Common amine protecting groups

Carbamate (urethane) protecting groups The best amino group protection is carried out by the formation of the urethane (or carbamate) protecting groups. Carbamates are 

These protecting groups withstand a variety of harsh reaction conditions. 

Boc is a good labile group because it is stable at room temperature and easily removed with dilute solution of TFA either neat or in dichloromethane. Other mineral acids or Lewis acids have also been used, although less frequently. 

Fmoc is a base labile protecting group which is easily removed by reaction with concentrated solutions of amines. Both Cbz and the acid labile tBoc are commonly used. These owe 

The different cleavage conditions for the above urethane protecting groups have enabled so-called orthogonal protection strategies to be developed, which in turn enable selective deprotection to be performed on different amines present in the same molecule. For example in peptide synthesis, the N-Boc group could be cleaved selectively using TMSOTf, followed by aqueous work up. 

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Only the azide anion amongst the multitude of possible nitrogen nucleophiles had reported utility in alkynyliodonium salt addition chemistry at the inception of this project. Therefore, extension of this chemistry to amines and amide derivatives occupied our attention at the outset. The requirement for a soft, polarizable nucleophile limited our options, and screening a primary amine as well as some common amide derivatives in the prototype transformation 35 + 36 - 38 led to the first sense that this goal was achievable (Scheme 6).5a c In fact, the common amine protecting group tosyl proved to be the most effective modulator of amine nucleophilicity in this assay. Interestingly, amide pKa does not... 

Alternatively, acid fluorides are used to activate the acid. Acyl fluorides are less sensitive to moisture and are more reactive toward primary and secondary amines than the corresponding acyl chloride. Furthermore, they are compatible with basic- (Fmoc and Cbz) or even acid- (Boc) labile amine protecting groups and less prone to promote racemization than their chlorinated homologs (26). Thus, the acid fluoride method is often used in peptide synthesis (27). Cyanuric fluoride 9 (28), TFFH (29), DAST (30), and deoxofluor (31) are used commonly as fluori-nating reagents (see Fig. 4). 

The BOC group is used extensively in peptide and heterocyclic synthesis for amine protection. It is not readily hydrolyzed under basic conditions and is inert to many other nucleophilic reagents. It is usually cleaved with strong acid, giving only f-BuOH or isobutylene and CO2 as by-products. As a result, it is one of the most commonly used protective groups for amines. In general, it is considered nonreactive, but there are many cases in which the BOC group participates in reactions—anticipated and unanticipated. ... 

Protection of an alcohol function by esterification sometimes offers advantages over acetal protecting groups such as the tetrahydropyranyl ethers. Generally, acetals are stable in base and labile in acid, while esters are more stable in acid than acetals and are readily hydrolyzed in base. Esters are notably useful in reactions such as oxidations, but are not satisfactory in organometallic reactions. Acetates and benzoates are the most common ester protecting groups they can be conveniently prepared by reaction of unhindered alcohols with acetic anhydride or benzoyl chloride, respectively, in the presence of pyridine or other tertiary amine. The use of reactive amides such as N-acylimidazoles (imidazolides) allows the reaction to be carried out in the absence of added bases ... 

Scheme 6.1 Common AG amine-protecting group strategies.

As fluorous Cbz-type hnkers are known to be partially deprotected in acidic medium, a base-labile amine-protecting group (19, Scheme 8.4) was developed as an orthogonal alternative. The peptide products were purified by both fluorous HPLC and FSPE [41]. The deprotection of the fluorous tag was carried out using 2% aqueous ammonia, a reagent that would raise concerns in the presence of common carbohydrate-protecting groups such as acetates. 

This isomerization was confirmed by means of a detailed kinetic NMR study (90T633), but is not detrimental to the synthesis of substituted 1,2,4-triazoles, because in all cases removal of the protecting group leads to a tautomeric mixture of 3- and 5-substituted products. The methods available for removal of the animal function actually depend upon the nature of the added C-5 substituent, with acid hydrolysis occurring only in some cases. More commonly, treatment with NaBH in refluxing ethanol is the method of choice (90T633). Lithiation and derivatization of the SEM protected compound (entry 6) can be achieved without the isomerization shown by the animal derivative, and deprotection can be achieved with either aqueous acid or anhydrous fluoride ion [92H(34)303], However, overall reaction yields are not as high as those for the aminal system. 

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