TLTN-2015 GVHD:TS. L Vit Tin

8Phn 1:TNG QUAN

81.1GII THIU DIPTEROCARPOL

81.1.1Ngun gc

111.1.2Cu trc ha hc.

111.1.3Danh php.

111.1.4Tnh cht vt l:

121.1.5Cc sn phm c tng hp t dipteroarpol.

141.2MT S PHN NG TRN MCH NHNH CA DIPTEROCARPOL.

141.2.1Phn ng oxi ha to lacton.

181.2.2Phn ng trn nhm OH.

191.2.3S to thnh ester.

191.2.3.1Phn ng ester ha Fischer gia acid carboxylic v alcol di s hin din ca acid v c.

201.2.3.2Phn ng t clorur acid

211.2.3.3Phn ng t anhydrid acid

221.2.3.4Phn ng t nitril.

221.2.4S to thnh eter.

221.2.4.1Tch nc ca alcol bng mt acid proton mnh.

221.2.4.2Tng hp Williamson

231.2.5Phn ng tng hp epoxid.

25Phn 2:THC NGHIM

252.1HA CHT, THIT B V DNG C TH NGHIM

252.1.1Ha cht:

252.1.2Dng c:

262.1.3Thit b:

262.2THC NGHIM

262.2.1iu ch 20(s)-hydroxydammar-24-en-3-ol.

262.2.2iu ch 20(s)-hydroxydammar-24,25-epoxyl-3 -ol.

272.2.3iu ch 20(s)-hydroxydammar-24,25-epoxy-3- p-toluenesulfonyl.

28Phn 3:KT QU V BIN LUN

293.1Kh nhm carbonyl vng A.

333.2Epoxid ha lin kt i C=C trn mch nhnh.

383.3Tosyl ha nhm OH vng A.

47Phn 4:KT LUN

Danh mc:9Hnh 1.1: Hnh dng cy l v qu ca cy du ri

10Hnh 1.2: Dammarendiol

10Hnh 1.3: Ocotillol

10Hnh 1.4: Dammardienon

10Hnh 1.5: Dipterocarpol

11Hnh 1.6: Cu trc Dipterocarpol

14Hnh 1.7: Mt s dn xut ca dipterocarpol

16Hnh 1.8: Monomer

17Hnh 1.9: Dimer

18Hnh 1.10: Phn ng lacton

20Hnh 1.11: Ester ha Fischer

20Hnh 1.12: Phn ng acil ha to ester

23Hnh 1.13: Phn ng tng hp epoxid

28Hnh 3.1: Mt s dn xut ca dipterocarpol

31Hnh 3.2: C ch phn ng to alcol dipterocarpol

32Hnh 3.3: Hp cht alcol dipterocarpol

35Hnh 3.4: C ch phn ng to epoxid dipterocarpol

36Hnh 3.5: Hp cht epoxid dipterocarpol

40Hnh 3.6: Trang thi cng hng tosyl clorur

42Hnh 3.7: C ch phn ng tosyl ha

43Hnh 3.8: Hp cht 3-tosyl epoxy dipterocarpol

Danh mc:

15Bng 1.1: Mt s phng php tng hp lacton

16Bng 1.2: T l sn phm thay i theo n.

20Bng 1.3: to thnh benzanilid t anilin vi cc tc cht khc nhau

29Bng 3.1: Mt s tc nhn cung cp hidrur

32Bng 3.2: D liu 1H ca 3-alcol dipterocarpol

37Bng 3.3: D liu 1H ca vng epoxy dipterocarpol

38Bng 3.4: D liu 13C ca vng epoxy dipterocarpol

44Bng 3.5: D liu 13C ca vng epoxyl dipterocarpol

45Bng 3.6: D liu 1H ca vng epoxy dipterocarpol

Danh mc:51Ph lc 1: Ph 1H NMR ca dipterocarpol

52Ph lc 2: Ph dn 1H NMR ca dipterocarpol

53Ph lc 3: Ph dn 1H NMR ca dipterocarpol

54Ph lc 4: Ph 1H NMR ca 3-alcol dipterocarpol

55Ph lc 5: Ph dn 1H NMR ca 3-alcol dipterocarpol

56Ph lc 6: Ph 1H NMR ca 3-alcol epoxy dipterocarpol

57Ph lc 7: Ph dn 1H NMR ca 3-alcol epoxy dipterocarpol

57Ph lc 8: Ph dn 1H NMR ca 3-alcol epoxy dipterocarpol

58Ph lc 9: Ph 1H NMR ca 3-tosyl epoxy dipterocarpol

59Ph lc 10: Ph dn 1H NMR ca 3-tosyl epoxy dipterocarpol

60Ph lc 11: Ph dn 1H NMR ca 3-tosyl epoxy dipterocarpol

61Ph lc 12: Ph 13C NMR ca 3-tosyl epoxy dipterocarpol

62Ph lc 13: Ph dn 13C NMR ca 3-tosyl epoxy dipterocarpol

63Ph lc 14: Ph dn 13C NMR ca 3-tosyl epoxy dipterocarpol

LI CM N Em xin t lng bit n su sc n thy L Vit Tin tn tnh hng dn em trong thi gian qua.

Em xin cm n ch Phan Thanh Tho, cc anh ch v cc bn chung phng lab gip em trong qu trnh lm thc nghim.

Em xin gi li cm n n cc thy c khoa ha tn tnh ch dy trong nhng nm thng ngi trn ging ng gip em trao di kin thc c th hon thnh tt bi tiu lun ny.

Mt ln na em xin gi li cm n n tt c v xin chc qu thy c li chc sc khe v thnh cng trn s nghip ca mnh. Chc cc anh ch v cc bn sc khe v thnh cng trong cng vic.

Trn trng cm n

TP.HCM ngy 22 thng 07 nm 2015

SV: V Thnh LunM UTrong tng hp hu c, nghin cu v m rng kh nng ng dng ca mt hp cht bt k, ngi ta to ra nhiu dn xut khc nhau bng s bin i a dng trn cht . Bin i c th l s oxid ha, s kh, ester ha v thng c tin hnh trn cc nhm chc nh carbonyl, hydroxyl, amin, aldehyd hay bin i t nhm chc ny sang nhm chc khc hot ng hn.

