Boc-protected

The secondary allylic methylamine 324 can be prepared by the allylation of A -methylhydroxylamine (323), followed by hydrogenolysis[201], Monoallylation of hydroxylamine, which leads to primary allylamines, is achieved using the jV,0-bis-Boc-protected hydroxylatnine 326. N -... 

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]. 

Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of A-f-Boc-protected o-alkylanilines. These intermediates are C-acylated by DMF or A"-methoxy-At-melhyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyelization product to acid[4]. Use of CO as the electrophile generates oxindoles. 

An experiment using Boc protection in the synthesis of a dipeptide can be found in the November 1989 issue of the Journal of Chemical Education pp 965-967... 

The actual process of solid phase peptide synthesis outlined m Figure 27 15 begins with the attachment of the C terminal ammo acid to the chloromethylated polymer m step 1 Nucleophilic substitution by the carboxylate anion of an N Boc protected C terminal... 

Step 1 The Boc protected amino acid is anchored to the resin Nucleophilic substitution of the benzylic chloride by the carboxylate anion gives an ester... 

Step 2 The Boc protecting group is removed by treatment with hydrochloric acid m dilute acetic acid After the resin has been washed the C terminal ammo acid IS ready for coupling... 

Step 4 The Boc protecting group is removed as m step 2 If desired steps 3 and 4 may be repeated to introduce as many ammo acid residues as desired... 

Protect glycine as its Boc derivative and anchor this to the solid support Remove the pro tecting group and treat with Boc protected phenylalanine and DCCI Remove the Boc group with HCl then treat with HBr in tnfluoroacetic acid to cleave Phe Gly from the solid support... 

It should be noted that when a BOC-protected amide is subjected to MeONa treatment the amide bond is cleaved in preference to the BOC group (85-96% yield) because of the difference in steric factors. The BOC group can be removed by the methods used to remove it from simple amines. 

Na/NH3, >54% yield. Methyl thioether cleavage of BOC-protected methionine. ... 

An important extension of the Knorr pyrrole synthesis developed by Cushman utilizes ketone enolates and BOC-protected a-amino aldehydes and ketones. Two examples (37, 38) are shown. 

In 2000, an efficient three-step procedure for the synthesis of 5-substituted 3-isoxazolols (without formation of undesired 5-isoxazolone byproduct) was published. The method uses an activated carboxylic acid derivative to acylate Meldrum s acid, which is treated with A,0-bis(ten-butoxycarbonyl)hydroxylamine to provide the N,0-di-Boc-protected P-keto hydroxamic acids 14. Cyclization to the corresponding 5-substituted 3-isoxazolols 15 occurs upon treatment with hydrochloric acid in 76-99% yield. 

The Henegar modification of the Friedlander reaction has been recently reported. The A-Boc protected derivative of o-aminobenzaldehyde (25, in this case prepared via directed ortho metallation of 24) is a stable, crystalline compound that can be stored for extended periods (in contrast with 4, which typically is freshly prepared). Treatment of 25 with ketone 26 in acetic acid results in deprotection of the aniline in situ and subsequent formation of 27, an intermediate in the synthesis of mappicine. 

Recently, the protected dimethoxy derivative 152 has been isolated in 70% yield from the Boc-protection of a nonseparable product mixture of the corresponding 2,8-dimethoxyindolo[3,2-h]carbazole 153 and the isomeric indolo[2,3-c]carbazole derivative (cf. Section VI) obtained by a double Fischer cycUzation using PPSE (00MI2). 

The feasibility of this approach was demonstrated with a model library of 36 compounds prepared from a combination of three Boc protected L-amino acids (valine 23, phenylalanine 24, and proline 25) and 12 aromatic amines (3,4,5-trimethoxyaniline (26), 3,5-dimethylaniline (27), 3-benyloxyaniline (28), 5-aminoindane (29), 4-tert-butylamline (30), 4-biphenylamine (31), 1-3-benyloxyani-line (28), 5-aminoindane (29), 4-tert-butylaniline (30), 4-biphenylamine (31), 1-aminonaphthalene (32), 4-tritylaniline (33), 2-aminoanthracene (34),... 

Amino groups are often protected as their tert-butoxycarbonvl amide, or Boc, derivatives. The Boc protecting group is introduced by reaction of the amino acid with di-fert-butyl dicarbonate in a nucleophilic acyl substitution reaction and is removed by brief treatment with a strong organic acid such as trifluoro-acetic acid, CF3C02H. 

Q A Boc-protected amino acid is covalently linked to the polystyrene polymer by formation of an ester bond (Sn2 reaction). 

A second Boc-protected amino acid is coupled to the first by reaction with DCC. Excess reagents are removed by washing them from the insoluble polymer. 

Two recent reports described addition of nitrogen-centered nucleophiles in usefully protected fonn. Jacobsen reported that N-Boc-protected sulfonamides undergo poorly selective (salen) Co-catalyzed addition to racemic epoxides. However, by performing a one-pot, indirect kinetic resolution with water first (HKR, vide infra, Table 7.1) and then sulfonamide, it was possible to obtain highly enantiomer-ically enriched addition products (Scheme 7.39) [71]. These products were transformed into enantioenriched terminal aziridines in straightforward manner. 

Good to excellent diastereoselectivities have been reported when 2-(trimethylsilyl)thiazole (3), an effective equivalent of an aldehyde group, is used as nucleophile24,27. Thus, addition to TV-Boc-protected amino aldehydes in dichloromethane at — 30 C afforded mixtures of amino alcohols in comparatively good yields with reasonable syn selectivity. However, the stereoselectivity decreased substantially when the reaction was carried out in tetrahydrofuran at 25 °C. 

---