The trimethylsilyl xylyl (TIX) ether: a useful protecting group for alcohols

A new protecting group for alcohols, the p-trimethylsilyl xylyl (TIX) group has been developed. The TIX group is used to protect various alcohols under acidic as well as basic conditions. The protected ethers thus formed had noteworthy chemoselectivity upon deprotection in the presence of other benzyl ethers and commonly used protecting groups. The stability of the TIX group towards various reagents has also been examined.     

Fluorous dimethylthiocarbamate (DMTC) protecting groups for alcohols

N,N-Bis(perfluoroalkyl)thiocarbamoyl chlorides (^FDMTC-Cls) were synthesized as reagent for the protection of alcohols. Using the crystalline ^FDMTC-Cls, the ^FDMTC groups were introduced into the alcohol molecules in excellent yields in the presence of sodium hydride in THF at room temperature. The products were separated from the excess alcohols by solid-phase extraction with a fluorous reverse-phase silica gel column (Fluorous Solid Phase Extraction; FSPE). The ^FDMTC groups were readily removed by oxidation with m-chloroperbenzoic acid (m-CPBA) and subsequent hydrolysis with KHCO₃.     

2-(Prenyloxymethyl)benzoyl (POMB) as a new temporary protecting group for alcohols

The 2-(prenyloxymethyl)benzoyl (POMB) group was introduced in high yields to hydroxyl functions using the crystalline reagent, 2-(prenyloxymethyl)benzoic acid, in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). 2-(Prenyloxymethyl)benzoic acid is readily available, in two steps, from phthalide in 65% overall yield. The POMB group can be cleaved, in two steps, by treatment with 2,3-dichloro-5,6-dicyanoquinone (DDQ) followed by intramolecular lactonisation of the resulting hydroxy ester induced by a catalytic amount of Yb(OTf)₃·H₂O. The reaction conditions are compatible with the presence of a number of protecting groups such as isopropylidene, benzyl, acetyl, chloroacetyl, benzoyl, levulinoyl, Fmoc and Boc groups.     

4-(tert-Butyldimethylsilyloxy)benzylidene acetal: a novel benzylidene-type protecting group for 1,2-diols

A novel 1,2-diol-protecting group, p-silyloxybenzylidene group, has been developed. In addition to the stepwise deprotection conditions including desilylation and the subsequent acidic hydrolysis of the p-hydroxybenzylidene group in AcOH-THF-H₂O, we have established the one-pot deprotection under basic conditions [K₂CO₃ (5 equiv), NH₂OH·HCl (5 equiv), and CsF (1 equiv) in MeOH-H₂O].     

1-Methyl 1′-cyclopropylmethyl (MCPM) as an anomeric protecting group

A pragmatic approach for preparing glycoconjugates of complex oligosaccharides is to prepare the oligosaccharide as a building block with most of its protecting groups exchanged to protecting groups whose cleavage and other manipulations are highly compatible with the functional groups of complex aglycones. For such an approach the reducing end sugar of the building bloc must be protected with a cleavable protecting group during the oligosaccharide synthesis. We demonstrate that the acid labile 1-methyl 1′-cyclopropylmethyl (MCPM) can be effectively used for this purpose. A trisaccharide glycolipid and a disaccharide glycoamino acid are prepared. The absolute chirality of the MCPM in one key acceptor is determined by a combination of NMR NOE measurements, DFT molecular modeling and Noyori catalyst catalyzed asymmetric reduction.     

The methylsulfonylethoxymethyl (Msem) as a hydroxyl protecting group in oligosaccharide synthesis

The methylsulfonylethoxymethyl (Msem) is introduced as a base-labile, non-participating protecting group in carbohydrate chemistry. Conditions to introduce the Msem on primary and secondary alcohols are described. Removal of the Msem is best achieved using a catalytic amount of tetrabutylammonium fluoride (TBAF), with or without a nucleophilic scavenger. Applicability of the Msem group is illustrated in the assembly of an all 1,3-cis-linked mannotrioside.     

