SYNTHESIS 



Three of the four possible racemic j3-biotins were synthesised by 

 Griissner et al. ® from 2-8-methoxybutyl-3-keto-4-carbethoxythiophan : 



CH— CO 



I I 

 CH2 CH . (CH2)3 . CH2OCH3 



\/ 

 S 



This was converted into the cyanhydrin, the cyano group of which was 

 converted into the carbethoxy group and the hydroxy group removed 

 by chlorination and hydrogenation. The two carbethoxy groups were 

 converted into amino groups via the dihydrazide, diazide and diureth- 

 ane, and the diamine was reacted with phosgene. The 8-methoxy 

 group was then converted into a carboxy group via the bromide and 

 cyanide. This method was patented by F. Hoffmann-La Roche & Co.^ 



From the dihydrazide, m.p. 20410 205° C, d^/-i/r-^-biotin, m.p. 221 to 

 222° C. (methyl ester, m.p. 149° C), was obtained, whilst the non- 

 crystalline dihydrazide fraction gave ^/-iso-jS-biotin, m.p. 182 to 183° C. 

 (methyl ester, m.p. 166 to 167° C.) and <^/-j8-biotin, m.p. 234 to 235° C. 

 (methyl ester, m.p. 130 to 132° C). ^Mso-j8-biotin and dl-ijj-p-bioim 

 were inactive towards Saccharomyces cerevisiae and Lactobacillus hel- 

 veticus. It was shown subsequently '^^ that dl-p-hioim was identical 

 with the synthetic biotin of Harris et al., but that neither " iso-j3- 

 biotin " nor " j/r-^-biotin " was a pure stereoisomer. 



Another method of synthesis was described by Baker et al.}^ in 

 which a general method of synthesising the cis and trans forms of 

 2-alkyl-thiophan-3 : 4-dicarboxylic acids was devised and used for 

 the synthesis of 2-(S-carboxybutyl)-thiophan-3 : 4-^mws-dicarboxylic 

 acid. In one method the following series of reactions was employed : 



Ho malonic 

 C2H5OOC . (CHa)^ . COCl > C2H5OOC . (CHa)^ . CHO . 



acid 



C2H5OOC . (CH2)4 . CH : CH . COOH > CH3OOC . (CHa)^ . CH : CH . COOCH3 



HS . CHa. COOCH3 CH3OOC . (CH2)4 . CH . CH2 . COOCH3 NaOCHa 



S . CH2 . COOCH3 + *°i"«"^ 



NCv 



CO— CH . COOCH3 HON /C CH . COOCH3 



I I ^ HO/ I I 



CH2 CH . (CH2), . COOCH3 CH2 CH . (CHa)^ . COOCH3 



V V 



NC . C CH . COOCH3 HOOC . CH— CH . COOH 



?^ CH CH . (CH2), . COOCH3 -5^ CH2 CH . (CH^)^ . COOH 



s s 



27 417 



