Thiazolines oxidative cyclization

A novel, biogenetic-type synthesis of the penicillin and cephalosporin ring-systems has been described. The key step in this approach is a stereo-controlled cyclization of the acyclic tripeptide (171) to the cu-)3-lactam (172), an intermediate which may be transformed into both penicillin and cephalosporins (Scheme 6). Alternatively, an oxidative cyclization of thiazoline (173) ulti-... 

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]. 

An alternative mechanism to form thiazoles and oxazoles is through oxidation of a dipeptide followed by cyclization from an enolate or thienolate precursor and subsequent dehydration (Scheme 7.2). This represents a higher-energy pathway and there is no accumulation of thiazoline or oxazoline intermediates [22-24]. 

Many desirable meat flavor volatiles are synthesized by heating water-soluble precursors such as amino acids and carbohydrates. These latter constituents interact to form intermediates which are converted to meat flavor compounds by oxidation, decarboxylation, condensation and cyclization. 0-, N-, and S-heterocyclics including furans, furanones, pyrazines, thiophenes, thiazoles, thiazolines and cyclic polysulfides contribute significantly to the overall desirable aroma impression of meat. The Maillard reaction, including formation of Strecker aldehydes, hydrogen sulfide and ammonia, is important in the mechanism of formation of these compounds. 

Azine approach. The fused pyrimidines can be synthesized in the same way as the pyridines, e.g. by the cyclization of vicinal aminothiocyanates (70JCS(C)2478>. Another useful method for aminoazines is the reaction with chlorocarbonylsulfenyl chloride, e.g. with the aminopyrimidine (440) (73LA1018). The reaction can be rationalized by initial acylation of the amino group which is then cyclized with formation of the 2(3//)-one (441). Another case is the reaction of the 6-aminouracil (442) with thionyl chloride (69JOC3285). The reaction is rationalized as an initial electrophilic substitution at the 5-position of the activated pyrimidine. Subsequently the chlorosulfinyl derivative (443) is cyclized to a thiazoline S-oxide which loses water to yield the thiazole. 

Azine approach. l,3-Dialkyl-6-hydrazinouradl is susceptible to electrophilic attack at C-5. Treatment of (736 R1 = H) with excess thionyl chloride at room temperature gives the fused uracil (737) in an exothermic reaction. The reaction is thought to involve initial formation of a sulfinyl chloride. Subsequently the electrophilic cyclization occurs at C-5 to form a thiazoline S-oxide which is dehydrated to yield (737). From a,3-dimethyl-6-hydrazinouracil (736 R1 = R3 = Me, R2 = H) the heteroaromatic betaine (738) is formed (78JOC1677). 

Oxidation of thioamides with I2, Br2 or H202 to diimino disulfides, followed by acid-catalyzed cyclization with elimination of amine, is an important route to symmetrically substituted 1,2,4-dithiazolylium salts (43) (79NKK389), and structures (47) (79CHE1187). The preparation of the 3-phenyl-l,2,4-thiazolines (35), and thus (36), is a related reaction. 

AG(E)135 05AG(E)4925>. A more recent protocol for the dehydrative cyclization of cysteine derivatives to thiazolines involves molybdenum (IV or VI) oxides as catalysts as exemplified by the formation of 82 from 81 <05OL1971>. 

The key to this approach was the formation of the oxazole ring in the presence of the thiazoline rings. Cyclization of 1298 with Burgess reagent" gave the expected intermediate oxazoline (not shown), but this could not be oxidized to 1299 using Ni02, NBS/benzoyl peroxide, or CuBr/tert-butyl perbenzoate. Thionyl chloride, phosphorus oxychloride, titanium tetrachloride, or triphenylphosphine/iodine did not effect cyclodehydration of the p-ketoamide produced from the Dess-Martin periodinane oxidation. 

FIGURE 4.12 A modified condensation domain facilitates the cyclization of serine or cysteine residues to the corresponding oxazoline or thiazoline. These heterocycles may remain untouched for the remainder of the biosynthesis or they may undergo enzymatic oxidation to the thiazole as in epothilone D or undergo enzymatic reduction to the thiazolidine as in yersiniabactin. 

The reaction of the thiazoline sulfur with iodine depended upon the side chain and reaction conditions (Micetich and Morin, 1976). The thiazoline (162) reacted to give complex A or B depending upon the stoichiometry. Addition of water to complex A gave the symmetrical disulfide (246) which on further iodination yielded the 3-iodocepham (247). Complex B with water gave 247 directly. Other workers have reported catalytic effects of free radical initiators or heavy metal oxides in this transformation (W. Germ. Patent 2,534,811 Micetich and Morin, 1977). It was postulated that the sulfenyl iodide intermediate (248) was obtained on aqueous treatment of the original complexes which then spontaneously cyclized to the cepham derivative. 

Type K (C—C—N—C—S) Syntheses.—Further examples of the dehydrative cyclization, by means of dicyclohexylcarbodi-imide, of N-benzyloxythio-carbonylamino-acids (109) to 2-benzyloxy-A -thiazolin-5-ones (110) have been reported. Compared with 2-phenyl-A -thiazolin-5-ones, the products show a greatly diminished tendency to enolization, probably attributable to the inductive effect of their benzyloxy-group." Their oxidation by iodine produces the corresponding 4,4 -bis-(2-benzyloxy-A -thiazolin-5-ones)... 

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