grupos protectores randolph alonso. formation formation 1. me 2 so 4, naoh, bu 4 n + i -, organic...
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![Page 1: Grupos Protectores Randolph Alonso. Formation Formation 1. Me 2 SO 4, NaOH, Bu 4 N + I -, Organic Solvent 60-90% 2. MeI or Me 2 SO 4, NaH or KH, THF 3](https://reader035.vdocuments.us/reader035/viewer/2022070303/54aee491497959bc0a8b6167/html5/thumbnails/1.jpg)
Grupos Grupos ProtectoresProtectores
Randolph Alonso Randolph Alonso
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FormationFormation
1. Me1. Me22SOSO44, NaOH, Bu, NaOH, Bu44NN++II--, Organic Solvent 60-90%, Organic Solvent 60-90%
2. MeI or Me2. MeI or Me22SOSO44, NaH or KH, THF, NaH or KH, THF
3. CH3. CH22NN22, Silica gel, 0-10 , Silica gel, 0-10 ooC, 100% yieldC, 100% yield
Methyl Ether ROMe
O O
H
OH
OH
SS
CH2N2, Et2O
Silica gel 83% O O
H
O
O
SS
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4. 4. MeI, Solid KOH, DMSO, 20MeI, Solid KOH, DMSO, 20oo, 5-30 min., 85%. Ref. T. Nakata, , 5-30 min., 85%. Ref. T. Nakata, Tetrahedron lett., 26, 6461 (1985)Tetrahedron lett., 26, 6461 (1985)
5. Debido al incremento de la acidez y un reducido 5. Debido al incremento de la acidez y un reducido requerimiento estérico del carbohydrato hydroxilo, requerimiento estérico del carbohydrato hydroxilo, tt-BuOK -BuOK puede usarse como una basepuede usarse como una base
Methyl Ether ROMe
O
O
O
OH
O
O
t-BuOK, MeI
THF, 100%O
O
O
O
O
O
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6. Me6. Me22SOSO44, DMSO, DMF, Ba(OH), DMSO, DMF, Ba(OH)22, BaO, rt. 18h, 98%, BaO, rt. 18h, 98%
Remoción
1. MeSiI, CHCl1. MeSiI, CHCl33, 25, 25ooC, 6h, 95%C, 6h, 95%
2. BBr2. BBr33, NaI, 15 crown-5 , NaI, 15 crown-5
Methyl Ester no son removidosMethyl Ester no son removidos
Methyl Ether ROMe
O
HO
CO2CH3
O
O
CO2CH3
H3C
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3. BBr3. BBr33. ETOAC, 1h, 95%, o BBr3, CH. ETOAC, 1h, 95%, o BBr3, CH22ClCl22, ,
4. BF4. BF33ETET22O, HSCHO, HSCH22-CH-CH22-SH, HCl, 15 h, 82%-SH, HCl, 15 h, 82%
5. 5.
OAc
OAc
H3CO
CO2CH3CO2CH3
BBr3, CH2Cl2
12oC
OAc
OAcCO2CH3
O
O H
-28
Methyl Ether ROMe
O
O
OH
OH
BzO
O-CH3
AlCl3/Bu4N+I-
CH3CN, 83%
O
O
OH
OH
BzO
OH
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Metoximetil EterMetoximetil Eter CH CH33OCHOCH22-OR-OR
1. CH1. CH33OCHOCH22-Cl, NaH, THF, 80%-Cl, NaH, THF, 80%
Mono MOMO Derivados de DiolesMono MOMO Derivados de Dioles
H3C-S-H2CO
CO2CH2CH2-TMS
O
HO DME, reflux, 12h, 88%
H3C-S-H2CO
CO2CH2CH2-TMS
O
MOM-O
Methyl Ether
OH
OH
(MeO)3CH
CH2Cl2, r.t. 24h
O
O O
DIBAH, -78o
10 min
OMOM
OH
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Remoción
1. Cat.HCl[], MeOH, 621. Cat.HCl[], MeOH, 62ooC, 15 min.C, 15 min.
2. 62. 6M M HCl, THF, 50HCl, THF, 50ooC, 95%C, 95%
Methyl Ether
H
OMOM
Dowex, 50w
MeOH, 93%
H
OH
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Tetrahydropirano Ether (THP-OR)Tetrahydropirano Ether (THP-OR) Dihydropirano, TsOH, CHDihydropirano, TsOH, CH22ClCl22. 2. 2ooCC
Remoción Explosión ocurre cuando se destilaExplosión ocurre cuando se destila
OOR
Methyl Ether
OHOTHP B2H6
H2O2- OH
OTHPO
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t-t-butil Éterbutil ÉterPuede ser preparado con varios alcoholes incluyendo alcoholes alílicos. Puede ser preparado con varios alcoholes incluyendo alcoholes alílicos. El éter es estable, excepto frente a los ácidos.El éter es estable, excepto frente a los ácidos.
