The carotenoid compounds, represented by lycopene, β-carotene, canthaxanthin, and astaxanthin, belong to the family of isoprenoid natural products, and have been industrially utilized as non-hazardous dyes for foodstuffs and key ingredients of cosmetics due to the characteristic red colors. The carotenoids are also widely utilized as functional food-additives and nutraceutical agents because of their anti-oxidizing efficiencies and prophylaxis effects on cancers of prostate, breast, lung, and etc.
The representative synthetic methods of carotenoids utilize the Wittig reaction, which have been the commercial process of BASF (Scheme 1). The reaction of two equivalents of the acyclic C15 phosphonium salt (A) and the C10 dialdehyde (C) produced lycopene of the Chemical Formula 1 (Ernst, H. Pure Appl. Chem. 2002, 74, 2213-2226). The Wittig reaction of two equivalents of the cyclic C15 phosphonium salt (B) and the C10 dialdehyde (C) provided β-carotene of the Chemical Formula 2 (Wittig, G.; Pommer, H. German Patent 954,247, 1956). These BASF processes are efficient in retro-synthetic point of view, but still have the problems related with the Wittig reaction: (1) the difficulty in separation of the by-product, phosphine oxide (Ph3P═O), (2) the formation of the biologically less active Z-configuration in the carbon-carbon double bonds. Non-trivial synthetic procedures for the above C15 phosphonium salts (A) and (B), and the C10 dialdehyde (C), all in E-configuration, have also demanded more efficient and practical synthetic pathway to the carotenoid compounds.

To overcome the afore-mentioned problems, we recently developed practical synthetic methods of the carotenoid compounds as illustrated in Scheme 2. The coupling reaction of two equivalents of the C15 allylic sulfone compound (D) with the C10 bis(chloroallylic) sulfide compound (F) or the C10 bis(chloroallylic) sulfone compound (G), followed by the Ramberg-Backlund reaction and then dehydrosulfonylation reaction produced lycopene of the Chemical Formula 1 (Ji, M.; Choi, H.; Jeong, Y. C.; Jin, J.; Baik, W.; Lee, S.; Kim, J. S.; Park, M.; Koo, S. Helv. Chim. Acta 2003, 86, 2620-2628). Two equivalents of the C15 allylic sulfone compound (D) were also reacted with the C10 dialdehyde compound (H) to give the C40 coupling product, in which the resulting diols were halogenated or converted to various diether functional groups before the double elimination reactions to provide lycopene of the Chemical Formula 1 (Guha, S. K.; Koo, S. J. Org. Chem. 2005, 70, 9662-9665).

On the other hand, the applications of the above procedures to two equivalents of the cyclic C15 allylic sulfone compound (E) and each of the C10 unit: bis(chloroallylic) sulfide compound (F), the C10 bis(chloroallylic) sulfone compound (G) or the C10 dialdehyde compound (H) nicely produced β-carotene of the Chemical Formula 2 (Choi, H.; Ji, M.; Park, M.; Yun, I.-K.; Oh, S.-S.; Baik, W.; Koo, S. J. Org. Chem. 1999, 64, 8051-8053; Choi, S.; Koo, S. J. Org. Chem. 2005, 70, 3328-3331; Guha, S. K.; Koo, S. J. Org. Chem. 2005, 70, 9662-9665).
The above sulfone-mediated processes for the carotenoid syntheses feature the following advantages in that the stable intermediate sulfone compounds are formed through the processes, which can be easily purified by recrystallization. Furthermore, biologically more active all-(E)-carotenoids can be produced stereoselectively by the dehydrosulfonylation reaction, in which the by-product, the sodium salt of benzenesulfinic acid can be easily removed from the reaction mixture by just washing with water.
However, the above sulfone-mediated carotenoid syntheses still need to be improved especially in the number of steps and the preparation procedures for the required C15 and C10 compounds (D), (E), (F), (G) and (H). It was thus requested to devise a short and much efficient preparation method of the above intermediate sulfone compounds in order to have an expeditious and practical synthetic method of lycopene and β-carotene with great economical values.
USPTO Backgrounds
USPTO Backgrounds