Download Lecture 8

Carbohydrate
Chemical Synthesis
March 31, 2015
Carbohydrates vs. Protein
•  Proteins and oligo-/polysaccharides
are biomacromolecules assembled
from basic building blocks (amino
Protein
acids and monosaccharides
CH3 H
respectively).
N
N
•  Their modular nature suggests both
H
O
classes of molecules as candidates
for stepwise synthetic strategies.
•  Residues in proteins are linked by
Carbohydrate
peptide (amide) bonds.
CH2OH
H
O H
•  Residues in oligo-/polysaccharides
H
OH H
are linked by glycosidic bonds.
O
O
H
OH
•  Unlike proteins which are linear,
oligo-/polysaccharides can be
branched.
O
OH
6
5
1
4
3
H
CH2OH
O H
H
OH H
2
O
H
OH
Glycosidic Bond
• 
• 
• 
• 
Glycosidic bonds are the
backbone linkages connecting
the monosaccharide residues in
oligo- and polysaccharides.
Cyclic monosaccharides are
essentially cyclic hemiacetals.
Glycosidic bonds are formed
when monosaccharides react
with other monosaccharides or
alcohols under acidic conditions,
forming a mixed acetal.
Glycosidic bonds can have either
α- or β-configurations.
H
CH2OH
O H
H
OH H
H
CH2OH
O H
H
OH H
O
HO
H
OH
OH
H
OH
Maltose: O-α-D-glucopyranosyl(1->4)-D-glucopyranose
H
CH2OH
O H
H
OH H
HO
H
OH
H
CH2OH
O H
H
OH H
HO
OH
OH
H
α-D-Glucopyranose
α-D-Glucopyranose
Glycosidic Bond
• 
Oligosaccharide synthesis requires:
I. 
A suitable glycosyl donor with an appropriate
leaving group on the anomeric carbon.
II.  Efficient and stereoselective coupling of the
glycosyl acceptor.
III.  Functional groups (-OH) on the glycosyl
acceptor and donor must be appropriately
protected.
R'O
1.) activation of
leaving group X
O
X
glycosyl donor
2.) nucleophilic
attack by -OH
HO
O
OR
glycosyl acceptor
R'O
O
O
OH
O
OR
Factors Influencing
Glycosidic Bond Formation
•  Neighboring group parNeighboring Groups:
ticipation (stereochemical):
O
O
–  Neighboring acyl groups at C2
O
O
position.
–  Formation of an acyloxonium Oxocarbenium
ion
ion intermediate.
–  Resulting dioxolenium ion
promotes 1,2-trans product.
•  Solvent affect:
O
O
O
O
Dioxolenium
ion
O
O
O
Solvent:
O
Et2O
XO
O
CH3CN
O
XO OR
Axial product
O
OX
O R
Orthoester
ROH
OEt2
–  CH3CN favors equatorial
product.
–  Et2O (in combination with
halogenated solvent)
promotes axial product.
1,2-trans product
O OR
ROH
O
ROH
XO N CCH
3
OR
XO
Equatorial product
Formation of 1,2-cis product
•  Participation of acyl groups in on C2 promote 1,2-trans glycosidation.
•  Preferential formation of 1,2-cis product presents a greater challenge.
–  A glycosidation reaction employing an SN2 mechanism could be used to
form the 1,2-cis product.
–  β-pyranosyl halides are too unstable for such an approach to be
practical.
–  α-pyranosyl bromides are less reactive than their β- analogs, but when
treated with tetraalkyl ammonium bromide, they form the β-anomer (in
in situ Anomerization
situ).
OBn
–  The β-anomer reacts
much faster than the αisomer, which results in
preferential formation of
the α-glycoside.
–  This strategy works well
with galactose and
fructose, but not with
glucose or mannose.