Oligoribonucleotide synthesis by the use of 1-(2-cyanoethoxy)ethyl (CEE) as a 2′-hydroxy protecting group

A novel method for the synthesis of oligoribonucleotides using 1-(2-cyanoethoxy)ethyl (CEE) as a 2′-hydroxy protecting group has been developed. A CEE group was introduced to the 2′-position of N-acyl-3′,5′-O-silyl-protected ribonucleosides under acidic conditions in good yields. The 2′-O-CEE group was found to be stable in an aqueous or ethanolic ammonia and was quickly removed by treatment with anhydrous tetrabutylammonium fluoride (TBAF). A combination of the use of N-acyl and 2′-O-CEE protecting groups enabled a reliable and complete two-step deprotection, first with NH₃–EtOH, then with TBAF in THF, without cleavage of internucleotidic linkages.     

Gold-catalyzed transesterification of ortho-alkynylbenzoic acid esters: a novel protecting group for alcohols and phenols

Treatment of ortho-alkynylbenzoic acid esters with excess amounts of EtOH in the presence of a gold catalyst results in the liberation of alcohols or phenols in high yields under mild conditions. The protection of alcohols and phenols proceeds smoothly by use of ortho-alkynylbenzoic acid or ortho-iodobenzoyl chloride. Highly chemoselective deprotections are described.     

Synthesis and application of an IL-supported diol as protecting group for aldehydes

A new IL-supported diol,1-(2,3-dihydroxypropyl)-3-methylimidazolium hexafluorophosphate has been synthesized and char- acterized by FT-IR,~1H NMR,~(13)C NMR and MS (ESI).Its physical properties such as freezing point,solubility and specific gravity and thermal stability were determined.Synthetic utilities of the resultant diol as a protecting group for aldehydes were also investigated.     

3,3-Dimethoxypropylsulfonyl Group: A new versatile protecting and activating group for amine synthesis

3,3-Dimethoxypropylsulfonyl (Dimps) chloride was prepared and used as a new versatile sulfonating agent for ammonia, primary and secondary amines to afford corresponding Dimps-amides in excellent yields. The resulting N-nonsubstituted and N-monosubstituted Dimps-amides, activated amines, were alkylated satisfactorily under new Mitsunobu conditions. The Dimps group was removed by treatment in aqueous solution under acidic followed by basic conditions. Furthermore, epilachnene, the defensive droplets from the Mexican bean beetle, Epilachna varivestis, was synthesized utilizing this Dimps methodology in short steps.     

Methyl esters: an alternative protecting group for the synthesis of O-glycosyl amino acid building blocks

The glycosyl amino acids α-GalNAc-Ser and α-GalNAc-Thr are fundamental building blocks for glycopeptide synthesis, Schmidt’s synthesis method often being chosen for this purpose. Methyl esters used as orthogonal carboxylic acid protecting group in this procedure were found to be an efficient and inexpensive alternative to other groups. The mild selective methyl ester deprotection by LiI improved the efficiency of the synthesis method.     

2-(Prenyloxymethyl)benzoyl (POMB) group: a new temporary protecting group removable by intramolecular cyclization

2-(Prenyloxymethyl)benzoates can be prepared from alcohols and readily available 2-(prenyloxymethyl)benzoic acid by standard acylation techniques or by Mitsunobu reaction with inversion of configuration. The POMB group can be cleaved first by oxidative removal of the prenyl group with DDQ followed by lactonization with expulsion of the alcohol catalyzed by Yb(OTf)₃. These reaction conditions are compatible with the presence of a large number of common protecting groups.     

1-Naphthylmethyl and 1-naphthylmethoxymethyl protecting groups: New members of the benzyl- and benzyloxymethyl-type family

1-Naphthylmethyl (NAP^I) and 1-naphthylmethoxymethyl (NAPOM^I) protecting groups were developed as new members of the benzyl- and benzyloxymethyl-type family. NAP^I and NAPOM^I can be introduced under conventional conditions, such as NAP^IBr/NaH/room temperature (rt), or NAPOM^ICl/i-Pr₂EtN/rt. They can also be removed under conventional conditions, e.g., by dichlorodicyanobenzoquinone (DDQ)- or ceric ammonium nitrate (CAN)-mediated oxidation, or by hydrogenolysis. The specific advantages of these new protecting groups are: i) a less costly synthesis of NAPOM^ICl compared to NAPOM^IICl, ii) the possibility to remove NAPOM^II selectively in the presence of NAPOM^I by DDQ-mediated oxidation, and iii) the compatibility with strong acids even in the presence of hard nucleophiles.     

