(3R)-3-Hydroxy-β-
ionone and (3S)-3-hydroxy-β-
ionone are two important intermediates in the synthesis of carotenoids with β-
end group such as
lutein,
zeaxanthin, β-
cryptoxanthin, and their stereoisomers. Among the various stereoisomers of these carotenoids, only (3R,3′R,6′R)-
lutein, (3R,3′R)-
zeaxanthin, and (3R)-β-
cryptoxanthin are present in commonly consumed
fruits and vegetables. There are 3 possible stereoisomers for
zeaxanthin, these are: dietary (3R,3′R)-zeaxanthin (1), non-dietary (3S,3′S)-zeaxanthin (2), and non-dietary (3R,3′S;meso)-zeaxanthin (3) which is a presumed
metabolite of dietary
lutein. Dietary lutein as well as 1 and 3 are accumulated in the human macula and have been implicated in the prevention of age-related
macular degeneration. (3R)-β-
Cryptoxanthin (4) is also present in selected ocular tissues at a very low concentration whereas its
enantiomer (3S)-β-
cryptoxanthin (5) is absent in foods and
human plasma.The present invention relates to a process for the synthesis of (3R)-3-hydroxy-β-
ionone and its (3S)-
enantiomer in high optical purity from commercially available (rac)-α-ionone. The key intermediate for the synthesis of these hydroxyionones is 3-keto-α-ionone ketal that was prepared from (rac)-α-ionone after protection of this
ketone as a 1,3-
dioxolane. Reduction of 3-keto-α-ionone ketal followed by deprotection, lead to 3-hydroxy-α-ionone that was transformed into (rac)-3-hydroxy-β-ionone by base-catalyzed
double bond isomerization in 46% overall yield from (rac)-α-ionone. The
racemic mixture of these hydroxyionones was then resolved by
enzyme-mediated
acylation in 96% ee. (3R)-3-Hydroxy-β-ionone and its (3S)-
enantiomer were respectively transformed to (3R)-3-hydroxy-(β-ionylideneethyl)triphenylphosphonium
chloride [(3R)—C15-Wittig salt] and its (3S)-enantiomer [(3S)—C15-Wittig salt] according to known procedures. Double Wittig condensation of these Wittig salts with commercially available 2,5-dimethylocta-2,4,6-triene-1,8-dial provided all 3 stereoisomers of zeaxanthin (1-3). Similarly, (3R)—C15-Wittig and its (3S)-enantiomer were each coupled with β-apo-12′-carotenal to yield 4 and 5.