Tổng hợp và chuyển hoá một số dẫn xuất của (an pha) d GLUCOZƠ và (an pha) d GLUCOZAMIN

DAI HOC QUOC GIA HA NOI TRUONG DAI HOC KHOA HOC TU NHIEN DE TAI NGHIEN CWU KHOA HOC TONG HQP VA CHUYEN HOA • MOT SO DAN XUAT CUA a-D-GLUCOZa VA a-D-GLUCOZAMIN Mas6: QT-05-16 CHU TRI DE TAI: PGS.TS NGUYEN DINH THANH CAN BO THAM GIA: Th.S Pham H6ng Lan Cac sinh vien phong THHC-l OAI HOC Q U O C GIA HA NO* TRUNG TAr.^ THOr.'G TIN THU VIEN pr/^t ^9 Ha Noi - 2005 BAO CAO TOM TAT a Ten de tai: TONG HOP VA CHUYEN HOA MOT SO DAN XUAT CUA a-D-GLUCOZO VA a-D-GLUCOZAMIN Ma so: b Chu nhiem de tai: QT-05-16 PGS TS Nguyln Dinh Thanh c Cdn bp tliam gia: Th.S Pham Hong Lan Cac sinh vien phong THHC-l d Muc tieu vd noi dung ngliien citu + Muc tieu: \ Tong hgp mot so hcrp chat glycozylamin co chua nhan di vong 1,3-thiazol va benzo-l,3-thiazol tren ca so a-D-glucozamin clohidrat va D-glucoza Tong hop mot so dan xuat tu glycozyl isothioxianat va cac aminouraxin, aminothiouraxin khac Nghien cuu (HN, CHTN-^H va '^C cua cac hgp chat tong hop dugc Khao sat hoat tinh sinh hoc (hoat tinh khuan, khang nam) cua cac hgp chat tong hgp dugc Nghien cuu moi quan he cau true-tinh chat hay cau true-hoat tinh bang viec su dung cac phuong phap hoa lugng tu {ab initio, AMI, PM3, ) + Ngi dung: Nghien cuu thuc hien phan ung cua D-glucozamin clohidrat va D-glucoza ciang nhu mot so dan xuat cua chung vai mot so 2-amino-l,3-thiazol va 2-aminobenzo-l,3thiazol Nghien cuu thuc hien cac phan ung chuyen hoa tren ca sa cac hgp chat nhan dugc a tren Nghien cuu moi quan he cau truc-tinh chat hay cau truc-hoat tinh bing cac tinh toan hoa lugng tu(aZ? initio, AMI, PM3, )hay ca hoc phan tu (MM+, AMBER, ) Cau true cua cac hgp chat nhan dugc se dugc xac nhan bing cac phucmg phap vat ly hien dai (pho hong ngoai, cong huang tu hat nhan proton va cacbon-13 va ph6 khoi lugng) Cac tinh chat sinh hgc cua cac chat tren se dugc khao sat bang cac phuang phap chuyen mon Ket qua dat du'oc + Ket qud /clioa iipc: I Da tong hgp dugc hgp chat 2-axetamido-2-deoxi-P-D-glucopiranoz}'lamin tiJ N-axetyl-P-D-glucozamin va mot so 2-amino-l,3-thiazol hay 2-aminobenzo-l,3-thiazol the khac Da tong hgp dugc hgp chat 4,6-0-etyliden-p-D-glucopiranoz>'lamin tu 4.6etyliden-P-D-glucopiranoza va mot so 2-amino-l,3-thiazol hay 2-aminobenzo-l,3-thiazol the khac Da tong hgp dugc hgp chat 3-(tetra-0-axetyl-a-D-glucopiranozylamino)isothiazolo[3,4-d]pirimidin-4,6-dion khac tir cac aminouraxin, aminothiouraxin voi glucozyl isothioxianat Da nghien cuu be mat nang lugng quay doi vai nhom hidroximet\i ngoai vong ciia a-D-2-amino-2-deoxyglucopyranoza va P-D-2-amino-2-deoxyglucopyranoza da dugc mo ta bang each sir dung phuang phap ab initio cac mirc li thuyet cao 6-31G(d) va 6-3 lG(2d, Ip).), va nhan thay rang su chuyen doi qua lai de dang nhat pha la giua cac cau dang TG va GT (trong ca hai truang hgp anome a va P) Da nghien ciru anh huang cau hinh cua nhom 2-axetamit den cau dang ben cua phan tir N-axetyl-D-glucozamin bang phuang phap toi im hoa hinh hoc theo phuang phap ca hoc phan tir AMBER va theo phuang phap ca hgc lugng tu AMI, va da nhan thay rang a phan tir N-axetyl-D-glucozamin, anome P ben han anome a ve mat nang lugng (khi khong co anh huang cua dung moi) va doi vai cac anome thi cau hinh ben nhat la cau hinh (E)-syn Cau true ciia cac hgp chat da tong hgp dugc xac nhan bang cac phuang phap vat ly hien dai (pho hong ngoai, cong huang tir hat nhan proton va cacbon-13 va khoi lugng) Da thir hoat tinh khang khuan va khang nam cua cac hgp chat da tong hgp dugc + Ket qua dao tao: 04 cir nhan hoa hoc + Ket qua cong bo: 02 bai bao va 03 bao cao khoa hoc Nguyln Dinh Thanh, Dang Nhu Tai, Pham Hong Lan, Phan img cuaglucopiranozyl isothioxianat voi mot so 6-aminouraxin va 6-amino-2-thiouraxin, Tap chi Hod hoc va (fug dung, N.9 (45) (2005), tr 24-27 Nguyen Dinh Thanh, Study on the molecular conformations of a-D-2-amino-2deoxyglucopyranose using ab initio method, Tap chi Hod hoc vd lfng dung, NIC (46) (2005), tr 37-41 Nguyln Dmh Thanh, Dang Nhu Tai, Mai Thi Thoa, Contribution to study on synthesis of someglucopyranozylamines containing thiazole and benzothiazole rings from 4,6-0-ethylidene-D-glucopyranose, Tuyen tap cdc cong trinh Hoi nghi Khoa hoc vd Cong nghe Hod Hiru ca todn quoc lan thu 3, Ha noi 11/2005, tr 150-153 Nguyln Dinh Thanh, Dang Nhu Tai, Biii Ngoc Linh, Gop phin tdng hgp mot s6 din xuat chira dj vong tham thiazol va benzothiazol ciia 2-axetyl-D-glucozamin, Tuyin tap cdc cong trinh Hoi nghi Khoa hoc vd Cong nghe Hod Huu ca todn qudc Idn thu 3, Ha noi 11/2005, tr 154-158 Nguyen Dinh Thanh, Dang Nhu Tai, Pham Nhat Quang, Gop phin nghien ciru anh huang cau dang cua nhom axetyl den cau dang ben cua phan tir N-axetyl-Dglucozamin, Tuyen tap cdc cong trinh Hoi nghi Khoa hoc vd Cong nghe Hod Hiru ca todn quoc Idn thic 3, Ha noi 11/2005, tr 227-230 ii TINH HINH SLT DUNG KINH PHI T6ng kinh phi dugc cip: 15.000.000 V'ND Phan bo kinh phi: nhu da ghi HDNCKH thuc hien de tai cap Dai hoc Quoc gia Ha Noi nam 2005, ma s6 QT-05-16 KHOA HOA HOC CHU TRI DE TAI Ih PGS.TS Trdn PGS.TS Nguyin Din/t Titt TliiNlmMai TRUTOfNG DAI HOC KHOA HOC TU' NTHEN PHOHlEu TfiUONG PBS.lS.UOAU/^juw^am^ 111 SUMMARY a Reaserching project: SYNTHESIS AND TRANSFOR]\L\TIONS OF SOME DERFV ATIVES OF a-D-GLUCOSE AND a-D-GLUCOSAAHNE Code Number: b Principal Researcher: QT-05-16 Assoc Prof Dr Nguyen Dinh Thanh c Cooperating Institution(s): MA Pham Hong Lan Some students in Organic Synthesis I Lab Hanoi University of Science, VNU, Hanoi d Objectives and contents + Objectives Synthesize some derivatives of glycosylamines of a-D-glucosamine hydrochloride and a-D-glucose by reactions of the ones with some 2-amino-l,3-thiazoles or 2aminobenzo-1,3-thiazoles Synthesize some derivatives from glycosyl isothioxianates and some different aminouracils and aminothiouracils Study on spectroscopies (IR-, ' H - and ^^C-NMR and MS) of synthesized compounds Investigate the biological