Dipterocarpol l mt tritepen chim hm lng cao trong nha cy thuc h Sao du (Dipterocarpaceae). Vi cu trc mch nhnh l alkenol, dipterocarpol c th cho nhiu phn ng nh ng vng alkenol to thnh lacton, phn ng trn alken v alcol. Trn vng A ca lacton cn nhm carbonyl c th chuyn ha thnh vng epoxid.Trong ti ny, chng ti tm hiu phn ng bin i nhm carbonyl trn vng A ca dipterocarpol thnh dn xut hydroxyl v tosylat, ngoi ra lin kt i trn mch nhnh c chuyn ha thnh dn xut epoxyl.Phn 1: TNG QUAN1.1 GII THIU DIPTEROCARPOL1.1.1 Ngun gc[1]Dipterocarpol l mt hp cht c tm thy trong nha du ca cc cy h Du (qu hai cnh) (Dipterocarpaceae). c bit, trong cc cy thuc ging du ri (Dipterocarpus), dipterocarpol chim hm lng rt cao (gn 50%)[1].

Hnh 1.1: Hnh dng cy l v qu ca cy du ri Vit Nam, cy h Du phn b t Bc n Nam nhng ph bin nht l cy du ri hay cn gi l du con ri trng hay du nc (l loi Dipterocarrpus alatus)[2]. V th Vit Nam, dipterocarpol ch yu c c lp t nha du (oleresin) tch t cy du ri[1].

Cc loi cy thuc h Sao du c cng dng trong cng nghip: lm sn bo v tu, lm mc in y hc: tr au nhc, l lot...

Nm 1966, G. Ourisson v Biset nghin cu phn cn ca nha cy thuc h Sao du, kt qu trong nha chai c 4 thnh phn ha hc chnh: dammadienon, ocotillol, dammarendiol v dipterocarpol. Trong , hp cht chim hm lng cao nht l dipterocarpol.

Hnh 1.2: Dammarendiol

Hnh 1.3: Ocotillol

Hnh 1.4: Dammardienon

Hnh 1.5: Dipterocarpol1.1.2 Cu trc ha hc.Dipterocarpol l mt tetracyclic triterpen (dammaran) gm 4 vng A, B, C, D, vi vng A cha nhm C=O ti C3 v mt dy nhnh cha mt nhm OH gn trn C20 v mt ni i C=C u mch.

Cng thc phn t: C30H50O2

Hnh 1.6: Cu trc Dipterocarpol1.1.3 Danh php. [2]Tn thng thng: Dipterocarpol, Hydroxydammarenon II.

Tn IUPAC:(5R,8R,9R,10R,14R)-17-((S)-1-hydroxy-1,5-dimetyl-hex-4-enyl)-4,4,8,10,14-pentametyl hexadecahydrocyclopenta[A]phenanthren-3-on, 20 hydroxy-3-oxodammar.

1.1.4 Tnh cht vt l[3]:

Dipterocarpol l mt cht rn mu trng, tinh th hnh kim.

Dipterocarpol khng tan trong nc v alcol lnh. N tan tt trong alcol nng, benzen, cloroform, dietyl eter.

Cng thc phn t: C30H50O2Trng lng phn t: 442.70 g/mol

Nhit nng chy: 135 1360C

1.1.5 Cc sn phm c tng hp t dipteroarpol[5] [9].

Cc sn phm tng hp t dipterocarpol rt a dng v dipterocarpol mang nhng nhm linh hot d dng bin i nh nhm ceton, alcol, alken.

Cc sn phm bin tnh t dipterocarpol ch yu c hot tnh sinh hc vi kh nng chng vim ng dng trong y hc.

T dipterocarpol c th cho ra nhiu dn xut khc nhau nh:

- To dn xut epoxyd bng cch cho phn ng vi m-CPBA sau thy phn

trong acid cho ra sn phm l diol.

- To dn xut lacton bng tc nhn O3, CH2Cl2.

- Bin tnh vng A bng cc tc nhn nh NaBH4 hoc phenylhydrazyn.

Dipterocarpol v mt s dn xut ca n cng mang nhng hot tnh ca cc hp cht triterprnoid c khung dammaran nh hot tnh khng vim, khng virus typ A v typ B. Trong hp cht 24-metyl-20(S),24(R)-epoxydammaran-3-one c coi l hp cht c tnh khng virus mnh nht. Tuy nhin, hp cht ny chim hm lng rt t trong thc vt. Trong khi , dipterocarpol chim hm lng cao hn v t n chng ta c th tng hp cht 24-metyl-20(S),24(R)-epoxydammaran-3-one mang li tim nng c th tng hp ra nhiu hp cht c tnh khng vim vi lng ln.

Mt s kho st hot tnh ca dipterocarpol v dn xut ca n c thc hin:

- Kho st tc dng khng vim cp tnh trn chut nht trng.

Ngi ta tim vo gan bn chn chut nht hp cht gy vim, sau chn nhng con c th tch chn b sng ph 50-100% tin hnh th nghim. Tip theo cho chut ung cc dung dch c pha dipterocarpol v cc dn xut khc ri theo di mc sng ph chn chut. Kt qu cho thy dipterocarpol v cc dn xut u c hot tnh khng vim nht nh.

- Kho st hot tnh khng u trn t bo[5] Ngi ta nui ly t bo ca cc khi u, cc khi u ny c ly trn cc b phn khc nhau ca c th nh gan, phi, thn... Sau cc t bo ny c nui dng pht trin, trong qu trnh nui dng ny ngi ta thm vo mi trng nui cc dn xut khc nhau ca dipterocarpol. Kt qu cho thy tc tng trng ca cc mu t bo khi u c thm dn xut th b chm li rt nhiu. T c th kt lun cc dn xut ca dipterocarpol trn c kh nng c ch s pht trin ca t bo ung th.