OBn
O
BnO
BnO
BnO Br
OBn
BnO
BnO
tight ion pair
in α-mode
R-OH
SN2-type
presence of
tetraalkylammonium
halide
O
R-OH
O Br
BnO
tight ion pair
in β-mode
OR
BnO
1,2-trans glycoside
BnO
BnO
SN1-type
Br
OBn
BnO
BnO
BnO Br
O
BnO
OBn
OBn
BnO
BnO
O
BnO
BnO
O
OBn
R-OH
BnO
SN1-type
R-OH
SN2-type
BnO
BnO
O
BnO OR
1,2-cis glycoside
Oxocarbenium Ion
O
+
OH H
O
H2O
Y
O
HO
O
Y
O
O
X
Glycosidic
Bond
Oxocarbenium
Ion
O
X
•  Three preferred synthetic strategies have been
developed that allow the synthesis of of most
oligosaccharides.
1.  Koenigs-Knorr type reactions employing glycosyl halides.
2.  Chemistry based on glycosyl trichloroacetimidates.
3.  Use of stable glycosides (i.e. thio- and n-pentenyl
glycosides)as glycosyl donors.
Common Abbreviations and
Protecting Groups
Me = Methyl
H3C
tBu = t-Butyl
Bn = Benzyl
Ac = Acetyl
O
H3C
H3C
H3C
H3C
PMB = p-Methoxybenzyl
Phth = Phthalimido
O
N
O
Isopropylidine
H3C
H3C
H3CO
N-protection
O
O
ketal
Koenigs-Knorr Method
OAc
AcO
AcO
OAc
HBr-HOAc
O
AcO
OAc
O
AcO
AcO
OAc
ROH
Ag2CO3, CH2Cl2
O
AcO
AcO
AcO
OR
AcO
Br
•  Oldest and most widely used chemistry for the stereospecific
formation of glycosidic bonds. (Koenigs & Knorr, 1901).
•  Utilizes glycosyl halides (Br, Cl or F) as glycosyl donors.
•  Order of reactivity: I>Br>Cl>F. (Glycosyl iodides are too reactive
for general use and glycosyl fluorides require special activation.)
•  Silver salts serve as promoters to generate oxocarbenium ion.
–  Insoluble salts: Ag2O and Ag2CO3
–  Soluble salts: AgOTf and AgClO3
•  Participating protecting groups @C2 position usually results in
exclusive formation of the 1,2-trans glycosides.
Koenigs-Knorr
•  Strategies have been
developed that utilize
mercury salts (HgBr2 and
Hg(CN)2) as activators.
•  Glycosyl bromides and
chlorides are readily
available from
peracetylated sugars or
those with free anomeric
-OH.
•  Two major disadvantages
associated with KoenigsKnorr chemistry:
OAc
CH3COCl
AcO
AcO
O
AcO
AcO
Oph
AcO
Cl
O
HO
HO
KOPh
AcO
OH
–  The intrinsic lability of
glycosyl halides.
–  Need for heavy metal salts in
near equimolar amounts.
OAc
O
OH
HO
OAc
D-glucose
CH3COBr
OAc
O
AcO
AcO
MeOH
Ag2CO3
AcO
O
AcO
AcO
OMe
AcO
Br
OAc
OAc
AcO
AcO
AcO
AcO
O
O
BnO
OH
O
AgOTf
PhtNH
O
PhtNH
BnO
O
O
O
OBn
Br
OBn
N
O
O
n-pentenyl glycoside
O
SR
alkyl thioglycoside
Br2
CH2Cl2
Br2/CH2Cl2
or
Bu4NBr/CuBr2
O
Br
Koenigs-Knorr
HF/Pyridine
(Glycosyl Fluorides)
CF3CHFCF2NEt2
O
O
OH
•  Glycosyl fluorides can be
prepared directly from
unprotected anomeric -OH
groups.
•  Can easily prepare β-glycosyl
fluorides.
•  Used more frequently than
other glycosyl halides.
•  Generally more stable to
hydrolysis under basic
conditions.
