Thiazolidine, structure

The thiazolidine structures in the dihydrothiazolyl hydrazones 53a and 54a were confirmed both by crystallography and in solution by NMR. The stability of the endocyclic N-3 (N-3/N-6 tautomerism) tautomeric forms 53b and 54b, in the gas phase and in water, were confirmed by energy calculations at the MP2/6-31- -G(d) level. These tautomeric structures are expected to be the most abundant form (>90%) of the molecule. The <7 A- -conformations observed in the crystal structures were retained in solution in agreement with stability predictions (Scheme 3) <2002J(P2)1012>. 

The P-lactam ring in the lactam-thiazolidine structure of penicillin (I) is much more sensitive to nucleophilic attack than simple P-lactams. The dibasic penicilloic acid (III) is the product formed under mild hydrolysis conditions in neutral and alkaline solutions. For penicillin G at constant temperature the reaction is first order with respect to penicillin and hydroxide ion concentrations. The mechanism in neutral... 

The 5-mercaptomethylproline residue is one of such devices used for promoting intramolecular NS acyl shift reactions (Scheme 10a) [66]. In an aqueous solution containing MPA, peptide 34a is transformed into the thioester of MPA. This reaction is promoted by microwave irradiation. The thiazolidine structure can substitute for proline (Scheme 10b) [67]. This thiazolidine ring is constructed from a cysteine residue on the solid support, which simplifies the preparation of the thioester precursor. 

The formula of penicillin (IV) has three asymmetric centers one corresponds to the a-carbon atom of the amino acid penicillamine (V) the second is derived from the substituted a-formyl-a -amino acid, penaldic acid (VI), while the third asymmetric center is produced by the condensation of these two components to the thiazolidine structure present in the penicillins. The penicillamine isolated from penicillin was shown to have n configuration by conversion to n-valine. Penaldic... 

Prior to the complete structural elucidation of penicillin some effort was directed towards the preparation of the erroneous oxazolone-thiazolidine structure (48) using (52) and penicillamine (53). Surprisingly trace amounts of bioactive penicillins corresponding to the fused P-lactam structure (49) were obtained 40). The first cyclisation of a penicilloate derivative was described by Sheehan 41) using the acid chloride of the phthalimido derivative (54) to give (55). 

Thiazolines and thiazolidines may also be prepared in this fashion, the structure of the final product determining the substitution pattern to be chosen in the reaction components. Reaction of ethyl bromoacetate with the substituted thioamide (71) resulted in formation of the thiazolidin-4-one (72) (70KGS1621). 

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

Cyclization of methyl (4R)-3-(2-diazo-3-oxobutanoyl)-thiazolidine-4-carboxylate (675) under basic conditions afforded 676 (91CC924). The reaction proceeded with retention of configuration and the structure was established by X-ray analysis (Scheme 140). 

The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of S in the penicillin thiazolidine ring (Fig. 5.1) with oxygen in the clavam oxazolidine ring (Fig. 5.5 A) and the absence of the side-chain at position... 

In 2000, novel thiazolidine derivatives were prepared from L-cysteine by Guan et al, showing good enantioselectivities of up to 90% ee when used as ligands in the addition of ZnEt2 to aldehydes. The results collected in Scheme 3.6 show that the catalytic efficiency of the thiazolidine derivatives was influenced by the different structures of the thiazolidine rings and the bulkiness of the moiety in... 

Over the years, many spiropyran structures have been prepared. The pyran component consists of benzopyran or naphthopyran and the heterocyclic part consists of indoline, benzothiazoline, benzoxazoline, benzoselen-azoline, phenanthridine, acridine, quinoline, benzopyran, naphthopyran, xanthene, benzodithiole, benzoxathiole, and saturated heterocyclic rings such as pyrolidine and thiazolidine. 

The (5-lactam antibiotics are now so extensively described that we cannot attempt to summarize the literature. Since our emphasis is on sulfur, we note that the sulfur atoms of the thiazolidine or dihydrothiazine rings derive from a common tripeptide, 8-(L-a-aminoadipyl)-L-cysteinyl-D-valine 1, ACV or Arnstein tripeptide . ACV is converted to a (5-lactam structure, isopenicillin N 2 and thereafter, the two pathways diverge, i.e. to benzylpenicillin 3 or to cephalosporin C 4 (Scheme 1). There have been extensive studies of the genes and enzymes involved in (5-lactam biosynthesis.18,19... 