V vy, chng ti hi vng c th tng hp thm nhiu dn xut khc ca

dipterocarpol vi nhng hot tnh khc, c th cho nhiu ng dng trong y hc.14-dimetyl-18-nortestosteron sau khi c Crabe nghin cu tng hp vo nm 1958 tuy cha mang li nhiu ng dng to ln nh mong i nhng y c xem l mt trong nhng nortestosteron c tng hp u tin m dng cho vic nghin cu cc nortestosteron khc c nhiu ng dng hn trong y hc gip ci thin cc tnh hnh sc khe ca con ngi.

Sn phm bin tnh amin mang li nhiu gi tr nghin cu cng nh thc tin vi kh nng chng vim da. S tng hp bin tnh amin cho hiu sut cao ng mong ch.

Phng php gn cc bin tnh ca dipterocarpol vo polymer mang li nhiu ng dng a dng cho vic ko di cc tc dng ca thuc gip con ngi thun tin hn trong vic dng thuc v trnh s khng thuc xy ra khi dng qu nhiu thuc.

Chnh v nhng ng dng ca cc sn phm bin tnh t dipterocarpol mang li m dipterocarpol tr thnh mt trong nhng cht c nghin cu nhiu nht.

Hnh 1.7: Mt s dn xut ca dipterocarpol

1.2 MT S PHN NG TRN MCH NHNH CA DIPTEROCARPOL.T dipterocarpol, chng ta c th thc hin bin tnh trn vng v bin tnh trn mch nhnh. Nhm carbonyl rt hot ng nn s tham gia vo cc phn ng hon nguyn, cng thn hch, kh amin ha cho bin tnh vng. Trong ti ny chng ti tm hiu mt s phn ng trn mch nhnh ca dipterocarpol.1.2.1 Phn ng oxi ha to lacton.Lacton l mt ester vng, thng gp l dng (vng 5) v -lacton (vng 6). S c mt ca nhm chc lacton lm cho cc hp cht c hot tnh sinh hc ln tim, c gi tr y dc. C nhiu phng php khc nhau ng vng lacton ty thuc vo c cu cht ban u cng nh cc loi tc cht phn ng. Trong , iu ch lacton t cht nn hydroxyl carboxylic acid l phng php c dung ph bin nht. Mt s phn ng lacton ha trong bng 1.1STTCht nnTc chtSn phmHiu sut(%)

1

m-CPBA H+, NuH

77-86

2

X= O, NHCO/H2Pd(OAc)2DPPB,1200C

>90

3

OsO4Oxone

-

4

1.Hg(OAc)2MeOH

2.NaBH4

-

5

H+,C6H5Cl

+

-

6

(CF3-Ph-CO)2OTiCl2(OTf)2Me3SiCl

CH2Cl2, +

-

7

CrO3/AcOH

-

Bng 1.1: Mt s phng php tng hp lactonNm 2003, Isamu Shiina tng hp lacton bng phng php ng vng cht nn hydroxyl carboxylic acid (phng php 6). Khi ng thay i cc iu kin phn ng nh nhit , nng xc tc, t l gia nng cht xc tc v cht nn th thu c nhiu t l sn phm monomer v dimer khc nhau. Phn ng cho hiu sut c lp monomer cao nht ti 50C v 5 mol ca TiCl2(OTf)2. Khi thay i gi tr n cng lm thay i t l sn phm nh trong bng 1.2.

Hnh 1.8: Monomer

Hnh 1.9: DimerSTTRn% monomer% dimer

1H10835

2C6H1310913

3H11803

4H12892

5H13885

6H14881

Bng 1.2: T l sn phm thay i theo n.

Do c cu cht nn dipterocarpol l alkenol nn chng ta c th p dng phng php s 3 v phng php 7, s dng tc cht OsO4, oxone (2KHSO5.KHSO4.KSO4) hay CrO3/AcOH cho phn ng xy ra iu kin nh nhng hiu sut cao. Nm 1958, G. Ourirron tin hnh oxi ha dipterocarpol trong chui phn ng iu ch dn xut ca testosterone l 8,14-dimethyl-1,8-nortestosteron, tc cht CrO3/AcOH(4)

Hnh 1.10: Phn ng lacton1.2.2 Phn ng trn nhm OH.Nhm hydroxyl cho hai loi phn ng chnh l s ct ni C-O v O-H.

C rt nhiu tc cht cho s ct ni C-O v ty vo tc cht c s dng m chng ta c th thu c sn phm l cc halogenur alikil tng ng hoc cc alken

Tc cht: SOCl2, HX, PX3.

Tc cht: H2SO4, Al2O3 (nhit cao), POCl3Mt phn ng khc cng kh quan trng trn alcol l phn ng oxi ha. Cc tc cht oxi ha thng dng l KMnO4, K2Cr2O7, CrO3. Ty vo c cu alcol ban u m chng ta c th thu c aldehid, acid carboxylic (t alcol bc nht), ceton (t alcol bc nh), alcol tam cp khng cho phn ng oxi ha.

Ct ni O-H to eter, ester l phn ng quan trng v thng gp trong tng hp hu c, mc ch to dn xut eter, ester hoc bo v alcol trong mt chui bin i hu c. 1.2.3 S to thnh ester.

Ester l cht c tm thy rt nhiu trong thin nhin. Mt s ester n gin l cht lng c mi thm d chu c dng nh hng liu trong ngnh thc phm cng nh m phm. Ngoi ra, trong k ngh, ester thng dng lm dung mi nh etyl acetate hay cht lm do cho polymer.Ester c th c iu ch bng nhiu cch:

1.2.3.1 Phn ng ester ha Fischer gia acid carboxylic v alcol di s hin din ca acid v c.

Di s hin din ca xc tc acid, alcol v acid carboxilic tc dng vi nhau co ra ester v nc. Phn ng thng c xc tc bi H2SO4 m c v un hon lu trong thi gian di.Phn ng xy ra theo c ch sau:

Hnh 1.11: Ester ha Fischer1.2.3.2 Phn ng t clorur acid

Hnh 1.12: Phn ng acil ha to esterAlcol tc dng vi clorur acid theo c ch phn ng th thn hch acil cho ra ester. Nhng phn ng loi ny thng xy ra di s hin din ca baz yu nh pyridin. Phn ng cho hiu sut cao vi cc loi alcol nht, nh, tam