activities of synthesized compounds (for example, antiviral, antifungal, ) Study on quantitative structure-activity relationship (QSAR) or quantitative structureproperty relationship correlations (QSPR) for these derivatives using the quantum chemical methods {ab initio, AMI, PM3, ) + Contents Study on performance of reactions of D-glucosamine hydrochloride and a-D-glucose with some with some 2-amino-l,3-thiazoles or 2-aminobenzo-l,3-thiazoles Study on performance of reactions of transformation of the synthesized above compounds Study on quantitative structure-activity relationship (QSAR) and quantitative structureproperty relationship correlations (QSPR) for these derivatives using the quantum chemical methods {ab initio, AMI, PM3, ) or molecular mechanics (MM+, AMBER, ) Structure of synthesized compounds will be confirmed by using modem physic methods (IR-, ' H - and ^^C-NMR, mass spectroscopies) Investigate the biological activities of synthesized compounds by using the professional procedures e Results obtained + Results in science: Five compounds of 2-acetamido-2-deoxi-P-D-gIucopyranosylamines from Niv acetyl-P-D-glucosamine and some different substituted 2-aminobenzo-l,3-thiazoles or 2amino-l,3-thiazoles Six compounds of 4,6-0-ethylidene-P-D-glucop}Tanosylamines from 4,6-0ethylidene-P-D-glucopyranos and some different substituted 2-aminobenzo-l,3-thiazoIes or 2-amino-l,3-thiazoles Eight compounds of 3-(tetra-0-acetyl-a-D-glucop>Tanosylamino)isothiazolo[3,4-d]pyrimidine-4,6-diones from different 6-aminouracils, aminothiouracils and glucopyranosyl isothiocyanate The rotational energy surface have been dscribed for the exocyclic hydroxymethyl group of a-D-2-amino-2-deoxyglucopyranose and of P-D-2-amino-2deoxygluco-pyranose using high-level ab initio methods These data definitively establish the potential energy surface along this coordinate in the gas phase Using geometry minimum by molecular mechanics (AMBER) and quantum mechanics (AMI), it showed that in N-acetyl-D-glucozamine, anomer P was more stable than anomer a in energy (when the influence of the solvent wasn't included in these calculations), and for both anomers the most stable configurations were the (E)-syn ones The structures of synthesized compounds have been confirmed using modem physical methods (IR-, ' H - and 'C-NMR and mass spectroscopies) Examination of anti-microorganism + Results in education: 04 bachelors of science + Publication: Five rearching articles have been reported: Nguyen Dinh Thanli, Dang Nhu Tai, Pham Hong Lan, 2005, Reaction of glucopyranosyl isothiocyanate with some 6-aminouracils and 6-amino-2-thiouracils, Journal of Chemistry and Application, N.9 (45), tr 24-27 Nguyen Dinh Thanh, Dang Nhu Tai, Mai Thi Thoa, 2005, Contribution to study on synthesis of some glucopyranozyl-amines containing thiazole and benzothiazole rings from 4,6'O'ethylidene-glucopyranose, Proceedings of the Third National Conference of Science and Technology in Organic Chemistry, Hanoi, 11/2005, pp 150-153 Nguyen Dinh Thanh, Dang Nhu Tai, Bui Ngoc Linh, 2005, Contribution to synthesis of some compounds contaning aromatic heterocycles thiazole and benzothiazole oflacetylglucosamine, Proceedings of the Third National Conference of Science and Technology in Organic Chemistry, Hanoi, 11/2005, pp 154-158 Nguyen Dinh Thanh, Dang Nhu Tai, 2005, Contribution to study on anomerism and tautomerism in glucosylhydrazine using quantum chemical methods AMI and PM3, Proceedings of the Third National Conference of Science and Technology in Organic Chemistry, Hanoi, 11/2005, pp 222-226 Nguyen Dinh Thanh, Dang Nhu Tai, Pham Nhat Quang, 2005, Contribution to study on the influence of conformation of acetyl group to stable confofmation of N-acetylD'glucosamine molecule Proceedings of the Third National Conference of Science and Technology in Organic Chemistry, Hanoi, 11/2005, pp 227-230 MUC LUC Trang M6DAU i + Muc tieu: + Noi dung: NQI DUNG CHINH A Tong quan 2.1 Tong quan ve glycozylamin 2.1.1 Danh phap 2.1.2 Tac dung sinh hoc cua glycozylamin 2.1.3 Phucmg phap tong hgp glucozylamin 2.1.4 Mot so tinh chat cua glucozylamin 2.2 Tong quan ve glycozyl isothioxianat 2.2.1 Giai thieu ve glucozyl isothioxianat 2.2.2 Phuang phap tong hgp glucozyl isoxianat/isothioxianat 2.3.3 Tinh chat hoa hoc ciia glucozyl isoxinat/isothioxianat B Phan thuc nghiem 2.3 Tong hgp cac 2-axetamido-2-deoxi-D-glucopiranozylamin (GlcNAcamin)) tir N-axetylp-D-glucozamin 2.3 Tong hgp 4,6-0-etyliden-D-glucopiranozylamin tij 4,6-0-etyliden-D-gIucoza (EtGIcamin) 12 2.4 Tong hgp 3-glucozylaminoisothiazolo[3,4-d]pirimidin (GAIP) tir glucoza 14 C Ket qua va ban luan 18 2.5 Tong hgp cac glucopiranozylamin (GlcNAcamin) tirN-axetyl-P-D-glucozamin 18 2.6 Tong hgp 4,6-O-etyliden-D-glucopiranozylamin (EtGIcamin) tir 4,6-0-etyliden-Dglucoza 19 2.7 Tong hgp cac hgp chat ciia 3-glucozylamino- isothiazolo[3,4-d] pirimidin 19 2.8 Phin tinh toan li thuylt 22 * Theo phuang phap AMBER: 24 * Theo phuang phap AMI 24 KET LUAN 25 TAI LIEU THAM KHAO 26 TOM T A T C A C CONG TRINH NCKH CUA CA NHAN 29 GIAI T H i C H CAC KY H I E U VA CHU* VIET T A T Me Metyl Et Etyl Bu-n n-Butyl Ac Axetyl EtGlc 4,6-0-Etyliden-D-glucoza ADGLCNAc N-axetyl-a-D-glucozamin BDGLCNAc N-axetyl-P-D-glucozamin GlcNAcamin 2-Axetamido-2-deoxi-D-glucopiranozylamin EtGIcamin 4,6-0-Etyliden-D-glucopiranozylamin Galamin Galactopyranosylamin GAIPl 2,3,4,6-tetra-0-axetylglucopiranozylaminoisothiazolo[3,4-d]pirimidin MODAU Nhu da biet, cacbohidrat thamgia vao phin ciia rat nhieu loai hgp chat hoa hoc thien nhien, tir cac duang dan co mat nhieu loai hoa qua nhu fructoza, cac disaccarit nhu saccaroza (duong mia) den cac polysaccarit nhu xenlulo, tinh bot, [l] Chinh vi the loai hgp chat da dugc nghien cim tir lau Mat khac, cac hgp chat tren ca sa cac monosaccarit co nhieu hoat tinh sinh hgc dang chu y [2,3,4], nhat la cac N-glucozit voi cac amin di vong (indol, quinolin, quinazolin, pyrimidin, imidazol, flavon) va da dugc quan tam nghien cuu ca ve mat ly thuyet ciing nhu thuc nghiem Cac monosaccarit thamgia phan cua nhieu hgp chat c6 hoat tinh sinh hgc, chang han, Ldaunozamin la hgp phan cua cac thuoc daunomycine va adriamycine, la hai loai thuoc manh dugc sir dung viec dieu tri cho benh nhan ung thu; L-vancozamin la hgp phan cua thuoc khang sinh vancomycine; sinigrin la mot S-glycozit va co donggop vao miii dac trung cua mil tat va tucmg hat cai; loai thuoc dugc sir dung rong rai nhat dieu tri benh nhan AIDS la zidovudine, cung dugc biet duoi ten ggi azidothymine, hay AZT (co ten hoa hpc la 3'-azido-2',3*-dideoxythimidin), va loai thuoc co hieu qua cao han hien la J^J (co ten hoa hgc la 2',3'-dideoxy-2',3'-didehidrothimidin), deu la cac Nglycozit ciia amin di vong chua nita la pirimidin va monosaccarit la dan xuat azit ciia ribofuranoza [6-11] Nhin chung, hoa hoc cacbohidrat chua dugc nhieu nha khoa hpc nuac nghien cim Trong mpt vai nam gan day da xuat hien mpt so cong trinh nghien cim ITnh vuc ciia cac tac gia Viet nam (xem tai lieu dan a duoi), song hau het la a ITnh vuc oligosaccarit hay polisaccarit, ma chii yeu la chi a mirc dp bien tinh cac polime Vi vay de tai ciia chiing toi co muc tieu va npi dung nhu sau: + Muc tieu: Tong hgp mpt so hgp chat glycozylamin c6 chira nhan di vong 1,3-thiazol va benzo-l,3-thiazol tren ca sa a-D-glucozamin clohidrat va D-glucoza Tong hgp mpt so dan xuat tir glycozyl isothioxianat va cac aminouraxin, aminothiouraxin khac Nghien cim (HN, CHTN-^H va '^C cua cac hgp chat tong hgp dugc Khao sat hoat tinh sinh hpc (hoat tinh khuan, khang nam) cua cac hgp chit t6ng hgp dugc Nghien cim moi quan he cau truc-tinh chat hay cau truc-hoat tinh bing viec sir dung cac phuang phap hoa lugng tir {ab initio, AMI, PM3, ).+ Noi dung: Nghien cim thuc hien phan ung cua D-glucozamin clohidrat va D-glucoza ciang nhu mpt so dan xuat ciia chiing vai mpt so 2-amino-1,3-thiazol va 2-aminobenzo-1,3thiazol Nghien ciai thuc hien cac phan img chuyen hoa tren ca sa cac hgp chit nhan dugc a tren Nghien cim moi quan he cau triic-tinh chat hay cau triic-hoat tinh bing cac tinh toan hoa lugng tir (aft initio, AMI, PM3, )hay ca hpc phan tir (MM+, AMBER, ) Cau true cua cac hgp chat nhan dugc se dugc xac nhan bang cac phuang phap vat ly hien dai (pho hong ngoai, cong huang tir hat nhan proton va cacbon-13 va kh6i lugng) Cac tinh chat sinh hpc cua cac chat tren se dugc khao sat bang cac phucmg phap chuyen mon NOl DUNG CHINH A Tong quan 2.1 Tong quan ve glycozylaniin 2.L1 Danhphdp Cac N-glycozyl dugc gpi ten la cac glycozylamin Trong truang hgp cac amin di vong phirc tap, nhu cac nucleozit, each gpi tuang tu dugc sir dung Vidu: ^^ Ten goi day dii: N-phenyl-P-D-glucopiranozylamin, Ten rut gon: N-phenyl-D-glucozylamin NH- OH \ 2.L2 Tdc dung sinh hgc cda / (khong goi Id anilin ^D-glucopiranozit glycozylamin Co mpt so rat 1cm cac hgp chat cacbonhydrat co chira nita Trong co nhi6u hgp chat CO nhieu cong dung dac biet Chung c6 nhieu hoat tinh sinh hpc quan trpng va glucozylamin cung la mpt cacbohidrat c6 chira nita co nhieu hoat tinh sinh hpc quan trpng 2.1.3 Phitomgphdp tong hpp glucozylamin Phuang phap thuong hay sir dung de dieu che glucozylamin la sir dung phan img ngung tu giira amin va duong khir dung moi metanol hoac etanol soi, c6 chira 10% lugng H2O va co mpt lugng nho axit lam xiic tac San pham tach duai dang tinh th6 sau cho bay hoi dung moi va lam lanh 2.1.4 Mot so tinh chdt cua glucozylamin Monosaccarit va dan xuat co cac cau true dang vong (furanozo, piranozo, septanozo) va dang khong vong Bang phuang phap nghien cim ciu true ciia cac andozylamin da chi rang dung dich, cac andozylamin ciing ton tai mpt can bing nhu tren tuong tu nhu cac monosaccarit Vi vay cac andozylamin c6 thi phan img tao cac dan xuat co the duai cac dang mach ha, hoac vong piran va fliran Su CO mat ciia nhom amin phan tir cua monosaccarit lam thay doi co ban tinh chat hoa hpc ciia no Khi xem xet cac tinh chat ciia glucoz\-lamin cin phan biet cac tinh chat von co ciia chung nhu tinh amin tinh chat dac trung ciia duong va nhijns tinh chat dac thii gay nen boi su tuong tac giua cac nhom hidroxi, amin, cac nhom thi Su ddo quay Sir dao quay cua cac glucozylamin co dugc la ton tai mot can bang xay su chuyen dich cac anome thong qua cac hgp chat trung gian khong vong bazo Schiff: CgHsNH CH H ^ HC—NHCgHs CgHgN^CH C—OH H H C—OH C—OH Doi vai cac glucozylamin khong nguyen tir hidro dinh voi nguyen tir nita thi CO the dugc giai thich la su hinh ion imonium khong vong viec tach mpt proton khoi ion amonium the: _(C6H5CH2)2N==CH (C6H5CH2)2NH—CH H H C—OH HC—N(C6H5CH2)2 H C—OH C—OH Su ddo quay moi truang axit Co che xay nhu sau: I HCNH2 HCNH2 HCNH' H2NCH + HA HCO HA HCOHA' HCO HCO —I I Su chuyen mpt cap electron tir nguyen tir nito ciia nhom amoni dan den su hinh ion imonium Tir dan den su chuyen tir dang vong den dang khong vong va ngugc lai Giira chiing co mpt can bang dugc hinh Sir ddo quay moi trudng baza Co che xav nhu sau: HCNi-^ HCNH HG=NH + B + BH.NCH HB ^ HjNCH -i-B ^ HCO HCO HC0- I HCO HCO I (1) Thuc chat bazo co it anh huong den tinh quay quang ciia cac glucoz>1amin vi nita it CO xu huong nhuang proton nen khong co sp (1) hoac co rat it can bang lech ve phia ben trai CONTRIBUTION TO STUDY ON SYNTHESIS OF SOME GLUCOPYRANOZYLAMINES CONTAINING THIAZOLE AND BENZOTHIAZOLE RINGS FROM 4,6-O-ETHYLIDENEGLUCOPYRANOSE Nguyen Dinh Thanh Dang Nhu Tai Mai Thi Thoa Hanoi University of Science, Vietnam National University Hanoi ABSTRACT Mot so hap chdt cua N-(henzothiazol-2-yl)-P-D-glucopyranosylamin va N-(4phenyhhiazol-2-yl)-p-D-glucopyranosyIamin da duac tong hap bdng phdn imggiica cdc 2amino-}, S-thiazol va 2-amino-1,3-benzothiazol ticang img vai 4.6-O-ethyliden-p-Dglucopyranoza Cdu true ciia cdc san pham duac khdng dinh bdng cdc phuang phdp vgt ly hien dai Nhom amino bac cdc phdn tu ndy co cdc ddc trirng nhu sau: bdng hdp thu cua