•  Require special promoter
chemistry:
DEAD/Ph3P/
Et3O+BF4-
OAc
OBn
AcO OBn
BnO
AcO
F
AcO
OAc
OAc
O
AcO
AcO
HF
OAc
AcO
AcO
Ac2O
AcO
AcO
H3C
O
O
X
F
X = Lewis acid or combination of Sn and Ag salts
O
OH
NPhth
O
O
OBn
OBn
OBn
Et2NSF3
BnO
OBn
AcO OBn
BnO
AcHN
O
BnO
AcO
Me
F
O
O
AcO
NPhth
O
OBn
O(CH2)6CO2tBu
NHAc
O
H3C
OBn
O
O
HO
OBn
OBn
OBn
O
O
O
O
O
HO OBn
OBn
MeO2C
OBn
OBn
AgOTf/HfCp2Cl2, CH2Cl2
4Å molecular sieves
BnO
OBn
AcO OBn
BnO
AcHN
O
BnO
O
AcO
Me
OBn
O
O
OBn
OBn
O
O
O
O
HO OBn
OBn
MeO2C
O
AcO
F
O
O
O
AcO
AcO
Br
O
O
AgF
OBn
MeO2C
BnO
AcHN
OAc
O
AcO
AcO
!  Lewis acids: BF3•Et2O, SnCl4,
AlMe3, TMSOTf or TiF4.
!  Alternatives: SnCl2/AgClO4,
SnCl2/TrClO4 or AgOTf
BnO
F
Et2NSF3 (DAST)
OBn
O
O
O
NPhth
AcO
H3C
OBn
O
O
OBn
OBn
O(CH2)6CO2tBu
NHAc
Glycosyl Trichloroacetimidates
•  The underlying chemistry of
forming glycosydic bonds via
glycosyl trichloroacetimidates is
similar to that of glycosyl
halides.
•  In glycosyl
trichloroacetimidates, the
anomeric oxygen is derivatized AcOAcO
providing a suitable leaving
group.
•  The anomeric -OH of an O–
BnO
protected reducing sugar is
BnO
deprotonated by treatment
with base (i.e. NaH, K2CO3 or
DBU).
•  The resulting oxyanion adds
across the triple bond of
trichloroacetonitrile.
AcO
AcO
O
K2CO3, CCl3CN
AcO
O
AcO
AcO
OH
AcO
O
CCl3
NH
BnO
BnO
O
BnO
BnO
NaH, CCl3CN
OH
BnO
O
BnO
O
CCl3
NH
Glycosyl
Trichloroacetimidates
•  Glycosyl trichloroacetimidates are
Ph
activated using
catalytic amounts O O
O
HO
of Lewis acid such AcO
BnO
AcO
as BF3•Et2O or
O
CCl
TMSOTf.
NH
•  These activated glycosyl
trichloroacetimidates are good
glycosyl donors requiring relatively
mild reaction conditions.
•  Normally, the glycosyl donor and
acceptor are combined in an inert
solvent (i.e. DCM or ACN) and the
Lewis acid catalyst is then added.
•  This chemistry usually results in good
yields in both small and large scale
reactions.
•  Donors with ether protecting groups
tend to be more reactive than
those with ester protecting groups.
Ph
OBn
BF3•Et2O
O
BnO
3
O
O
OBn
O
CH2Cl2
AcO
OBn
AcO
O
O
BnO
BnO
OBn
BnO
OBn
BnO
OBn
O
BnO
OBn
O
HO
BnO
O
BnO
O
O
BnO
N3
CCl3
OBn
NH
TMSOTf
Et2O, -20°C
BnO
OBn
O BnO
BnO
OBn
OBn
O
BnO
O
BnO
O
BnO
O
N3
OBn
•  Thioglycosides are widely used
as glycosyl donors in the
synthesis of oligosaccharides.
•  Thioglycosides are versatile
glycosyle donors, stable in the
absence of thiophilic promoters.
•  Thioglycoside formation:
–  Glycosyl halides and acetates
can be converted to
thioglycosides using thiolate
ions) and catalytic Lewis acid.
–  Tin-mediated thioalkylation
(Bu3SnSR) can be used to
prepare thioglycosides from
glycosyl halides and acetates.
–  Glycosyl acetates can be
converted directly to thioglycosides using an alkyl/aryl thiol
and catalytic Lewis acid.
