Download Reactions hydroxyl groups part-I

LECTURE 5 REACTIONS HYDROXYL GROUPS PART I NOTHING NEW OR MYSTERIOUS The complica,ons arise only because of there are so many of them!! As nucleophiles, analog to non-­‐sugar alcohols The majority of the chemistry is related to the forma,on of esters and ethers. Carboxylate esters Acetates –O(CO)CH3 or –OAc Benzoates –O(CO)C6H5 or –OBz Sulfonate esters Tosylate –O(SO2) C6H4CH3 or –OTs Mesylate –O(SO2) CH3 or –OMs Triflate –O(SO2) CF3 or –OTf Ethers Benzyl –OCH2C6H5 or –OBn Trityl –OC(C6H5)3 or –OTr Trimethylsilyl –OSi(CH3)3 or –OTMS Tert-­‐butyldimethylsilyl –OSi(CH3)2(C(CH3)3) or –OTBS or –OSiMe2But or -­‐OTBDMS Tert-­‐butyldiphenylsilyl –OSi(C6H5)2(C(CH3)3) or –OTBS or –OSiPh2But or -­‐OTBDPS HO
HO
OH
O
OH
OH
primary OH-6
HO
HO
OH
O
OH
OH
secondary OH-2,3,4
HO
HO
OH
O
OH
OH
anomeric OH-1
The functionality at the anomeric center can react
in two ways
as an alcohol or as an aldehyde
act as aldehyde to form acetal Effec,vely protect the anomeric center and prevents further reac,vity Equilibrium of α- and β-hydroxyls at the anomeric position
Potential competing inter-conversion between
α and β forms
inter-conversion between pyranose and furanose
forms
Solubility: very polar in nature
very soluble in polar solvents, especially
with possible H-bonding
Insoluble in non-polar solvents for organic
reactions, pdt purification and manipulation
Selective protection of particular
hydroxyl groups allows the regioselctive
rxn of those unprotected
Common starting point: protect the
majority or even all of the free -OH
AcetylaKon
Ester
Acetals
Ether
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
Esters: non-­‐nucleophilic and stable to a wide range of Condi,ons Frequently used protect groups Less polar than the corresponding alcohols Acetyla,on Most commonly used esters SKrring the alcohol with aceKc anhydride and a base Base mop up the aceKc acid generated, and catalyses the rxn itself Nucleophilic catalysis and base Uncatalysed rxn is very slow at rt Lewis acid catalysis But with possible compeKng process of mutarotaKon 1. Acetyla,on with ace,c anhydride/
pyridine propor,ons as solvents Equal HO
HO
OH
O
OH
Ac2O, pyridine
fast
OH
Sugars in a boYle is a mixture of α and β. /(py/fu) HO
HO
AcO
AcO
OAc
OAc
slow
OH
O
OAc
O
+
Ac2O, pyridine
OH
OH
Ra,o depends on par,cular sugars fast
AcO
AcO
OAc
O
OAc
OAc
2. Acetyla,on with ace,c anhydride/
sodium acetate Rela,vely weak base, sluggish rxn at rt Carry out at 100°C, usually generate β-­‐acetates Mutarota,on is much faster than the acetyla,on HO
HO
OH
O
OH
OH
fast
HO
HO
OH
O
OH
OH
Ac2O, NaOAc
100oC
slow
AcO
AcO
OAc
O
OAc
β Hydroxyl is more nucleophilic than the axial α οne OAc
β-­‐ occupies a less hindered equatorial than the axial of α-
repulsive effect between the ring oxygen lone pair orbitals and the lone pair orbitals on the β-­‐
anomeric oxygen atom
KineKc anomeric effect 3. Acetyla,on with ace,c anhydride/
Lewis acid catalysis Strong Lewis acid catalyses the equilibrium of α-­‐ and β-­‐, a^er catalyses the rxn Thus equilibrium of α-­‐ and β-­‐acetates will occur a^er the rxn Anomeric effect leads us α-­‐acetates Protec,ng groups Sa,sfy several important criteria 1) They should be formed in good yield, 2) they should be stable to subsequent rxn condi,ons, 3) They should be readily removed under appropriate condi,ons AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
Benzyl ethers (ROBn) HO
HO
OH
O
NaH, BnBr
OH
OMe
RO-
DMF
BnO
BnO
OBn
O
OBn
OMe
RO
Br
SN2
Tetrabutylammonium iodide NH
HO
O
HO
OMe
OH
OH
Ph
O
CCl3
CF3SO3H
BnO
O
BnO
OMe
OBn
OBn
Cleavage Cataly,c hydrogena,on Heterogeneous catalyst Palladium on carbon (Pd/C) When the metal is distributed over finely-divided carbon,
the surface area is larger and the catalyst is more reactive.
Palladium hydroxide (Pearlman’s catalyst) For the removal of sterically inaccessible/mul,ple benzyl groups OR
MeO
para-methoxybenzyl (PMB)
Single electron oxidising reagent (NH4)2Ce(NO3)6 Ceric ammonium nitrate (CAN) O
Cl
CN
Cl
CN
O
DDQ
2,3-­‐Dichloro-­‐5,6-­‐Dicyanobenzoquinone Trityl ethers Triphenylmethyl ether Very selec,ve for the primary hydroxyl group Forma,on via an SN1 type process By treatment of unprotected sugar etc. etc.