dao dong hod tri cua nhom N-H a 3385-3299 cm'' hong ngoai vd tin hieu duplet a 8.34-8.54 ppm phd CHTN-H L INTRODUCTION Cyclic acetals and ketals play the important role in the synthetic chemistry of carbohydrates and widely utilized in specific protections for simultaneously two or more hydroxyl groups In particular, alkylidene derivatives of monosaccharides are formed from interaction of these ones or their derivatives with aldehydes or ketones in the presence of acid as catalyst [1-5] In all of alkylidene derivatives, the ethylidene ones of monosaccharides have received more attention than other particularly for the synthesis partially substituted sugars On the other hand, some derivatives of carbohydrate containing nitrogen include nucleic acids, coenzymes, polysaccharides, some virus components and some of the members of vitamin B group Furthermore, these compounds made up by union of proteins with carbohydrates are of possible wide occurrence and major biological importance [5-8] Contributing to researches in carbohydrate chemistry, in this article, some derivatives of 4,6-0-ethylideneglucopyranosylamines containing heterocyclic aromatic thiazole and benzothiazole rings have been synthesized RESULTS AND DISCUSSION 2.7 Synthesis of 4,6-0-ethylidene-D-glucose Derivative 4,6-0-ethylidene-D-glucopiranose has been synthesized by reaction between D-glucose and paraldehyde in the presence of sulphurc acid as calahst as described in reference [5] except the solid KOH has been used for neutralizing the obtained reaction solution 150 2.2 Synthesis of4,6-0-ethylidene-N-glucosylamines The 4,6-0-ethyIidene-N-glucosylamines containing thiazole and benzothiazole nng have been synthesized from 4,6-0-ethylidene-D-glucopyranose as following reactions: ^ H,C f^ H.N-4J1^\= Ri R,=H{I);CH3(11);C1(III) HX R|=H(IV);CH3(V);C00Et(VI) A simple procedure has been adopted to synthesize different N-glucosylamines of the partially protected glucose with different type of amines Glacial acetic acid has been used as catalyst for these reactions The amines were substituted 2-amino-4phenylthiazoles and substituted 2-aminobenzothiazoles Obtained N-glucosylamines were crystalline solid with high melting point, dissolving in common organic solvents (ethanol, DMF, dioxane, ) Their structures have been confirmed by using spectral methods (FTIR-, 'H-NMR-, '^C-NMR- and mass spectra) The formation of the N-glucosylamines was observed by comparing the FTIR spectra of the products I-VI with the spectra of the saccharide, 4,6-0-ethylidene-Dglucopyranose and the amines For example, when 2-amino-4-phenyl-l,3-thiazole reacted with the saccharide, the bands corresponding to the primary amine in region 3450 and 3320 cm" were absent, and that of the secondary was shifted to higher frequency due to the formation of the N-glucosylamines Table N-(4-phenylthiazol-2-yl)-4,6-0-ethylidene-D-glucopyranosylamines and N(henzothiazol-2-yl)-4,6-0-ethylidene-P-D-glucopyranosylamines No Compound m.p., T Yield, % VQH \'NH ^'C=0(esiei I 11 R|=H I, Ri=CH, III, R,-C1 IV, R2=H V, R2=CH, VI, R.^COOEt 180-182 136-138 170-172 193-194 239-240 228-230 30 28 35 38 40 38 3365 3308 3365 3466 3460 3365 3220 3114 3220 3275 3284 3299 - 151 ^TIR Spectra, cm"' - 1699 The vibrations corresponding to the anomeric properties of these Nglucosylamines were observed in the FTIR spectra Strong bands were observed for (Panomer,750-757 and 695-698 cm"'), (a-anomer, 737-745 cm"') indicating the presence of the corresponding anomers This is consistent with the observations made by NMR studies In FTIR-spectrum of 4,6-0-ethylidene-N-(benzothiazol-2-yl)-p-Dglucopyranosylamines and 4,6-0-ethylidene-N-(4-phenylthiazol-2-yl)-p-Dglucopyranosylamines, there were absorption bands in region 3460-3308 cm"' characterizing for stretching vibrations of OH-alcohol groups in carbohydrate part The secondary amino group had an absorption band in region 3299-3114 cm"' The C=C and C=N bonds in heterocyclic aromatic have been characterized some absorption bands in regions 1549-1528 and 1465-1464 cm"' (see Table 1) H-NMR spectra of these compounds were split into two remarkable regions, corresponding with two proton types in molecules of N-(benzothiazol-2-yl)-P-Dglucopyranosylamines and N-(4-phenylthiazol-2-yl)-P-D-glucopyranosylamines: aromatic protons in benzene ring (5H) and proton at position in thiazole ring (IH) had resonance signals in multiple lines in region 7.22-8.35 ppm; the protons in 4.6-0ethylidene-D-glucopyranose had magnetic resonance signals in region 1.24-5.30 ppm The protons of hydroxyl groups specified by the chemical shifts at 4.86-5.30 ppm, the protons in pyranose ring had signals in region 3.13-4.89 ppm, and methyl protons had chemical shifts at 1,07-2,51 ppm EXPERIMENTAL PART Melting point of the synthesized compound was measured by using Thiele's apparatus in capillary and uncorrected The FTIR-spectra were recorded on Magna 760 FT-IR Spectrometer (NICOLET, USA) in form of mixing with KBr and using reflexmeasure method at the Petrol-Chemical Center (Hanoi University of Science, VNU) The ' H - N M R was recorded on an AVANCE Spectrometer (BRUKER, German) at 500 MHz, solvent was DMSO-t/^, with the internal reference TMS (at the Room of Structural Analysis-Institute of Chemistry-Vietnam Academy of Sciences and Technology) General Methodfor Synthesis ofN-(4-phenyl-I,3-thiazol-2-yl)- and N-(} ,3-henzo-thiazol2-yl)- 4,6-0-ethylidene-N-glucopyranosylamines To a solution of 0.005 moi of substituted 2-amino-4-phenyl-l,3-thiazoIes or 2amino-l,3-benzothiazoles in 20 ml of absolute ethanol was added 0.005 moi (1.03 g) of 4,6-0-ethyliden-D-glucose Then 0.1ml of glacial acetic acid was added dropwise to obtained above solution The mixture was heating in the bath in 6-8 hrs After that, the solvent was evaporated in reduced pressure, filtered and cr}Stallized from 96% ethanol CONCLUSION Six derivatives of