488 THE TOCOPHEROLS 



trimethylhydroquinone with phytyl bromide, zinc chloride being the cata- 

 lyst. Except for lacking optical activity the product had physical and chem- 

 ical properties identical with those of naturally occurring vitamin E. 

 Lateral • ^^ this synthetic product was shown also to have practically the 

 same physiological properties as vitamin E, and thus a unique event hap- 

 pened in organic-biochemical history — the synthesis of a complex sub- 

 stance before its actual constitution was known! 



A span of approximately fifteen years had elapsed between the first recog- 

 nition of the existence of vitamin E and the synthesis of physiologically 

 active tocopherol. The last two years of this period witnessed as rapid a 

 succession of significant events as has ever been seen in any field of bio- 

 chemical endeavor. 



The Karrer synthesis with phytyl bromide was duplicated by Smith and 

 his colleagues without a catalyst^^ and by the use of dienes (phytadiene)"^* 

 and of allyl and crotyl compounds and butadiene .^^ For the construction 

 of the phytol chain, John and Pini^^ used (tetra)farnesol, Smith and Sprung*^ 

 used citral. 



Further proof for the existence of a chroman nucleus was provided by 

 permanganate oxidation,"*^ which produced the same decisive lactone, and 

 later by another method of synthesis, via carbinols,^^ and by the quantita- 

 tive conversion of tocopherol (from purified tocopherylquinone via a ter- 

 tiary halide) into the diacetate.^" 



For /3-tocopherol, John-^ and also Karrer et al}^ had proposed the same 

 general structure as that of the a-tocopherol, less one of the methyl groups, 

 and John^^ had concluded from the products of hydriodic acid treatment 

 of /3-tocopherol that the methyl groups were in the 5,8 positions. Emerson^^ 

 confirmed the general structure by obtaining the same lactone from both 

 /3- and 7-tocopherol. Both these dimethyl compounds had been synthesized 

 from dimethylhydroquinones and phytyl bromide, ^^^ ^^ the ^ from the 'para 



" P. Karrer and V. Demole, Schweiz. med. Wochschr. 68, 954 (1938). 



42 P. Karrer, H. Fritzsche, B. H. Ringier, and H. Salomon, Helv. Chim. Acta 21, 820 



(1938). 

 " L. I. Smith and H. E. Ungnade, /. Org. Chem. 4, 298 (1939). 

 « L. I. Smith, H. E. Ungnade, H. H. Hoehn, and S. Wawzonelv, J. Org. Chem. 4, 



311 (1938). 

 4^ L. I. Smith, H. E. Ungnade, J. R. Stevens, and C. C. Christman. J. Am. Chem. 



Soc. 61, 2615 (1939; L. I. Smith and J. A. King, ibid. 63, 1887 (1941). 

 4« W. John and H. Pini, Z. phijsiol. Chem. 273, 225 (1942). 

 " L. I. Smith and J. A. Sprung, /. Am. Chem. Soc. 65, 1276 (1943). 

 « 0. H. Emerson, Science 88, 40 (1938). 



"9 L. I. Smith and H. C. Miller, /. Am. Chem. Soc. 64, 440 (1942). 

 "M. Tishler and N. L. Wendler, /. Am. Chem. Soc. 63, 1532 (1941). 

 " O. H. Emerson, /. Am. Chem.. Soc. 60, 1741 (1938). 

 82 F. Bergel, A. M. Copping, A. Jacob, A. R. Todd, and T. S. Work, J. Chem. Soc. 



1938, 1382. 



