Thioesters, to protect thiols

The thiation procedure described here is an example of a general synthetic method for the conversion of carbonyl to thiocarbonyl groups. Similar transformations have been carried out with ketones, carboxamides,esters,thioesters, 1 actones, " thiol actones, - imides, enaminones, and protected peptides. ... 

Following preparation of the protected thiol derivative 29 (overall retention of configuration is observed when using Val), a mixed anhydride was prepared and converted into the amide 30 with ammonia. The acetyl group of 30 was then removed and the resulting thiol compound condensed with Z-Arg-OH to give the thioester dipeptide 31. 

In order to facilitate the generation of peptide thioesters, several groupst have developed generalized versions of the thioester linker pioneered by Hojo and Aimoto.f A 3-sulfanylpropanoic acid residue is generated on an acid-labile linker such as Boc-Leu-PAM-resin or Boc-Leu-MBHA-resin. It is important to have a one-residue spacer between the MBHA linker and the thiol for optimal acid stability of the amide bond.f All twenty Boc-protected amino acids can be coupled to this thiol on the solid support to generate the thioester.Despite the potential reactivity of the thioester to the amino terminus, the formation of a dioxopiperazine is not generally observed when using in situ neutralization protocols. However, when the sequence was Leu-Tyr-Arg-Ala-Pro, 20% of a dipeptide deletion product, Leu-Tyr-Arg, was observed. It is likely that sequences such as C-terminal Pro-Gly would also be subject to this side reaction.t ... 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

In addition to thioesterifications employing the C-terminal condensation with alkyl-thiols, the Danishefsky group demonstrated an alternative type of thioesterification (Scheme 11.6) [74], A suitably side chain-protected peptide acid is condensed with an amino acid 2-dithioethyl phenyl ester. The 2-dithioethyl phenyl ester is prone to rearrangement to a thioester through O S transesterification under reducing (NCL) conditions. 

The reaction of cyclohexenamides with nucleophiles such as water, alcohols, or thiols, produced carboxylic acid, esters, or thioesters. Reaction with acetylenic dipolarophiles in acidic conditions produced highly functionalized pyrroles via a complex mechanism, implying as intermediates 1,3-dipoles and bycyclic cycloaddition products. Reaction of cyclohexenamides containing protected hydroxylic functions with AcCl/MeOH produced < -lactones, while cyclohexenamides, bearing in Ri an o-aminophenyl group, easily cyclized to 1, 4-benzodiazepine-2, 5-diones. 

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