N-(benzothiazol-2-yl)-P-D-glucopyranosylamines and N-(4phenylthiazol-2-yl)-P-D-glucopyranosylamines have been synthesized from 152 corresponding substituted 2-amino-l,3-thiazoles and 2-amino-1,3-benzothiazoles and 4,6-O-ethyliden-P-D-glucopyranose Their structure has been confirmed using modem spectroscopic methods The secondary amino group in these molecules had specific spectral characteristics as following, an absorption band for N-H stretching vibration in region 3385-3299 cm'' in FTIR-spectra, a doublet signal for proton in NH group at 8.348.54 ppm Acknowledgment This publication is completed with financial support from the Asia Research Center and Grand QT-05-16, Vietnam National University, Hanoi REFERENCES J.A Mills, The Stereochemistry of Cyclic Derivatives of Carbohydrates, in Advance in Carbohydrate Chemistry, Vol 10 (1955), pp 1-53 G.P Ellis and Honeyman, Glycosylamines, in Advance in Carbohydrate Chemistry, Vol 10 (1955), pp 95-168 J.E Hodge, The Amadori Rearrangement, in Advance in Carbohydrate Chemistry, Vol 10 (1955), pp 169-205 A.N DeBelder, Cyclic Acetals of the Aldoses and Aldosides: Highlights of the Literature Since 1964 and a Supplement to the Tables, in Advance in Carbohydrate Chemistry and Biochemistry, Vol 34 (1977), pp 179-241 R.L Mellies, CL Mehltretter and CE Rist, Some Cyclic Acetals of D-Glucose and its Derivatives, J Am Chem Soc, Vol 73 (1951), pp 294-296 Mohamed A Saleh, Youssef A Abbas, Synthesis and antiviral evaluation of Nglycosides derived from 6-amino-3-aryl-2-metyl-4-(3H)-ciuinazolin(>nes, Nucleosides, Nucleotides & Nucleic Acids, Vol 20 N 10 & 11 (2001), pp 18911902 Mohamed A Saleh, Mohamed A Abdo, Mohamed F Abdel-Megeed & Gamal A El-Hiti, Amadori rearrangement of N-glucosides of 6- substituted 3-amino-2-aryl4(3H)-quinazolinones, Indian J Chem., Vol 35B, (1996) pp 147-150 T Mohan Das, Chebrolu P Rao, Erkki Kolehmainen, Synthesis characterisation of N-glycosyl amines from the reaction between 4,6-benzylidene-D-glucopyranose and substituted aromatic amines and also between 2-(o-aminophenyl)benzimidazole and pentoses or hexoses, Carbohydr Res., 334 (2001), pp 261-269 Tajmir-Riahi, H.A., Carbohydr Res., 190 (1989), pp 29-37 153 G O P P H A N T O N G H O P M O T SO D A N X U A T C H I T A DI VONG THOM T H I A Z O L VA B E N Z O T H I A Z O L CUA 2-AXETYLGLUCOZAMIN Nguyin Dinh Thanh, Dgng Nhu Tai, Bui Ngoc Lmh Khoa Hoa hoc, truang Dai hoc Khoa hoc Tu nhien, DHQG Hd noi ABSTRACT Some compounds of N-(4-phenylthiazol-2-yl)-2-acetamido-2-deoxy-PD-glucopyranosylamines and N-(henzothiazol-2-yl).2.acetamido-2-deoxy-^D-gl'ucopyranosyl ammes have been synthesized by interaction between 2-acetamido-2-deoxi-a-Dglucopyranosylamine and different substituted 2-aminothiazoles and ^aminobenzothiazoles in the presence of glacial acetic acid as catalyst The structures of obtamed products have been confirmed by the spectral data (!R- and 'H-NMR spectroscopies) The absorption bands at 3385-3299 cni^ specifying for the stretching vibrations of second amino group in glucopiranozylamine molecules, a double signal for proton in NH group at 8,344-8,534 ppm l.MdDAU Glucozamin la mpt aminomonosaccarit dugc su dung rong rai y hoc d^ lam thuoc dieu tri cac benh v^ xuoTig a nguai Da co nhieu nghien cuu chuydn hoa amin cac cac dan xuat khac [1-3] Trong bai bai bao nay, chiing toi tiln hanh nghien ciru tong hgp mot s6 dan xu4t N-glucozamin cua 2-axetamido-2-deoxi-glucopiranoza co chua cac nhan di vong thiazol va benzothiazol KET QUA VA THAO LUAN 2.7 Ve dieu che D-glucozamin hidroclorua tir vo torn vd chuyin hod 2- axetamidO'2-deoxi-/3-D'glucopiranoz(T Trong ban bao cao nay, chiing toi da su dung vo tom kho lam ngudn nguyen lieu dau de dieu che a-D-glucozamin, qua trinh tach chitin va thiiy phan nhu sau: Trong vo tom dugc su dung nhu la nguon nguyen lieu ban dau dugc mua tren thj truang co chua nhieu tap chat (nhu dau torn, thuc an nuoi tom sot lai, ), vay can phai loai bo cac tap chat truac decanxi hoa Cac loai tap chat tan nuac dugc loai bo bang each rua vo torn kho nhieu lan bang nuac Sau vo tom da rira sach dugc ngam dung dich NaOH 10% 24 gia a nhiet dp phong, rua sach va tiep tuc ngam dung dich HCl 2N de tien hanh decanxi hoa Su decanxi hoa can tien hanh tu tir de tranh sir mat mat sui bgt qua muc Phan can thu dugc mau trang hong dugc rira sach bang nuac va say kho de lay chitin tho Chitin tho dugc chuyen hoa tiep a-D-glucozamin ma khong can tinh che truac Sir thuy phan dugc tien hanh nha tac dung ciia axit clohidric dam dac tren noi each thuy soi su6t 2,5 gia Duai tac dung cua moi truang axit manh nhom axei\ chitin bi thuy phan ddng thai vai su phan each cac lien ket 1.4-glicozit phan tu chitin Trong ph6 h5ng ngoai ciia a-D-glucozamin clohidrat xuat hien cac bang song hap 154 thu rong 3100-3350 cm"' dac tnmg cho dao dong hoa tri ciia nhom NH^^ cac bang song hap thu a 1616 cm"' dac trung cho dao dong biSn dang khong d6i xiing va a 1394 cm-1 d§c trung cho dao dong bien dang doi xung ciia nhom Nhom hidroxi-ancol phan tu co cac bang song hap thu a 2393 cm"' dac trung cho dao dong hoa tri cua nhom -OH (hen hop gi&a cac phan tu), a 1250, 1184, 1140, 1116, 1093 va 1036 cm' dac ' Z I ' ^ I R Z ^ A " " ^ "'" t ^ ' T ^ : - " ^ ""g Ph^" t"; Nh6m CH, co cac hip thu d , ? \ ^ f 2-axetamido-2-deoxi-p-D-g]ucopiranoza (N-axetyi-p-D-glucozamin) dugc dieu che bang phuang phap axyl hoa chpn lpc a-D-glucozamin, nhom axy chi dl vao lien ket voi nguyen tu N ciia nhom amino, cac nhom hidroxi khong bi axyl hoa Tu a-D-glucozamin ban dau, sau phan ung axetyl hoa nhan duoc 2-axetamido-2deoxi-P-D-glucopiranoza (N-axetyl-p-D-glucozamin), nhu vay qua trinh phan ung da xay su anome hoa nhom hidroxi o Cl tir vi tri axial chuyin din vi tri equatorial dieu cung^phu hprp voi hoa lap the cua cac monosaccarit, vi su co mat cua cac nhom axetyl cong kenh gan voi nguyen tu nita lien kk vdi C2 lam cho can bang giua hai ddng phan a va p cua vong piranozo chuydn