714 VII. VITAMINS A 



shortly thereafter, numerous attempts at synthesis were undertaken, using 

 i8-ionone as a starting material. However, although the Grignard reaction 

 can be applied successfully to the a-ionone molecule, ^^^ it does not react in 

 the expected maimer with /3-ionone, so that attempts to use this method of 

 approach have been unsuccessful. 



Ruzicka and Fischer^^^ did succeed, in 1934, in preparing tetrahydrovi- 

 tamin A (I), starting with /3-ionone, which was partially hydrogenated in 

 alcohol with nickel to yield dihydro-(8-ionone. However, the tetrahydro- 

 vitamin A was found to be devoid of growth-promoting activity, as would 

 be expected in view of the fact that the conjugated double bond system is 

 lacking. Synthesis of the triethenoid aldehyde, /S-ionylideneacetaldehyde 



H3C C H3 H3C C H3 



C CH, CH, C CH, 



HjC C- CHz'CHj' CrCH'CHs'CHa'CCCH'CHzOH HjC C • C : C • C : C • C-H 



I II I II 



HzCC HzCC 



\ / \ \ / \ 



CH3 C CHj 



H2 Hz 



(I) Tetrahydrovitainin A (II) j3-Ionylideneacetaldehyde 



(H), which is probably a key intermediate in the synthesis of vitamin A, Avas 

 attempted by Davies et al.^^^ They started with /3-ionone, which was con- 

 densed with acetjdene in the presence of sodamide to produce an acid cor- 

 responding to the desired aldehyde. The barium salt of this acid was dis- 

 tilled with barium formate under reduced pressure to yield /3-ionylidene- 

 acetaldehyde. The aldehyde so formed, although having the empirical 

 formula, C15H22O, did not have the expected absorption spectrum at 320 

 m/i, but only an inflection in the region of 280-310 m^t. 



The first asserted synthesis of vitamin A was that of Fuson and Christ"® 

 in 1936. These authors condensed /8-cyclocitral with /3-methylcrotonalde- 

 hyde (dimethylacrolein), making use of piperidine acetate as a catalyst. 

 After reduction of the crude condensate with aluminum isopropoxide, a sub- 

 stance was obtained which exhibited an absorption band at 328 m/z and de- 

 veloped a blue color with the Carr-Price reagent. However, Heilbron et 

 al.^^'^ proved that the pentaethenoid acyclic alcohol farnesinol (HI), rather 

 than vitamin A, was the product obtained. This alcohol could be synthe- 

 sized by the condensation of /3-methylcrotonaldehyde with itself. More- 

 over, Heilbron and Jones pointed out that the condensation between /3- 

 cyclocitral and /8-methylcrotonaldehyde is an impossible one under the 



'^^ L. Ruzicka and W. Fischer, Helv. Chim. Acta, 17, 633-641 (1934). 

 »5 W. H. Davies, I. M. Heilbron, W. E. Jones, and A. Lowe, /. Chem. Soc, 1935, 584- 

 587. 



"6 R. C. Fuson and R. E. Christ, Science, 84, 294-295 (1936). 



1" I. M. Heilbron and W. E. Jones, Chemistry & Industry, 55, 813-814 (1936). 