There are several naturally occurring variations on the lactam-thiazolidine or lactam-dihydrothiazine structures, leading to other useful antibiotics or to inhibitors of the (5-lactamases, enzymes that hydrolyze the (5-lactam unit. One group, termed carbapenems 5 has a five-membered ring in which the thiazolidine sulfur is replaced with CH2- Such compounds may still contain sulfur in a thioethylamine side chain (derived from L-cysteine) as in thienamycin 6, originally isolated from Streptomyces cattleya (Scheme 2). 

Efforts to find potent and selective DPP-4 inhibitors in the a-amino acid amide series were made in parallel with those in the (3-amino acid amides series. The structural origin of the earliest P-amino acid amide DPP-4 inhibitors traces back to two Merck HTS hits proline derivative 25 and piperazine derivative 26. These two screening leads were further progressed to P-amino acid amide DPP-4 inhibitors incorporating thiazolidine, proline and piperazine amide moieties (Figure 17.5). 

FIGURE 8.8 A peptide sequence containing an oxazolidine ring that gives rise to a serine residue on acidolysis and a thiazolidine ring that gives rise to a cysteine residue on acidolysis. Substituents at C-2 can be H2, H,Me, or Me2. A structure with a methyl group at C produces a threonine residue on acidolysis. 

Abstract This presentation is a brief review on the resnlts of our work on iodine interaction with thioamides, selenoamides and amides. The thioamides, benzothia-zole-2-thione (BZT) (1), 6-n-propyl-2-thiouracil (PTU) (2), 5-chloro-2-mercap-tobenzothiazole (CMBZT) (3), N-methyl-benzothiazole-2-thione (NMBZT) (4), benzimidazole-2-thione (BZIM) (5), thiazolidine-2-thione (TZD) (6), 2-mercapto-pyridine (PYSH) (7), 2-mercapto-nicotinic acid (MNA) (8), 2-mercapto-benzoic acid (MBA) (9) and 2-mercapto-pyrimidine (PMT) (10) react with producing three type of complexes of formulae [(HL)IJ(l2) (HL= thioamide and n= 0, 1), [(HL) [I3 ] and [(HL-L)]+[l3 ]. The interaction of seleno-amides, derived from, 6-n-propyl-2-thiouracil (RSelJ) (R= Me- (11), Et- (12), n-Pr- (13) and i-Pr- (14)) with I, have also been studied and produced the complexes [(RSeU)IJ of spoke structure. These complexes are stable in non-polar solvents, but they decompose in polar solvents, producing dimeric diselenide compounds or undertake deselenation. 

It has been shown by thermodynamic calculations (89TH1) that, under equal structural conditions, the ratio of the tautomeric equilibrium constants for the reversible addition reaction of the SH group and that for the OH group should be 10 in favor of the sulfur addition product. A similar result (>10 ) was estimated (90T6545) from a comparison of the stability of the 1,3-thiazolidine ring with that of the 1,3-oxazolidine ring. 

Cuscutic resinoside A (1 tetradecanoic acid, (115)-[[6-deoxy-3-(9-(6-deoxy-a-L-mannopyranosyl)-4-0-[(2/ ,3R)-3-hydroxy-2-niethyl-l-oxobutyl]-a-L-nianno-pyranosyl]oxy]-intramol. l,2 -ester) was obtained from the ethyl acetate-soluble fraction of a methanol extract prepared from the seeds of Cuscuta chinensis Lam. The purification of this compound employed a combination of column and preparative-scale HPLC. The structure was deduced from spectroscopic evidence and acid hydrolysis 14). The degradative process gave convolvuUnolic acid, nilic acid, and L-rhamnose. The sugar components were identified by GC analysis after being converted to their thiazolidine derivatives. This disaccharide has a unique macrocyclic lactone, which is placed between C-1 and C-2 of the first rhamnose moiety. 

Penicillins are the most widely used of the clinical antibiotics. They contain in their structures an unusual fused ring system in which a four-membered P-lactam ring is fused onto a five-membered thiazolidine. Both rings are heterocyclic, and one of the ring fusion atoms is nitrogen. These heteroatoms do not alter our understanding of molecular shape, since we can consider that they also have an essentially tetrahedral array of bonds or lone pair electrons (see Section 2.6.3). 

Penicillin and cephalosporin antibiotics are usually classed as P-lactam antibiotics, since their common feature is a lactam function in a four-membered ring, typically fused to another ring system. This second ring takes in the P-lactam nitrogen atom and also contains sulfur. In the case of penicillins, e.g. benzylpenicillin, the second ring is a thiazolidine, and in the cephalosporins, e.g. cephalosporin C, this ring is a dihydrothiazine. What is not readily apparent from these structures is that they are both modified tripeptides and their biosyntheses share a common tripeptide precursor. 

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