Carbothioates synthesis

The literature describes a general method for the synthesis of l,4-dioxo-3,4-dihydrophthalazine-2(l/7)-carbothio-amide 655 based on heating an equimolar mixture of phthalic anhydride and thiosemicarbazide at 160 °C for 30 min in the presence of PPA. However, it has been reported that this treatment provides 654 instead (Scheme 107) <2003JHC1011>. 

The first total synthesis of a protein by the chemical ligation approach utilized nonnative bonds at the site of ligation. In the early 1990s the Kent laboratory pioneered a thioester forming ligation that utilized a highly chemoselective reaction between a peptide with a C-terminal carbothioate group 1 and a N-terminal bromoacetyl peptide 2 at pH <4 (Scheme 2). 

Peptide carbothioic acids were synthesized using a thioacid linker 4 developed by Blake (Scheme 4).P - l A generalized synthesis of this Boc-Xaa-thioacid-linker has been described by Canne et The thioadd-resin was synthesized by dissolving Boc-Xaa-thioacid-linker DCH A salt (1.1 equiv) and HBTU (1.1 equiv) in a minimum volume of DMF and activated for 2 min. This mixture was added to amino-methyl-polystyrene-resin (1.0 equiv, -l.Ommol-g loading of amine) and coupled for Ih or until the reaction proceeded to >9 5% as monitored by the quantitative ninhydrin test. 

This classification is illustrated in Scheme 317. Imidazole synthesis under this category is uncommon, as noted in CHEC(1984) and CHEC-II(1996). One example, in which secondary amino-AT-carbothioic acid (phenyl- -tolylimino-methyl)amides 1258 react with dimethyl acetylenedicarboxylate to form 4-aminoimidazoles 1259, has been reported. A reaction mechanism including the formation of a seven-membered cyclic intermediate followed by the extmsion of thioglyoxylic ester has been proposed (Scheme 318) <2004TL8945>. 

Phillipps GH, Bailey EJ, Bain BM, et al. Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17(3-carbothioates and -17(3-carboselenoates. J Med Chem 1994 37 3717-3729. 

Synthesis of S-phenyl carbothioates from the corresponding silylated acids can be carried out with PhSTMS under Lewis acid catalysis (eq 26). The choice of Lewis acid has direct impact on the chemoselectivity of the reaction. 

The same catalysis system, namely, fluorous hydrazine-carbothioate together with NCS, was also employed in the synthesis of polysubstituted 1,2-dihydroquinolines through a tandem reaction of a-ketoesters and arylamines (Scheme 7.33) [49]. With this multi-component reaction protocol, polysubstituted 1,2-dihydroquinolines... 

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