SYNTTTESTS OF VITAMIN A AND RELATED rOMPOIINDR 715 



conditions stated. Tliis conclusion was subsequently confirmed by Kuhn 

 and Morris. ''* 



CH3 CH-5 CH3 



I H H H I H H H I H 

 CH3-C:C-C:C-C:C-C:C«C:C- CH.GH 



(III) FiinichiiioP" 



(S) Kuhn-Morris Synthesis 



Kuhn and INTorris"'' were the first to prepare an authenticated vitamin A 

 sam])le by synthesis. They used as their starting material the Cn ester 

 formed b.y condensation of (3-ionone and ethyl bromoacetate by the Re- 

 formatsky reaction. The ester was converted by a series of reactions to 13- 

 ionylideneacetaldehyde, which possesses a high intensity of absorption at 

 320 mn and 3 conjugate double bonds. ^^^ In contrast to /3-cyclocitral, the 

 aldehyde was shown to condense readily with /3-methylcrotonaldehyde in 

 piperidine acetate. On reduction with aluminum isopropoxide, a mixture 

 of alcohols was formed which had a biological potency of about 7.5% of 

 that of pure vitamin A. ^^^ According to our present standards, the vitamin 

 A potency of the synthetic material was probably considerably less than the 

 above figure. 



However, the results of Kuhn and Morris have not gone unchallenged. 

 A number of investigators who have attempted to repeat this synthesis have 

 failed to obtain an active product in any case.i^^'2''°~202 Karrer and 

 Riiegger^™ found that the material obtained on reduction of the product 

 formed on condensation of j8-ionylideneacetaldehyde and /3-methylcrotonal- 

 dehyde was indeed a mixture of polyenes ; the main one showed an absorp- 

 tion maximum at 602 m^ when treated with antimony trichloride. How- 

 ever, since this predominant polyene can be readily separated from vitamin 

 A chromatographically, it certainly cannot be identical with it. Krauze 

 and Slobodin^"^ were unable to demonstrate any biological activity in the 

 total polyene mixture, even in doses of 40 /xg. daily; thus the synthesis of 

 any significant amounts of vitamin A by the Kuhn-Morris method is open 

 to question. 



One of the chief faults with the Kuhn-Morris synthesis is related to the 

 diflSculty of obtaining jS-ionylideneacetaldehyde. Although Davies et 

 al.'^^^ reported the formation of this compound on vacuum distillation of its 

 barium salt with barium formate, Sobotka, Bloch, and Glick^^^ obtained a- 



»8 R. Kuhn and C. J. O. R. Morris, Ber., 70, 853-858 (1937). 



>99 R. Kuhn, J. Chem. Soc, 1938, 605-614. 



2«« P. Karrer and A. Ruegger, Helv. Chim. Acta, 23, 284-287 (1940). 



201 M. V. Kj-auze and Y. M. Slobodin, /. Gen. Chem. U.S.S.R., 10, 907-912 (1940); 

 Chem. AbsL, 35, 3237 (1941). 



20* N. A. Milas and R. O. Edgerton, Unpublished results. Cited by R. A. Milas, 

 Vitamins and Hormones, 5, 2 (1947). 



