Synthesis of A2-Thiazolines

This type of ring closure has been widely applied in the synthesis of A2-thiazolines. N-(fi -Substituted alkyl)amides (341 X=halogen, OH, SH, OAc) yield thiazolines (342) on treatment with phosphorus pentasulfide (Scheme 220) (35JA1079). A2-ThiazoIine itself... 

One of the most valuable methods for the preparation of A2-thiazolines is of this class. The reaction of 2-haloalkylamines (334) with thioamides, metal thiocyanates or carbon disulfide give 2-alkyl- or -aryl- (335), 2-amino- (336), and 2-mercapto- (337) A2-thiazolines, respectively (Scheme 218) (17CB804). A method derived from the last procedure leads to a convenient synthesis of 2-phenyl-A2-thiazolines (340) under very mild conditions and consists of the condensation between a-aminothiols (338) and thiobenzoylmercaptoacetic acid (339 Scheme 219) (74TL1863) (this method could be better classified under Type E, Section 4.19.3.2.5). 

The mechanism of the Hantzsch synthesis has been established and is shown in Scheme 165. Substitution of the halogen atom of the a-halo ketone by the sulfur atom of the thioamide occurs first to give an open-chain a-thioketone (232), which under transprotonation proceeds to give a 4-hydroxy-A2-thiazoline (233) in aprotic solvents, or a thiazole (234) by acid-catalyzed dehydration of the intermediate thiazoline in protic solvents. 

A convenient synthesis of thiazolo-fused 2-pyridones 41 has been developed <07JOC4917>. Thus, A2-thiazolines 39 undergo acyl ketene imine cyclocondensation with Meldrum s acid derivatives 38 to give the dihydro thiazolo-fused 2-pyridones 40, which transform to 41 via bromination-elimination process. Pyridones 41 are converted to the 2-substituted analogs 43 and the saturated products 42 by Heck coupling and conjugate addition, respectively. 

Figure 17-14. Enzymatic synthesis of L-cysteine from D,L-2-amino-A2-thiazoline-4-carboxylate.

L-Cysteine had been produced by extraction from hair after hydrolysis with strong acid. However, this process has many problems such as too high energy costs, occurrence of bad smell, production of much acidic waste, and an unreliable supply of hair. In the 1970s a three-step enzymatic method was established by Ajinomoto Co. to produce L-cysteine from DL-2-amino-A2-thiazoline-4-carboxylate(DL-ATC), a starting material of the chemical synthesis of L-cysteine. The enzymes catalyzing this process are dl-ATC racemase l-ATC hydrolase and S-carabamoyl-L-cysteine (SCC) hydrolase ... 

Much of the world s cysteine is isolated from keratin, mostly obtained in the form of hair. The process, which is based on an acid hydrolysis of the protein, is smelly, and it produces waste products which are difficult to treat. It is progressively being replaced by an enzymatic synthesis which once again couples a stereospecific hydrolysis with a racemisation process. Methyl-2-chloroacrylate is converted into DL-amino-A2-thiazoline-4-carbo-xylate, and both enantiomers of this intermediate are then hydrolysed by an enzyme from Pseudomonas thiazolinophilum or Sarcina lutea directly to L-cysteine. The necessary racemisation occurs spontaneously during the reaction (Scheme 6.10). 

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