43 IChO 2011: The Preparatory Problems

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THPT Chuyn Lng Vn Chnh

Problem 29 : -amino acid mch h Trong nhng nm gn y, -amino axit mch h thu ht s ch , c bit l sau vic n c cng nhn l mt phn quan trng ca cc hp cht trong vic thit to v tng hp cc loi thuc dc phm tim nng nh Taxol (paclitaxel) v cht tng t l Taxotere (docetaxel), hin ang c coi l mt trong nhng thuc quan trng nht cho iu tr ung th bng ha tr. Ngun cung duy nht ca Taxol l v ca cy thy tng Thi Bnh Dng, Taxus brevifolia, nhng n cha hm lng Taxol tng i thp. Trong n lc khc phc vn ngun cung ny, cc nh ho hc nghin cu da trn s bn-tng hp. Nhng phng php ny lin quan n vic tng hp khp ni ph, side-chain coupling vi C13-OH nh d dng c sn cc dn xut ca Baccatin III nh c a ra di y, c th c phn lp vi nng sut cao hn t u kim chch ca cc loi Taxus khc nhau (v d nh Taxus baccata).

a) Qu trnh tng hp racemic ca chui bn, side-chain, bt u bi s chng ct hi lu benzaldehyde vi p-anisidine trong toluene kh nng to hp cht A. Phn ng tip theo ca hp cht A vi acetoxyacetyl chloride, c mt triethylamine cho ta hn hp racemic ca cc hp cht cyclic B1 v B2 vi cng thc chung l C18H17NO4. Hn hp sn phm racemic ca B1 v B2 b enzyme phn gii bng cch s dng Lipase (Amano PS). Lipases cng c bit r l cc cht xc tc sinh hc thy phn cc n v ester. H thy phn chn lc ch mt enantiomer ca hn hp racemic. Sau khi thy phn, mt hn hp gm B1 (l enantionmer khng phn ng) v C (sn phm thy phn) tch ra. B1 c cu hnh tuyt i 3R, 4S trong khi , C c 3S, 4R.
O H + OCH 3 p-anisidine Lipase (Amano PS) pH 7 NH 2 toluene reflux O AcO Cl

A
N(Et)3 , CH2 Cl2

B1

B2

racemic mixture

B1

V cu trc ca cc hp cht A, B1, B2, C vi cc lp th ng c p dng.

43 IChO 2011: The Preparatory Problems

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THPT Chuyn Lng Vn Chnh

b) Nhm hydroxyl ca hp cht C c bo v vi triethylsilyl chloride, c mt pyridin v 4dimethylaminopyridine (DMAP) to ra hp cht D. X l D vi ammonium nitrate xeri (IV) (CAN), mt thuc th kh thi cho vic oxy ha ct lin kt N-aryl, ri trung ha vi dung dch NaHCO3 to ra sn phm chnh mong mun E. Cht ch -lactam N-unit c bo v vi bis(tert-butyl)dicarbonate (Boc)2O sinh ra hp cht F. Trong bc cui cng, Baccatin III cha chuyn ha c kt hp vi F c mt NaH trong THF.

Cl

Si

C
Pyridine, DMAP CH2 Cl2

i) (NH 4) 2Ce(NO 3) 6 (CAN) ii) NaHCO3

E
O O O O O

((Boc) 2O)

Baccatin-III-O G

Baccatin III-OH NaH, THF

V cu trc ca hp cht D, E, F v G vi lp th chnh xc.