–  Trimethylsilyl thiothers in and
catalytic Lewis acid can be
used to form thioglycosides from
glycosyl esters.
Thioglycosides
OAc
OAc
O
AcO
AcO
OAc
X
X
Bu3SnSR
SnCl4
Br
– OR –
TMSSR
BF3•Et2O
1.) MeSH, K, MeOH
2.) Ac2O, NaOAc
OAc
– OR –
TiCl4
EtSH
O
AcO
AcO
SR
X
alkyl/aryl
β-D-thioglucopyranoside
– OR –
RSH
BF3•Et2O
X = OAc or NHPhTh
OAc
OAc
p-NO2PhSH, NaH
O
AcO
AcO
O
AcO
AcO
AcO
O
AcO
AcO
HMPA
Cl
AcO
SPhNO2
OAc
BF3•Et2O, EtSH
O
AcO
AcO
O
AcO
AcO
HMPA
AcO
AcO
SEt
OAc
Thioglycosides
•  Thiophilic promoters that
can be used to activate
thioglycosides include:
–  Sources of Br+ (Br2/AgOTf, N–
bromosuccinimide)
–  Alkylating agents (i.e.
MeOTf).
–  Sulfenylating agents (i.e.
DMTS).
O
O
Br+
SR
O
R'OH
OR'
[Me2SSMe]+TfO-
SMe
O
O
OBn
OAc OAc
AcO
O
AcO
AcO
AcO
O
SMe
O
HO
BnO
O
BnO
OBn
OAc
CuBr2
Et4NBr
AgOTf
OAc OAc
AcO
OR'
OTf
OTf
•  Glycosidation is believed
to occur through formation
of oxocarbenium ion.
•  Selection of reaction
conditions and promoter
chemistry can be used to
control anomeric
preferences.
DMTS:
O
R'OH
S R
OBn
O
AcO
AcO
AcO
O
O
O
BnO
O
BnO
OBn
OAc
dimethyl(methylthio)sulfonium triflate
Thioglycosides
CO2Me
•  The stability of thioglycosides
provides greater flexibility and
utility.
•  Highly specific methods have
been developed for activation.
•  In the absence of thiophilic
promoters:
OBn
O
O
O
BnO
O
BnO
O
HO
BnO
SR
BnO
NH
CCl3
TMSOTf
CO2Me
OBn
–  Thioglycosides are stable to
activation conditions associated
with glycosyl donors such as
glycosyl trichloroacetimidates.
–  Thioglycosides are also stable to
OH
alkaline conditions associated
with the removal acetyl
HO
protecting groups.
–  Stability allows removal and
replacement of O-protecting
OAc
groups.
O
O
O
O
AcO
O
BnO
AcO
BnO
SR
OH
1. DMP, acetone, pTsOH
2. 4,4'-MeOTrCl, pyridine, 70°C
O
SR 3. NaH, PMB-Cl, DMF
4. HCOOH, CH2Cl2
5. AcCl, pyridine, CH2Cl2
HO
O
O
SR
PMBO
OBz
O
SR
AcO
OAc
O
O
1. NaOMe/MeOH
2. DMP, pTsOH
3. BzCl, pyridine
OAc
O
SR
O
NPhth
NPhth
Thioglycosides
OAc
•  Thioglycosides are
exceptionally versatile
molecules.
•  Thioglycosides can be
converted to
alternative activated
glycosyl donors (i.e.
halides and trichloroacetimidates).
•  Thioglycosides can
also be used to
generate glycosyl
acetates.
AcO
AcO
OAc
AcO
AcO
O
AcO
OAc
OAc
O
AcO
OH
AcO
AcO
RSH, R=Ph or Et
BF3•Et2O
O
AcO
Br
NBS
H2O
Br2
OAc
AcO
AcO
NIS
AcOH
O
SR
AcO
alkyl/aryl
β-D-thioglucopyranoside
NBS
DAST
OAc
OAc
AcO
AcO
R'OH
promotor
O
AcO
OAc
AcO
AcO
O
AcO
OAc
AcO
AcO
O
AcO
OR'
NBS = N-bromosuccinimide
DAST = diethylaminosulfur trifluoride
NIS = N-iodosuccinimide
F
Glycals
OR
OR
RO RO
OR
RO RO
E
O R'OH
E+
E
OR
O
O
red.
