Trng i hc Khoa hc T nhin Thnh ph H Ch Minh Khoa Ha Chuyn ngnh Ha Hu c

Seminar Tng hp Hu c

TNG HP TON PHN (-)-OVATOLIDE

HO O O NH HO OH O O

HO

H v tn sinh vin: Ng Th Chu Ng MSSV: 0914148 Gio vin hng dn: Tn Hong Nm hc: 2012-2013

MC LC Li m u3 1.Gii thiu4 2.Tng hp5 Kt lun10 Ti liu tham kho..11

LI M U Hp cht hu c l cc hp cht ha hc m trong phn t ca chng c cha cacbon, ngoi tr cc cacbua, cacbonat, cacbon oxit (monoxit v dioxit), cyanua. Cc hp cht hu c c tm quan trng to ln trong mi lnh vc ca i sng. Qu trnh tng hp cc hp cht hu c l qu trnh chuyn ho t mt hp cht ny thnh mt hp cht khc di tc dng ca cc tc nhn phn ng v iu kin phn ng. Cc hp cht hu c phc tp hn nhiu so vi cc hp cht v c, do vic tng hp cc hp cht hu c pht trin thnh mt trong nhng ngnh rt quan trng ca ha hc hu c. Bi seminar ny xin c gii thiu v tnh cht, ng dng v phng php tng hp (-)-ovatolide.

1.Gii thiu: (-)-Ovatolide l mt dn xut -glucosyl thuc nhm indole alkaloid (indole - C6H4(CHNH)CH l sn phm phn hy ca tryptophan)[1] c 4 vng trong phn t, trong c 1 vng 8 cnh ether-lacton[2,3]. (-)-Ovatolide c phn lp t l cy Bridelia ovata Decne hoc Bridelia siamensis Craib (Euphorbiaceae), mt loi tho mc ca Thi Lan c s dng lm thuc nhun trng, thuc h st v cht lm se trong y hc dn gian[1][2]. Chp X quang tinh th (-)-ovatolide cho thy cu trc phn t cha -glucoside l mt phn ca h thng pyrano[2,3-b][1,4]dioxocane c gn vo v tr C3-C4 ca nhm indole[1].
4 5 2 6 7 3

O OH N H NH2

N H
1

Indole

Tryptophan
HO

HO HO

O
HO

O NH

OH OH beta-glucosyl

HO OH

O O

(-)-Ovatolide

(-)-Ovatolide l cht rn, kt tinh nhit thng do c O trong phn t, trn nguyn t N cn i in t t do nn c tnh baz yu, tan c trong nc nh hnh thnh lin kt hidro gia cc nhm OH trong phn t vi cc phn t nc. Do nhng im c bit trong cu trc cng vi nhu cu mt lng ng k (-)-ovatolide dng lm nguyn liu trong nghin cu sinh hc (mt kg l kh

ch phn lp c vi milligram (-)-ovatolide)[1] nn vic tng hp (-)-ovatolide l thc s cn thit. 2.Tng hp[1]: Phng php tng hp ton phn (-)-ovatolide c pht minh bi Delgado v Clardy vo nm 1992[1][2]. Phn tch tng hp ngc (-)-ovatolide dn ra hai phng php (A v B), c hai u c mt bc quan trng l xy dng h thng pyrano[2,3-b][1,4]dioxocane t dn xut glucoindole.
(-)-Ovatolide A B RO RO RO RO RO O O OH O OH OR N H (1) N H (2) HO HO O O OR OR

Phng php A to ni ester u tin, sau vng 5-oxo-heptanolide c hnh thnh t phn ng ceton ha. Cn trong phng php B, chui phn ng hnh thnh cc lin kt c tin hnh ngc li. Trong phng php A, glucoside (5a) c ngng t vi acid 4(benzyloxy)indole-3-carboxylic (3). Mc d vn ha tan (5a) cn tr s ngng t nhng dn xut N-benzyl (4) ca acid kh nng to ra ester (6) vi hiu sut va phi. Sau , s kh bo v hon ton v cetan ha (6) c thc hin ng thi. Tuy nhin vic kh nhm benzyl trong mi trng acid khng th to ra sn phm cetan ha, m thu c mt hn hp nhit ng ca hemicetan (8). Hn hp ny khng thay i khi tip xc vi mi trng acid nhit thng trong mt thi gian di, v b phn hy hon
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ton nhit cao. Do phi s dng mt phng php khc, l thc hin cetan ha ni phn t sau kch hot nhm hydroxyl amenoric ca (9) bng phn ng Mitsunobu. Nh vy, s ngng t indole (4) vi ng (5b) s cho ra (7) sau loi b nhm benzyl v tr ortho ra khi glucoindole (9). X l (9) vi Ph3P-DEAD trong THF cho ra mt hn hp t l xp x 1:1 hai ng phn carbon anomer (10) vi hiu sut c lp khong 30%. Mc d phng php ny c th to thnh h thng pyrano[2,3-b] [1,4]dioxocane nhng hiu sut khng cao v kh c lp cc ng phn (10).
RO RO RO COOH O OBn HO 5a. R=Bn 5b. R=TBS N R 3. R=H 4. R=Bn Ph 1. 4, 2,4,6-trichlorobenzoyl chloride/THF 2. 5a or 5b, DMAP, benzene, reflux N 6. R=Bn 7. R=TBS RO RO O O RO O OBn

