Human plasma and tissues contain in excess of 12 dietary carotenoids and several metabolites that originate from consumption of fruits and vegetables. The major hydroxycarotenoids absorbed by humans are: (3R,3′R,6′R)-lutein (1), (3R,3′R)-zeaxanthin (2), (3R,6′R)-α-cryptoxanthin (3), and (3R)-β-cryptoxanthin (4) and their E/Z-stereoisomers. In addition, several hydroxycarotenoids that result from metabolic transformation of 1 have also been identified in human plasma and ocular tissues. Epidemiological and experimental evidence to date suggest hydroxycarotenoids may protect against chronic diseases such as cancer, cardiovascular disease and age-related macular degeneration (AMD). Therefore, supplementation with these carotenoids in individuals with a low dietary intake of fruits and vegetables is essential. However, with the exception of 1 and 2, industrial production of 3 and 4 have not yet materialized. A relatively straightforward semisynthetic process has been developed that transform 1 into a mixture of 3 (12%) and 4 (80%). Hydroxycarotenoid 3 can also be directly prepared from allylic deoxygenation of 1 in a single step in an excellent yield. These two processes provide an easy access to optically active 3 and 4 that are normally prepared by numerous synthetic steps.

(3R,3′R,6′R)-Lutein (1) is a major dietary carotenoid that is abundant in most fruits and vegetables commonly consumed in the U.S. and that accumulates in the human plasma, major organs, and ocular tissues. Numerous epidemiological and experimental studies have shown that 1 has important biological activities and may play an important role in the prevention of age-related macular degeneration (AMD). While the total synthesis of 1 has been previously reported in a poor overall yield, the total synthesis of the other seven stereoisomers of lutein has not yet been accomplished. We have developed a relatively straightforward methodology for the total synthesis of 1 and three of its stereoisomers, (3R,3′S,6′S)-lutein (2), (3R,3′S,6′R)-lutein or 3′-epilutein (3), and (3R,3′R,6′S)-lutein (4) by C15 + C10 + C15 Wittig coupling reactions. Employing this methodology, the other four stereoisomers of lutein that are enantiomeric to the aforementioned lutein isomers can be similarly prepared. One of the important features of this strategy is its application to the total synthesis of 13C-labeled luteins and their metabolites with appropriate stereochemistry for metabolic studies in animals and humans. This synthesis also provides access to the C15-precursors of optically active carotenoids with a 3-hydroxy-ε end group that are otherwise difficult to synthesize.