Amides to protect acids

This procedure is restricted mainly to aminodicarboxyhc acids or diaminocarboxyhc acids. In the case of neutral amino acids, the amino group or carboxyl group must be protected, eg, by A/-acylation, esterification, or amidation. This protection of the racemic amino acid and deprotection of the separated enantiomers add stages to the overall process. Furthermore, this procedure requires a stoichiometric quantity of the resolving agent, which is then difficult to recover efficiendy. Practical examples of resolution by this method have been pubUshed (50,51). 

This vinylogous amide has been prepared in 70% yield to protect amino acid esters. It is cleaved by treatment with either aqueous bromine or nitrous acid (90% yield). ... 

Protective group chemistry for these amines has been separated from the simple amines because chemically they behave quite differently with respect to protective group cleavage. The increased acidity of these aromatic amines makes it easier to cleave the various amide, carbamate, and sulfonamide groups that are used to protect this class. A similar situation arises in the deprotection of nucleoside bases (e.g., the isobutanamide is cleaved with methanolic ammonia ), again, because of the increased acidity of the NH group. 

Isopropylidene and benzylidene" groups have been used to protect simultaneously amide nitrogens and a neighboring hydroxyl. They can be removed by acid hydrolysis or hydrogenolysis (Pd-C, hydrazine, MeOH, 95% yield), respectively. 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

TV-Acyl indoles derived from amides have been employed for the conversion of lactones into protected hydroxyacids. Thus, (chloromethyl)alumi-num 2-(2-propenyl)anilide reacts (120) with 1,4- and 1,5-lactones, as for example per-O-terZ-butyldimethylsilyl-D-ribono-1,4-lactone (104), to afford hydroxyamides. After protection of the free hydroxyl group, these amides were converted by ozonolysis into TV-acyl indoles, 105, which were readily saponified to the acid 106. 

Ester formation is the main and most efficient means of protecting carboxylic acids. The protection of a carboxylic acid as an amide is infrequent, as its removal normally requires drastic conditions. Most of the work concerned with the use of light-sensitive protecting-groups for carboxylic acids is in peptide synthesis. Carboxylic acids are protected as photosensitive esters, including ester linkages to polymer supports or as (difficult to prepare) photosensitive amides. Many of these techniques may be readily applied to sugar acids. 

What is not included here is the need also to protect any vulnerable functional groups in the amino acid side-chains. A range of methods is available to protect amino, carboxyl, thiol, and hydroxyl groups and prevent them reacting during the amide bond synthesis. Such groups also have to be removed after their job is done, using conditions that do not... 

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