Butoxycarbonylation

The /-butoxycarbonyl group (Boc, "t-box ) has been eMens vely used in peptide synthesis, and Boc derivatives of many amino acids are commercially available. The customary reagent for the preparation from the amine is t-butyl azidoformate in water, dioxane/water, DMSO, or DMF. The cleavage by acids of medium strength proceeds with concomitant loss of isobutene and carbon dioxide (L.A. Carpino, 1957, 1973 see section 4.1.2.2). 

The protecting group Y of the amine is generally an alkoxycarbonyl derivative since their nucleophilicity is low. Benzyloxy- or tert-butoxycarbonyl derivatives usually do not undergo azlactone formation. 

To illustrate the specific operations involved, the scheme below shows the first steps and the final detachment reaction of a peptide synthesis starting from the carboxyl terminal. N-Boc-glycine is attached to chloromethylated styrene-divinylbenzene copolymer resin. This polymer swells in organic solvents but is completely insoluble. ) Treatment with HCl in acetic acid removes the fert-butoxycarbonyl (Boc) group as isobutene and carbon dioxide. The resulting amine hydrochloride is neutralized with triethylamine in DMF. 

Preparation of primary allylamines by the selective monoallylation of ammonia is not possible and they are prepared by indirect methods. The monoallylation of Li and Na amides of di-/-butoxycarbonyl (Boc) (305), followed by hydrolysis, affords a primary allylamine (306)[184],... 

A solution of At-(tcrt-butoxycarbonyl)-6-methoxy-2-methylaniline (11.9 g, 50 mmol) was cooled to — 40°C and s-BuLi (96 ml of 1.3 M in cyclohexane. 125mmol) was added. The mixture was stirred at —45°C to —55°Cfor 30min and then allowed to warm slowly to — 15"C over 60 min. The yellow solution was recooled to —45 C and DMF (5.8 ml, 75 mmol) was added. After 5 min the reaction mixture was diluted with water (250 ml) and the product was extracted with EtOAc (2 x 150 ml). The extract was washed with w ater (200ml) and then concentrated in vacuo. The residue was dissolved in THF (100 ml) and 12 N HCl (2 ml) was added. The solution was stirred for 5 min at room temperature and then diluted with ether (250 ml). The solution was washed with water (250 ml), sat. aq. NaHCOj (250 ml), and brine (250 ml), dried (Na2S04) and evaporated. The product was purified by chromatography using 2% EtOAc in hexane for elution. The yield (9.3 g) was 75%. 

A related N terminal protecting group is tert butoxycarbonyl abbreviated Boc... 

Hydrogen bromide may be used to remove either the benzyloxycarbonyl or tert butoxycarbonyl protecting group The benzyloxycarbonyl protect mg group may also be removed by catalytic hydrogenolysis... 

Pig. 4. Synthesis of tigemonam where Boc is the /-butoxycarbonyl group PyrH" is the pyridinium ion and the numbers given are percent yield of product. 

Fig. 5. Synthesis of monophosphatams where Boc is /-butoxycarbonyl R is either CH or OCH and TFA is trifluoroacetic acid.

In order to exploit the reactions of the C-lithio derivatives of iV-unsubstituted pyrroles and indoles, protecting groups such as t-butoxycarbonyl, benzenesulfonyl and dimethyl-amino have been used 81JOC157). This is illustrated by the scheme for preparing C-acylated pyrroles (211) (8UOC3760). 

Furfural — see Furan-2-oarbaldehyde, 532 Furfuryl acetate, o -(butoxycarbonyl)-anodic oxidation, 1, 424 Furfuryi acrylate polymerization, 1, 279 Furfuryl alcohol configuration, 4, 544 2-Furfuryl alcohol polyoondensation, 1, 278 reactions, 4, 70-71 Furfuryl alcohol, dihydro-pyran-4-one synthesis from, 3, 815 Furfuryl alcohol, tetrahydro-polymers, 1, 276 rearrangement, 3, 773 Furfuryl chloride reactions... 

R,5S,6R)-4-(t-Butoxycarbonyl)-5,6-dlphenyl-3>[(sthoxycarbonyt)methyl]-2,3,5,6-tetrahydro-4H-oxazln-2-one (6) To a stirred solution of erode 4 (226 mg 0 48 mmoQ m CH2CI2 (11 mL) was added ketene acetal 5 (450 mg, 2 42 mmol) followed by addition of 2nCl2 (575 mL, 0 44 mmol, 0 76M m THF) Alter 4 min ( was quenched with water Radial chromatography (silica gel EtOAc hexane 1 4) afforded 179 mg of 6 (78%)... 

An aiyl 4-picolyl ether is stable to trifluoroacetic acid, used to cleave an N-t-butoxycarbonyl group. ... 

AcOH, HBr, 10°, 10 min, 70% yield. Phthaloyl or trifluoroacetyl groups on amino acids are stable to these conditions benzyloxycarbonyl (Cbz) or /-butoxycarbonyl (BOC) groups are cleaved. 

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