Isobutilene, BFIsobutilene, BF33ETET22O, HO, H33POPO44, 100%, 100%
Remoción
NN22, CF, CF33COOH, 0-20COOH, 0-20oo, 1-16 h, 80-90%, 1-16 h, 80-90%
Methyl Ether
OH
O
O-t-Bu
O
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Benzyl Ether (Br-OR) PhCHBenzyl Ether (Br-OR) PhCH22-O-R-O-R1. BnCl, KOH, 1401. BnCl, KOH, 140ooC, 86%C, 86%
2. BnCl, Bu2. BnCl, Bu44NN++HSOHSO44--, 50% KOH, Benzene., 50% KOH, Benzene.
3. NaH, THF, BnBr, Bu3. NaH, THF, BnBr, Bu44NN++II-- 20 20oo, 3h, 100%, 3h, 100%
Benzyl Ether
OO
HO O
O
BnO
BnBr, DMF
AgO2, 48 h, rt
76%
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Remoción
1. H1. H22/Pd-C, EtOH, 95% Pd<, J. Org. Chem., 29, 3725, 1964./Pd-C, EtOH, 95% Pd<, J. Org. Chem., 29, 3725, 1964.
2. Raney Nickel W4, EtOH, H2. Raney Nickel W4, EtOH, H22
3. NaNH3. NaNH33, 15 seg., 97%, 15 seg., 97%
Benzyl Ether
HO
H
CO2CH3
OBn
HO
H
CO2CH3
OH
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Benzyl Ether
Phenyl benzyl Ether p-C6H5-C6H4-CH2-OR / NaHRemoción Pd/C H2 / EtOAc 52% Ref. Am Chem. Soc, 113, 6320, 1991.
O
O
OH
OH
O
CO2H
OO
O No Clivabenzil eter
O
O
OH
OH
OH
CO2H
OHO
HO
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Trimetil Silano Éter (TMS-OR) Trimetil Silano Éter (TMS-OR) Formación MeFormación Me33SiCl, EtSiCl, Et33N, THF, 25N, THF, 25oo, 8h, 90%, 8h, 90%
Remoción : :
1. Bu1. Bu44NN++FF--, THF, Conditions Apróticas., THF, Conditions Apróticas.
2. K2. K22COCO33, MeOH Anhydrous, 0, MeOH Anhydrous, 0ooC 100C 100ooCC
Éter de Silano
HOOH
0,5 Eq, HMDS, THF
1 gota TMS-Cl, RefluxHO
OTMS
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Trietilsilano (TES-OR) EtTrietilsilano (TES-OR) Et33SiORSiOREtEt33SiCl, PyrSiCl, Pyr
Remoción 2% HF o HF/Pyr. 2% HF o HF/Pyr.
tt-Butil Dimethylsilylether -Butil Dimethylsilylether TBDMS-OR (TBDMS-OR (tt--BuMeBuMe22-SiOR)-SiOR)
TBDMS-Cl, Imidazole, DMF, 25TBDMS-Cl, Imidazole, DMF, 25ooC, 10h, C, 10h, %%
Éter de Silano
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Éter de Silano
OH
R
NH2
COOH TBDMS-Cl, DBU
CH3CN, 0o, 24 h, rt.
OTBDMS
R
NH2
COOH
SO2Ph
OH
HO
TBDMS-CL/ Im
DMF, 79%
SO2Ph
OH
TBDMSO
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RemociónBuBu44NN++FF--, THF, 25, THF, 25ooC, 1h > 90% yieldC, 1h > 90% yield
El ión Fluoruro es muy básico, especialmente en El ión Fluoruro es muy básico, especialmente en condiciones anhidras. condiciones anhidras.
Ésta puede ser controlada con la adición de ácido Ésta puede ser controlada con la adición de ácido acético.acético.
Comercial 1 TBAF, contiene HComercial 1 TBAF, contiene H22O, O, rendimiento rendimiento Molecular Sieve 2.3%Molecular Sieve 2.3%
2 KF, 18-Crow-62 KF, 18-Crow-6
Éter de Silano
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Remoción selectivo de R-OH Primarios en presencia de selectivo de R-OH Primarios en presencia de Secundarios.Secundarios.