Theo nghin cu nm 2003, Satya Paul v cng s cho thy hiu sut ca phn ng acyl ha bng clorur acid ph thuc vo cht xc tc c th hin bng 1.3.Tc chtThi gian (pht)Nhit (oC)Hiu sut (%)

PhCOCl/SiO2

PhCOCl/K10

PhCOCl/p-TsOH/SiO2PhCOCl/Al2O3

PhCOCl/TFA/SiO2

PhCOCl/H2SO4/Si2

PhCOCl/DMSO/SiO2

PhCOCl-Py/Al2O3 3

8

10

8

10

4

2

162-64

59-61

39-41

52-54

51-53

52-54

50-52

92-9489

71

48

64

45

84

77

100

Bng 1.3: to thnh benzanilid t anilin vi cc tc cht khc nhauT bng 1.3, ta thy s acyl ha vi PhCOCl cho hiu sut cao, phn ng xy ra vi thi gian ngn. Tuy nhin, s acyl ha bng acid clorur c s hin din ca pyridin vi cht xc tc l Al2O3 cho hiu sut t n 100% vi thi gian rt ngn 1 pht.iu cn chng t rng PhCOCl l mt tc nhn acyl ha rt tt (cho hiu sut cao trong iu kin n gin khng c dung mi) c th c dng phn ng to ester benzoat mt cch d dng hn cc tc nhn khc nh acid benzoic, benzoic anhydrid, benzoyltetrazol 1.2.3.3 Phn ng t anhydrid acid

V d:

y l mt phng php tiu chun dng diu ch ester. Phn ng c xc tc bng acid ( H2SO4) hay baz ( pyridin).

1.2.3.4 Phn ng t nitril.

V d:

1.2.4 S to thnh eter.C 2 phng php iu ch eter

1.2.4.1 Tch nc ca alcol bng mt acid proton mnh.Hai phn t alcol tch mt phn t nc cho ra mt phn t eter i xng.

1.2.4.2 Tng hp Williamson

c tm ra vo nm 1850, tng hp Williamson sm tr nn mt phng php tt nht trong vic iu ch c eter i xng v bt i xng.

u tin chuyn ha alcol thnh alkoxid, sau cho alkoxid ny tc dng ci halogenur alkil

Vi eter bt i xng ROR cn phi bit chn phn no (R hay R) l halogenur alkyl trnh phn ng tch nc to ra alken

1.2.5 Phn ng tng hp epoxid.Phn ng ng vng epoxid c pht hin vo nm 1961 bi A. William Johnson v c nguyn cu su hn bi EJ Corey v Michale Chaykovsky.Trimetylsulfoxonium iodl mui sulfoxonium.N c s dng to ra dimetyloxosulfonium metyl bng phn ng vi natri hydride. Hp cht dimetyloxosulfonium metyl c s dng ng vng epoxid.

Hnh 1.13: Phn ng tng hp epoxidNgoi phn ng ng vng epoxid Corey Chaykovsky cn ng dng cho nhiu nhm chc khc.

X: O, CH2, NR2, S, CHCOR3, CHCO2R3, CHCONR2, CHCN.

Ngoi ra, ngi ta cn s dng m-CPBA tng hp epoxid t alken.

Phn 2: THC NGHIM2.1 HA CHT, THIT B V DNG C TH NGHIM2.1.1 Ha cht: Dipterocarpol (Hydroxydammarenone II)Ngun: Cc nhm thc nghim trc.

m-CPBA(Acid 3-chloroperoxybenzoic)Hng sn xut: c NaBH4(Natri bohidrur)Hng sn xut: Trung Quc Na2SO4(Natri sunfat)Hng sn xut: Trung Quc HCl (Acid chlohidric)Hng sn xut: Trung Quc CH3COONa (Natri acetat)Hng sn xut: Trung Quc Pyridin (Azine; Azabenzene)Hng sn xut: Trung Quc Tosyl clorur (4- methyl- benzenesulfonylchlorid)Hng sn xut: Trung Quc SilicagelHng sn xut: c Eter duHng sn xut: Chemsol EtanolHng sn xut: ChemsolMetanolHng sn xut: Chemsol CloroformHng sn xut: Chemsol HexanHng sn xut: Chemsol Etyl acetatHng sn xut: Chemsol2.1.2 Dng c:

Bnh cu 100mL

Becher 100mL

Erlen 100mL

Bnh lng 150mL

ng hon lu

Bn mng silicagel Merk, Kielsegel 60F254, 250m

Silicagel - n

2.1.3 Thit b:

Bp un v khuy t hiu ARE-VELP My c quay hiu EYELA My o nhit nng chy - Wagner & munz- POLYTHERMA Heiztisch Mikroskop

My o ph NMR hiu Brucker 500MHz, dung mi CDCl3.2.2 THC NGHIM

2.2.1 iu ch 20(s)-hydroxydammar-24-en-3-ol.20(s)-hydroxydammar-24-en-3-ol l sn phm ca phn ng hon nguyn vi tc nhn hidrur thnh alcol. Phn ng c thc hin nh sau:

Ha tan 0.44g (1mmol) dipterocarpol trong 30ml dung mi EtOH trong erlen 250ml, sau cho thm vo hn hp phn ng 0.1g NaBH4 (2.6mmol), khuy t trong 4h. Sau khi phn ng kt thc, cho vo hn hp phn ng 20ml dung dch HCl 5%. Lc sn phm v ra sn phm nhiu ln vi H2O, kh, kt tinh li nhiu ln sn phm trong MeOH, chng ti thu c 0.42g sn phm sch, tinh th trng, hiu sut : 94%, Tnc=134-135C. Cu trc sn phm c xc nh bng ph 1H-NMR v 13C-NMR.2.2.2 iu ch 20(s)-hydroxydammar-24,25-epoxyl-3 -ol.20(s)-hydroxydammar-24,25-epoxyl-3-ol l sn phm ca phn ng to epoxy ca dipterocarpol. Chng ti tin hnh phn ng nh sau:

