Protection chemistry

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Introduction

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Introduction

The part of organic syntheses where a-halo ethers are most frequently used, is probably in protection chemistry.[Greene, 1991] This is partly due to the high reactivity of a-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 a-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 a-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]

 

 

(2) Benzyloxymethyl chloride (BOMCl)

Since the introduction of a-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 Pd-C.[Tanner, 1987] BOMCl has also been used for protection of the p-system nitrogen of the histidine derivative 1, preventing side-chain induced racemization in peptide synthesis.[Brown, 1981]

 

 

(3) Metoxyethoxymethyl chloride (MEMCl)

An a-chloro ether that has been widely used to protect hydroxy groups, is the 2-metoxyethoxymethyl chloride 1 (MEMCl).[Corey, 1976] The MEM group can be introduced under basic condition. 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.

     

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 MEM-group is cleaved without affecting the methyl ether or the ester group. [Rigby, 1984]

(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.[Pinto, 1990] Thus the SEM protecting group in the sugar 2 is cleaved by 1.5 % HCl in MeOH.

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]

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]

     

(5) (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-t-butylsilyloxy)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]

 

(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 2 was effected by 1.2 -1.5 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room temperature.[Horita, 1986]

 

(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.

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]

 

(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.

 

(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 a-chloro ether 2 can be prepared by photochemical chlorination of t-butyl methyl ether 1 [Pinnick, 1978] or by cleavage of t-butyl methylthiomethyl ether 3 with SO2Cl2.[Jones, 1986]

 

(11) 2-Chlorotetrahydrofuran (THFCl)

A THF protected tertiary alcohol can be cleaved in the presence of a primary one.[Kruse, 1979]

 

(12) Ethoxyethyl chloride (EECl)

EE chloride has proven to be an effective reagent for the protection of the imidazole nitrogen.[Manoharan, 1988]

 

 

(13) b,b,b-Trichloroethoxymethyl chloride (TCEMCl)

TCEM ethers can be reductively removed under conditions that do not effect MOM ethers i. e. Zn in acetic acid.[Jacobson, 1979]

 

(14) (1R)-Menthoxymethyl chloride (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]

 

(15) Protection of carboxylic acids

The a-chloro ethers 1 have been used in the protection of carboxylic acids.[Alpegiani, 1984 #331]

 

(16) o-Nitrobenzyloxymethyl chloride

o-Nitrobenzyloxymethyl chloride has been introduced as a protecting group for ribonucleoside 2'-hydroxyls. This permits fast and effective solid phase synthesis of RNA. [Schwatz, 1992], [Gough, 1996]

 

(17) Protection of quinolones

[Horchler,2007].

(18) Protection of sulfur

Aromatic and aliphatic thiols can be protected by reaction with t-BuMe2SiOCH2Cl in DMF in the presence of a base.[Wang, 2011]