SYNTHESIS OF VITAMIN A AND RELATED COMPOTTNDR 717 



a. Milas "A" Method. A typical procedure in this category as de- 

 scribed by Milas-"'^ involves the treatment f)f tlie aldeli>^de (\) i)repared by 

 decarboxylation of glycidic acid, with lithium acetylide in liquid ammonia 

 to give the acetylenecarbinol (VI). This product (VI) is condensed with a 

 ketone, CHsCOCHoCHoOR/, using the Grignard reaction, to form a glycol 

 (VII). R' may represent ;m alkyl or an acyl group, under which condi- 

 tions a vitamin A ether or an ester, respectively, will result. The glycol is 

 then dehydrated to jaeld an acetylenic compound (VIII) Avhich, upon hy- 

 drogenation with a poisoned catalyst, gives rise either to a vitamin A ether 

 or to alcohol (IX), depending upon the nature of Ri. These reactions are 

 represented here.^"" 



CH-i f\ CH-i - 



\ /y I H CHjCOCHjCHjOR 



R- CH:CH-CH-C-H R • CH : CH -CH • C • C : CH ► 



3: 51 OH 



CH3 CHj CHj CH3 



R'CH:CH'CH'C*C:C'C-CH2-CH20R ►R- CH '.CH-C'-CH-C: C-CrCH'CHjOR 



I I 



Vrr OH OH TTTT 



CH, CH, 



R- CH:CH-C: CH'CH:CH-C:CH-CH20R 



IK 



Synthesis of Vitamin A (Milas "A" Method) 



b. Milas "B" Method and Isler Procedure. Thase two methods are 

 practically identical. In the Milas "B" method^"^ a hydroxyl acetylene 

 derivative (X) is synthesized directly. This is dehydrated in a manner 

 similar to that employed in the Milas "A" procedure, and the latter product 

 is changed to the vitamin A ether or ester by controlled hydrogenation. 

 The technic proposed by Isler et al.^'^^ follows the same course; Milas^' 

 believes that the latter preparation consists of a mixture of cis and trans 

 isomers which are apparently not foiTned by the ordinary Milas methods. 

 A vitamin A methyl ether which had a potency as high as that of |S-carotene 

 has been prepared by the Milas "B" method. 



2M N. A. Milas, Science, 103, 581-583 (1946). 



^o^ In the following formulas, illustrating the synthesis of vitamin A, R is used to repre- 

 sent the cyclic group below: 



HjC CHi 



\ / 

 C 



/ \ 

 HzC C- 



HsC C 



\ / \ 

 C CH3 



Hi 



208 0. Isler, M. Kofler, W. Huber, and A. Ronco, Experieniin, 2, 31 (1940) 