Cho 1.76g (4mmol) 20(s)-hydroxydammar-24,25-epoxyl-3 -ol vo erlen nt nhm 250ml, thm 80ml CHCl3, lc u cho tan ht. Dng bc nylon en bc kn xung quanh erlen, thm 1.60g (10.40mmol) m-CPBA vo erlen, khuy t trong 24h.Sau khi kt thc phn ng, ra hn hp phn ng vi dung dch mui CH3COONa 10% (3x30ml), ra li vi H2O (2x30ml) v lm khan bng Na2SO4. C quay thu hi dung mi v kt tinh li nhiu ln vi MeOH thu c 1.51g sn phm sch, tinh th trng, hiu sut 82%, Tnc=160-162C. Cu trc sn phm c xc nh bng ph 1H-NMR v 13C-NMR.2.2.3 iu ch 20(s)-hydroxydammar-24,25-epoxy-3- p-toluenesulfonyl.Cho 0.46g cht s 8 vo bnh cu 100ml, ha tan vi 2ml pyridin. Sau , cn 0.28g p-toluenesulfonyl clorur cho vo hn hp trn, un hon lu hn hp trong khong 8h. ngui hn hp phn ng, trung ha vi 40ml HCl 5%, c kt ta trng c to thnh, lc ly kt ta, ra li vi nc nhiu ln vi H2O. Kt tinh hn hp sn phm vi methanol, thu c 0.12g sn phm sch hiu sut 38%. Cu trc sn phm c xc nh bng ph 1H-NMR v 13C-NMR.Phn 3: KT QU V BIN LUNTrong bi tiu lun ny, chng ti tin hnh phn ng oxid ha ni i trn nhnh thnh vng epoxyl, kh nhm carbonyl thuc vng A ca dipterocarpol thnh alcol, v gn nhm tosyl v nhm alcol to thnh.

Hnh 3.1: Mt s dn xut ca dipterocarpol

3.1 Kh nhm carbonyl vng A.Kh nhm carbonyl c th tin hnh bng nhiu phng php vi cc tc cht phn ng khc nhau, ph bin nht l cng thm anion hydride vo nhm carbonyl cho ra alkoxid anion, sau acid ha to thnh alcol.Hai tc cht cung cp hydrur ph bin nht l: lithium aluminum hydride (LiAlH4) v sodium borohydride (NaBH4).

Tc chtDung miPhn ng Tinh ch

Sodium Borohydride NaBH4 Ethanol; ethanol +15% NaOH Trnh acid mnh. Aldehyde ( 1 alcol. Ketone ( 2 alcol.1. Trung ha2. Chit sn phm

Lithium Aluminum Hydride LiAlH4 Ether; THF Trnh alcol, amin, acid mnh. Aldehyde ( 1-alcol. Ketone ( 2-alcol. Acid carboxylic ( 1-alcol. Ester ( alcol. Epoxid ( alcol Nitril & amid ( amin. Halide & tosylate ( alkan1. Cn thn khi thm nc.2. Loi mui nhm.

3. Chit sn phm.

Bng 3.1: Mt s tc nhn cung cp hidrur

Phn ng kh nhm carbonyl trn vng A, chng ti s dng tc cht NaBH4 v tc cht bn trong iu kin thng, cho phn ng vi hiu sut cao v d dng tinh ch sn phm.Chng ti lm phn ng trn s sau:

SHAPE \* MERGEFORMAT

C ch phn ng c m t nh sau:

u tin, tc nhn thn hch l ion hidrur tn cng vo carbon ca nhm carbonyl. i in t t do trn ion hydride hnh thnh lin kt vi carbon ca nhm C=O, cc in t ca lin kt ca C=O dch chuyn n O, cho ra alkoxid.Sau khi hnh thnh ion alkoxid, ion ny s ly mt ion hydrogen t phn t nc to thnh alcol.

Hnh 3.2: C ch phn ng to alcol dipterocarpolChng ti kh 0.44g dip bng 0.1g NaBH4 trong dung mi EtOH ti nhit phng trong 4 gi.Kim tra vi sc k bn mng , h dung mi ED:EA=8:2, sn phm khng hin mu UV, hin mu vi dung dch vaniline th ta thy sn phm l mt m trn, duy nht. Chng ti kt tinh sn phm nhiu ln trong MeOH, thu c 0.42g tinh th trng.Chng ti tin hnh em mu i xc minh cu trc vi my ph 1H-NMR v 13C-NMR. Thu c kt qu nh sau:

Hnh 3.3: Hp cht alcol dipterocarpolD liu 1H ca 3-alcol dipterocarpol:

V trMi(H, ppm (s H)

C3i i3.20

C24Ba5.12

Bng 3.2: D liu 1H ca 3-alcol dipterocarpol

Ti v tr: =3.20ppm, H ca C3 trn vng A, gi tr ca c trng cho CH-OH v H ghp spin vi hai H C2 khng tng ng nn c hin tng ch mi 4.Ti v tr: =5.12ppm, gi tr ca c trng cho H trn ni i C=C, do hin tng ghp spin vi hai H trn C23 tng ng nhau nn ph ch mi ba.

Vy c th kt lun c, phn ng thnh cng trong vic bin i nhm C=O thnh nhm OH trn vng A v ni i C=C vn cn trn cu trc. 3.2 Epoxid ha lin kt i C=C trn mch nhnh.Hin nay, c rt nhiu phng php vi cc tc cht a dng bin ni i C=C thnh vng epoxyl nh: phn ng vi O2 trong s c mt ca Ag nguyn t, phn ng ca -halohydroxyl vi baz mnh, phn ng vi peroxy acid.

m-CPBA l mt tc nhn oxy ha mnh, thng c s dng cho cc phn ng: aldehyde v keton thnh ester (Bayer-Villiger), olefin thnh epoxy, sulfide thnh sulfoxide and sulfone, amin thnh nitroalkan, nitroxide hocN-oxide.

V l do kinh t m ngy nay m-CPBA t c s dng, thay vo l hydrogen peroxide vi xc tc thch hp v cc peracid n gin hn nh peracetic acid hoc ozon.Tuy nhin, trong nhiu phn ng m-CPBA vn c a chung bi tnh chn lc cao hn so vi hydrogen peroxide v cc peracid khc.

