BIOTIN 



A better method of synthesising this tricarboxylic acid, which gave 

 a 23 % over-all yield from pimelic acid in seven steps, was as follows : 



Br. NaSH 



CH3OOC . (CH,)6 . COOCH3 — ^ CH3OOC . CHBr . (CH,), . COOCH3 -h 



COOCH3 



CH3OOC . CH . (CH,), . COOCH3 cHa-.CH.COOCH, ™2 COOCH3 



L 



CH2 CH.(CH2)4.COOCH, 



NaOCHs 



COOCH3 

 CH— CO 



CH, CH . (CHa)^ . COOCH3 



and thence via the cyanhydrin as before. 



The conversion of the tri-carboxylic acid into 2-(8-carboxybutyl)- 

 3 : 4-diaminothiophan involved the selective degradation of the two 

 nuclear carboxyl groups without affecting the side-chain carboxyl 

 group. This was accomplished by degrading the carboxyl groups one 

 at a time. The ^mws-diamino-carboxylic acid thus obtained yielded 

 ^/-g_/)mllobiotin on treatment with phosgene. Biotin resulted by the 

 similar treatment of the czs-diamino-carboxylic acid prepared by a 

 rather different series of reactions from a common intermediate, a 

 cis-uracil with the structure : 



CgHj 



CO— N 



NH 



CO 



CH— CH 



CH2 CH. (CH2),.COOH 



This synthesis confirmed that biotin had a c^'s-configuration at the 

 bridgehead of the two rings, whilst g^^allobiotin and allobiotin had 

 the /raws-configuration. 



A fourth stereoisomer of biotin, known as e_/)i"biotin was obtained 

 from the cis-diamino-carboxylic acid that yielded biotin itself, dl-epi- 

 Biotin, m.p. 190 to 191° C, was biologically inactive when assayed with 



418 



