Secondary amines deprotection with

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

The Fmoc group protection is common in solid-phase peptide synthesis. Fmoc is resistant to acidic conditions and easily deprotected by weak bases, particularly secondary amines. Deprotection occurs through base-catalyzed abstraction of the (3-proton of the protecting group with elimination leading to formation of dibenzofulvene (1.83) (Scheme 1.36). 

This group was developed for the protection of amino acids. It is formed from 4-ethoxy-l,l,l-trifluoro-3-buten-2-one in aqueous sodium hydroxide (70-94% yield). Primary amino acids form the Z-enamines, whereas secondary amines such as proline form the -enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane at rt. ... 

Figure 15.5 A trityl-protected pyrrolidine derivative of Cgg can be prepared by the reaction of N-trityl-oxazolidinone with a fullerene. Deprotection of the trityl group using methanesulfonic acid gives the secondary amine, which can be used in further conjugation reactions.

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

Products from reactions with diacylamines or nosylamines can be very easily deprotected to give primary aUylamines. These were used as nucleophiles in allyhc substitutions to give secondary amines, which were transformed into unsymmetri-cally 2,5-disubstituted 2,5-dihydropyrroles (Scheme 9.28) [28aj. Thus, the allylic... 

Palladium-catalyzed, Allylic Amination. Allylic substitution of mono-saccharidic hex-2-enopyranoside 4-acetates with secondary amines in the presence of tetrakis (triphenylphosphine)palladium(O) liad led to a large variety of 4-aminated 2-enosides, with retention of configuration (56-58). The method was applied to the disaccaridic enoside 1 to give, with benzylmethylamine or dibenzylamine, the 4-amino sugar derivatives g in yields of 92 and 67% (46). Studies concerning hydrox-ylation of t)ie double bond and subsequent deprotection are incomplete. 

An alternative strategy preventing fnrther oxidation of hydroxylamines is based on concomitant O-protection of the hydroxyamino gronp. Reaction of primary amines with benzoyl peroxide affords O-benzoyl hydroxylamines of type 139 (equation 92) that can be deprotected under mildly basic conditions. The oxidation is compatible with a number of functionalities and does not interfere with other functionalities snch as an isolated double bond in the molecule of amine. This reaction is versatile and a number of hydroxylamines has been prepared in this way, although yields are only moderate in most cases . Oxidation of secondary amines with benzoyl peroxide is also possible and usually proceeds in better yields. 

The benzyne route to dibenzopyrrocoline alkaloids with the 1-benzyltetrahy-droisoquinolines (40) listed in Table II was investigated by Kametani et al. (28), Kessar et al. (29), and Gibson and Ahmed (31). Secondary amines protected as 7-0-benzyl ethers, affording unstable tetrahydro intermediates with benzyl ether functions difficult to deprotect, were less favored than the corresponding N-methyl-substituted analogs, affording the desired quartemary alkaloids directly. 

The synthesis of quinapril begins with formation of the AT-carboxyalkyl alanine intermediate 26 (Scheme 10.6) (Hoefle and Klutchko, 1982 Kaltenbronn et al., 1983 Klutchko et al., 1986). Displacement of ethyl-2-bromo-4-phenylbutanoate (24) by (S)-alanyl-tert-butyl ester provided the secondary amine as a diastereomeric mixture. Deprotection of this mixture allowed for the selective recrystalhzation of the undesired (/ ,S)-isomer, and isolation of the desired (6,6)-isomer 26 from the mother liquor. 

Unfortunately, A-(9-fluorenylmethoxycarbonyl)aziridine-2-carboxylic acid cannot be used in peptide synthesis, since N-deprotection of the respective peptides with secondary amines leads to oxazoline or dehydroamino acid side products. Similarly, N-(tert-butoxy-carbonyl)aziridine-2-carboxylic acid is inappropriate due to the instability of the aziridine moiety to TFA treatment. Attempts to convert A-tritylaziridine-2-carboxylic acid into homogenous and stable active esters as useful intermediates in peptide synthesis leads to positive results only in the case of the pentafluorophenyl ester. 47 Consequently, this active ester seems to be the method of choice for acylating peptides. The related Abhydroxysuc-cinimide and A-3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine ester could not be isolated in pure form and have therefore been used as crude products. 47 Access to 2-carbonylazir-idine peptides is also possible by carbodiimide-mediated coupling. Additionally, alkylamides of A-tritylaziridine-2-carboxylic acid are prepared by the azide method,1 5 yet this method fails in peptide coupling steps. 85 ... 

Nitro- or 2,4-dinitrobenzenesulfonamides of primary or secondary amines can be hydrolyzed under mildly basic conditions, and are increasingly being used for amine protection (see Section 10.1.10.7 [123,139,140]). /V-(2-Nitrobenzenesulfonyl)amino acids can be used as an alternative to TV-Fmoc amino acids for the solid-phase synthesis of peptides [141]. Deprotection is achieved by treatment of the polystyrene-bound sulfonamide with a solution of PhSH (0.5 mol/L) and K2C03 (2 mol/L) in DMF for 10 min at room temperature [141], conditions that do not lead to cleavage of esters (e.g. of the Wang linker) or to racemization. The condensation of polystyrene-bound sulfinamides H2N-SO-Pol with aldehydes yields /V-sulfinylimines, which add... 

The toluenesulfonyl group in these reactions is also a protecting group for nitrogen, for example in 3, but it must be removed subsequently to liberate the free secondary amine. There are various methods for achieving this deprotection step which are compatible with ether linkages. The two most useful involve either the use of hydrogen bromide in acetic acid in the... 

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