RO
RO
RO
RO
OR'
O
OR
OR
O O
O
RO RO
OR'
ZnCl2
R'OH
O
RO
RO
OR'
O
•  The glycal method originally used in the synthesis of 2–
deoxyglycosides.
•  Strategy capitalizes on the electron-rich olefin of the enol
ether present in glycals.
•  A 3-membered onium ion species can be generated by
treating the glycal with an elecrophile (E+). (Suitable
lectrophiles include: N-iodosuccinimide, phenylselenyl chloride
or phenylsulfenyl chloride.)
•  The onium speices is then glycosidated. (usually results in αconfiguration)
•  The elcrophile, E, can then be reductively removed to afford
the 2-deoxyglycoside.
Glycals
OR
OR
RO RO
OR
RO RO
E
O R'OH
E+
E
OR
O
O
red.
RO
RO
RO
RO
OR'
O
OR
OR
O O
O
RO RO
OR'
ZnCl2
R'OH
O
RO
RO
OR'
O
•  While glycals were originally used in the synthesis of 2deoxyglycosides, Danishefsky and coworkers devised a
glycal strategy that afforded 2-hydroxyglycosides.
•  Glycals are initially treated with dimethyldioxirane which
transfers an oxygen bond to the glycal resulting in an epoxide.
•  The epoxide is then activated using a Lewis acid such as ZnCl2.
•  The glycosidic bond is then formed by treating the activated
epoxide with the desired acceptor.
•  This strategy usually affords β-glycosides.
•  Glycosyl epoxides are relatively stable and they can be
isolated.
Carbohydrate Protecting
Groups
Selective hydroxyl group
protection and deprotection
Protecting Groups in
Carbohydrate chemistry
•  Amino acids and
proteins have a range
of functional group
chemistries.
•  Carbohydrate
protecting group
chemistry is a matter
of differentiating
between -OH groups.
– 
– 
– 
– 
– 
The anomeric -OH
1 vs 2 alcohols
Equatorial vs axial diols
Vicinal diols
Cis- vs trans- diols.
OH
O
HO
HO
OH
OH
OH
OH
O
OH
HO
OH
Ethers
Acetals
Esters
O
O
O R
O
R
O
R
R
Protection at the Anomeric Center
Hemiacetal
•  Due to the reactivity of the
anomeric center, it is usually
protected before other -OH
groups.
•  Glycoside protection chemistry
should be stable to a range of
conditions, but must allow for
selective deprotection of the
anomeric group.
•  The simplest strategy is to generate
the acetal (the glycoside) via acidcatalyzed reaction with an alcohol
(Fischer glycosylation).
O
HO
HO
OH
OH
H+
H2O
OH
OH
O
HO HO
HO
O
HO HO
Oxocarbenium ion
HO
ROH
H+
Glycoside (acetal)
OH
O
HO
HO
OR
OH
OH
OH
Deprotection
–  Limited to low-boiling alcohols
(methanol, ethanol and alllyl
alcohol).
–  Acidic ion-exchange resin is usually
used as the acid catalyst.
–  Yields a mixture of anomers.
Usually the most stable product is
formed in excess.
OH
O
HO
HO
O
HO
HO
OR
OH
OH
OH
R = ME: strong acidic conditions and high
temperature.
Allyl: [Pd], p-TsOH and elevated
temperature.
Benzyl: [Pd], H2, room temperature.
Alternative Strategies for
Protection of Anomeric OH
•  For oligosaccharides it is often
necessary to resort to protection
schemes that allow for selective
deprotection of the anomeric OH using mild conditions.
•  2-(trimethylsilyl)ethyl (TMSET)
glycosides meet this
requirement.
•  Easily formed using standard
Koenigs-Knorr glycosylation
chemistry and 2-(trimethylsilyl)
ethanol.
•  Compatible with most
deprotection and glycosylation
reaction conditions.
