Download 4. a-Monohalo Ethers in Protection Chemistry

Protection Chemistry
Introduction
The part of organic syntheses where -halo ethers are most frequently used, is probably in
protection chemistry.[Grenne, 1991] This is partly due to the high reactivity of -halo ethers in
nucleophilic displacement reactions, which in many cases assures a complete introduction of the
protecting group. Another point of great importance in protection chemistry, is the removal of the
protecting group. Those derived from -halo ethers are often easily removed, e.g. the acetal
carbon, which is formed from the protection of an alcohols, is readily cleaved under mild acid
conditions.
(1) Methoxymethyl chloride (MOMCl)
The -halo ethers that first was used as a protective reagent was methoxymethyl chloride 2
(MOMCl) in the early seventies.[Kluge, 1972] Since then it has been extensively used for
protection of alcohols (MOM ethers) and a number of cleavage methods for MOM ethers have
been deviced.[Kluge, 1972] Mild acid conditions being the most general. Selective removal of
MOM ethers has been done in the presence of acetonides.[Woodward, 1981] Monoprotection of
the diol 1 has been achieved with MOMCl.[Ihara, 1988]
Bn
OH
N
+
OH
1
ClCH2OMe
NaH
Bn
OMO
M
N
61 %
2
OH
MOMCl
(2) Benzyloxymethyl chloride (BOMCl)
Since the introduction of -halo ethers into protection chemistry they have been developed to
meet special needs. For instance the benzyloxymethyl ethers (BOM ethers), which are usually
prepared in good yields by reacting benzyloxymethyl chloride 2 (BOMCl) with the alcohol under
basic conditions,[Krebs, 1992] can be selectively removed with H2 in the presence of PdC.[Tanner, 1987] BOMCl has also been used for protection of the -system nitrogen of the
histidine derivative 1, preventing side-chain induced racemization in peptide synthesis.[Brown,
1981]
BocNH
BocNH
CO2Me
N
+
ClCH2 OBn
N
Boc
1
1. Et2O, 20 o C
2. NEt3, MeOH
CO2Me
BO
NM
62 %
2
N
BOMCl
(3) Metoxyethoxymethyl chloride (MEMCl)
An -chloro ether that has been widely used to protect hydroxy groups, is the 2metoxyethoxymethyl chloride 1 (MEMCl).[Corey, 1976] The MEM group can be introduced
under basic condition as for BOMCl. Standard conditions to remove the MEM group is treatment
with ZnBr2 in dichloromethane.[Smith, 1987] However, treatment of the MEM-protected diol 2
with ZnBr2 in EtOAc resulted in 1,3-dioxolane formation.[Boynton, 1992] A proposed
mechanism for this reaction has been given.
ClCH2 OCH2 CH2OCH3
1
MEMCl
O
O
ZnBr 2
EtOAc
MEMO
O
OMEM
O
2
O
CH O
O
O
ZnBr 2
CH OMEM
CH O
CH O
CH2
O
Zn
O
Br
O
Br
It has also been reported that the MEM group could not be removed with ZnBr2.[Yasumori,
1984],[Ireland, 1981] Other cleaving agents has been developed,[Corey, 1976],[Barton, 1972],
[Rigby, 1984] sometimes showing good selectivity for cleaving the MEM group as seen in the
reaction of the MEM-protected alcohol 3 with trimethylsilyl iodide in acetonitrile. The MEMgroup is cleaved without affecting the methyl ether or the ester group. [Rigby, 1984]
OMe
OMe
Me3SiI, NaI
MeCN
- 20 oC, 15 min
79 %
MEMO
HO
O
O
O
O
3
(4) 2-(Trimethylsilyl)ethoxymethyl chloride (SEMCl)
2-(Trimethylsilyl)ethoxymethyl chloride 1 (SEMCl) [Lipshutz, 1980] have gained wide
popularity in the protection of alcohols for several reasons: the SEM ethers are easily prepared,
[Lipshutz, 1980] they are stable to a number of synthetic transformations and they are easily
removed. [Lipshutz, 1980] In carbohydrate chemistry the SEM group has shown distinct
advantages over groups such as the MEM and the MOM groups, because the SEM group is
removed under milder acidic conditions.[πinto, 1990] Thus the SEM protecting group in the
sugar 2 is cleaved by 1.5 % HCl in MeOH.
ClCH2 OCH2 CH2SiMe3
1
SEMCl
Me
BnO
HO
OAll
OBn
94 %
SEMCl
i-Pr2NEt, CH2Cl2
HCl in MeOH (1.5 %),
16 h
BnO
OAll
Me
SEMO
OBn
80 %
2
The SEM protected carboxylic acid 3 is stable enough for chromatography, but are readily
deprotected without affecting either acid or base-sensitive functionalities. It has been suggested
that the very easy solvolysis of the SEM group in the case above, is due to anchimeric assistance
by the phosphate group.[Logusch, 1984]
O
O
C OSEM
MeOH
C OH
OPO3Ph2
OPO3Ph2
3
H
O
C O
O
O
P
PhO
SiMe3
O
OPh
The SEM group has also been utilized in the protection of nitrogen atoms in a variety of
heterocyclic compounds [Muchowski, 1984], [Kline, 1985], [McCharthy, 1985], [Lipshutz,
1986],[Matthews, 1987] In the SEM protected indole 4 the aminal oxygen is used to direct
lithiation to the 2-position.[Edwards, 1986] A similar approach has been used in pyrroles and
imidazoles.[Edwards, 1986], [Whitten, 1986], [Edwards, 1983]
n-BuLi, DME
- 20 o C to - 5 oC
Li
N
N
O
OSEM
SiMe3
4
Me3SiCl
- 20 o C to - 10 oC
57 %
SiMe3
N
OSEM
(4) (Dimethyl-t-butylsilyloxy)methyl chloride (SOMCl)
The usual was to cleave SEM ethers is by treatment with fluoride ions. It has, however, been
reported that fluoride cleavage of SEM ethers has failed.[Kozikowski, 1987] In such cases and for
the protection of sterically hindered alcohols a related protective reagent, (dimethyl-tbutylsilyloxy)methyl chloride 1 (SOMCl), has been developed.[Gundersen, 1989] The SOM
ethers are cleaved under conditions where the SEM ethers are stable, i.e. tetraethylammonium
fluoride in acetonitrile [Gundersen, 1989] SOMCl can also be used in the protection of nitrogen
atoms as demonstrated in a selective synthesis of the N3-alkylated thymine 2.[Benneche, 1988]
ClCH2 OSiMe2 -t-Bu
1
SOMCl
OTMS
Me
N
+ ClCH2 OSiMe2 -t-Bu
TMSO
N
CH3 CN
0 oC to r.t.
