1160-66 O N H OH CONCLUSION X: H, OH X R N H R O O X N HO O R O O R1 : H, Alkyl, Aryl R N O O X: H, OH O OH Peak: 164.7 °C Heat: 114 J/g R1 : H, Alkyl, Aryl CH3 H O CH3 H3C H3C Cl H H N H Cl N NH2 HCl H H N O HO CH3 N HO N O R X X: Cl, N3, Amine, Ac R N THPC O O R 1 O Y Y: Cl, OH, NO2, N3, Amine N H O N N R N R R N H O O OH This work was performed at the Institute of Chemistry, Graz (Austria) Under the Supervision of Uni.-Prof Dr STADLBAUER I would like to express my sincere thanks to everybody in Institute of Chemistry, Karl Franzens University Graz I would like to thank Vietnamese Government for Ph.D scholarship THANK YOU FOR YOUR ATTENTION ... REACTION OF AZIDES AND AMINE RING CONTRACTION OF 5-HYDROXYPYRIDOCARBAZOLONES CONCLUSION Pyridocarbazoles in Bioactive Structures N R R N O O Strychnine (R = H) Brucine (R = OMe) Seeds of Strychnos... performed at the Institute of Chemistry, Graz (Austria) Under the Supervision of Uni.-Prof Dr STADLBAUER I would like to express my sincere thanks to everybody in Institute of Chemistry, Karl Franzens... aeruginosa Scanning electron micrograph CDC Alkaloids from several plants(e.g Haplophytin) Contents from bacteria (Pseudomonas aeruginosa) antibiotic Retrosynthesis of Pyridocarbazoles Carbazole N H N