dich vk phia ben phai Trong phd hdng ngoai cua dan xuat N-axetyl-p-D-glucozamin, xuk hien cac bang sdng hdp thu d 3463 cm'' dac trung cho dao dpng hda trj cua nhdm NH, vach amit (bang sdng hip thu cua nhdm C=0 ) xuat hien a 1628 cm , vach amit II (bang sdng hip thu dao ddng bi6n dang cua NH va dao dpng_cua lien ket C-N) xuat hien d 1553 cm', ddng thdi cac bang sdng hip thu a 1616 cm va a 1394 cm dac trung cho dao ddng biln dang khdng ddi xung cua nhdm -NH2 bien mat Dieu chung td ring nhdm NH2 da bi axetyl hda Trong phd cdn xuit hien bang sdng hap thu d 3328 cm"' dac trung cho dao ddng hda tri cua nhdm hidroxiancol d trang thai lien hap (trang thai mlu rin), va su ving mat ciia cac bang sdng hip thii d viing 1710-^1750 cm"' (dac trung cho dao dong ciia nhdm cacbonyl este) chung td rang phan ung axetyl hda chpn Ipc d tren da chay tdt: cac nhdm hidroxi-ancol khdng bi axyl hda ma chi cd nhdm amino ciia a-D-glucozamin tham gia phan img San pham thu dugc la chat rin tinh thi cd mau tring, ndng chay d 203-205''C Hieu suit san phim dat 92-96% Dp quay cue rieng [a]D21 +42° (d diim can bing c 2, nude) 2.2 Tong hop mpt so glucozylamin tir cdc dan xudt cua thiazol vd benzothiazol vd Naxetyl-P-D-glucozamin Bang each cho dan xuat 2-aminothiazol va 2-aminobenzothiazol vdi N-axetyl-PD-glucozamin etanol 96%, thdi gian phan iing trung binh tir 30-50h se thu dupe cac san pham glucozylamin vdi hieu suit tuang ddi cao (50 - 60%) Phan ling la loai phan ung tach nude, nen thdng thudng thi phan img dugc tien hanh dung moi khan Nhung N-axetyl-a-D-glucozamin la chit it tan etanol nen neu tien hanh dung mdi etanol khan thi phan img xay d dang di the rat khd khan, chinh vi vay phan img dugc tien hanh dung mdi etanol 96° vira tao dieu kien cho phan img xay de dang vi hgp chat nam dung dich ddng thdi vdi ndng dp 96% khdng anh hudng den can bang loai nude ciia phan img Phan img can xiic 155 tac axit, thong thuong la axit axetic bang Bdng I Cdc hop chdt N-(4-phenylthiazol-2-yl)-2-axetamido-2-deoxi-/3-DglucopiranozylaminvdN-(benzothiazol-2-yl)-2-axetamido-2-deoxi-P-Dglucopiranozylamin ^^^ Cl r\ So TT NHAc (V) Hgp chat Dnc, °C Hieu suat,% I,R=H II, R=CH3 III, R=COOMe IV, R^COOEt 228-230 186-188 220-222 236-238 218-220 50 49 67 58 62 V GtcNAc = •NHGlcNAc R' ^^ 'S NHGlcNAc R=H (I), CH3 (II), COOMe (III), COOEt (IV) Pho long ngoai, cm'' VoH 3455 3459 3447 3365 3459 VNH 3326 3385 3362 3299 3327 Vc=o 1628 1628 1647 1650 1628 SNH 1549 1550 1562 1562 1549 Vc=0{este) 1698 1699 - Cau tnic cua cac N-axetylglucozylamin dugc xac nhan bang each ghi phd hdng ngoai va phd ' H - C H T N Trong phd hdng ngoai ciia cac N-(benzothiazol-2-yl)-2axetamido-2-deoxi-p-D-glucopiranozylamin va N-(4-phenylthiazol-2-yl)-2-axetamido-2deoxi-P-D-glucopiranozyl-amin cd cac bang sdng hap thu dac trung cho cac nhdm the cd mat phan tir: nhdm OH d 3459-3365 cm"'( VQH lien hgp); nhdm NH d 3385-3299 cm''; nhdm chiic amit cd cac hip thu vc=o (amit) d 1650-1628 cm''(vach amit I) va 5NH d 1562-1549 cm'' Ngoai phd cdn xuit hien mdt so bang sdng hap thu dac tnmg cho dao dpng hoa tri ciia lien kit C=C nhan di vdng thom d viing 1549-1528 va 1465-1464 cm'' Trong ' H-CHTN ciia cac glucozylamin ndi tren, cd hai viing tin hieu cdng hudng, tuang iing vdi hai loai proton phan tir: cac proton nhan thom benzen va nhan di vdng thiazol cd cac tin hieu cdng hudng nim viing 7.112-8,543 ppm; cac proton cua hgp phin cacbohidrat cd tin hieu cdng hudng d vimg 'lamin cd tin hieu a dang duplet o 8,344-8,534 ppm Ngoai phd CHTN cdn cd cac tin hieu dac trung cho cac nhom proton ciia cac nhdm metyl va etyl timg phan tu rieng biet III P H A N T H U ^ C N G H I E M Nhiet dd ndng chay duac bang phuang phap mao quan._ Pho hdng ngo^i duoc ghi t i n may phd FTIR Magna 760 (NICOLFT My) ta, Irung tam Hoa hoc Dau ^ ; ; ^ ; H ; T^Lg BHKHTN) bang J.ng^;.P-^^^^^ ^ - - - - ^ ^ ^ S X : vS c S t t i T l ^ r ^ S rPhon P,ian „.i Can true V,en Hoa boc 156 Vien Khoa hoc va Cong nghe Viet nam) 3,L Diiu chi a-D-glucozamin hidroclorua Phuang phap dihu che dugc ti^n hanh theo tai lieu [4] tu vo torn kho Phan ung thuy phan chitin tho dugc tien hanh theo tai lieu [5] 3.2 Tong hap 2-axetamido-2-deoxi-^D-glucopiranoz(r (N-axetyl-p-D-glucozamin Phan ung dugc ti^n hanh theo tai lieu [66] 3.2 Tong hop cdc N-(thiazol-2'-yl)- va N-(benzothiazol-2'-yl)-2-axetamido-2-deoxi-/3D-glucopiranozylamin Cho 0,005 moi 2-aminothiazol hay 2-aminobenzothiazol the va 0,005 moi (l,12g) N-axetyl-P-D-glucozamin da dugc nghien vao 25ml etanol 96° binh cau day tron dung tich 50ml Them vao 0,3ml axit axetic bang Hon hgp phan ung dugc dun hoi luu tren noi each thuy vai gia Cat loai V^^ lugng dung moi, sau lam lanh dung dich thi san pham tach duoi dang tinh the San pham dugc loc va rua bang etanol va lam kho ngoai khong Ket tinh lai tu etanol 96o Hieu suat 49-52% Ket qua tong hgp dugc dan bang KET LUAN Da t6ng hgp dugc hgp chdt cua day N-(4-phenylthiazol-2-yl)-2-axetamido-2deoxi-p-D-glucopiranozylamin va N-(benzothiazol-2-yl)-2-axetamido-2-deoxi-P-Dglucopiranozylamin b^ng phan ung cua 2-axetamido-2-deoxi-a-D-glucopiranozylamm voi cac hgp chdt 2-amino-4-phenylthiazol hoac 2-aminobenzothiazol the khac su CO mat cua xuc tac axit axetic bang CAu true cua cac san pham dugc xac nhan bing cac du kien phd hdng ngoai qua bang song hap thu a vung 3385-3299 cm d^c trung cho dao dgng hoa tri cua nhom amino bac hai Proton cua lien ket amit co tin hieu cong huang a 5,768-6,435 ppm Nhom amino bac cua glucozylamin co tin hieu cong huong a dang duplet a 8,344-8,534 ppm Cong trinh duac hoan thank vai su tdi tra kinh phi cua Tnmg tdm Ho tra Nghien cuu chau A (Dai hoc Qudc gia Ha Noi) vd Di tdi nghien cuu cap DHQG Ha Soi, ma so QT-05-16 TAI LIEU THAM KHAO Paul Fowler, Bruno Bernet and Andrea Vasella A ' H - N M R Spec^ros^^^ Investigation of the Acetam.do Group m ^^-^^^J"'''^^^^^^^^^^ Allosamine and D-Glucosamine Heiv Cl.m Acta 79 ^V_^^^^^^ ^^^ ^_ Karim Mazeau Serge Perez and Marguerite