II. CHEMISTRY AND INDITSTRIAL PREPARATION 55 



and still show vitamin A activity. Retrovitamiu A methyl ether (CIV),'" 

 whicli is assumed to he the methyl ether of CUT, has only a trace of bi- 

 ological activity. Its spectrum shows two maxima at 348 and 367 mn, with 

 -^^Tcni. values of 2190 and 1770, respectively. It also gives no isogeronic acid 

 on ozonolysis, confirming the structure assigned to it. a?/o-Vitamin A ethyl 

 ether (CV, m.p. 28 to 30°)i99 has essentially the same spectrum (X„,ax 330, 

 348, and 367 m^; /i'^^ni. values 1690, 1830, and 1520, respectively) as re- 

 hydrovitamin A, but on ozonolysis it yields geronic acid, showing the pres- 

 ence of a )8-ionone ring. 



9. Synthetic Homologs and Analogs of Vitamin A 



AND Related Products 



It would be beyond the scope of this section to discuss the synthesis of 

 each of the various homologs and analogs of vitamin A and related products 

 which have been found to be biologically active. Table XV lists these 

 products together with some of their physical and biological properties. 



10. Chemical Constitution and Biological Activity 



From the biological potency of the various compounds given in Tables 

 X, XII, XIII, XIV, and XV, one may derive certain generalizations. To 

 have a high \'itamin A activity a compound must have: (1) a 2',6',6'-tri- 

 methylcyclohexen-l'-yl or j8-ionone ring; (2) a side chain of at least eleven 

 carbon atoms containing four double bonds in conjugation with one an- 

 other and with the double bond in the ring and attached to the ring in 

 carbon atom 1'; (3) the two methyl groups in the side chain should be at- 

 tached to carbon atoms 3 and 7; (4) the terminal group can be an hydroxyl, 

 carbonyl (aldehyde), or carboxyl (in the form of its sodium salt); (5) all 

 double bonds in the side chain must have a trans configuration as in struc- 

 ture LXXXVIII. A slight modification of this structure has the tendency to 

 diminish or even destroy the biological activity of the compound. For 

 example, replacing one of the trans double bonds with a cis double bond 

 (neovitamin A) or with a triple bond (see Table XV) diminishes the bio- 

 potency of the compound. Moreover, if the methyl groups in the ring or 

 side chain are replaced Avith hydrogen atoms, or attached to some other 

 carbon atoms, the new compounds have very little or no biological ac- 

 tivity. 



It has also been found that when one of the double bonds in the side 

 chain is hydroxylated the resulting compound is highly toxic and acts as 

 an antivitamin A. This toxic compound was produced when /3-carotene or 



>'» N. A. Milas, E. Sakal, J. T. Plali, J. T. Rivers, J. K. Gladding, F. X. Grossi, Z. 

 Weiss, M. A. Campbell, and H. F. Wright, J. Am. Chem. Soc. 70, 1597 (1948). 



