574 BIOTIN 



acetate of the cyclic form of the corresponding aldehydo acid, 3,4-(l',3'- 

 dibenzyl-2'-ketoimidazoUdo)-2-keto-5-acetoxytetrahydrofuran (VI) . Com- 

 pound VI, when treated under suitable conditions with hydrogen sulfide in 

 the presence of hydrogen chloride, followed by a reductive treatment of 

 the intermediate formed, gives 3,4-(l',3'-dibenzyl-2'-ketoimidazolido)- 

 2-ketothiophane (VII). 



The thiolactone (VII) can be converted to biotin by several routes. In 

 the preferred method, it is reacted with 3-ethoxypropyl magnesium bromide 

 to give 3 ,4-(l' ,3'-dibenzyl-2'-ketoimidazolido)-2-hydroxy-2-(a>-ethoxypro- 

 pyl)thiophane (VIII). The latter is dehydrated to the corresponding 

 unsaturated compound IX, which is then hydrogenated to 3,4-(l',3'-di- 

 benzyl-2'-ketoimidazolido)-2-(aj-ethoxypropyl)thiophane (X), using Raney 

 nickel as a catalyst. When compound X is treated with hydrogen bromide 

 in acetic acid, it forms 3,4-(l',3'-dibenzyl-2'-ketoimidazolido)-l ,2-trimeth- 

 ylenethiophanium bromide XI. The thiophanium bromide is then converted 

 to the corresponding d-camphorsulfonic acid salt by treatment with silver 

 d-camphorsulfonate. This d-camphorsulfonate represents a mixture of two 

 diastereomeric salts which can be readily separated. Crystallization from 

 isopropanol gives the Z-3,4-(l',3'-dibenzyl-2'-ketoimidazolido-l,2-trimeth- 

 ylenethiophanium c?-camphorsulfonate (XII), the optical configuration of 

 which corresponds to that of the natural d-biotin. When this Z-thiophanium 

 d-camphorsulfonate is treated with sodium diethylmalonate in toluene, it 

 forms a Zew-rotatory 3,4-(l',3'-dibenzyl-2'-ketoimidazolido)-2-(aj,co-dicar- 

 bethoxybutyl)thiophane (XIII). This product can be converted to d-biotin 

 (XIV) in a one-step reaction by simply boiling it with concentrated hydro- 

 bromic acid. This treatment causes saponification of the two ester groups 

 present in the side chain and decarboxylation of the corresponding free 

 malonic acid, to form the co-carboxy butyl side chain present in biotin. 

 Simultaneously, the two benzyl groups which protect the nitrogen atoms of 

 the imidazolidone ring throughout the synthesis are removed in form of 

 benzyl bromide. In spite of the drastic conditions employed in this reaction 

 the yield is surprisingly good, and only a small part of the biotin formed 

 is hydrolyzed to the corresponding diamino acid (XV). The latter can be 

 readily reconverted to d-biotin by treatment with phosgene. 



The synthesis is highly stereospecific. No epibiotin is formed, and since 

 the required cis configuration is present from the beginning, the two trans 

 isomers, allobiotin and epiallobiotin, are also absent. 