20 h
54 %
1
ClCH2 OBn
NaH, DMF
r.t., 4 h
48 %
OBz
O
N
SOM
Me
N
Me
HN
O
N
O
O
Bu4NF, THF
r. t., 75 min
63 %
SOM
OBz
O
Me
N
O
N
H
2
(6) p-Methoxybenzyloxymethyl chloride (PMBMCl)
Protection of alcohols as their p-methoxybenzylmethyl ethers (PMBM ethers) has been found
useful where SEM ethers could not be cleaved off at the end of the synthesis. PMBM ethers are
prepared by reacting p-methoxybenzyloxymethyl chloride 1 (PMBMCl)[Benneche, 1983] with
the alcohol in dichloromethane, using diisopropylethylamine as a base. Deprotection of the
PMBM ether 2was effected by 1.2 -1.5 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) at room temperature.
ClCH2OCH2
OMe
1
PMBMCl
OH
ClCH2OCH2PhOMe-p
(i-Pr)2 NEt, CH2 Cl2
r.t., 5 h
N
Ts
DDQ, CH2 Cl2-H2 O
r.t., 2 h
63 %
PMBM
N
Ts
2
96 %
(7) Guaiacolmethyl chloride (GUMCl)
Reaction of guaiacolmethyl chloride 1 (GUMCl) with alcohols affords the corresponding ethers
in high yield under standard basic conditions.[Loubinoux, 1981] Using phase transfer catalysis a
primary alcohol 2 can be protected in the presence of a secondary alcohol 3.
MeO
ClCH2O
1
GUMCl
OH
OH
+
2
ClCH2 OC6H4OMe-o
50 % NaOH, benzene
Bu4N+HSO4-
3
OH
OGUM
+
80 %
The GUM ether is readily cleaved by ZnBr2 in dichloromethane at 25 oC.
(8) p-Anisyloxymethyl chloride (p-AOMCl)
An isomer of GUM chloride, p-anisyloxymethyl chloride 1(p-AOMCl) has also been used as a
protecting reagent for alcohols. Deprotection is effected by oxidation with ceric ammonium
chloride (CAN).[Masaki, 1989]
ClCH2O
OMe
1
p-AOMCl
(9) (Phenyldimethylsilyl)methoxymethyl chloride (SMOMCl)
Sugar hydroxyls have been protected with (phenyldimethylsilyl)methoxymethyl chloride 1
(SMOMCl).[Boons, 1990] The SMOM ether in 2 can be removed selectively in the presence of
benzyl ethers by oxidation with KBr/AcOOH. It is also stable to Bu4NF for 15 h at 20 oC.
ClCH2 OCH2 SiMe2Ph
1
SMOMCl
OSMOM
BnO OBn
O
BnO
AcOOH, KBr
AcOH/AcONa
20 oC, 1.5 h
OH
BnO OBn
O
BnO
92 %
OMe
OMe
2
(10) t-Butoxymethyl chloride
t-Butoxymethyl chloride 2 has been recommended as a reagent for the protection of
alcohols[Pinnick, 1978] and histidine side-chains.[Colombo, 1984] The -chloro ether 2 can be
prepared by photochemical chlorination of t-butyl methyl ether 1 [πinnick, 1978] or by cleavage
of t-butyl methylthiomethyl ether 3 with SO2Cl2.[Jones, 1986]
t-Bu
OCH3
1
NCS
CCl4
UV
t-Bu
OCH2 Cl
2
SO2Cl2
CH2 Cl2
r.t., 30 min
90 %
t-Bu
OCH2 SCH3
3
(11) 2-Chlorotetrahydrofuran (THFCl)
A THF protected tertiary alcohol can be cleaved in the presence of a primary one.[Kruse, 1979]
Cl
O
THFCl
(12) Ethoxyethyl chloride (EECl)
EE chloride has proven to be an effective reagent for the protection of the imidazole
nitrogen.[Manoharan, 1988]
Me
Cl
OEt
EECl
(13-Trichloroethoxymethyl chloride (TCEMCl)
TCEM ethers can be reductively removed under conditions that do not effect MOM ethers i. e. Zn
in acetic acid.[Jacobsen, 1979]
ClCH2 OCH2 CCl3
TCEMCl
(14) (1R)-Menthoxymethyl chlolride (MMCl)
The MM ether from the reaction of the chiral MMCl with (S)-ethyl lactate, has been used as a
simple means of measuring enantiomeric excess in a reaction sequence.[Dawkins, 1992]
ClCH2O
MMCl
(15) Protection of carboxylic acids
The -chloro ethers 1 have been used in the protection of carboxylic acids [Alpegiani, 1984
#331].
R
Me
R = H, Cl, NHAc, NO 2
O
1
Cl