o Ácido Trifluoroacético, Ho Ácido Trifluoroacético, H22O, CHO, CH22ClCl22, (9:1), rt, 96h, (9:1), rt, 96h
Éter de Silano
O
BOC-HN
TBDMSO OTBDMS
O
AcOH, H2O
THF, 15 h, O
BOC-HN
TBDMSO OH
O
O
OTBDMSO
OTBDMS
O
OHO
OTBDMS
BB
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R = TBDMS o TBDPSR = TBDMS o TBDPS
O
OTBDMSRO
OH
B
K2CO3, MeOH
48 h, rt
O
OTBDMSHO
OH
B
Éter de Silano
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El TBDPS-OR (El TBDPS-OR (tt-BuPh-BuPh22-Si-O-R)-Si-O-R)100 > más estable TBDMS100 > más estable TBDMS
El TBDPS < estable frente a una base que TBDMSEl TBDPS < estable frente a una base que TBDMS
KK22COCO33/MeOH/MeOH
99MM MH MH44OH 60OH 60ooCC
Estable Estable
80% ACOH que cliva a TBDMS80% ACOH que cliva a TBDMS
HBr/AcOHHBr/AcOH
Éter de Silano
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FormaciónFormaciónTBDPSi-Cl, Imidazol, DMF, rtTBDPSi-Cl, Imidazol, DMF, rt
Remueve con BuRemueve con Bu44NN++FF--, THF, 25, THF, 25ooC, 1-5h, 90%C, 1-5h, 90%
Py, HF, THFPy, HF, THF
LiAlHLiAlH44 en algunos casos puede remover en algunos casos puede remover
Éter de Silano
CO2CH3
CONH2
TBDPSO
LiAlH4
CH2OH
CH2NH2
HO
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Tricloro acetatoTricloro acetatoFormación ClFormación Cl33C-COCl, Py, DMF, 20C-COCl, Py, DMF, 20ooC, 2 días, 87%C, 2 días, 87%
Remoción, NH, NH33, EtOH, CGCl, EtOH, CGCl33, 6h, 81%, 6h, 81%Es selectivo en presencia de acetatoEs selectivo en presencia de acetato
Acetato
O
HO
HO
TMSOOH
S
O
HO
HO
TMSO
O
S
OCl3
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ÉÉster Benzoate (Bz-OR) PhCOster Benzoate (Bz-OR) PhCO22-R-REl El ÉÉster de Benzoato es uno de los más comunes ster de Benzoato es uno de los más comunes
éésteres usados para protección de alcoholes, steres usados para protección de alcoholes,
> estables que acetatos> estables que acetatos
Formación BzCl o BzFormación BzCl o Bz22O, Py, 0O, Py, 0ooC Benzoilchloride / C Benzoilchloride / CHCH22ClCl22
Éster de Benzoato
OH
OH
O
O
O
OBz
OBz
O
O
O
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Remoción selectiva selectiva
O
BzO
OBzBzO
BH2NNH2, ACOH, Py
20 C, 7 dias, 80%
O
BzO
OHBzO
B
T.L. 35, 9717, 1994
Éster de Benzoato
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Metilen AcetalMetilen Acetal1. 40% CH1. 40% CH22O, conc. HCl, 50O, conc. HCl, 50ooC, 4 díasC, 4 días
2. Paraformaldehido, H2. Paraformaldehido, H22SOSO44, AcOH, 90, AcOH, 90ooC, 1 h.C, 1 h.
3. (MeO)3. (MeO)22CHCH22, lutidine, lutidine
4. CH4. CH22BrBr22, KOH, DMSO, rt, 49%, KOH, DMSO, rt, 49%
Protección con cíclico acetales y cetales
CO2CH3
OBn OBn
OH OH
CO2CH3
OBn OBn
O O
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Remoción 1. BCl1. BCl33, CH, CH22Cl, -80Cl, -80ooC, 30 min.C, 30 min.
2. HF, EtOH, THF, 0-52. HF, EtOH, THF, 0-5ooC, 14hC, 14h
Protección con cíclico acetales y cetales
O
HO
O
O
O
O
O
HO OH
O OH
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Ethylidiene AcetalEthylidiene AcetalCHCH33CHO, CHCHO, CH33CH(OMe)CH(OMe)22 o Paraldehyde, [ ] H o Paraldehyde, [ ] H22SOSO44/ /
TsOH, HTsOH, H22O, THF, 72%.O, THF, 72%.
Protección con cíclicos acetales y cetales
HO
HO
OH
O
O
OOH
O
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Acetonida (Isopropylidena Cetal)Acetonida (Isopropylidena Cetal)
Más comúnmente utilizado en 1,2 diol.Más comúnmente utilizado en 1,2 diol.