•  Can be converted to glycosyl
halides, free -OH and 1-O-acyl
derivatives.
OAc
OAc
O
AcO
AcO
AcO
SiMe3
HO
SiMe3
O
AcO
AcO
Ag-salt
O
AcO
Br
1. NaOMe, MeOH
2. "protecting steps"
OR
SiMe3
O
RO
RO
O
RO
Cl2CHOCH3
ZnCl2
BF3•Et2O
Ac2O
OR
TFA
OR
O
RO
RO
RO
O
RO
RO
OR
Cl
O
RO
RO
OH
RO
OAc
RO
Alternative Strategies for
Protection of Anomeric OH
•  Silyl ethers are frequently
used for the protection of
alcohols.
•  They are stable to conditions
involved with removal of Acprotecting groups and
thioglycoside chemistry.
•  TBSOtf is a very reactive
reagent for silylation of
alcohols.
•  Can be selectively removed
under mild conditions using
TBAF (fluoride source).
OBn
O
AcO
BnO
PhSO2 NH
OBn
O
AcO
BnO
PhSO2 NH
TBSOTf, 2,6-lutidine
CH2Cl2
OH
OTBS
TBAF, AcOH
TBSOTf = tert-butyldimethylsilyl triflate
TBAF = tetra-N-butylammonium fluoride
2,6-lutidine =
OBn
N
O
AcO
BnO
PhSO2 NH
OH
Acyl Protecting Groups
Ac2O R = Ac
•  Acyl-based protecting groups
are frequently used in
carbohydrate chemistry.
•  Complete acetylation of an
unprotected monosaccharide
using Ac2O is often an initial
synthetic step. (per
benzoylation may also be
implemented).
•  Esters are readily cleaved under
basic conditions.
•  Rather than saponification, a
transesterification procedure is
used (Zemplén procedure).
•  Benzoates are generally slower
to deprotect than acetates.
BzCl
OH
R = Bz
OR
O
HO
HO
O
RO
RO
OH
HO
OR
RO
NaOMe, MeOH
O
R OH
R O
N
N
O
O
O
O
O
O
O
O
O
O
Acetate group
Benzoylate group
O
O
Pivaloate group
Selective Acylation
OH
OH
O
HO
HO
Pyridine, CH2Cl2
-40°C
OCH3
BzO
BzO
O
HO
HO
O
BzCl
OAc
OH
OBz
OH
HO
OCH3
~90%
AcCl
Pyridine
OH
O
AcO
AcO
OAc
AcO
O
O
OAc
HO
OH
HO
O
O
AcO
HO
•  Regioselective acylation provides route to selective
protection patterns.
•  At lower reaction temperatures, primary and equatorial OH groups are usually benzoylated before axial ones.
•  Order of reactivity of the -OH groups on a pyranose ring
will vary depending on the sugar.
•  Sterics can play a significant role when acylating
oligosaccharides.
•  Acyl groups can migrate (change position inter and
intramolecular). Acetyl groups are most prone to
migration. Benzoyl groups to a lesser extent and pivaloyl
groups essentially do not migrate.
Selective Deacylation
•  An assortment of methods have been
developed for the selective deacylation of the
anomeric center.
•  Generally 1 equivalent of base is used.
–  Acetyl esters: hydrazine acetate, hydrazine hydrate,
piperidine and 2-amino ethanol, or ethylenediamine/
AcOH.
–  Benzoyl esters: ethanolic dimethylamine in pyridine.
•  Removal of anomeric benzoyl groups generally
takes longer than the removal of acetyl groups.
OAc
OAc
O
AcO
AcO
OAc
AcO
1 equiv. base
O
AcO
AcO
OH
AcO
Ether Protecting Groups
•  Alkyl ethers are generally very stable and resistant to
strong base/acid. (making them too stable)
•  Benzyl and allyl ethers are the ether variants used
most frequently.
•  Ether and ester derivatives combine to provide
orthogonality in protection chemistry.
•  Ethers can be formed using Williamson reaction
conditions (NaH or NaOH and an alkyl/aryl halide-Br
or Cl). [these conditions may not be suitable for most
ester protecting groups.]
