34 VITAMINS A AND CAROTENES 



became clarified,^^- "^' ^^^ it was recognized that in the dehydration of the 

 hydroxy ester XLIX^^' large quantities of the undesirable /3,7-isomeric 

 ester were produced in which the entire conjugated system shifted to the 

 left of the terminal group so that the double bond in the ring was found to 

 be in the same position as that present in the a-ionone ring. These unde- 

 sirable intermediates led to a final preparation which had very little or 

 no biological activity. 



The discovery of the selective reduction properties of lithium aluminum 

 hydride"* and its immediate application to the synthesis of the Cis-ke- 

 ^Qj^gios, 115 (XLVIII through LIV) led to a renewed interest in the synthesis 

 of vitamin A via this route. The synthesis was completed by Schwarzkopf 

 ei aL,"^ by Wendler et aL,"^ the latter going through the Ci5-aldehyde, 

 LIII, and by Cawley et al}^^ The last group of investigators"^ claim the 

 separation of the undesirable isomers from the dehydration products of 

 both XLVIII and LV and their catalytic conversion, in the presence of 

 catalysts such as phosphorus oxychloride, to the desirable isomers. 



The Ci8-ketone was first prepared'^"' ^^^ by the Reformatsky reaction on 

 /3-ionone using ethyl-7-bromocrotonate to form ethyl-/3-ionylidenecrotonate, 

 LX, which was hydrolyzed to the corresponding acid, LXI. When this 

 acid Avas treated with methyl lithium a high yield of the Cis-ketone was 

 obtained. This was converted by a second Reformatsky to the ester LVI, 

 which was hydrolyzed to vitamin A acid.^-'^ The vitamin A acid was also 

 synthesized by a slightly different route. ^^^ These syntheses suffer the same 

 limitations as the previous ones in that the undesirable isomers produced 

 reduce considerably the over-all yield of the \dtamin. In view of the crystal- 

 in H. Sobotka, E. Bloch, and D. Glick, J. Avi. Chevi. Soc. 65, 1961 (1943). 

 i'2 W. G. Young, L. J. Andrews, and S. J. Cristol, /. Am. Chem. Soc. 66, 520 (1944). 

 i'3 p. Karrer, H. Solomon, R. Morf, and O. Walker, Helv. Chim. Acta 15, 878 (1932). 



114 A. E. Finholt, A. C. Bond, and H. I. Schlesinger, /. Am. Chem. Soc. 69, 1199 (1947). 



115 N. A. Milas and T. M. Harrington, J. Am. Chem. Soc. 69, 2247 (1947); 70, 4275 

 (1948). 



118 O. Schwarzkopf, H. J. Cahnmann, A. D. Lewis, J. Swidinskj', and H. M. Wuest, 



Helv. Chim. Acta 32, 443 (1949). 

 11' N. L. Wendler, H. L. Slates, N. R. Trenner, and M. Tishler, /. Am. Chem. Soc. 



71,3267 (1949); 73, 719 (1951). 



118 J. D. Cawley, C. D. Robeson, E. M. Shantz, L. Weisler, and J. G. Baxter, U. S. 

 Pat. 2,576,103 (Nov. 27, 1951). 



119 E. M. Shantz, C. D. Robeson, and H. M. Kascher, U. S. Pat. 2,576,104 (Nov. 

 27, 1951). 



120 J. F. Arens and D. A. van Dorp, Nature 157, 190 (1926); Rec. trav. chim. 66, 759 

 (1947) ; see also ref. 116. 



121 D. A. van Dorp and J. F. Arens, Nature 160, 189 (1947). 



i2ia D. A. van Dorp and J. F. Arens, Rec. trav. chim. 65, 338 (1946). 



122 N. A. Milas, U. S. Pat. 2,424,994 (Aug. 5, 1947). 



