Dithioesters, synthesis

Scheme 8. Oxepane synthesis by photo-induced ring closure of dithioesters. The term dithioester is used in this chapter to describe compounds of type 39 even though such systems are sometimes referred to as dithionoesters or dithioxoesters.

Scheme 11. Bis(oxepane) synthesis using a photochemical dithioester cyclization and a reductive hydroxy ketone cyclization.

Beside thioamides, dithioesters are the most stable and accessible thiocarbonyl compounds. Their specific reactivity, in particular towards nucleophiUc reagents and their apphcations to the formation of carbon-carbon bonds, have already been reviewed [8]. However, as shown below, the presence of a phosphonate function alpha or beta to the thiocarbonyl group in phosphonodithioformates and phosphonodithioacetates makes these difunctional compounds very versatile building blocks. Moreover, for the phosphonodithioacetates, the substitution of the methylenic hydrogen atoms by fluorine increases again their potential as intermediates for the synthesis of modified natural and bioactive phosphorylated structures. 

Fluorinated dithioester 39 has also been involved in thioacylation reaction of enantiopure aminoalcohols leading to the corresponding hydroxylated thioamides. The later, treated either by SOCVpyridine, CH3SO2CI, or PhjP/DEAD, cyclise into thiazolines 42 without epimerisation and in excellent yields. An interesting application of this reaction is the synthesis of a new type of modified nucleotides such as 43 and 44 by a one pot reaction simply by mixing the dihydroxy substituted thioamide (obtained from 39 and the 2-amino-l,3-... 

The synthesis of numerous thiadiazoles substituted in the 5-position with carbamoyl or heteroaryl moieties and hydroxyl or amino groups in the 2-position (Scheme 20), was achieved by reacting dithioesters with semicarbazide or thiosemicarbazide and cyclizing the resulting acylated sem-... 

As mentioned above, the grafting to technique enables in a one-pot reaction the synthesis of Au NPs stabilized by sulfur-containing polymers, which bear functional groups such as dithioester, trithioester, thiol, thioether and disulfide at the end of a polymer chain or in the middle. This method leads to nanoparticles similar to those obtained by the Brust-Schiffrin method in which alkanethiol-protected Au NPs of small size are obtained. This grafting to technique leads to very stable nanomaterials that also present a high surface graft density of polymer brush on the Au NP surface. 

An alternative solid-phase synthesis of peptide thioamides that uses methyl dithioesters to introduce the sulfur involves addition of DMAP and cesium trifluoroacetate. 24 These additives greatly accelerate the thioamide-forming reaction and give low levels of racemi-zation according to Marfey s test analysis 25 of an Alaip[C(=S)—NH]Val product. 

Extensive studies of enzyme-substrate complexes by resonance Raman spectroscopy (RR) have prompted the synthesis of new peptide bond modifications such as thionoesters and dithioesters (Scheme l7)t82-83l within simple model substrates. The resulting acyl-enzyme complexes are especially amenable to RR analysis with cysteine proteases such as papain due to formation of the transient dithioester intermediates. 

The first synthesis of acylglycine dithioester derivatives was described by Storer et al.[86l Their synthesis begins with the Pinner reaction 86 88 89 of the corresponding aminoacyl nitrile 39 in the presence of ethanethiol and HC1 gas to produce a thioimidoester hydrochloride 40. Use of an alcohol instead of a thiol gives the thionoesterJ90 The thioimidoester 40 was then treated with H2S gas in the presence of pyridine to yield the dithioester 41 (Scheme 18).[861... 

An attractive method of preparation of the dithioesters of N-protected amino acids was described by Thorsen et a I.194 The methyl dithioesters were used in an activated form of amino acids for the synthesis of thioamide-modified peptides (see Section 10.9.1). 

An indirect method makes possible the general use of lithium as well as magnesium organometallic reagents for the synthesis of dithioesters their addition to phenylisothiocyanate followed by alkylation gives A-phenylimidothioesters (themselves valuable intermediates), which are readily sulfhydrolysed [151,152],... 

Ketenedithioacetals (1) can formally be considered as S.S-dialkylated dithioacids. However, their reactivity pattern is quite different from that displayed by compounds like dithioacids and dithioesters bearing a thiocarbonyl group, and their syntheses and properties are usually treated apart. The review by Kolb [59] and its 254 references give access to most of the literature in the field (see also [60]). a-Oxoketenedithioacetals (2) are particularly versatile compounds as three-carbon synthons in organic synthesis, and some reviews deal specifically with them [61, 62]. Many efficient procedures are available for their syntheses [59, 61], and number of these make use of the reactions of carbon disulfide with carbanionic species followed by alkylation at the sulfur atoms (see [63] and [64] for the reactions of CS2). 

Synthesis of dithioesters from 5-thioesters and La wesson s reagent... 

Synthesis of saturated and unsaturated dithioesters through reaction of Grignard reagents with phenylisothiocyanate, alkylation and sulfhydrolysis... 

A few a-acylamino dithioesters were successfully synthesized by the Pinner reaction in the early 1970s. 6 9 However, many amino acid and peptide dithioesters have now been prepared by this procedure and used for the synthesis of endothiopeptides 10 and spectroscopic studies of dithioesters. 1 ... 

Amino acid dithioesters have been used as building blocks for the synthesis of en-dothiopeptides, the dithioesters will condense with a-amino groups of N-unprotected amino acids to form thioamides. Preparation of optically active amino acid dithioesters and subsequent formation of thioamide bonds without racemization are two problems that need to be addressed when using this approach to prepare endothiopeptides. The Pinner reaction (Section 15.1.11.1) 1 and Lawesson s procedure (Section 15.1.11.2)M have been successfully used to prepare optically active amino acid dithioesters a modification of Lawesson s procedure via thioamides is also successful.[81... 

The Comprehensive Organic Functional Group Transformations series includes up-to-date overviews of the synthesis of thioaldehydes and thioke-tones [12], thionoesters [13], dithioesters [14], and thioamides [15, 16]. 

The high electrophilicity of dithioesters towards amines was applied to the synthesis of phosphonothioamides [35, 36] and thiohydroxamic acids [37]. Dithioacid salts may also be used as starting materials for this thio-acylation with catalysis by boron trichloride [38]... 

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