544 BIOTIN 



D. SYNTHESIS OF BIOTIN 



The conclusions regarding the structure of biotin as they arose from the 

 excellent investigations of du Vigneaud and his coworkers received complete 

 confirmation by the synthesis of biotin first accomplished by Harris and his 

 colleagues in the Merck laboratory.^^-^^ j^ this synthesis cysteine (I) was 

 condensed with chloroacetic acid as starting materials. After benzoylation 

 and esterification this condensation product (II) was treated with sodium 

 methoxide. The resulting compound (V) has undergone decarboxylation 

 after treatment with hydrochloric acid in an aqueous acetic acid solution 

 (VI). Compound VI contains the tetrahydrothiophene ring, one amino 

 group, and one potential amino group in the ketone. 



The methyl 7-formylbutyrate used to introduce the valeric acid side chain 

 was prepared from glutaric acid as starting material. Glutaric acid an- 

 hydride (VII) was treated with methyl alcohol to give glutaric acid methyl 

 ester (VIII), which was in turn converted to 7-carbomethoxybutyryl chlo- 

 ride (IX), and finally on treatment with a Rosenmund catalyst and hy- 

 drogen was converted to the aldehyde (X). 



The condensation of the ketotetrahydrothiophene (VI) with the al- 

 dehydo acid (X) was achieved (XI) with the use of piperidine and acetic 

 acid as catalyst. The unsaturated ketone gave after treatment with hydrox- 

 ylamine in pyridine solution the unsaturated oxime XII. This compound 

 contains the complete carbon skeleton of biotin with two nitrogen atoms 

 and the sulfur atom in the proper position. The reduction of the oximino 

 group and of the double bond to a completely saturated compound was 

 accomplished in two steps. First, treatment of compound XII with zinc 

 dust and acetic acid in the presence of acetic anhydride resulted in two 

 compounds (XIII and XIV) which differed only by the position of the 

 double bonds. In the second step, hydrogenation of these compounds, using 

 a palladium catalyst and hydrogen gas, yielded completely saturated iso- 

 meric compounds (XV). Saponification with NaOH resulted in compound 

 XVI. Both compounds XV and XVI were converted, following the proce- 

 dure of du Vigneaud and his coworkers,-^ after treatment with barium 

 hydroxide, to a diaminocarboxylic acid XVII. As the corresponding natural 

 product, this synthetic diaminocarboxylic acid yielded upon treatment with 



« S. A. Harris, D. E. Wolf, R. Mozingo, and K. Folkers, Science 97, 447 (1943). 

 " S. A. Harris, D. E. Wolf, R. Mozingo, R. C. Anderson, G. E. Arth, N. R. Easton, 



D. Heyl, A. N. Wilson, and K. Folkers, J. Ayn. Chem. Soc. 66, 1756 (1944). 

 " S. A. Harris, N. R. Easton, D. Heyl, A. N. Wilson, and K. Folkers, J. Am. Chem. 



Soc. 66, 1757 (1944). 

 " S. A. Harris, R. Mozingo, D. E. Wolf, A. N. Wilson, G. E. Arth, and K. Folkers, 



J. Am. Chem. Soc. 66, 1800 (1944). 

 « S. A. Harris, D. E. Wolf, R. Mozingo, G. E. Arth, R. C. Anderson, N. R. Easton, 



and K. Folkers, /. Am. Chem. Soc. 67, 2096 (1945). 