R=
O
1. base (NaH or NaOH)
OH
O
OR
2. R-Hal (Hal = Cl or Br)
Benzyl ether (Bn)
Ether Protecting
Groups
•  Benzyl ethers:
✽  Removed by
catalytic
hydrogenation (10%
Pd-C). Usually results
in quantitative
deprotection.
✽  Substituted benzyl
ethers occassionally
used (i.e. pmethoxybenzyl
[pMBn])
✽  pMBn can be
oxidatively removed
using CAN or DDQ.
(Bn ethers stable to
these conditions.)
• Allyl ethers:
Allyl ether
p-Methoxybenzyl ether
OAc OBn
OAc OBn
AcHN
O
pMBnO
O
AcO
AcO
OR
O
AcO
O
AcHN
O
DDQ, CH2Cl2, H2O
HO
OR
O
AcO
OBn
OBn
O
NC
Cl
2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ)
NC
Cl
O
Allyl ether
OAc
OAc
O
AcO
AcO
AcO
Isomerization
O
OAc
O
AcO
AcO
AcO
Mild acid
O
O
AcO
AcO
OH
AcO
(2-propenyl ether)
✽  Cleaved under mild conditions and compatible with most protection,
deprotection and glycosylation chemistries.
✽  Allyl groups are converted to 2-propenyl ethers (isomerization) by
treating with metal catalyst: Pd(0), Rh(I) or Ir(II).
✽  2-propenyl ether readily hydrolyzed with mild acid.
✽  Alternative: in presence of sensitive groups (isopropylidienes) a mixture
of HgO and HgCl2 in aqueous acetone for enol cleavage.
Ether Protecting Groups
(Trityl ethers)
•  Trityl ethers: selective for
• 
• 
• 
• 
primary alcohols.
Introduced under basic
conditions (pyridine) and trityl
chloride.
Trityl groups can be cleaved
under mild acidic conditions
(mineral acid in ether).
Cleavage conditions may be
mild enough to leave
isopropylidene groups intact.
Substituted trityl groups can be
used for even milder
deprotection conditions (silica
gel or Lewis acid).
•  Silyl ethers: becoming
• 
• 
• 
• 
• 
(OTr or OTrt)
OH
O
Ph3CCl
DMAP, pyridine
O
HO
HO
HO
O
HO
HO
HO
OCH3
OCH3
Trityl chloride
OCH3
Cl
OCH3
H3CO
Cl
Cl
Monomethoxytrityl (Mmt)
chloride
increasingly important as hydroxyl
protecting groups.
Large number of variations
demonstrating a range of
reactivities and stability.
Generally prepared using
appropriate silyl chloride (or
triflate) and base (pyridine or
imidazole) in DMF. (May also use
hexamethyldisilazane in DMF.)
t-Butyldimethylsilyl (TBDMS or
TBS)group is commonly used in silyl
ethers.
Silyl ethers can be deprotected
under acidic conditions or with
fluoride ions (tetrabutylammonium
fluoride).
Deprotection with fluoride allows
removal of silyl ethers in the
presence of acid sensitive groups.
Dimethoxytrityl (Dmt)
chloride
Ether Protecting
Groups (Silyl ethers)
R3Si-Cl
OH
base
O-SiR3
acid or
OH
fluoride
OH
TBDMS-Cl
O
HO
HO
pyridine
HO
OCH3
OTBDMs
O
HO
HO
HO
OTBDMs
O
HO
HO
TBDMSO
TBDMS-Cl
imidazole, DMF
OCH3
TBDMS-Cl allows for selective
protection of primary OH.
Use of imidazole as a catalyst
results in 2,6-O-silylated product
OCH3
Acetal/Ketal Protecting Groups
•  Cyclic acetals/ketals
allow the simultaneous
protection of two
hydroxyl groups.
•  The most common
examples are
isopropylidene and
benzylidene derivatives.
•  Acetal/ketal formation is
generally an acid
catalyzed process.
•  Acetal/ketal protecing
groups are stable to
nucleophiles and basic
conditions, but are acid
labile.
