SYNTHESIS 



Zn + HOAc 

 + AcaO 



Ba(0H)2 



NH . CO . CeHs 



I 



CH— C . NH . CO . CH3 



I II 



CH2 C . (CHa)^ . COOCH, 



S (V) 



NH2 NH2 



I I 



CH— CH 



CH2 CH.(CH2)4.COOH 



V 



o (VII) 



NH . CO . C.Hg 



I 

 Pd + H2 CH— CH . NH . CO . CH3 



CHa CH . (CHa)^ . COOCH, 



S (VI) 



CO 



NH 



CHj CH . (CHj). . COOH 

 \ / 



S Vill) 



COCI2 



NH 



I 

 -CH 



+ NaHCOa 



The methyl y-formylbutyrate used to introdace the valeric acid 

 side-chain was prepared from glutaric acid via the anhydride, the 

 monomethyl ester and y-carbomethoxy butyryl chloride. 



A method of preparing compound II via the di-ethyl ester of 



N-benzoyl-(carboxymethyl-mercapto)-alanine from N-benzoyl-serine 



was used as an alternative step : 



HOCH2 . CH . COOH CICH2 . CH . COOC2H5 



I — I 



NH . CO . CeHs NH . CO . CeHg 



C2H5OOC . CH2 . S . CH2 . CH . COOC2H5 



NaS . CH2 . COOC2H5 



> (11) 



NH . CO . CeHg 



Fractional crystallisation of VI yielded two racemates of methyl 

 3-acetamido-4-benzamidotetrahydrothiophene-2-valerate. These on 

 hydrolysis yielded the corresponding 3 : 4-diamino-tetrahydrothio- 

 phene-2 -valeric acids (VII) as sulphates. Treatment with phosgene 

 yielded two racemates of 2'-ketoimid-azolidino-(4' : 5' : 3 : 4) thiophan- 

 2-valeric acid (VIII) which are distinguished as ^/-biotin, m.p. 232° C. 

 and ^/-allobiotin, m.p. 194 to 196° C. The former wa-s resolved 

 through its esters with /-mandelic acid to give a compound identical 

 with natural biotin. Subsequently,* the " unnatural " isomer, 

 Z-biotin, was obtained by esterification of racemic biotin with mandelic 

 acid. A better method of preparing /-biotin was to crystallise the 

 quinidine methydroxide salt ; this gave the ^-isomer in poor yield and 

 in an impure state. The best method of preparing ^-biotin was by 

 means of the L-arginine salt. 



Subsequently the preparation of a third isomer of j8-biotin from 

 the reduction product of compound VI was described ; ^ this is termed 

 dl-epiaAlohiotin and it decomposes without melting, commencing at 

 195° C. This compound on hydrogenolysis with Raney nickel gave 



415 



