Chemical structure and biological activity 



acid so far isolated is the, of course, optically inactive indoleacetic acid. It 

 seems to me a reasonable speculation that the latter is perhaps the biological 

 ultimate result of breakdown in the plant of similar acids of longer and 

 partially branched side chains, just as in the explanation of the breakdown 

 in the carbon pairs of the simpler a>-acids, postulated by Synerholm and 

 Zimmerman (1947), except that in the latter case the starting acids were not 

 potentially optically active. 



The first conscious effort then to resolve any hormone acid with the idea of 

 finding out something of the contrasted activities of the enantiomorphs was 

 made by Kogl and Verkaaik in 1944 in synthetic a- (indole-3) propionic acid 

 (1944). It is notable, as pointed out above, that they found that the (+) 

 isomer had thirty times the activity of the ( — ) in one test and that in another 

 test the differences were negligible. 



At about the same time our group in the Agricultural Chemicals Division 

 of the American Chemical Paint Company in Ambler, after launching the 

 2:4-D type of compounds for the use of American agriculture, turned our 

 attention to homologues of this substance and particularly to a-(2:4- 

 dichlorophenoxy) propionic acid. We had already found that the corre- 

 sponding /i-substituted propionic acid had practically no potential applica- 

 tions, the oj-series being later expanded by Synerholm and Zimmerman 

 (1947) and by Wain and Wightman (1954), who discovered the /^-oxida- 

 tion series of activities referred to above. 



The asymmetric carbon atom, of course, was a magnet, and we shortly 

 obtained by the methods described below the ( + ) isomer of a-(2:4-dichloro- 

 phenoxy)propionic acid which was tested at Harvard for us in 1947 by 

 Professor Thimann in comparison with the racemic form (Thimann, 1947). 

 His report stated that the ( + ) form in the pea test showed about 2-5 times 

 the activity of the racemic, indicating that the ( — ) isomer has very low 

 activity. These results were further discussed by Thimann at the Madison, 

 Wisconsin, meeting on Plant Growth Substances in 1949 and finally in 

 book form as edited by Skoog (1951), this being the official account of the 

 papers given at this meeting. Results were confirmed by Matell (1952). 

 For various reasons the work on optical resolutions which we had initiated 

 as above was shelved. Later on, Aberg, Fredga, and Matell at Uppsala, 

 Veldstra at Amsterdam, and Wain and others at Wye College carried out 

 very many resolutions of hormone acids, so that today we have upwards of 

 twenty such acids which have been completely resolved and tested and which 

 work has led to some very interesting conclusions by W'ain and others on the 

 physiological action of such compounds. 



METHOD FIRST USED FOR RESOLUTION OF 



a- (2 : 4-dichlorophenoxy) propionic acid 

 Since the time of Pasteur very little in the way of new methods of optical 

 resolution have been put forward. The three standard methods: (i) hand 

 picking of large crystals of the appropriate enantiomorph salts, (n) use of 

 biological means such as moulds, fungi, etc. which will preferably grow at 

 the expense of one of the isomers leaving the other, and {in) separation by 

 fractional crystallization in a suitable solvent of the mixture of enantio- 

 morph salts with a suitable optically active base. The last method is the one 



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