Rinaudo Pred ctcd intlucnu ol % '• ^Ty^ G ^ r C — on the - n ^ r m ^ a l F.ten.,on oi Chum and Chnosan Chains, J Carbohydr Chem 19 (9) PP^ - ^ f j " ^ ' , " Buyong Ma Henry F Schaeter III ^^^^^^J^^npotential energy surfaces and composuun, o1 157 j,,,,,,,,,,, , , , „ , , ,/„ a.ul P-kcol Am, Chem Soc, 120,3411-3422(1998) ^ ^ ^, , , , , , Nguyln Dinh Thanh Dang Nhu Tai, Dang Quoc Cuong, Gop phan nghien cuu tach 2-amino-2-dezoxi-a-D'glucoza tit vo torn, Tap chi Hoa hgc va Cong nghiep hoa chat, No.5, 8-10(1998) M Stacey and J.M Webber, Methods in Carbohydrate Chemistry, Reaction of Carbohydrates, vol.1 , Ed R.L.Wistler and M.L Wolfrom, Acad Press, N.Y., p 228-230(1962) D Horton, Methods in Carbohydrate Chemistry, General Carbohydrate Methods, vol.VI, Ed.'R.L.Wistler and J.N Bemiller, Acad Press, N.Y., p 224-225 (1972) 158 HOl NGHI KHOA HQC vA CONG NGHE HOA HlTU CO TOAN QUOC LAN THU' III GOP PHAN NGHIEN CUtJ ANH HU'ONG CAU DANG NHOM AXETYL DEN CAU DANG BEN CUA PHAN Tir N-AXETYL-D-GLUCOZAMIN Nguyen Dinh Thanh, Dgng Nhir Tai, Pham Nhdt Quang Khoa Hod hoc, tru&ng Dai hoc Khoa hoc Tic nhien, DHOG Ha noi ABSTRACT Using geometry minimum by molecular mechanics (AMBER) and quantum mechanics (AMI), it showed that in N-acetyl-D-glucozamine, anomer /? was more stable than anomer a in energy (when the influence of the solvent wasn V included in these calculations), andfor both anomers the most stable configurations were the (E)-syn ones LMdDAU Glucozamin la mot aminomonosaccarit dugc su dung rong rai y hoc dk lam thuoc dieu tri cac benh ve xuong a nguoi Da co nhi^u nghien cuu chuydn hoa amin cac cac dan xuat khac [1,2] Mot s6 tac gia da tiln hanh cac nghien cuu \h ckn dang cua glucozamin [3,5] cung nhu cac dan xuat N-axyl cua no [1,2,6] Mat khac nguoi ta da biet rang, axetamit va cac dan xuat N cua no co the ton tai cau dang khac mot can bang sir quay quanh cac lien ket C(H)-N va N-C(O) [1] Trong bai bai bao nay, chung toi tien hanh nghien cuu anh huong cua su quay den cau dang ben cua phan tu N-axetylglucozamin MO HINH TINH TOAN D6 nghien cuu c^u hinh cua nhom a.xetamido CH3C0-XH a phan tu N-axetyl-Dglucozamin chung toi da su dung phucmg phap co hoc phan tu AMI va AMBER dua tren ph4n m8m Hyper Chem 7.0 Vkn d§ vl cau hinh cua phan tu N-axetyl-D-glucozamin a day dac biet dugc chu y a cho, tuong tu nhu axetamit nhom axetamido co the a bon dang cau hinh la (Z)-anti va (Z)-syn, (E)-anti va (E)-syn (xem hinh 1) Danh phap (Z) va (E) dua tren su sip xep cua cac nhom the xung quanh lien ket N-C(O) danh phap syn va anti thi dugc xet theo su dinh huong xung quanh lien kit C2(H)-N cua nguyen tu hidro cua vong piranozo va nguyen tu hidro ha> cua nhom thi R tren nguyen tu nito-amino Khi vong exo nam cung phia voi nhom C=0 so voi lien kit C-N thi ta co c^u hinh Z \'a nim khac phia thi ta co cau hinh E danh phap s\n dc chi vi tri cua hai nguven tu hidro dinh voi C2 va N nim ciing phia voi va neu chung nim khac phia thi se duoc goi la anti Cac anome cua N-axetyl-D-glucozamm dugc ki hieu nhu sau: N-axetyl-a-D-glucozamin la ADGLCNAc N-axetyl-p-D-glucozamin la BDGLCNAc Tron^ cac tinh toan AMI d6i voi phan tu cau dang cua nhom hidroxylmetyl ngoai^ong doc theo lien kit C5-C6 la cau dang trans gauche [3.5] cac nguyen tu va o vi tri trans doi vol cac nguyen tu C4 va a vi tn gauche voi 227 HOnv/GHJ KHOA HQC VA rONG NGHE HOA HU'U CO TOAN QUOC L A N THU" III X N^ quay xung quanh N-C(O) H CH, CH3 I R R (E)-anti (Z)-anti quay xung quanh C(H)-N quay xung quanh C{H)-N quay xung quanh N-C(O) CH •N' H3C (Z)-syn ^0 (EJ-syn Hmh L Cdn bdng nhan duac bdng su quay quanh cdc lien kit C(H)-N vd N-C(O) a axetamit (R^Hhay CH3) KET QUA VA THAO LUAN Ket qua tinh toan nang lugng cua cac cau hinh tren dugc dan bang 3, hinh dang cua cac ciu dang nhan dugc sau t6i uu hoa hinh hoc duoc dan trons hinh 2a \a 2b ^ ADGLCNAc-(E)-anti ADGLCNAc-) E)-s\n ADGLCNAc-(Z)-ant ADGLLNAc-(Zi-i>n Hinh Cdc cdu hinh co the c6 cua nhom axetamit a \-axetyl-a-D-olueozamm hinh hoc bdng phmvig phdp AMh (tdi icu hod 228 i HOI NGHI KHOA HOC vA CONG NGHE HOA HUU CO TOAN QUOC LAN THIJ" III Dua vao bang s6 lieu tren ta co the so sanh nhu sau ve mat nang lugng cua cac cau hinh khac cua hai anome a N-axetyl-D-glucozamin * Theo phiromg phdp AMBER Ta nhan thay ring ca hai ciu hinh N-axetyl-a-D-glucozamin va N-axetyl-P-Dglucozamin dang (E)-syn co muc nang lugng toi thieu thap hon ca, dieu c6 nghia la cac dang co ciu hinh ben nhat Trong cau hinh N-axetyl-a-D-glucozamin (Z)-anti va ciu hinh N-axetyl-P-D-glucozamin (Z)-syn co muc nang lugng cao nhit, nhu vay chung se kem ben nhat Tuy nhien phuang phap AMBER chi tdi uu hoa vl mat hinh hgc (tuc la coi cac nguyen tu phan tu nhu nhiing qua ciu) do voi ciu hinh (E)-syn co su t6i uu nhat vai luc day giira cac qua cau nguyen tu BdngS The ndng phdn tu, ndng luang tuyet doi vd tuang doi cua cdc cdu hinh co the co cua N-axetyl-a-D-glucozamin vd N-axetyl-P-D-glucozamin tinh theo phuang phdp AMBER vdAMI Theo phucmg phap AMBER Cau hinh The nang E (kcal/mol) Theo phuong phap AMI AE (kcal/mol) Nhiet tao AH (kcal/mol) AG(kJ/mol) Anome a ADGLCNAc(E)-anti -22.752171 6.070927 -288.8976521 ADGLCNAc-(E)-syn -16.681244 -283.6751875 -0.0835 ADGLCNAc(Z)-anti -26.455299 9.774055 -288.7447276 | 19.9295 ADGLCNAc-(Z)-syn -23.277287 6.596043 -288.8210196 ' 0.8960 Anome (3 i -286.7690256 ' BDGLCNAc-(E)-anti -25.595922 4.663513 BDGLCNAc-(E)-syn -20.932409 i -283.0558053 -0.19549 BDGLCNAc-(Z)-anti -26.017303 5.084894 i -289.5734293 -0.62127 BDGLCNAc-(Z)-syn -36.684071 15.75166 -287.0747285 1.76128 * Theo phirffng phdp AMI Phucmg phap dugc sir dung sau phan tir da dugc toi uu hoa bang phucmg phap AMBER, do ma cau tnic t6i uu phuang phap se co chinh xac cao han Tuy vay theo ca hai phuang phap ta thiy su sai lech ve cau hinh ben nhat va kem bSn nh4t la'khong dang kk Dua vao bang s6 lieu va d6 thi ta thdy cau true anome-p va anome-a van se c6 c^u hinh bSn nh4t vai c4u hinh (E)-syn Sir triing lap ve ca cau