II. CHEMISTRY AND IXDrSTRIAL PREPARATION 33 



accounts for its formation from /3-carotene (p. 24). That such a structure 

 is capable of existence in cis and trans isomeric forms will be discussed 

 elsewhere. 



e. S7jnthesis 



The synthesis of ^'itamin A has been the subject of numerous publications 

 and patents, and the importance of this field may be judged by the ap- 

 pearance of several reviews in the short span of five years. This field has 

 been reviewed by Embree,'"- Milas/"^ Johnson,'"'' Heilbron,'"^ Karrer,'''^ 

 Knobloch,^" Inhoffen and Bohlmann,"'^ Hunter,!''^ Isler,^^ and Baxter.^^ It 

 will be beyond the scope of this section to give a complete review of this 

 field. However, an attempt will be made to give an accurate account of 

 the important developments which led to our present knowledge of the 

 synthesis of ^dtamin A. 



There are three important routes to the synthesis of \itamin A, each of 

 which is based on the application of some well-known reactions or key inter- 

 mediates or both. One of these routes is based on the RefoiTnatsky reaction 

 or the addition of ethoxyacetylene to /S-ionone. Another is based on the 

 Darzens reaction for the synthesis of the key intermediate, Cn-aldehyde. 

 A third synthesis is based on the use of 2,6,6-trimeth3dcyclohexanone as 

 the key intermediate. It is now well recognized, '"^ however, that some of 

 the synthetic routes (Fig. 6 and part of Fig. 8) which lead to intermediates 

 containing h3^droxyl groups in direct allylic relationship to the double bond 

 in the cyclohexyl ring are not suitable for the preparation of vitamin A in 

 good yields. Although \'itamin A has been prepared by such methods, the 

 o^'er-all yields were low and purification could be achieved only l)y elaborate 

 methods to remove the undesirable isomeric intermediates. 



(1) Synthesis via the Reformatsky and Ethoxyacetylene Reactions. The first 

 attempt to synthesize vitamin A via the Reformatsky reaction was made by 

 Kuhn and Morris,''" but owing to a failure to separate the undesirable 

 intermediates the yield of vitamin A in the final product was very small, 

 and for the same reason suV)se(iuent investigators were unable to repeat 

 the synthesis.'"^ As our knowledge of the structiu'e of the intermediates 



">2 N. D. Embree, Ann. Rev. Biochem. XVI, 323 (1947). 



'"' N. A. Milas, Vitamins and Hormones 5, 1 (1947). 



">* A. W. Johnson, Science Prog. 36, 496 (1948). 



105 I. Ileilbron, J. Chem. Soc. 1948, 386. 



'«« P. Karrer, Osterr. Chem. Ztg. 49, 215 (1948). 



"" H. II. Inhoffen and F. Bohhnann, Fortschr. chem. Forsch. 1, 175 (1949). 



•»s R. F. Hunter, Research {London) 3, 453 (1950). 



'*" H. O. Huisman, A. Smit, S. Vromer, and L. G. M. Fischer, Rec. trav. chim. 71, 



899 (1952). 

 "» R. Kuhn and C. J. O. R. Morris, Bcr. 70, 853 (1937). 



