The chemistry of novel xanthophyll carotenoids

Abstract

Natural product isolates are typically not developed as drug candidates because of the difficulty in obtaining the desired stable molecular orientation (ie, stereochemistry), purity, and scale required to meet pharmaceutical industry standards. Recent advances in medicinal and process chemistry have played key roles in transforming a class of dietary natural products-carotenoids-into potential medical therapeutics. Carotenoids are natural pigments derived from the acyclic C40 isoprenoid lycopene, which can also be classified as a tetraterpene. Carotenoids are classified on their chemical composition as either carotenes or xanthophylls. There are 5 C40 carotenoids manufactured synthetically on an industrial scale, including lycopene, ss,ss-carotene, and canthaxanthin (which are achiral compounds); zeaxanthin (produced in enantiopure form, as the 3R,3'R enantiomer); and astaxanthin (produced as mixture of configurational isomers) for use as nutritional supplements and for animal feed additives in poultry farming and aquaculture that are essential for the animals' growth, health and reproduction. The xanthophyll astaxanthin shows pharmaceutical potential, but the configurational complexity has thus far made it difficult to synthesize an enantiopure form on a large scale. Astaxanthin has 2 identical asymmetric carbon atoms (position 3 and 3') and can therefore exist in 4 different configurations, providing 3 different configurational isomers: (3S,3'S) and (3R,3'R), which are enantiomers, and (3R,3'S) and (3S,3'R), which are identical (a meso form). An enantiopure industrial scale synthesis of astaxanthin (3S,3'S) has recently been developed by BASF AG. The desired stereochemistry (chirality) is introduced early in the synthetic process by a proprietary catalytic reaction using an intermediate of the existing technical astaxanthin production process as a substrate. By controlling this essential process, it is possible to produce pharmaceutical quality astaxanthin in quantities large enough to support drug development programs for medical therapies.