hinh kem hkn nhat ciia N-axetyl-a-D-glucozamin (Z)-anti cang khang dinh them ve su dung dan cua hai phuang phap Tuy nhien dn hinh kem bin nhat theo phuong phap AMI cua N-axetylP-D-glucozamin lai CO chenh lech so vai su tinh toan theo phuang phap AMBER, dieu cung khong phai la v4n da quan trgng, chi la su sai khac phep toan cua moi phuang phap ma thoi 229 HQl NGH{ KHOA HQC vACONG NGHE HOA HU'U CO TOAN QUOC LAN THU' III Nhu vay, bing tfnh toan cu the chung toi da nhan thiy ring N-axetyl-D-glucozamin CO ciu hinh b^n nhit la ciu hinh (E)-syn Dieu co the dugc giai thich mot each don gian su diy giua cac nhom lan (coi Oxi la nhom lan lien k§t C-N cung voi vong exo) a ciu hinh (E) la be nhit, d6ng thai voi ciu hinh syn cua lien ket C2-N, nhom axetyl (CH3C0) cung khong bi tuang tac vai nhom hidroxi Cl Con tat ca cac cau hinh khac, sir tuang tac la dang ke, dac biet doi voi cau hinh (Z)-anti Tom lai, qua tinh toan nang lugng cua he bang phuong phap AMI cho thay cau hinh b§n nhat ciia nhom N-axetyl N-axetyl-D-glucozamin la N-axetyl-D-glucozamin (E)-syn KET LUAN Bang phuang phap toi uu hoa hinh hgc theo phuong phap co hgc phan tu AMBER va theo phuang phap co hgc lugng tu AMI, da nhan thay rang a phan tu N-axetyl-Dglucozamin, anome P ben hon anome a ve mat nang lugng (khi khong co anh huong cua dung moi) va doi voi cac anome thi cau hinh ben nhat la cau hinh (E)-syn Cong trinh duac hoan vai su tdi tra kinh phi cua Trung tdm Ho tra Nghien ciru chau A (Dai hoc Quoc gia Hd Noi) vd De tdi nghien cim cap DHQG Hd Noi, md so QT-05-16 TAI L I E U THAM KHAO Paul Fowler, Bruno Bernet and Andrea Vasella, A H-NMR Spectroscopic Investigation of the Acetamido Group in Some Derivatives of N-Acetyl-D-AUosamine and-D-Glucosamine, Helv Chim Acta., 79, pp 269-287 (1999) Karim Mazeau, Serge Perez and Marguerite Rinaudo, Predicted Influence ofN-Acetyl Group Content on the Conformational Extension of Chitin and Chitosan Chains, J Carbohydr Chem., 19 (9), pp 1269-1284 (2000) Nguyen Dinh Thanh, Dang Nhu Tai, Nghien cicu cdu dang phdn tu cua o.- va /]-D-2 amino-2-deoxiglucopiranoza bdng phuang phdp oh initio, Tuyen tap bao cao Hoi nghi Hoa hgc toan qu6c lin thu IV, Ha Noi 20/10/2003 tr.49-50 Buyong Ma, Henry F Schaefer III and Norman L Allinger, Theoritical studies of the potential energy surfaces and composition of the D-aldo- and D-ketohexoes J Am Chem Soc, 120 3411-3422 (1998) Nauven Dinh Thanh Dang Nhu Tai, Study on the molecular conformation of p-D-2amino-2-deoxyglucopiranose using ab initio method Tap chi hoa hpc 42(2) pp.2]> 220 (2004) , , Audra Vektariene, Arvydas Juodvirdis, G>tis Vektaris Substitution Efiects on Reactivity of N-Acyl-2amino-2-deoxyglucopyranoses Qucuumi Chemu^d Stu^ Fourth Intemational Conference on Synthetic Organic Chemistry (ECSOC-4, www.mdpi.org'ecsoc-4.html Sep 30- 2000 [A0046] 230 PHIEU DANG KY KET QUA NGHIEN ClTU KHOA HOC Ten De tai: TONG HOP V A CHUYEN HOA M Q T SO DAN XUAT CUA OrD-GLUCOZO VA a-D-GLUCOZAMIN Mas6: QT-05-16 Cor quan chu tri de tai: Truang Dai hgc Khoa hoc Tu nhien, DHQG Ha Noi Dja chi: 334 Nguyln Trai, Quan Dong Da, Ha Noi Dien thoai: (4) 858 4529; Fax: 858 5277 C Pho bien rong rdi [X] So dang ky De tai > Pho bien han che > Bdo mat Ngay / /2005 Ngay / /2005 Tom tat ket qua nghien ciru: Da tdng hgp dugc hgp chit 2-axetamido-2-deoxi-p-D-glucopiranozylamm tu N-axetyl-p-D-glucozamin va mot s& 2-aininobenzo-l,3-thia2oI hay 2-amino-l,3-thiazol th^ khac Da tong hgp dugc hgp chit 4,6-etyliden-P-D-glucopiranozyIamin tir 4,6etyliden-P-D-glucopiranoza va mot so 2-aminobenzo-l,3-thiazol hay 2-amino-1,3-thiazol th§ khac Da t6ng hgp dugc hgp chit 3-(tetra-(9-axetyl-a-D-glucopu-anozylamino)isothiazolo[3,4-d]pirimidin-4,6-dion khac tu cac aminouraxin, aminothiouraxin voi glucozyl isothioxianat Da nghien cuu be mat nang lugng quay doi vai nhom hidroximetyl n cua a-D-2-amino-2-deoxyglucopyranoza va P-D-2-amino-2-deoxygluco-pyr dugc mo ta bang each su dung phuang phap ab initio a cac muc li thuylt cao 66-31G(2d,lp), va nhan thiy ring su chuyin d6i qua lai de dang nhit pha km m ^.uc* cac cau dang TG va GT (trong ca hai truong hgp anome a va P) Da nghien cuu anh huang cau hinh cua nhom 2-axetamit din ciu dang bin cua phan tu N-axetyl-D-glucozamin bang phuang phap toi uu hoa hinh hgc theo phuang phap ca hoc phan tu AMBER va theo phuang phap co hgc lugng tu AMI, va da nhan thiy ring a phan tu N-axetyl-D-glucozamin, anome P ben hon anome a ve mat nang lugng (khi khong CO anh huong cua dung moi) va doi voi cac anome thi cau hinh bin nhit la ciu hinh (E)-syn Cau true ciia cac hgp chat da tong hgp dugc xac nhan bang cac phuang phap vat ly hien dai (pho hong ngoai, cong huong tu hat nhan proton va cacbon-13 va ph6 kh6i lirgng) Da thu hoat tinh khang khuan va khang nam cua mot s5 hgp chat da tong hgp duac I Kien nghj ve quy mo va doi tugng ap dung ket qua nghien cuu: • Viec gan ket phan tu monosaccarit co the lam tang kha nang kha nang phan ung ciing nhu tac dung sinh hgc cua cac dan xuat nhan dugc, van de can dugc nghien cuu them • Cac ket qua nghien cuu dong gop vao linh vuc hoa hgc cacbohidrat Chirc vu Chu nhiem Ditai Thu truong Co* quan chu tri de tai Ho va ten Nguyen Dinh Thanh Trdn Nghi Hoc ham, Hoc vi Pho Giao su, Tien sy GS Tien sy Chu tich Hoi dong danh gia chfnh thuc Thu truong Co quan quan ly De tai KiLjih Iko^i I hdi :7^^; " ^ ... dinh ddi voi P -D- glucopiranozylamin la rat nhd, dieu dd chung td toan bd san pham thu dugc d dudi dang P-anome Phan img dugc tien hanh dung mdi la etanol tuyet ddi, dun ndng, dd ca amin va dan... nhdm axetamit a N-axetyl-a -D- glucozamin hod hinh hoc bdng phuang phdp AMI) 23 (tdi iru Bdng The ndng phdn tic, ndng luang tuyet ddi vd tucmg ddi cua cdc cdu hinh cd thi cd ciia N-axetyl-a -D- glucozamin. .. d dang p Dd cd the la mdi trudng axit su ddi quay ciia D- glucozylamin diln rat nhanh va nhat la nhdm the cd the tich Idn N-thiazolyl hay N-benzothiazolyl Su thay ddi ve dp dao quay xac dinh ddi