Urethanes protecting groups

Scheme 6. Carbohydrate based urethane protecting groups...

Synthesis of the Palmitoylated and Farnesylated C-Terminal Lipohexapeptide of the Human N-Ras Protein by Employing an Enzymatically Removable Urethane Protecting Group, H. Waldmann, E. Nagele, Angew. Chem. 1995,107, 2425-2428, Angew. Chem. Int. Ed. 1995, 34, 2259-2262. 

X urethane protecting group OA = hydroxy acid R1 = alkyl, aryl... 

The amine 27 was coupled to protected peptides 14 and then the side-chain bromide was further functionalized. This approach was found to be more effective than protecting the amino group of 27 with commonly used urethane-protecting groups although the Boc form of 27 has been prepared and successfully used to prepare Boc-boroArg-pinanediol. 

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

For example, urethane protecting groups such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and (fluorenylmethoxy) carbonyl (Fmoc) are easily introduced as shown in Scheme 1.34 ... 

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. 

For the complete solid-phase synthesis of H- and A-Ras peptides, the hydrazide linker turned out to be the linker of choice (14). This linker is cleaved by oxidation to an acyldiazene that is then attacked by a suitable nucleophile. The linker is orthogonal to classic urethane protecting groups such as Boc, Fmoc, and... 

Urethane Protecting Groups Derived from Primary Alcohois... 

Scheme 8 Base-Labile Urethane Protecting Groups o...

A further urethane protecting group derived from a secondary alcohol is the 2-ada-mantyloxycarbonyl group.It is more stable toward acidic reaction conditions than the corresponding 1-adamantyloxycarbonyl group (1-Adoc, Section 2.1.2.2.3.3.2), but it is removed with trifluoromethanesulfonic acid or anhydrous HF in a few minutes at... 

Another urethane-protecting group has been derived from carbohydrates. 2,3,4,6-Tetra-O-benzylglucosyloxycarbonyl protected amino acids are coupled with different amino acid tert-... 

Depending upon whether mono-A -, bis-A -, or bis-A -arginine derivatives are used, the efficiency of urethane protecting groups in terms of side reactions (see Section 2.6.1.2) varies to a great extent. Moreover, the orthogonality of this type of protection over N -protection is... 

Of all the methods described, the most convenient laboratory preparation of NCAs is the reaction of Boc-protected amino acids with thionyl chloride in THF. The method provides NCAs in good yields, which may then be purified by crystallization. Typically, a urethane-protected amino acid in THF is treated with 1.1-4 equivalents of thionyl chloride at 0°C. The NCA is formed in 30 minutes to 24 hours, depending on the annino acid and the urethane protecting group. Conversely, direct phosgenation of an amino acid is the preferred industrial process and modifications, such as trimethylsilylation, allow preparation of NCAs... 

The lipase from the fungus Rhizopus niveus accepts a variety of protected dipeptide heptyl esters (33) and hydrolyzes the ester function in high yields at pH 7 and 37 °C without damaging the urethane protecting groups and the peptide bonds. The N- and C-terminal amino acid can vary over a wide range, but, with increasing steric bulkiness and hydrophobicity of the amino acids, especially the C-terminal one, the reaction rates decrease. 

A fourth urethane protecting group, the TV-allyloxycarbonyl group (Alloc) is introduced in the usual way using allyl chloroformate or diallyl dicarbonate. Its main interest concerns its removal by a Pd-catalysed hydrostannolysis with tri-butyltin hydride (Scheme 7.4). It thus provides orthogonal protection without the need to expose the peptide to acid, conditions that would cleave, for example, O-gly-coside derivatives of peptides. 

Another means of overcoming the sterically very demanding coupling reactions is to reduce the bulkiness of the residues, inherent to the presence of both the C"ra-disubstitu-tion, and the urethane protecting group. This has been demonstrated by the use of a-azi-do acids in which the azide is the precursor of the amino function [113]. These monomers can be activated as acid chlorides, and their preparation is also compatible with the presence of the side chain protecting group used in Fmoc-based peptide synthesis. This approach has been exploited in the solid-phase synthesis of a-aminoisobutyric acid (Aib)-rich peptides [114]. 

---