Protective groups for amines

SR Chhabra, B Hothi, DJ Evans, PD White, BW Bycroft, WC Chan. An appraisal of new variants of Dde amine protecting groups for solid phase synthesis. (Ddiv group) Tetrahedron Lett 39, 1603, 1998. 

Amine oxides, anhydrous, SO, 55, 58 Amines, protecting group for, 50,12 AMINES FROM MIXED CARBOXYLIC-CARBONIC ANHYDRIDES 1-PHENYLCYCLOPENTYL-AMINE,51,4S... 

Alenylacetylenes, 50,101 Aluminum chloride, with ethylene and p-methoxyphenylacetyl chloride to give 6-methoxy-/3-tetralone, 51,109 with propylene and acetyl chloride to give 4-chloropentan-2-one, 51,116 Amine oxides, anhydrous, 50, 55, 58 Amines, protecting group for, 50,12 AMINES FROM MIXED CARBOXYLIC-CARBONIC ANHYDRIDES 1-PHENYLCYCLOPENTYLAMINE,... 

Orthogonal amine-protecting groups for the solid phase synthesis of branched peptides... 

Primary and secondary amines are susceptible to oxidation and replacement reactions involving the N—H bonds. Within the development of peptide synthesis numerous protective groups for N—H bonds have been found (M, Bodanszky, 1976 L.A. Carpino, 1973), and we shall discuss five of the more general methods used involving the reversible formation of... 

It is widely recognized that an allyl group is a useful protecting group for acids, amines, and alcohols. Facile formation of a Tr-allylpalladium complex from... 

A number of imine derivatives have been prepared as amine protective groups, but most of these have not seen extensive use. The most widely used are the ben-zylidene and diphenylmethylene derivatives. The less used derivatives are listed, for completeness, with their references at the end of this section. For the most part, they are prepared from the aldehyde and the amine by water removal cleavage is effected by acid hydrolysis. 

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

The benzyloxycarbonyl protecting group for amines is introduced in high yield using benzyl imidazole-carboxylate with a catalytic amount (5%) of dimethylamino-pyridine.[1953... 

The triphenylmethyl function, also known as trytil (Trt), is a valuable bulky protecting group for peptide chemistry. Trytil groups confer acid-labile protection onto amines, but effective removal can also be achieved by catalytic hydrogenolysis. 

Scheme 8.5. Enzyme-triggered fragmentation of protective groups for amines, alcohols and carboxylic acids.

Problematic functional groups, however, are thioethers and disulfides [28] as well as free amines which poison catalysts of type 1 [4c]. In case of amines this problem is easily solved by choosing either an appropriate protecting group for nitrogen (e.g. amide, sulfonamide, urethane), or simply by protonation since ammonium salts were found to be compatible with 1 [4c]. As will be discussed in Sect. 4, free amines can also be metathesized in supercritical C02 as the reaction medium [7]. 

FIGURE 6.16 Protecting groups for carboxamides. Derivatives are obtained by reaction of the carboxamide with an alcohol or the acid with an amine. Mbh = 4,4 -dimethoxybenzhydryl64 Trt = trityl [Sieber Iselin, 1991] Xan = 9-xanthenyl63 Dmb = 2,4-dimethoxybenzyl66 Tmb = 2,4,6-trimethoxybenzyl65 BHR = benzhydryl-resin.68... 

The electrochemical behavior of a series of nitrobenzenesulfonamides (48 and 49) were examined by cyclic voltammetry and other techniques in connection with the use of such arenesulfonyl groups as protecting groups for amines. Interestingly, the behavior of the 2-nitro derivative 48a and the iV.iV-dialkyl 4-nitro derivative 49 differed from that of the 3-nitro and 4-nitro monosulfonamides 48b and 48c62. Ortfco-derivative 48a and 49... 

An alternative approach is the cleavage of a UV-active protecting group from the resin, such as the widely used Fmoc Test. The quantitation of the 9-fluorenyl-methyloxycarbonyl (Fmoc) protecting group for amines is used in SPPS as an indirect method to determine the extent of a peptide coupling reaction. Similar approaches have also been recently reported for the quantitation of supported thiols [151, 154] and have also been the subject of an excellent review [148]. 

The sulphonyl chloride 23 is proposed as a protecting group for the Gabriel synthesis of secondary amines from primary amines. At the deprotecting stage, carbon-sulphur bond cleavage is achieved using zinc and acid as the electron source [109]. 

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