Ascorbic acid analogs synthesis

L-Rhamnosone was prepared by the action of hydrochloric acid on L-rhamnose phenylosazone9 and was identified by reconversion to the osazone. This method was later employed186 as a stage in the synthesis of the ascorbic acid analog, L-rhamnoascorbic acid. The benzaldehyde decomposition of the osazone gave a low yield of osone93 and o-nitrobenzaldehyde was not a satisfactory aldehydic substitute. 

It will be seen that the enediolic system can theoretically be written in the isomeric 2-keto (II) or 3-keto (III) forms and these in turn are seen to be derived from the 2-keto and the 3-keto acids IV and V, respectively (compare with benzoin which reacts with iodine in an analogous fashion to L-ascorbic acid). Consequently the synthesis of L-ascorbic acid and of its analogs has consisted in devising methods for the formation of 2-keto or 3-keto hydroxy acids followed by their enolization and lactonization. Four main methods are available for the synthesis of analogs of L-ascorbic acid containing the characteristic five-membered unsaturated enediolic ring. 

The reaction of D-glucosone and other osones with cyanide, as a first stage in the synthesis of ascorbic acid and its analogs, has been reviewed by Smith.136... 

In this article, an attempt has been made to provide a complete summary of methods developed for the synthesis of L-ascorbic acid. Included are the methods of preparation of precursors in the various syntheses. The syntheses of analogs and isomers of L-ascorbic acid are not covered. Many of the methods used for the preparation of analogs are obvious as they are based on the procedures used for the synthesis... 

This general synthesis—the addition of cyanide to an aldos-2-ulose, followed by cyclization and hydrolysis—proved of great value in the preparation of analogs of ascorbic acid,80 but is not competitive with later syntheses of L-ascorbic acid, because an efficient and inexpensive method for the synthesis of 9 has not yet been developed. 

Reichstein and Griissner also prepared di-O-benzylidene and di-O-(2-butylidene) acetals of L-sorbose, and found them to be useful intermediates in synthesis of L-ascorbic acid. By analogy, therefore, their structures are 2,3 4,6-di-0-benzylidene-a-L-sorbofuranose (30) and 2,3 4,6-di-0-(2-butylidene)-a-L-sorbofuranose (102). 

Ault RG, Baird DK, Carrington HC, Haworth WN, Herbert RW, Hirst EL, Percival EGV, Smith F, Stacey M. Synthesis of d- and 1-ascorbic acid and of analogous substances. J Chem Soc 1933 1419-1423. 

It is generally assumed today that cholesterol is the raw material from which the adrenal cortex makes its hormones, despite the theoretical doubts of the chemists (see Sayers, 1950). If ascorbic acid were necessary for this synthesis, it might have been expected that scurvy would result in a piling-up of unused cholesterol in the gland, on the analogy of the accumulation of colloid in the thyroid gland deprived of iodine. In fact,... 

Murad, S., Tajima, S., Johnson, G. R., Sivarajah, A., and Pinne, S. R., 1983, Collagen synthesis in cultured human skin fibroblasts Effect of ascorbic acid and its analogs, J. Invest. Dermatol. 81 158-162. 

Cyanohydrin Synthesis from Osones (14 )- For this method, 3-keto aldonic acids are formed as intermediates which are not isolated. The first product, the nitrile, immediately enolizes with simultaneous ring formation to an imino analog (XI) of the ascorbic acid, and the latter is formed by... 

We see that in this series it is essential that the configuration of the hydroxyls on carbon atoms 2 and 3 of the aldohexose should be n and L, respectively this is true of n-galactose but not of D-mannose. Consequently, we might expect to find the synthesis of ascorbic acid being promoted through an analogous series of intermediates from D-galactose as follows. 

---