546 BIOTIN 



sodium carbonate and phosgene the cychc urea compound XVIII, having 

 the structure of the natural biotin. 



The synthesis of biotin was complicated by the fact that it contained 

 three asymmetric carbon atoms. Thus, there should exist four diastereo- 

 isomers or eight optically active modifications corresponding to the struc- 

 ture of biotin. All the racemic diastereoisomers, d^biotin,'*^■^2 di-epibiotin,^^ 

 dZ-allobiotin,*^-^^ and d^epiallobiotin,^i' ^- have been synthesized. dZ-Biotin 

 (m.p. 232°) and d/-allobiotin (m.p. 232°) originate from compound XIII; 

 d^epibiotin (m.p. 190 to 191°) and c?Z-epiallobiotin (fuses above 195°) 

 from compound XIV. 



The structure of these various racemic forms was successfully elucidated 

 by their conversion into the corresponding desthio derivatives, using re- 

 duction with Raney nickel as first employed on natural biotin. ^^ In desthio- 

 biotin the asymmetry of the original carbon atom 2 in the biotin molecule 

 is destroyed, and in consequence the resulting compound allows only two 

 instead of four racemic forms. d^Biotin and d/-epibiotin yielded the same 

 c?Z-desthiobiotin, while the alio forms furnished among themselves identical 

 dZ-allodesthiobiotin. Thus, biotin and epibiotin differ by being epimeric at 

 carbon 2 where the side chain is attached. The same conclusion applies 

 to the alio forais. Compared with the epimeric biotins the allobiotins show 

 easier conversion to diamino compounds and are in turn less easily recon- 

 verted by the action of phosgene into the original than are epimeric biotins. 

 The instability of the urea group in dZ-allobiotin and dZ-epiallobiotin in- 

 dicates a strained transfusion of the two rings^* with a ti'ans configuration 

 of the nitrogens in the urea group (XIX). In contrast, dZ-biotin and dl- 

 epibiotin must have a cis ring structure (XX). 



^0^. /CO 

 NH. ,11 IT >^H IslI jj NH ^ 

 ^c^:^ ^C C -^ C' 



H2C. .CH(CIIv),COOH HoC. .Cn(Cn;)4C00H 



AUobiotin, cpiallobiotin Biotin, epibiotin 



XIX XX 



dZ-Biotin contained only one-half the biological activity of natural biotin. 

 Its resolution into its two components met first with difficulties since it 

 did not form crystallizable salts with ordinary alkaloids. The resolution 

 was successfully accomplished by combining the racemic synthetic product 



" B. R. Baker, W. L. McEwen, and W. N. Kinley, J. Org. Chem. 12, 322 (1947). 

 " S. A. Harris, R. Mozingo, D. E. Wolf, A. N. Wilson, and K. Folkers, J. Am. Chem. 

 Soc. 67, 2102 (1945). 



