Protecting groups alkylation

Protecting groups Alkylation Acetalation Acylation Carbonylation Silylation Phosphorylation... 

AdeninyUiydroxypropanoic acid alkyl esters [(R,5)-AHPA esters, (30)] represent a new class of broad-spectmm antiviral agents, which are, like (3)-DHPA, targeted at SAH hydrolase (62). The free acid, (R,3)-AHPA, is only weakly active as an antiviral agent. Thus the alkyl moiety merely serves as a protecting group to faciUtate uptake of AHPA by the cells. Within the cells, the AHPA alkyl esters would be hydroly2ed to release the free acid, which should then interact with SAH hydrolase. 

Historically, simple Vz-alkyl ethers formed from a phenol and a halide or sulfate were cleaved under rather drastic conditions (e.g., refluxing HBr). New ether protective groups have been developed that are removed under much milder conditions (e.g., via nucleophilic displacement, hydrogenolysis of benzyl ethers, and mild acid hydrolysis of acetal-type ethers) that seldom affect other functional groups in a molecule. 

An ether that would not undergo rearrangement to a 3-alkyl derivative during acid-catalyzed removal of — NH protective groups was required to protect the phenol group in tyrosine. Four compounds were investigated (9-cyclohexyl-, (9-isobomyl-, 0-[l-(5-pentamethylcyclopentadienyl)ethyl]-, and O-isopropyltyro-sine. 

A comparison has been made with several other common protective groups for tyrosine, and the degree of side-chain alkylation decreases in the order Bn >... 

The related 2-/-butyl derivative has also been prepared and used to advantage as a temporary protective group for the stereogenic center of amino acids during alkylations. ... 

S-Benzyl and substituted S-benzyl derivatives, readily cleaved with sodium/ammonia, are the most frequently used thioethers. n-Alkyl thioethers are difficult to cleave and have not been used as protective groups. Alkoxymethyl or alkylthio-... 

When cysteine reacts with an alkyl or aiyl chloroformate, both the —SH and —NH groups are protected as a thiocarbonate and as a carbamate, respectively. Selective or simultaneous removal of the protective groups is possible. 

I-Substituted 3,5-Dinitro-4-pyridonyl, 360 SPECIAL -NH PROTECTIVE GROUPS N-Alkyl and A-Aryl Amines... 

To minimize racemization, the use of nonpolar solvents, a minimum of base, low reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) is effective. (A carbamate, R = O-r-Bu, has been reported to form an oxazolone that appears not to racemize during base-catalyzed coupling.) ... 

The imine, prepared from an amine and (C5H4N)(Me3C JH2)CO (TiC, toluene, reflux, 12 h NaOH, 80% yield), can be cleaved with coned. HCl (reflux). The protective group was used to direct a-alkylation of amines. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

It is possible to change the stereochemical result of the alkylation by replacing the 3-ketal protecting group with a A -enol ether. This structural change eliminates a severe 1,3-diaxial interaction to a-face methylation and results in the formation of the 5a-methyl steroid (15) in about 35% yield, ... 

Catalytic hydrogenolysis of an O-benzyl protective group is a mild, selective method introduced by Bergmann and Zervas to cleave a benzyl carbamate (>NC0-0CH2C6H5 —> >NH) prepared to protect an amino group during peptide syntheses. The method has also been used to cleave alkyl benzyl ethers, stable compounds prepared to protect alkyl alcohols benzyl esters are cleaved by catalytic hydrogenolysis under neutral conditions. 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

To minimize racemization, the use of nonpolar solvents, a minimum of base, low-reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) are effective. 

The BOC group can be cleaved with TBDMSOTf and the intermediate silyl carbamate converted to other nitrogen-protective groups by treatment with fluoride followed by a suitable alkylating agent. ... 

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