BnO

OBn

RO O Hydrogenolysis RO RO O O OH Mitsunobu (from 9) TBSO OH TBSO O N O N Ph 8. R=Bn 9. R=TBS 10 Ph TBSO O O

Phng php B da vo phn ng kim sot vng v phn ng kim sot lp th m vng epoxide ca 1,2-epoxyglycals. Phn ng gia 4hydroxy-5(benzyloxy)indole (17) vi epoxyglucal (18) gip hnh thnh lin kt -glucosyl da trn s chn lc vng v lp th, t khc phc c mt trong nhng nhc im ln ca phng php A.
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Nitrat ha 2,3-bis(benzyloxy)benzaldehyde (11) c mt hn hp dn xut 5- v 6-nitro, tch bng sc k ct. Monodebenzyl ha ng phn 6-nitro (12) cho ra (13), sau thc hin acetyl ha ri ngng t vi nitromethane, tip tc dehydrat ha to ra dinitrostyrene (15), tin hnh phn ng hon nguyn to vng (15) c mt silica gel v Fe/AcOH to thnh acetylindole (16).
OBn BnO CHO HNO3, H2SO4 NO2 11 MgBr2/Et2O 12. R=Bn 13. R=H 14. R=Ac Ac2O, NaOAc BnO OR CHO i) CH3NO2, KF, 18-c-6 ii) Ac2O, NaOAc

OAc BnO NO2 15 NO2 Fe, SiO2, AcOH

OR BnO N H NaOH-Na2S2O4 16. R=Ac 17. R=H

Kh bo v acetylindole (16) trong dung dch nc NaOH-Na2S2O4 v ngng t vi (18) trong DMF-H2O to ra dn xut glucosyl (19). Phn ng ca indolylglucoside (19) vi TFFA trong DMF ti 0oC trong 1 gi cho ra dn xut bis(trifluoroaccetyl) (20) vi hiu sut cao ( khong 80%). Trong cc bc phn ng tip theo vi NaHCO3, c th xut hin sn phm thy phn (21). Tuy nhin c hai sn phm (20) v (21) u c th s dng cho bc tng hp k tip.

BnO BnO BnO O BnO BnO 18 O 16 DMF-H2O BnO HO

OBn

O O

TFAA, DMF

N H 19 BnO BnO CF3COO O O BnO N H 20 N H 21 CF3 O BnO base work-up HO O O CF3 O OBn BnO BnO OBn

Nhm [(trimethylsilyl)ethoxy]-methyl (SEM) c s dng bo v NH indole. Thc hin alkyl ha (20) v (21) 50C vi NaH trong THF c s hin din ca SEMCl thu c (22) vi tinh khit v hiu sut cao (75%). Tin hnh phn ng gia (22) vi NaH trong dung dch DMF 2% to hydroxyl acid (23) vi tinh khit v hiu sut cao (79%). S dng phng php lacton ha to vng cho (23) s thu c h thng 5-oxoheptanolide (24) vi hiu sut 70-75%. Loi b nhm SEM bng 1.0M Bu4NF trong THF cui cng tin hnh hydrogen phn (Pd(OH2), EtOAc, AcOH) s thu c (-)ovatolide vi hiu sut 73%.

BnO BnO HO

OBn

BnO BnO

OBn

20 NaH, THF, SEMCl 21 50C

O O CF3 O

NaH, DMF-H2O 50 C
0

HO

O HO O O

BnO N 22 SEM

BnO N SEM 23

BnO O O N BnO OBn 24 BnO O O NH BnO OBn O O HO HO OH O HO O NH O O (-)-ovatolide O O SEM Bu4NF, THF

lactonization

BnO

BnO

Pd(OH)2, EtOAc AcOH

KT LUN C hai phng php tng hp v cc hp cht t nhin c trnh by trn y c c tnh vt l ging nhau, do chng minh c cu trc xc thc ca (-)-ovatolide c mt phn gn lin vi (-)-glucose. Cc nghin cu sinh hc ang c thc hin xc nh dc tnh ca (-)-ovatolide vi hy vng s c nhiu ng dng hu ch trong y hc.

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TI LIU THAM KHO [1] Antonio Delgado, Jon Clardy. Total synthesis of (-)-ovatolide. Journal Organic Chemistry. Volume 58. Page 2862-2866. 1993. [2] Helena M. C. Ferraz, Fernanda I. Bombonato, Myrian K. Sano, Luiz S. Longo Jr. NATURAL OCCURRENCE, BIOLOGICAL ACTIVITIES AND SYNTHESIS OF EIGHT-, NINE-, AND ELEVENMEMBERED RING

LACTONES. Quim. Nova. Volume 31. No. 4. Page 885-900. 2008. [3] E. Soepadmo, Cornelis Gijsbert Gerrit Jan Steenis. Flora Malesiana: Spermatophyta, Flowering plants. Volume 8, part 2, Revisions, Ulmaceae. Page 304. Sijthoff & Noordhoff International Publishers. 1977. The Netherlands.

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