Protección con cíclicos acetales y cetales
OH
OH
OH
Acetona, TsOH
rt, 100%
3 pentanone, THF, TsOH90%
OH
O
O
+
O
OH
O
(9:1)
OH
O
O
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IsomerizaciónIsomerización
Remoción1. 1N HCl, TFH1. 1N HCl, TFH
2. 2N HCl, 802. 2N HCl, 80oo, 6h, 6h
3.BCl3.BCl33, Et, Et22OOCFCF33COCO22, THF, H, THF, H22O, 83%O, 83%
OH
O
O
O
HO
O
TsOH
1:10
Protección con cíclicos acetales y cetales
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Ethoxietilene HC(OMe)Ethoxietilene HC(OMe)33 o HC(OEt) o HC(OEt)33, Ácido catal, Ácido catalííticotico..
Remoción 98% Ácido Fórmico, HCl 98% Ácido Fórmico, HCl
Protección con cíclico acetales y cetales
OO
HO OH
HO70%
OO
O O
HO
O
O
O
O(t-Bu)2AlH
OMOM
OH
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Metil ÉterMetil Éter
FormaciónFormación
1. MeI, K1. MeI, K22COCO33, Cetona , Reflux, 6h, Cetona , Reflux, 6h
2. Me2. Me22SOSO44, NaOH, EtOH, reflux, 3h, NaOH, EtOH, reflux, 3h
3. LiCO3. LiCO33, MeI, DMF, 55, MeI, DMF, 55ooC, 18h, 54-90%C, 18h, 54-90%
Protección de Fenoles
OCH3
H3CO
O
Me2SO4, NaOH
OH
HO
O
MeI, KCO3
catona, reflux, 6h
OH
O
O
O
HO
HO
O
HO
O
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Diazometano, Éter, 80%Diazometano, Éter, 80%
OH O
O
BnO OH
CH2N2, eter
80%
OH O
O
BnO O
Methyl Ether Ph-OMe
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Remoción
1. Me1. Me33SiI, CHClSiI, CHCl33, 25, 25ooC, 72%C, 72%
2. K2. K++, Tolueno, 18crow-6, 100%, Tolueno, 18crow-6, 100%
3. Sodio Benzylselenide PhCH3. Sodio Benzylselenide PhCH22SeNa o SeNa o
sodio Tiocresolato pCHsodio Tiocresolato pCH33-Ph C-Ph C66HH44SNa en DMFSNa en DMF
RefluxReflux
N
O
ON
O
HO
Methyl Ether Ph-OMe
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Methyl Ether Ph-OMe
NO2
O
O
RQuinolina
NO2
OH
O
R
LiI
Remoción
O
OH
t-BuOK
Microondas
O
O
KF, Al2O3
5h, 210 oC
OH
O
J prakt. Chem / Chem Ztg., 337, 405, 1995
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Methyl Ether Ph-OMe
O
O
O
AlCl3, 75&
Oo C, 3h.
OH
O
O
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Benzil Éter PhCH2-O-R
OH
OH
CO2CH3
OBn
OH
CO2CH3
K2CO3, BnBr
cetona, 71%
Remoción, H2 / Pd/ C / Ac2O
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Aril toluen sulfonato
ArOSO2C6H4-p-CH3
TsCl, K2CO3,cetona
CH3I,K2CO3
OH
OH
O OTs
OH
O
NH2
OH
NH2
OTs
TsCl, CH2Cl2
NHTs
OH
Py
Et3N
Remoción KOH, H2O, EtOH
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Protección de Catecoles
Acetato de MetilenoFormación CH2Br, NaOH,76%
BrCH2Cl, DMF, CsCO3, 86%Remoción AlBr3, CH3SCH3,
BCl3,CH3SCH3,83%, 98%
O
O
OH
OH
OHNaOH
Fosgeno
OH
O
O
O
Carbonato Cíclico
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Acetales o Cetales R2(OCH3)2
MeOH, HCl seco, 2 min.
O
O O
H
O
O O
HO
MeOH, MH4Cl, reflux, 1.5 h, 66%
O
O
H
O
O
H O
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1,3 Dioxano y 1,3 Dioxolanos
H
O
O
H
O
O
OH
OH
TsOH, 91%
O
O
O
OH
OH
H+
O
O O
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1,3 Dioxano y 1,3 Dioxolanos
Remoción pyridium tosilato (PPTS), Cetona, Agua, calor, 100%5% HCl, THF, 25o, 20 h.
O
OAc
OAc
CO2CH3
O
O
O
OAc
OAc
CO2CH3
O
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N-t-Butoxicarbonilamida (BOC-NRCO-)
t-C4H9OCO-NRCO-Formación (BOC)2O, Et3N, DMAP, 25o C, 15h, 78-96 %
BuLi, (BOC)2O
Remoción MeONa, LiOH, NH2NH2, TMSOTf, CH2Cl2
N
H
BOC
O
OH
HO
O
O
TMSOTfCH2Cl2/ PhSH
0oC , 1h
NH
H
O
OH
HO
O
O