O
H3C
O
CH3
CH3
CH3
O
isopropylidene
OH
OH
O
H
O
O
H
benzylidene
Benzylidene Acetals
•  Benzylidene acetals
mostly form 6membered rings with
the phenyl group in an
equatorial position.
•  Generally prepared
using free sugar,
benzaldehyde and
ZnCl2 catalyst.
•  Generally used for 4,6O-protection in
hexopyranosides.
•  Can form either cis- or
trans-fused rings. (trans
generally hydrolyze
more quickly.)
H
Ph-CHO
ZnCl2
O
HO
HO
trans-fused
Ph
OH
O
O
O
HO
HO
HO
OCH3
OCH3
Ph
H
OH
OH
O
Ph-CHO
ZnCl2
O
cis-fused
O
O
HO
HO
HO
HO
OCH3
OCH3
OH
O
HO
HO
OH
HO
O
O
HO
OH
HO
H
Ph
Ph-CH(OMe)2
O
O
O
OH
HO
p-TsOH
HO
O
O
HO
OH
HO
Benzylidene Removal
OH
•  Benzylidene groups can
be removed using acidic
conditions or by
hydrogenation.
•  Additional (selective)
cleavage chemistries:
✽  Radical oxidative opening
(NBS).
✽  Reductive opening with LAH
& AlCl3 in ehter.
✽  Reductive regioselective
opening of the aetal using
sodium cyanoborohydride in
HCl-ether.
OH
O
HO
O
BzO
RO
RO
RO
RO
OCH3
H2, Pd(OH)2
EtOH
OCH3
NBS, CCl4 Δ
H
Ph
O
O
O
RO
RO
OCH3
NaCNBH3, THF
HCl-Et2O
LAH, AlCl3
ether
OBn
OH
O
HO
O
BnO
RO
RO
RO
RO
OCH3
OCH3
Isopropylidine Ketals
•  Often used in the
protection or cis-1,2-diols.
•  Introduced using dry
acetone and an acid or
Lewis acid catalyst (ZnCl2).
•  5-membered dioxolane
rings are generally formed
•  Can also be introduced
via transacetalization and
2,2-dimethyloxypropane.
•  2-methyloxypropene can
be used, tends to form 1,3dioxane rings.
2,2-dimethyloxypropane
O
H3C
CH3
H3CO
OCH3
H3C
CH3
2-methyloxypropene
OCH3
O
Thermodynamic
control
Kinetic
control
OCH3
-orO
CH3
H3CO
OCH3
H3C
CH3
CH3
H3C
O
OH
O
O
OH
HO
O
HO
HO
CH3
HO
[H+]
OH
HO
O
H3C
CH3
H3C
O
H3C
O
OH
O
O
O
CH3
CH3
Isopropylidine Ketals
•  Use of varied Lewis acids
with acetone can result
in formation of different
isopropylidenes.
O
Acetone
10% H2SO4
H3BO4
O
O
O
O
O
HO
•  Acetalization of
unprotected pyranoses/
furanoses/ alditols affords
useful propylidene
protected building
blocks with limited
numbers of free OH
groups.
HO
OH
HO
OH
OH
D-mannitol
O
O
OH
Acetone
HO
ZnCl2
O
O
Selective Hydrolysis of
Isopropylidenes
•  Isopropylidene groups are
removed under acidic conditions
(i.e. AcOH, H2SO4 in MeOH or silica
gel).
•  Conditions have to be optimized
for specific isopropylidene
derivatives.
•  Optimization of conditions can
allow for the selective removal of
one or more isopropylidene
groups while leaving others intact.
•  In pyranoses and furanoses, a 1,2O-isopropylidene is generally more
stable than are isopropylidenes at
other positions.
•  Five-membered dioxolanes are
more stable than 6 membered
dioxanes.
HO
aqueous acid
HO
O
O
OH
OH
O
O
O
O
O
O
1,2:3,4:5,6-tri-O-isopropylidene D-glucitol
HO
HO
OH
acetone
HO
dry HCl gas
OH
OH
D-mannitol