Chng ti chn m-CPBA lm tc cht cho phn ng epoxid ha lin kt i C=C. Quy trnh thc hin phn ng c m t nh s sau:

SHAPE \* MERGEFORMAT

C ch phn ng c m t nh sau:Phn t ca m-CPBA trong gn ging vi acid carboxylic nhng c thm mt O. Lin kt O-O ny rt yu (khong 138kJ/mol), nn rt d t ni tham gia hnh thnh lin kt mi.

Mt c im khc ca phn ng to epoxy t alken s dng m-CPBA l tnh chn lc lp th, mt cis-alken s cho ra mt cis-epoxy v mt trans-alken s cho ra mt trans-epoxy.Phn ng xy ra thng qua mt trng thi chuyn tip, lin kt O v C=C hnh thnh ng thi vi s t ni ca lin kt O-O, proton c dch chuyn t nhm OH sang C ca nhm C=O.

Hnh 3.4: C ch phn ng to epoxid dipterocarpolChng ti tin hnh kho st phn ng oxid ha ni i C=C trn mch nhnh ca dipterocarpol bng tc cht m-CPBA trong dung mi chloroform, phn ng trong iu kin bng ti, khuy t trong 24h.Kim tra vi sc k bn mng , h dung mi ED:EA=8:2, sn phm khng hin mu UV, hin mu vi dung dch vaniline th ta thy sn phm l mt m trn, duy nht.Kt tinh li sn phm nhiu ln vi MeOH, chng ta thu c 1.51g sn phm dng tinh th mu trng sng.

Chng ti tin hnh em mu i xc minh cu trc vi my ph 1H-NMR v 13C-NMR. Thu c kt qu nh sau:

Hnh 3.5: Hp cht epoxid dipterocarpolD liu 1H ca vng epoxy dipterocarpol:

V trMi(H, ppm (s H)

C30n0.76

C18n0.83

C19n0.86

C28n0.94

C29n0.96

C26n1.10

C27n1.12

C21n1.20

C3i i3.27

C24Ba3.72

Bng 3.3: D liu 1H ca vng epoxy dipterocarpol

T d liu trn ph 1H-NMR, chng ti thy:Ti v tr: =3.27ppm, J1=15Hz, J2=25Hz, mi bn, do H ti C3 ghp spin vi 2H ca C2, m 2H ny khng tng ng nhau v mt v tr xch o v mt trc, nn ph cho ra bng mi vi tn s ghp khc nhau.Ti v tr =3.72ppm, cho ra mt mi ba c trng ca s ghp spin vi 2H tng ng, H ca C24 tc H duy nht ca vng epoxyl l ph hp vi gi tr v hnh dng mi.Ngoi ra, cc mi c th xc nh cn li u c dng mi n, nn c th nh danh, y l cc H trn cc nhm CH3 ca sn phm:Ti v tr =1.20ppm, mi n, v tr c trng ca H ca C-OH, C21.Ti v tr =1.12 v 1.11ppm, mi n, H ca hai nhm CH3 trn vng epoxyl.

Ti v tr = 0.94 v 0.96ppm, mi n, H ca hai nhm CH3 trn C4.

Ti v tr =0.86 v 0.83ppm, mi n, ln lt l H ca hai nhm CH3 trn C8 v C10.

Ti v tr =0.78ppm, mi n, H ca nhm CH3 trn C14.D liu 13C ca vng epoxy dipterocarpol:V tr(C, ppm (loi C)

C2571.45

C2478.94

C2083.32

C386.42

Bng 3.4: D liu 13C ca vng epoxy dipterocarpol

T d liu ph 13C-MNR, chng ti nhn thy:Ti v tr =71.45 v 78.94ppm, mi n, C ca vng epoxyl ln lt l C25 v C24, do C25 c hai nhm CH3 c kh nng cho in t gy hiu ng chn lm C25 cng hng trng yu hn C24.

Ti v tr =83.32 v 86.42ppm, mi n, C gn trc tip vi cc nhm OH, do C20 cha mt nhm C y in t, gy ra hiu ng chn mnh lm gim trng cng hng nn C20 cng hng v tr thp hn C3.3.3 Tosyl ha nhm OH vng A.Alcol l mt hp cht kh ph bin, c to thnh d dng t nhm carbonyl, hp cht ph bin hn, alcol l mt hp cht tng i bn, v chng cha nhm xut km.Nhm xut tt l bazo lin hp ca acid mnh, thng thng, mt nhm xut tt nh alkyl halide th gi tr pKa acid hydrohalic phi thp hn -3.

Cc hp cht trung ha in v mnh nh acid hydrohalic c th k n nh: phosphoric acid, nitric acid and sulfuric acid nhng chng kh tham gia cc phn ng hu c. Cc acid hu c ph bin nht c th k n l:

Methanesulfonic acid (mesylic acid)

MsOH pKa = 3

Trifluoromethanesulfonic acid (triflic acid)

TfOH pKa = 14

Para-toluenesulfonic acid (tosylic acid)

TsOH pKa = 6

Chuyn ha alcol thnh mt ester sunfonate l mt qu trnh n gin, alcol c cho phn ng vi sunfonyl clorur, gi r v d tm, cho ra sn phm l mt ester d dng.Qu trnh phn ng ca chng ti c thc hin nh sau: SHAPE \* MERGEFORMAT

Nguyn t lu hunh phn cc dng trng thi oxid ha cao. Cu trc cng hng ca tosyl clorur c biu din nh sau:

Hnh 3.6: Trang thi cng hng tosyl clorurV nguyn t sunfur c cha vn o 3d trng nn c kh nng nhn thm mt nhm th th nm. Alcol phn cc m v pha nguyn t oxygen, nn i in t t do trn oxygen tn cng thn hch mnh ln tm phn cc dng ca sunfur hnh thnh lin kt mi. Clorur l mt nhm xut tt, nn n c th ra i phn t tr v trng thi bn.

