reactions hydroxyl groups part-i
TRANSCRIPT
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
O
HO
OH
OH
OH
HO
primary OH-6
O
HO
OH
OH
OH
HO
secondary OH-2,3,4
O
HO
OH
OH
OH
HO
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
Potential competing inter-conversion between α and β forms
Equilibrium of α- and β-hydroxyls at the anomeric position
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�
Acetals�
Ether�
Ester ��
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
SKrring the alcohol with aceKc anhydride and a base
Most commonly used esters
Nucleophilic catalysis and base
Lewis acid catalysis
Base mop up the aceKc acid generated, and catalyses the rxn itself
Uncatalysed rxn is very slow at rt
But with possible compeKng process of mutarotaKon
1. Acetyla,on with ace,c anhydride/pyridine
O
HO
OH
OH
OH
HO Ac2O, pyridine
fast
OAcO
OAc
OAc
OAc
AcO
slow
OHO
OH
OH
OH
HO Ac2O, pyridine
fast
OAcO
OAc
OAc
OAc
AcO
+
Sugars in a boYle is a mixture of α and β. /(py/fu)
Ra,o depends on par,cular sugars
Equal propor,ons as solvents
2. Acetyla,on with ace,c anhydride/sodium acetate
OHO
OH
OH
OH
HO Ac2O, NaOAcfastO
AcO
OAc
OAc
OAc
AcO
slow
OHO
OH
OH
OH
HO
100oC
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
β Hydroxyl is more nucleophilic than the axial α οne
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)
BrRO-
SN2
RO
OBnO
OBnOMe
OBn
BnONaH, BnBrOHO
OHOMe
OH
HO
DMF
Tetrabutylammonium iodide
O
OH
OMe
OHHO
HO Ph O CCl3
NH
CF3SO3H
O
OBn
OMe
OBnBnO
BnO
Cleavage
Palladium on carbon (Pd/C)
Palladium hydroxide (Pearlman’s catalyst) For the removal of sterically inaccessible/mul,ple benzyl groups
Cataly,c hydrogena,on
Heterogeneous catalyst
When the metal is distributed over finely-divided carbon, the surface area is larger and the catalyst is more reactive.
OR
MeO
para-methoxybenzyl (PMB)
O
O
CN
CN
Cl
Cl
DDQ
Ceric ammonium nitrate (CAN) (NH4)2Ce(NO3)6
2,3-‐Dichloro-‐5,6-‐Dicyanobenzoquinone
Single electron oxidising reagent
Trityl ethers
etc. etc.
Resonance stabilisationof the trityl cation
Triphenylmethyl ether
Very selec,ve for the primary hydroxyl group
Forma,on via an SN1 type process
By treatment of unprotected sugar
OHO
OHOMe
OHOH
Pyridine
Ph3CCl O
HO
OH
OMe
OCPh3OH
NaH
BnBr
O
BnO
OBn
OMe
OCPh3OBn
AcOH O
BnO
OBn
OMe
OHOBn
Silyl ethers
Si
R'
R''R'''ClR OH
-H+
Si
R'
R'' R'''
ClOR
'ate' complex
Si
R'
R''R'''
OR
NN HSi
Ph
But
But
Imidazole acts as a nucleophilic catalyst and forms intermediates, e.g.
OHO
OH
OMe
OH
HO
Pyridine
Me3SiCl OMe3SiO
OSiMe3
OMe
OSiMe3
Me3SiO
O
HO
OH
OMe
OH
HO
imidazole
ButPh2SiCl O
HO
OH
OMe
O
HO
Si
Trimethylsilyl (TMS)
Tert-‐Butyldimethylsilyl (TBDMS or TBS)
cleavage
Tetrabutylammonium fluoride (TBAF) Rela,ve rate of acid hydrolysis (stability increase in order)
R-OSiMe3
R-OSiMe2But
R-OSiPh2But
1
1E-3
1E-5
acid, may also cause removal of othe racid labile protec,ng groups
AcetylaKon� Acetals� Ether�
Ester � Nucleophilic SubsKtuKon� oxidaKon�
ReducKon�
O OR
= R---OBz
benzoyl ester
Removed by nucleophile
Potassium carbonate in methanol
Sodium methoxide in methanol (zémplen deacetyla,on)
Acetate, and
Most commonly methoxide in trans-‐esterifica,on rxn
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
ProtecKng group
Leaving group
S MeRO
O
O
mesylate
methanesulfonate
toluenesulfonate
SRO
O
O
tosylate
Me
trifluoromethanesuflonate
S CF3RO
O
O
triflate
O
OHOH
OMe
HO
HOSCl
O
O
pyridine, 0oC
O
OHOH
OMe
HO
TsO
AcetylaKon� Acetals� Ether�
Ester � Nucleophilic SubsKtuKon� oxidaKon�
ReducKon�
Nucleophilic subs,tu,on RXN
SN2 not SN1 β-‐oxygen effect
O
HO
LG
OMe
LG
HO
Nu
Retarded by the presence of electron withdrawing oxygen which are β to the carbon atom at which the displacement is taking place
Electron withdrawing effect greatly destabilises any carbonium in in SN1
O
OTs
OMe
DMF
NaN3OO
PhO
N3
OMe
OO
Ph
OHO
HO O
O Ph3P
Imidazole, I2
OI
HO O
O
O
OH
OMe
OO
Ph
TsO
KOH O
OOMe
OO
Ph
Nu-
NaN3 or
LiAlH4
O
OH OMe
OO
PhNu
Nu = N3 or H
SN2 trans trans
AcetylaKon� Acetals� Ether�
Ester � Nucleophilic SubsKtuKon� oxidaKon�
ReducKon�
Oxida,on
O
HO O
O
O
O
diacetone glucose
PCC
O
O O
O
O
O
NaBH4
O
HO O
O
O
O
diacetone allosePh3P=CH2
O
O
O
O
O
BH3
then
NaOH, H2O2
O
O
O
O
O
HO
PCC Oxida,on
Pfitzner–Moffa` oxidaKon
Swern oxidaKon
O
O
O
O
O
HODMSO
oxalyl chloride
O
O
O
O
O
O
H
RuCl3
NaIO4
O
O
O
O
O
O
OH
uronic acid
O
OH
OMe
OH
HOHO
Pt, O2O
OH
OMe
HO
HO
O
HO
SelecKve oxidaKon to primary hydroxyl group
O
OH
OH
OH
HOHO
HNO3
COOH
OHH
HHO
OHH
OHH
COOH
aldaric acid
HO
HO
I
O
OO
-O O
O
I
O
HO
HO
-O
O
O
Sodium periodate
O
OH
OH
OH
HO
OH
NaIO4O
OH
O
O
HO
OH
NaIO4
O
O
O
O
O
OH
+
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
HO O
O
O
O CS2, NaOH
then MeI
O
O O
O
O
O
MeS
S
Bu3SnH
AIBN
O
O
O
O
O
Barton-‐McCombie deoxygenaKon Xanthate ester
RO SMe
S
Bu3Sn
RO SMe
SBu3Sn
R H SnBu3
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