Thiazoline moieties

Direct transformation of thiazoline-azetidinones 2 into 3 -thio-substituted cephalosporins 6 has been performed by ring opening of the thiazoline moiety with sulfenyl chloride followed by ring closure with ammonia in dimethylformamide and simultaneous displacement of the allylic chlorine atom with the leaving thiolates. 

The group of Park and Jew developed the efficient reaction systems for the preparation of optically active a-alkylserine and a-alkylcysteine derivatives (Scheme 6.15) [40], The group developed the oxazoline-based substrate for serines 52a and the thiazoline-based substrate 52b for cysteines, respectively. The oxazoline and thiazoline moieties fulfilled a dual function the activation of the a-proton and the protection of both the amino and the side chain hydroxy groups. The ortho-biphenyl derivatives 52a and 52b were specifically designed for the cinchona PTC 54, and solid cesium hydroxide monohydrate was chosen as an optimal base. The PTC 29 was also found to be as effective as the PTC 54 for the asymmetric alkylation of 52a. 

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)... 

In the total synthesis of didmolamides A and B, the thiazoline moiety is formed from the trityl protected cysteine 83 by a nucleophilic attack of the cysteine thiol group on the phosphorus-activated amide carbonyl group of the preceding residue (see 84) <05TL2567>. 

Kelly s biomimetic methodology, first reported in 2003 (03AG(E)83), has become one of the most reliable routes to thiazolines. In this approach, the phosphorus-activated amide carbonyl group undergoes nucleophilic attack by the cysteine thiol group to provide the thiazoline moiety For example, amide 25 is treated with triphenylphosphine oxide and triflic anhydride to provide thiazoline ester 26 in good yield (13TL3150). 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

That the Indo-Pacific (Fig. 7.1.II) is an area of high natural product diversity was first revealed by the studies carried out in the 1970 s at the Roche Research Institute on the Great Barrier Reef (Baker 1980). Studies worldwide have since confirmed this richness, unsurpassed by any other area, either in the sea or on land. The variety of small peptides from the Indo-Pacific is impressive, characterized, particularly with the ascidians, by the condensation of the cysteine NH2 and SH groups with the COOH group of an adjacent amino acid. Thiazole and thiazoline rings are formed, which alternate with the normal peptide bonds formed by the other amino acids (Chart 7.2.P1-3). Correspondingly, threonine forms methyloxazoline moieties (Chart 7.2. A, 7.2.P1,7.2.P2). These condensations inqiose a drastic conformational bias to peptides (Abbenante 1996). 

The structurally novel antimitotic agent curacin A (1) was prepared with an overall yield of 2.5 % for the longest linear synthesis. Three of the four stereogenic centers were built up using asymmetric transformations one was derived from a chiral pool substrate. Key steps of the total synthesis are a hydrozirconation - transmetalation protocol, the stereoselective formation of the acyclic triene segment via enol triflate chemistry and another hydrozirconation followed by an isocyanide insertion. For the preparation of the heterocyclic moiety of curacin A (1) the oxazoline - thiazoline conversion provides efficient access to the sensitive marine natural product. 

Thiazoline-azetidinones 1 derived from penicillins G and V4) are potential intermediates for penicillin-cephalosporin conversion, where the oxidative functionalization of the methyl group of the 3-methyl-3-butenoate moiety is an essential step. The direct chlorination of 1 with chlorine (25 °C, 3 days) or /-butyl hypochlorite (—60% yields) gives the corresponding chlorinated compounds 2, bearing benzyl, phenyl, p-tolyl, and phenoxymethyl groups as the R3 substituents 5). 

The reaction of azetidine-3-thiol hydrochloride 20 with 2-methylthio-l,3-thiazoline 21 in the presence of a catalytic amount of triphenylphosphine afforded 2-(3-mercaptoazetidin-l-yl)-l,3-thiazoline hydrochloride 22 (Equation 2), which is useful for the pendant moiety of new oral 1/3-methylcarbapenem antibiotic L-084 <2002H(56)433>. 

On heating the neat sample or a solution in a variety of solvents, 2-allyloxythiazole (125) undergoes a thermal rearrangement to N-allyl-A-4-thiazoline-2-one (126) in excellent yield (Scheme 64) (283). Deuterium labeling reveals the complete inversion or the allylic moiety in the rearrangement. First-order rate law is found, and activation parameters show a negative entropy in accord with that measured in most of Claisen rearrangements. 

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. 

The reaction of a wide range of imines and other compounds containing the C=N moiety with 14 leads to the formation of azacyclopentenones, e.g. 337 (equation 100). Certain of the product heterocycles undergo oxidative dimerization Moreover, related five-membered ring systems result from analogous reactions of 14 with l-(r-pyrrolidinyl) acenaphthylene and thiazoline-5-thiones. ... 

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