Protecting groups urethane-type

For a-amino protection, the urethane-type protecting groups derived from secondary alcohols do not offer improved properties compared to those of more classical groups derived from primary alcohols. The main advantage possibly derived from the use of this type of urethane-derived N -derivative is the increased solubihty, e.g. such as that reported for the 2-adamantyloxycarbonyl derivatives (see Section... 

Permanent protection compatible with Fmoc is often provided by -butyl-type protecting groups (urethane, ester, ether). In addition, triphen-ylmethyl (Trt) [59,60], 2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc) [61],... 

Analogously to these reactions of imidazolium carboxylates, the introduction of urethane-type amino-protecting groups can be accomplished with the following mesoionic azolides [194]... 

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]. 

The suitability of the Aloe group for the construction of lipidated peptides is emphasized by the synthesis of the maleimidocaproyl-modified, S-palmi-toylated and farnesylated heptapeptide 16 which corresponds to the N-Ras C-terminus (Scheme 10).1211 In contrast to classical urethane-type protecting groups, the Aloe group can be removed in the presence of additional functional groups and under neutral conditions. It is therefore a very convenient protecting group for the synthesis of very hydro-phobic lipid-modified peptides, which are not soluble in the aqueous media required for enzyme catalyzed transformations. 

These reactions were effected by RuO /aq. Na(10 )/Et0Ac when the reactants bore urethane-type protecting groups (n = 1, R =Boc, R =Me, NBzl n = 2,... 

Optically pure piperazine-2-carboxylic acid (22) and related derivatives, substituted at position 5, are synthesized from piperazine-2,5-diones 50 derived from Xaa-Ser dipeptides as educts, where the substitution R1 at position 5 depends on the side group of the aminoacyl moiety (Scheme 10). After reduction of the piperazine-2,5-diones 50 to 5-alkyl-2-(hy-droxymethyl)piperazines 51 and urethane-type protection of both the imino groups, the desired A,A -bis-protected piperazine-2-carboxylic acid or related 5-alkyl derivatives 52 are obtained by selective oxidation of the hydroxymethyl group. 240 ... 

Table 1 Urethane-Type Protecting Groups Most Frequently Used for N -Protection of Amino Acids...

The use of ethoxycarbonyl-protected amino acids as well as methoxycarbonyl derivatives for peptide synthesis was reported in 1903 by Fischer, although the protecting groups in related peptide derivatives could not be cleaved without affecting the peptide bonds,f since urethanes derived from aliphatic primary alcohols are about as stable as the amide bond. Thus, this type of carbamate can only be used for reversible protection of amino groups, at least in... 

Acylation of anoino acids or peptides with Z-protected amino acids can be performed with aU known methods including the a-amino acid Al-carboxyanhydrides (NCAs), since protocols for the preparation of the highly reactive Z-protected NCAs are now available (see Section 3.4.2).t l Moreover, since formation of oxazol-5(4//)-ones is very slow with urethane-type protecting groups, racemization, at least by this mechanism, is largely suppressed (see Sections 1.2.1.2 and 7.4).[ 5.n,52]... 

The reagents for the synthesis of Al -l-adamantyloxycarbonyl amino acid derivatives are similar to those used for other urethane-type protecting groups (Scheme 36). Although the related 1-adamantyl chloroformate (Adoc-Cl, 68) is obtained as crystalline solid, the acylation of amino acids under Schotten-Baumann conditions leads to significant decomposition of the reagent and thus its use does not result in satisfactory yields in all cases. Better results are obtained with 1-adamantyl fluoroformate (Adoc-F, 69) (yields of A -Adoc amino acids 85-95%)P I which is conunerciaUy available or readily prepared from adamantan-l-ol and... 

Urethane-type Protecting Groups Derived from Primary Alcohols... 

As has been demonstrated, 2-(trimethylsilyl)ethoxymethyl (SEM) esters are selectively removed from amino acids and peptide derivatives in the presence of the most common N- and O-protecting groups applied in peptide chemistry including the urethane-type Boc, Z, Fmoc, and Troc as well as Bzl, tBu, and TBDMS ethers.The SEM ester is removed by acidolysis or with a fluoride ion source, e.g. TBAF in THF or HMPA or with aqueous HF in MeCN (—10°C).f l Deprotection with magnesium bromide in EtjO represents an even milder alternative that allows increased selectivity toward fluoride-labile silyl ethers or Fmoc groups. The SEM esters are prepared in 60-80% yield by stirring a mixture of 0.25 M N-protected amino acids in DMF with 0.8 equivalents of SEM-Cl and 1.1 equivalents of lithium carbonate at room temperature for 16 hours. 

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... 

In peptide synthesis the use of a suitable protection for the N-terminal amino group is required not only to prevent the formation of a complex mixture of oligo- and cyclo-peptides, but an additional demand on the functionality applied for this purpose is that it should prevent possible racemization of the activated amino acid. Racemization usually takes place via an intermediate oxazolone (7) that forms readily from A -acyl-protected amino acids (Scheme 2). This side reaction can be mostly suppressed by using a carbamate as an N-terminal-protecting group. Therefore, nearly all blocking functions currently applied in this field are of the urethane type. 

Table 1 Selected Benzyl Urethane-type Protecting Groups...

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