Nguyn t oxygen ca alcol c ba lin kt nn n mang in tch dng, H+ c tch ra mi trng v c trung ha bng pyridin c sn trong phn ng.Tng qut, nguyn t Cl ca tosyl clorur c thay th bng -OR ca alcol, to thnh mt ester lu hunh v c, HCl c hnh thnh trong phn ng c trung ha bi pyridin.

C ch phn ng c th hin nh sau: tc nhn thn hch oxygen tn cng vo tm sunfur thn in t trn tosyl clorur, nhm clorur tch ra di tc ng ca nhm y O-, pyridin c thm vo trung ha H+, sn phm alkyl sunfonate ch nhm xut tt OTs, alkyl sunfonate d dng chuyn ha thnh cc nhm chc khc qua cc phn ng nh: SN2, SN1, E1, E2.

Hnh 3.7: C ch phn ng tosyl haChng ti tin hnh kho st phn ng ca 20(s)-hydroxydammar-24,25-epoxyl-3-ol v tosyl clorur trong dung mi pyridin ti nhit phng v trong thi gian 4h.Trch sn phm, kim tra bng sc k bn mng, gii ly bng ED:EA=8:2, hin hnh vi vanilin, kt qu: c s hnh thnh sn phm mi di dng vt.

Phn ng tip n 24h, kim tra vi sc k bn mng, gii ly bng ED:EA=8:2, hin hnh bng vanilin, kt qu: c s hnh thnh sn phm mi dng vt, m m trn bn mng gn nh thay i khng ng k.Nng nhit phn ng ln 40C, phn ng trong 8h, trch sn phm, kim tra bng sc k bn mng, gii ly bng ED:EA=8:2, hin hnh vi vanilin, kt qu: c s hnh thnh sn phm mi, hm lng khng ng k so vi tc cht ban u.Cho hn hp phn ng vo h thng hon lu, un trong 4h, trch sn phm, kim tra bng sc k bn mng, gii ly bng ED:EA=8:2, hin hnh vi vanilin, kt qu: c s hnh thnh sn phm mi ng k so vi tc cht ban u, nhng m tc cht vn cn rt m so vi sn phm nn chng ti quyt nh tin hnh phn ng vi thi gian di hn, un qua m.Kt qu: Kim tra bng sc k bn mng, gii ly bng ED:EA=8:2, hin hnh vi vanilin, chng ti nhn thy, tc cht bn u by gi ch cn hin mt m rt nh so vi cc sn phm c ti thnh, sn phm to thnh c nhiu m nhng trong c mt m trn v m nht, nm tch kh xa vi cc tc cht v cc sn phm khc, chng ti quyt nh c lp sn phm ny xc nh cu trc bng phng php chy ct sc k v thu c sn phm sch.

Sn phm thu c sau khi tinh ch c tin hnh xc minh cu trc bng ph 1H-NMR v 13C-NMR:

Hnh 3.8: Hp cht 3-tosyl epoxy dipterocarpolD liu 13C ca vng epoxy dipterocarpol:

V tr(C, ppm (loi C)

C378.95

C2078.93

Ce21.39

Cb133.84

Cc134.05

Ca139.87

Cd140.18

C24215.10

C21115.86

C20117.50

Bng 3.5: D liu 13C ca vng epoxyl dipterocarpolT d liu trn ph 13C-NMR, chng ti nhn thy:

Ti v tr =215.18ppm, v tr ny c trng cho C ca nhm C=O.Ti v tr =140.18, 139.87, 134.05, 133.84ppm v =21.39ppm, cc v tr c trng cho C trn vng tosyl, vy tosyl gn ln khung ca hp cht chng ta.

Ti v tr =115.86ppm, v tr c trung cho C ca nhm alken u mch.

Ti v tr =78.95 v 78.93ppm, cc v tr c trng cho C lin kt trc tip vi O.

C th d on, vng epoxyl b t v c s hnh thnh ca nhm carbonyl v ni i C=C.

D liu 1H ca vng epoxy dipterocarpol:

V trMi(H, ppm (s H)

C22a5.31

C23a5.37

C17a5.94

C26i6.06 6.08

C26i6.08-6.11

C3Ba6.30

Vng tosyla6.80

Bng 3.6: D liu 1H ca vng epoxy dipterocarpol T d liu trn ph 1H-NMR, chng ti nhn thy:

Ti v tr =6.80ppm, mi a, c trng H trn vng tosyl.Ti v tr =6.30ppm, mi ba, H trn C lin kt vi nhm OTs, H tng tc spin vi hai H ca C2 ch mi ba.

Ti v tr =6.06 6.08 v 6.08-6.1, mi i, l hai H u mch ca ni i C=C, hai H ny ghp spin vi nhau nn ph c dng mi i.

Ti v tr = 5.31 v 5.37ppm, l H ca hai C22 v C23, do chng ghp spin vi nhau nn c dng mi ba.

Ti v tr =5.94ppm, mi a, H ca C17, do H ghp spin vi 3H khng tng ng nn c dng mi a.

Lin kt vi d liu ph 13C-NMR, c th kt lun rng nhm tosyl c gn ln vng A v vng epoxyl b phn hy to thnh nhm C=O v C=C lin k nhau.Phn 4: KT LUN

1. tng hp c 20(s)-hydroxydammar-24-en-3-ol t dipterocarpol bng phn ng kh vi NaBH4 trong ethanol. Hiu xut 94%, Tnc= 134-135C v cu trc c xc minh bng ph 1H-NMR.

2. tng hp c 20(s)-hydroxydammar-24,25-epoxyl-3-ol t 20(s)-hydroxydammar-24-en-3-ol bng phn ng oxid ha vi m-CPBA trong chloroform. Hiu xut 82%, Tnc= 160-162C v cu trc c xc minh bng ph 1H-NMR v 13C-NMR.3. tng hp c 20(s)-hydroxydammar-24-en-3-ol t 20(s)-hydroxydammar-24,25-epoxyl-3-ol. Hiu xut 38% v cu trc c xc minh bng ph 1H-NMR v 13C-NMR.

TI LIU THAM KHO[1] Nguyn trng Giang (2012), Bin tnh vng A ca Dipterocarpol, lun vn thc s, khoa ha, i Hc Khoa Hc T Nhin TPHCM, 2,3.

