4     Amine protecting groups.

4.1     Amide - like Protecting Groups

The main purpose of the amine protecting group is to inhibit its participation in chemical reactions due to its basic and nucleophilic nature. Primarily this is achieved by delocalisation of the lone pair of electrons. Perhaps the most obvious choice is the formation of an amide and use of the formyl group was suggested by Fischer and Warburg in 1905. While the amino group was successfully rendered inert, the formyl group did not provide conservation of chiral purity. This is because the electron withdrawing effect from the amide group enhances the acidity of the a-proton. To limit this problem a less electron withdrawing substituent is required. The Phthalimide group has been successfully used since the electron withdrawing power of the two carbonyl groups is ameliorated by delocalisation around the p-system. Deprotection with hydrazine, in a hot solution or in the cold for a prolonged period, affords the peptide and phthalic acid hydrazide (figure). Treatment with even weak aqueous base results in the opening of the ring and the resulting amide is more difficult to destroy.



4.2     Urethane Protecting Groups

Perhaps the greatest advance in the field of amino group protection was the development of the urethane (or carbamate) protecting groups. This can be seen as a logical extension from the use of N-carboxyanhydrides, shown in figure (figure), which provide simultaneous activation and protection. The disadvantage of the N-carboxyanhydrides is that decarboxylation of the intermediate carbamic acid is almost instantaneous and thus formation of poly amino acids is a serious problem.


However, the half esters of carbamic acid are stable compounds and can be used as a form of amine protection. The corresponding protecting group is a urethane or carbamate. The electron withdrawing nature of the carbonyl group is reduced by the donation of a lone pair from the oxygen, which also renders the carbonyl carbon not susceptible to nucleophiles. The urethane protecting groups are often introduced as either the corresponding acid chloride or the form of an active ester. Deprotection is achieved with similar conditions to those used for deprotection of the corresponding carboxylic ester.  Once formed, the resulting carbamic acid spontaneously decomposes.  These principles and examples of common urethane protecting groups are illustrated in figure a) and figures b and c.


The initial innovation was the benzyloxycarbonyl group (denoted Z), which is still used today.  This group is removed by acidolysis with strong acids or exceptionally cleanly by catalytic hydrogenation producing carbon dioxide and toluene as side products.


Not surprisingly, urethane derivatives are the most widely used protecting groups, almost to the exclusion of all others.  Despite the enormous range of possible derivatives, only a few are put to regular use. In addition to the benzylaxycarbonyl (Z), the acid labile tert-butyloxycarbonyl (BOC) is commonly used. These owe their lability to the stability of the carbocation produced on deprotection.  The BOC GROUP, which generates a stable tertiary cation on deprotection, is thus prone to deprotection by weaker acids than Z.


It is desirable to have a range of protecting groups available that can be selectively, and preferably orthogonally, removed.  Two protecting groups are said to be orthogonal when they are removed by totally different classes of reagents (e.g. one by acid and the other by base). The Fluorenylmethyloxycarbonyl (Fmoc) group has achieved wide acceptance due its resistance to acidic conditions and the ease of deprotection using weak bases, particularly secondary amines. Deprotection occurs through base catalysed abstraction of the b-proton of the protecting group with elimination leading to formation of dibenzofulvene. The importance of Fmoc in solid phase peptide synthesis will be elucidated later.

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