824 IX. THE VITAMIN E GROUP 



Coumarin, like chromene, has a double bond between carbons 3 and 4; 

 it also has a carbonyl group on carbon 2. Although no chromenes were 

 found which have biological activity, the presence of the double bond at the 

 3,4 position does not' exclude activity, since 3,4-dehydro-a-tocopherol is 

 active. 



Coumarin and its dihyroderivative (dihydrocoumarin) are both inactive. ^^^ 

 Coumarin, in fact, was shown to be toxic at a 100-mg. level. 5,7,8-Tri- 

 methyl-6-hydroxy-3,4-dihydrocoumarin is also without activity. ^^^ How- 

 ever, 3-carbethoxy-5,7,8-trimethyl-6-hydroxycoumarin is exceedingly po- 

 tent (1 Rat Unit = 20 mg.), although the corresponding 3-carboxy com- 

 pound was inactive at this dosage. It is the compound, aside from the 

 tocopherols, which for some mysterious reason possesses the highest 

 vitamin E activity. Even more strange is the fact that the free acid and 

 the isoamyl ester are both inactive. ^'^ 



CHj H 

 HOC C CCOOC2H5 



^C 



CH3 



3-Carbethoxy-5,7,8-triniethyl- 

 6-hydroxycouinarin 



(4) Coumarans and Coumarones 



Despite the profound change in the heterocyclic structure of the couma- 

 rans, several active derivatives have been reported. 2-Methylcoumaran 

 was found, in one assay, to possess considerable potency when fed in 50- 

 mg. doses; however, in 3 other assays at 25, 50, and 100 mg., it was found 

 to be inactive."^ Further work is needed to clear up this discrepanc5^ 

 However, two other coumarans, namely, 2,2,7-trimethylcoumaran and 

 2,3,4,6,7-pentamethyl-5-hydroxycoumaran, were found to be active. ^^* 

 On the other hand, 3-methyl-,"« 2,4,6,7-tetramethyl-,"« 2,4,6,7-tetramethyl- 

 5-hydroxy-,"*''^° and 4,6,7-trimethyl-2-n-heptadecyl-5-hydroxycouma- 

 rans,^*^ are all entirely inactive. Coumaran itself is without activity. ^^0 



"2 F. Bergel, A. Jacob, A. R. Todd, and T. S. Work, /. Chem. Soc, 193S, 1375-1382. 



