P-Hydroxy thioamide

The aldol condensation of benzaldehyde with the thioacetamide carbanion (RCHCSNRV), derived from the desilylation of the silyl-thioether with tetra-/i-buty-lammonium fluoride, is stereoselective at—80°C producing the erythro isomer of the p-hydroxy thioamide preferentially (Scheme 6.18, R = Me, erythro threo 95 5) via a conformationally mobile intermediate. However, when R is bulky, a greater amount of the threo isomer is formed. Predictably, as the reaction temperature is raised, so the stereoselectively decreases. This procedure contrasts with the corresponding condensation catalysed by titanium salts, where the complexed intermediate produces the threo isomer [47, 48],... 

Thiazolines can also be obtained through cyclodehydration of the compounds bearing C(=S)-NH-C-C-OH moiety (P-hydroxy thioamide). The utility of this strategy is demonstrated in the total synthesis of siomycin A, a member of the thiostrepton family <07TL1331 >. Exposure of thioamide 77 with DAST results in intramolecular cyclization to provide an excellent yield of thiazoline 78, which is converted to siomycin A in four steps. Compound 77 represents one of the most complex substrates for DAST-induced thiazoline formation. 

As described previously, thiazohnes are versatile intermediates to thiazoles. In addition, thiazoline rings are structural motifs found in numerous natural products. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. In the total synthesis of cyclopeptide YM-216391, (diethylamino)sulfur trifluoride (DAST) is used as the cyclodehydrating agent for the conversion of P-hydroxy thioamide 76 to thiazoline 13 <05CC797>. A similar strategy has been used in the construction of the thiazoline moiety in two independent total syntheses of hahpeptin A (77 to 78 79 to 80)... 

Cyclodehyd i° of P-hydroxy thioamide 41 can also be effected by fluoroalkanosulfonyl fluorides. Treatment of 41 with -C4F9S02p and tri-ethylamine in dichloromethane at room temperature affords thiazoline 42 in good yield (13TL5788). 

Very high diastereoselectivities are observed in the aldol condensations of secondary thioamide dianions (Z-configuration) with aldehydes. In this reaction the magnesium dianions afford threo aldol products, whereas the monoanion generated from the A -silyl derivatives of the same secondary thioamides affords the cry/Aro-alcohol. This therefore presents a versatile and selective synthesis of both isomers of P-hydroxy-thioamides. 

This protocol has been successfully applied to the reactions of carboxylic acid derivatives such as thioamides and thione esters (cqs 3 and 4). 3-Acetylthiazolidine-2-thiones are quite suitable substrates for the tin(ll) enolate mediated asymmetric aldol reaction and various optically active p-hydroxy 3-acetylthiazolidine-2-thiones are obtained by using chiral diamine 1 (eq 5). ... 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

Condensation of thioamides with a-bromoketoesters under mild conditions gives 4-hydroxy-2-thiazolines which are easily dehydrated to afford thiazoles <86JHC577,86S992,88JHC289>. 2-Amino-4-arylsulfonylimino-2-thiazolines (320) can be prepared by reacting thiourea (or thiourea hydrochloride) with A-alkyl- or A, iV-dialkyl-iV -p-toluensulfonyl-a-chloroacetamidines (Equation (57)) <88JHC1849>. 

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