[2]Phm Thanh Thut (2013), Tm hiu phn ng bin i nhm carbonyl trn vng A ca lacton dipterocarpol thnh epoxyd , tiu lun tt nghip, khoa Ha Hc, trng i Hc Khoa Hc T Nhin TPHCM, 4- 6.

[3]Robert D. Bach, Carlo Canepa, Julia E. Winter, Paul E. Blanchette (1997), Mechanism of acid- Catalyzed Epoxidation of Alkenes with peroxy Acids, J. Org. Chem, 62, No. 15, 5191-5197. [4]. L Ngc Thch, Ha Hc Hu C (Cc Nhm nh Chc Chnh), NXB i Hc Quc Gia Tp. HCM, Thnh ph H Ch Minh, 283-301 (2002). [5]o Thi Thu Huong, Tran Thi Thu Thuy, Tran Thi Hien, Nguyen Thanh Tra, Nguyen Quyet Tien, E.Smirnova, O. B. Kazakova, E.M. Minnibaeva, G. A. Tolstikov (2013), Synthesis and Cytotoxicity of Derivatives of Dipterocarpol, Metabolite of Dipterocarpus Alatus, Chemistry of Natural Compounds, 49, No. 1, 58-64.

[6]HiDayat Hussain, Ahmed Al- Harrasi, Ivan R. Green, Ishtiaq Ahmed, Ghulam Abbas, Najeeb Ur Rehman (2014), meta-Chloroperbenzoic acid (m-CPBA): A Versatile Reagent in Organic Synthesis, RSC Advances, Accepted Manuscripts, 5-7. [7] Wang, Zerong (2010), Comprehensive Organic Name Reactions and Reagent Prilezhaev Reaction, Journal of Medicinal Chemistry, American Chemical Society, 2270-2273.

[8] Jacqueline, Seyden-Penne (1991), Reductions by the Alumino-and Borohidrides in Organic Synthesis, 2nd edition, Wiley VCH, New York, 5-6.

[9] A. D. Zorina, L. V. Balykina, O. V. Nazarova, A. A. Rebezov (2006), polymeric Derivatives of Dipterocarpol, a Dammarane Triterpenoic, Russian Journal of Applied Chemistry, 79, No.4, 654-659. [10] http://www.organic-chemistry.org/synthesis/O1S/sulfonates.shtm (ngy truy cp 09/06/2015)[11] https://www2.chemistry.msu.edu/faculty/reusch/VirtTxtJml/aldket1.htm (ngy truy cp 09/06/2015)[12] http://www.organic-chemistry.org/synthesis/C1O/epoxids2.shtm (ngy truy cp 09/06/2015)[13] http://www.organic-chemistry.org/chemicals/oxidations/meta-chloroperbenzoicacid.shtm(ngy truy cp 10/06/2015) [14] http://www.masterorganicchemistry.com/2011/06/17/reagent-friday-m-cpba-meta-chloroperoxybenzoic-acid/(ngy truy cp 09/06/2015) [15]https://pubchem.ncbi.nlm.nih.gov/compound/Dipterocarpol#section=Substance-Categorization-Classification (ngy truy cp 01/06/2015). [16]http://www.organic-chemistry.org/chemicals/oxidations/meta-chloroperbenzoicacid.shtm (ngy truy cp 09/06/2015).

[17] http://www.organic-chemistry.org/synthesis/C1O/epoxides2.shtm (ngy truy cp 09/06/2015). [18]Don Thi Tnh, C s Ha Hc Hu C, Tp 1, NXB Khoa Hc v K Thut, H Ni, 142-176, 2001.[19]B.D Mistry, A handbook of Spectroscopic Data Chemistry, Oxford book company, Jaipur India, 2009.PH LC:

Ph lc 1: Ph 1H NMR ca dipterocarpol

Ph lc 2: Ph dn 1H NMR ca dipterocarpol

Ph lc 3: Ph dn 1H NMR ca dipterocarpol

Ph lc 4: Ph 1H NMR ca 3-alcol dipterocarpol

Ph lc 5: Ph dn 1H NMR ca 3-alcol dipterocarpol

Ph lc 6: Ph 1H NMR ca 3-alcol epoxy dipterocarpol

Ph lc 7: Ph dn 1H NMR ca 3-alcol epoxy dipterocarpol

Ph lc 8: Ph dn 1H NMR ca 3-alcol epoxy dipterocarpol

Ph lc 9: Ph 13C NMR ca 3-alcol epoxy dipterocarpol

Ph lc 10: Ph 1H NMR ca 3-tosyl epoxy dipterocarpol

Ph lc 11: Ph dn 1H NMR ca 3-tosyl epoxy dipterocarpol

Ph lc 12: Ph dn 1H NMR ca 3-tosyl epoxy dipterocarpol

Ph lc 13: Ph 13C NMR ca 3-tosyl epoxy dipterocarpol

Ph lc 14: Ph dn 13C NMR ca 3-tosyl epoxy dipterocarpol

Ph lc 15: Ph dn 13C NMR ca 3-tosyl epoxy dipterocarpol

HH phn ng

Sn phm th

0.1g NaBH4Khuy 24h

0.44g Dip + 30ml EtOH

Thm 20ml HCl, lc

Ra vi CH3COONa v H2O

Sn phm sch

Kt tinh vi MeOH

HH phn ng

Sn phm th

m-CPBAKhuy t 24h

0.46g cht 4 + 2ml CHCl3

Thm 20ml HCl, lc

Ra vi CH3COONa v H2O

Sn phm sch

Kt tinh vi MeOH

0.46g cht 8 + 2ml Pyridine

HH Phn ng

Sn Phm Th

0.28g p-toluenesulfonyl clorur

un hon lu 8h

Ra vi HCl 5% v H2O

Sn Phm sch

Kt tinh vi MeOH

2657

_1498742044.cdx

_1498742061.unknown

_1498742069.cdx

_1498810881.cdx

_1498984105.unknown

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_1498988704.unknown

_1498992354.cdx

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_1498742029.cdx