Resonance stabilisation
of the trityl cation
OH OCPh3
OH OH
HO
O
OH
OMe
Ph3CCl
HO
Pyridine
OH
OMe
OBn OH
AcOH
O
BnO
O
OBn
OMe
OBn OCPh3
NaH
BnBr
BnO
O
OBn
OMe
Silyl ethers R OH
R'
Si
R''
Cl
R'''
-H+
R'
R
O Si Cl
R'' R'''
'ate' complex
Ph
But Si N
But
N H
Imidazole acts as a nucleophilic catalyst and forms intermediates, e.g. R
O
R'
Si
R''
R'''
Trimethylsilyl (TMS) HO
HO
OH
OH
O
Me3SiCl
Pyridine
Me3SiO
Me3SiO
OSiMe3
OSiMe3
O
OMe
Tert-­‐Butyldimethylsilyl (TBDMS or TBS) OMe
Si
HO
HO
OH
OH
O
ButPh2SiCl
imidazole
OMe
HO
HO
O
OH
O
OMe
cleavage acid, may also cause removal of othe racid labile protec,ng groups Tetrabutylammonium fluoride (TBAF) Rela,ve rate of acid hydrolysis (stability increase in order) R-OSiMe3
R-OSiMe2But
R-OSiPh2But
1
1E-3
1E-5
AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
Acetate, and R O
Removed by nucleophile O
= R---OBz
Most commonly methoxide in trans-­‐esterifica,on rxn benzoyl ester
Potassium carbonate in methanol Sodium methoxide in methanol (zémplen deacetyla,on) In both cases, methoxide in cataly,c Milder condi,ons, such as treatment with primary amines, are also effec,ve for the removal of certain esters, and can do selec,ve deprotec,on rxn Sulfonate esters O
RO S
O
O
RO S Me
Leaving group ProtecKng group O
mesylate
Me
tosylate
toluenesulfonate
methanesulfonate
O
RO S CF3
O
triflate
trifluoromethanesuflonate
O
HO
O
OMe
Cl
S
O
HO
OH
OH
pyridine, 0oC
TsO
O
HO
OMe
OH
OH
AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
Nucleophilic subs,tu,on RXN Retarded by the presence of electron withdrawing oxygen which are β to the carbon atom at which the displacement is taking place SN2 not SN1 Electron withdrawing effect greatly destabilises any carbonium in in SN1 β-­‐oxygen effect Nu
LG
HO
HO
O
LG
OMe
Ph
O
O
HO
O
NaN3
OTs
OMe
DMF
O
HO
Ph
N3
O
OMe
I
Ph3P
O
Imidazole, I2
O
O
O
O
O
HO
O
NaN3 or
Ph
NuPh
O
O
TsO
O
OH
OMe
SN2 trans KOH
Ph
O
O
O
O
OMe
LiAlH4
O
O
Nu
O
OH
OMe
Nu = N3 or H
trans AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
Oxida,on O
O
PCC
O
O
HO
O
NaBH4
O
O
O
O
O
O
O
O
O
HO
diacetone glucose
O
diacetone allose
Ph3P=CH2
O
O
O
O
BH3
O
O
O
then
NaOH, H2O2
O
HO
O
O
O
PCC Oxida,on Pfitzner–Moffa` oxidaKon Swern oxidaKon H
OH
O
O
O
O
O
DMSO HO
O
oxalyl chloride O
O
O
O
O
O
O
RuCl3
O
NaIO4
O
O
O
uronic acid OH
HO
HO
O
OH
OMe
HO
Pt, O2
HO
HO
O
O
OH
OMe
SelecKve oxidaKon to primary hydroxyl group OH
HO
HO
-O
O
I
O
OH
HNO3
OH
O
HO
O
HO
H
HO
H
H
COOH
OH
H
OH
OH
COOH
aldaric acid HO
O
HO
I
-O
O O
O
O
Sodium periodate OH
OH
O
HO
OH
OH
OH
O
+
O
O
O
HO
O
NaIO4
O
OH
OH
O
O
NaIO4
Par,cularly useful for cleavage of the carbohydrate backbone at a specific point Since the reagent will only cleave between two cis alcohol groups Also useful for shortening of the carbohydrate chain AcetylaKon
Acetals
Ether
Ester
Nucleophilic SubsKtuKon
oxidaKon
ReducKon
Reduc,on to prepare deoxy sugars O
O
O
O
O
HO
O
O
CS2, NaOH
O
then MeI
S
MeS
O
O
O
Bu3SnH
O
O
AIBN
O
O
Xanthate ester Barton-­‐McCombie deoxygenaKon Bu3Sn
Bu3Sn
S
R
O
SMe
R
O
S
O
R
H
SnBu3
SMe
RH + Bu3Sn
product
chain carrier
regenerated
Other possible ways Nucleophilic displacement of leaving groups, e.g. OMs or OTs, with hydride from reducing agents such as LiAlH4 is not generally a good route Nucleophilic subs,tu,on is much slower in carbohydrates due to the β-­‐oxygen effect Under basic condi,ons, side reac,ons such as elimina,on rxns occur preferen,ally with reducing agents Hydrogenolysis of halides in the presence of mild base is prefered. summary Describe the three types of hydroxyl groups found in sugars Remember anomeric center acts as an alcohol or aldehyde Describe the three types of hydroxyl groups found in sugars Realize the importance of protec,on to allow regioselec,ve rxns of those unprotected Explain the pdts of acetyla,ons under different condi,ons Know how to selec,vely protect the primary hydroxyl group Recall the method in forming and cleaving ethers and esters