Chemical synthesis of bioactive siRNA in solution phase by using 2-(azidomethyl)benzoyl as 3′-hydroxyl group protecting group

A protecting group AZMB was introduced to ribonucleosides 3′-hydroxyl group to facilitate solution phase synthesis of siRNA. The protection and cleavage reaction were carried out in mild conditions, that is protection by acyl chloride and cleavage by triphenylphosphine. The synthesized siRNA showed good biological activity to suppress targeted superoxide dismutase gene expression.     

Total synthesis of bidensyneosides A2 and C: remarkable protecting group effects in glycosylation

Bidensyneosides are a group of five recently identified polyacetylenic glucosides from Bidens parviflora WILLD, a traditional Chinese medicinal plant that contains rich bioactive natural products. It was shown that bidensyneosides inhibited both histamine release and nitric oxide production. The synthesis of bidensyneoside A2 (2) and C (4) as well as 3-deoxybidensyneoside C (5) are described. These syntheses establish a synthetic entry to the bidensyneosides and confirm the stereochemistry at C3. Furthermore, a remarkable protecting group effect on orthoester formation was observed during the glycosylation reaction.     

Bis(4,5-dimethoxy-2-nitrophenyl)ethylene glycol: a new and efficient photolabile protecting group for aldehydes and ketones

Synthesis of a new photolabile protecting group, bis(4,5-dimethoxy-2-nitrophenyl)ethylene glycol (4) from 4,5-dimethoxy-2-nitrobenzyl alcohol in three steps in good yields is described. The acetals and ketals of 4 are stable against acidic and basic reaction conditions and are cleaved smoothly on irradiation at 350 and 400 nm with regeneration of carbonyl compounds in high yields and efficiency.     

The development of N-aryl trifluoroacetimidate-based benzyl and allyl protecting group reagents

An exploration of the role of para-substituents on the balance between stability and reactivity of N-phenyl trifluoroacetimidates prompted the discovery of new reagents for the addition of allyl and benzyl protecting groups, namely O-allyl and O-benzyl N-(p-nitrophenyl)trifluoroimidates. These compounds are stable and crystalline at ambient temperature, making them ideal alternatives to existing benzylating and allylating reagents used under acidic conditions.     

A colourful azulene-based protecting group for carboxylic acids

An intensely blue-coloured protecting group for carboxylic acids has been developed. The protecting group is introduced through a Steglich esterification that couples 6-(2-hydroxyethyl)azulene (AzulE) and the carboxylic acid substrate. Deprotection is effected under basic conditions by the addition of the amidine base DBU, whereupon cleavage occurs, accompanied by a colour change. A two-step deprotection methodology comprising activation with oxalyl chloride and deprotection with a very mild base was developed for use with base-sensitive substrates. The AzulE esters were found to be compatible with other commonly employed protecting groups – silyl ethers, MOM acetals – by studying their orthogonal and concomitant deprotections. The stability of the new protecting group towards various synthetic processes – oxidation, reduction, cross-coupling, olefination and treatment with base – provided the basis of a versatility profile. This indicated that AzulE esters are sensitive to strongly oxidising and basic agents while being compatible with reducing conditions and selected other reactions. The convenience of a highly coloured protecting group for tracking material (and avoiding loss of compound) through laboratory processes warrants further investigation of this and/or related species.     

An efficient method for para-methoxybenzyl ether formation with lanthanum triflate

PMB ethers of alcohols are prepared in high yields and short reaction times using the trichloroacetimidate of PMB alcohol and lanthanum triflate. The mild conditions allow protection of acid-sensitive alcohols.     

A mild and efficient method for the oxidation of benzylic alcohols by two-phase electrolysis

Electrochemical oxidation of benzylic and substituted benzylic alcohols by two-phase electrolysis yields the corresponding aldehydes as products. The reaction was carried out in a single compartment cell with platinum electrodes at room temperature in chloroform using an aqueous sodium bromide solution (25%) containing a catalytic amount of HBr. The two-phase electrolysis resulted in high yields (74-96%) of benzaldehyde from primary alcohols and secondary alcohols were oxidized to the corresponding ketone but only in low yields under these conditions.