Total Synthesis of (3R,3'R,6'R)-Lutein, (3R,3'R)-Zeaxanthin and Their Stereoisomers

Abstract

(3R,3'R,6'R)-Lutein (1) and (3R,3'R)-zeaxanthin (5) are dietary carotenoids that are found in most fruits and vegetables. Numerous studies have shown that 1 and 5 play an important role in the prevention of age-related macular degeneration (AMD) that is the leading cause of blindness. To date, the metabolic pathways of 1 and 5 in ocular tissues of an animal model in relation to AMD have not been explored. This is primarily because of the lack of a viable method for the synthesis of 1 and 5 that can be labeled with a stable isotope. Among the eight possible stereoisomers of lutein, only 1 has been previously prepared by total synthesis in 14 steps in an overall yield of 0.5%.

The total synthesis of lutein, zeaxanthin, and their stereoisomers from (rac)-alpha-ionone has been accomplished by a C15+C10+C15 coupling strategy. Therefore, (3R,3'R,6'R)-lutein (1, 8%), (3R,3'S,6'S)-lutein (2, 7%), (3R,3'S,6'R)-lutein (3, 6%), and (3R,3'R,6'S)-lutein (4, 7%) were each prepared in a high optical purity in 7 steps. 3-Hydroxy-alpha-ionylideneacetaldehyde served as a common precursor to afford luteins 1 - 4 by a much shorter synthetic sequence and a higher overall yield than that of a published method for 1. The other four stereoisomers of lutein can be similarly prepared.

(3R,3'R)-Zeaxanthin (5, 12%) and (3S,3'S)-zeaxanthin (6, 11%) were prepared in 8 steps from (rac)-alpha-ionone via 3-hydroxy-alpha-ionone which was transformed into 3-hydroxy-beta-ionone (3R-42, 22%) and its enantiomer (3S-42, 21%), respectively. The key intermediates, 3R-42 and 3S-42 were converted into the corresponding C15-Wittig salts 3R-16 and 3S-16 that were used in a double Wittig reaction with the C10-dialdehyde 17 to afford 5 (98% ee) and 6 (98% ee).

Utilizing Wittig salts 3R-16 and 3S-16, (3R)-beta-cryptoxanthin (135, 8%) and (3S)-beta-cryptoxanthin (136, 9%) were each prepared in optical purity of 98%.

The most important feature of the strategies presented here is its application to the total synthesis of isotopically labeled and optically pure lutein, zeaxanthin, and their stereoisomers for metabolic studies. This synthesis also provides access to the C15-precursors of optically active carotenoids with 3-hydroxy-alpha- and 3-hydroxy-beta-end groups that are otherwise difficult to synthesize.