Vitamin total synthesis

Covalent synthesis of complex molecules involves the reactive assembly of many atoms into subunits with aid of reagents and estabUshed as well as innovative reaction pathways. These subunits are then subjected to various reactions that will assemble the target molecule. These reaction schemes involve the protection of certain sensitive parts of the molecule while other parts are being reacted. Very complex molecules can be synthesized in this manner. A prime example of the success of this approach is the total synthesis of palytoxin, a poisonous substance found in marine soft corals (35). Other complex molecules synthesized by sequential addition of atoms and blocks of atoms include vitamin potentially anticancer KH-1 adenocarcinoma antigen,... 

During this 70 year period, all 13 of the substances now recognized as vitamins were discovered and isolated ia pure form. Stmcture elucidation for each vitamin was completed, as was its total synthesis (Table 1). 

The complexity of the vitamin molecule makes it extremely unlikely that total synthesis will ever be employed for preparation of commercial... 

The study of the biosynthesis of vitamin B 2 is a saga whose resolution, due primarily to Battersby (80—83) and Scott (84,85), requited an effort on the same magnitude as the total synthesis. It was only when recent molecular biology tools became available to complement en2ymology, isotopic labeling, chemical synthesis, and spectroscopy that solution of this problem became possible. 

Total Synthesis. Poor yields encountered duriag the manufacture of vitamin D stimulated early attempts to synthesize vitamin D. In 1959 Inhoffen synthesized vitamin from 3-methyl-2-(2-carboxyethyl)-2-cyclohexenone (40), uskig the Wittig reaction extensively (103). 

In March 1976, M.A. Wuonola and R.B. Woodward accomplished the conversion of cobyric acid (4) to vitamin B12 (1). The total synthesis of vitamin B12 can thus be claimed, see reference Id, footnote 11, p. 1420. The formal total synthesis of 1 had been accomplished in 1973. 

Sapphyrins were discovered serendipitously by Woodward33 during the course of synthetic studies directed towards the total synthesis of vitamin B, 2. The sapphyrins were the first example of expanded porphyrins in the literature. Due to sapphyrin exhibiting a deep-blue color in the crystalline state and intense green in solution. Woodward coined the expression sapphyrin with reference to the deep-blue color of sapphire stones. 

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

This procedure illustrates a broadly applicable method which is essentially that of Roth, Dubs, Gotschi, and Eschenmoser,2 for the synthesis of enolizable /1-dicarbonyl compounds. Although there are various methods for the preparation of /3-dicarbonyl systems,3 the scheme of sulfide contraction widens the spectrum of available methods. The procedure can also be utilized in the synthesis of aza and diaza analogs of /3-dicarbonyl systems. Eschenmoser2 has utilized the method to produce vinylogous amides and amidines in connection with the total synthesis of corrins and vitamin B12.4... 

The total synthesis of vitamin Bi2 is a monumental synthetic work published by R. B. Woodward (Harvard) and A. Eschenmoser (Swiss Federal Institute of Technology) ... 

Industrial synthesis of vitamin A (Hoffman-La-Roche) goes through partial hydrogenation of an enyne (equation 161)277. A number of syntheses of pheromones, where the reduction of an enyne to a diene is the key step, have been devised. A few selected examples are given in Table 29278. During the total synthesis of endiandric acids, Nico-laou employed hydrogenation of a polyenyne intermediate with a Lindlar catalyst to generate an intermediate which underwent symmetry-allowed cyclizations to result in the natural product (equation 162)279. 

Wick, A. E. Felix, D. Steen, K. Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425. Albert Eschenmoser (Switzerland, 1925-) is best known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Woodward in 1973. He now holds appointments at ETH Zurich and Scripps Research Institute, La Jolla. Felix, D. Gschwend-Steen, K. Wick, A. E. Eschenmoser, A. Helv. Chim. Acta 1969, 52, 1030. 

Since its discovery in 1909, the elucidation of its structure by Karrer in 1931 [5] and its first total synthesis [6], vitamin A has represented a challenging target molecule for chemists [7], The first industrial synthesis of retinol was performed at Hoffmann-La Roche (H-L R) [8], followed by other approaches of the Baadische Anilin- Soda Fabrik (BASF AG) [9], and Rhone-Poulenc (R-P) (today Aventis) [10]... 

By any standards, the successful total synthesis of vitamin Bi2 which was accomplished by the combined efforts of the Harvard and E.T.H. Zurich groups under Woodward and Eschenmoser, respectively, must rank as a landmark in synthetic organic chemistry. 

A total synthesis of vitamin B12 was announced in 1972, as the result of a collaborative effort between R. B. Woodward (Harvard) and A. Eschenmoser (Zurich). The synthesis was completed after 11 years of effort involving 100 co-workers from 19 countries. A number of important techniques and reactions of synthetic value were developed during the course of this work, including the principle of conservation of orbital symmetry (the Woodward-Hoffman rules, Section 21-10). The biochemical action of vitamin B12 is considered in Chapter 31. 

Initial cyclizadons were effected by the addition of an enamine to an imidate ester, both groups being suitably located by ligand coordination.263 An analogous process can be carried out on a thioimidate but a sulfide is formed and removal of sulfur with consequent ring contraction yields the corrin (100).264 These two complementary routes can be effected with different metal ions, nickel(II), palladium(II) and cobalt(III) in the first route, zinc(II) in the second. Removal of zinc ions easily provides the free corrin macrocycle. These two routes are summarized in Scheme 64. The sulfide contraction route was used in the Eschenmoser-Woodward total synthesis of vitamin Bn-265... 

M. E. Jung and T. Shaw, Total synthesis of (R)-glycerol acetonide and the antiepileptic and hypotensive drug (-)-y-amino-/l-hydroxybutyric acid (GABOB) use of vitamin C as a chiral starting material, J. Am. Chem. Soc., 102 (1980) 6304-6313. 

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