University System of Maryland

The Catholic University of America

The United States of America as Represented by the Secretary of

Frederick Khachik

An-Ni Chang

Gary R Beecher

Yufa Liu

Betty W Li

Holly Showalter

The present invention relates to a process for converting commercially available lutein and/or lutein esters from extracts of marigold flower petals to (3R)-&#x3b2;-cryptoxanthin (major) and (3R,6'R)-&#x3b1;-cryptoxanthin (minor) in ratios ranging from 95:5 to 98:2 in a one-pot reaction at room temperature. Because the entire process can be carried out by employing safe and environmentally friendly food-grade reagents, the resulting mixture of these carotenoids is suitable for human consumption as a dietary supplement.

Process for a direct one-pot transformation of lutein to &#x3b2;-cryptoxanthin via its acetate ester

The present invention is in the field of organic and natural product chemistry. The present invention relates to an efficient process for purification, simultaneous extraction, and separation of monohydroxycarotenoids from dihydroxycarotenoids in various natural products or in synthetic mixtures. Similarly, the process can also be applied to the simultaneous extraction, saponification, and separation of esterified mono- and dihydroxycarotenoids in natural products and their oleoresins or in their synthetic mixtures. Therefore, esterified and unesterified monohydroxycarotenoids such as (3R)-&#x3b2;-cryptoxanthin and (3R,6'R)-&#x3b1;-cryptoxanthin can be efficiently separated from their corresponding dihydroxycarotenoids such as (3R,3&#x2032;R,6&#x2032;R)-lutein and (3R,3&#x2032;R)-zeaxanthin that are found in various plants or in synthetic mixtures.

Process for simultaneous extraction and separation of esterified and unesterified monohydroxycarotenoids

Disclosed is a process for the synthesis of (3R)-3-hydroxy-&#x3b2;-ionone and its (3S)-enantiomer in high optical purity from commercially available (rac)-&#x3b1;-ionone. The key intermediate for the synthesis of these hydroxyionones is 3-keto-&#x3b1;-ionone ketal that was prepared from (rac)-&#x3b1;-ionone after protection of this ketone as a 1,3-dioxolane. Reduction of 3-keto-&#x3b1;-ionone ketal followed by deprotection, lead to 3-hydroxy-&#x3b1;-ionone that was transformed into (rac)-3-hydrox-&#x3b2;-ionone by base-catalyzed double bond isomerization in 46% overall yield from (rac)-&#x3b1;-ionone. The racemic mixture of these hydroxyionones was then resolved by enzyme-mediated acylation in 96% ee. (3R)-3-Hydroxy-&#x3b2;-ionone and its (3S)-enantiomer were respectively transformed to (3R)-3-hydroxy-(&#x3b2;-ionylideneethyl)triphenylphosphonium chloride [(3R)-C-Wittig salt] and its (3S)-enantiomer [(3S)-C-Wittig salt] according to known procedures. Double Wittig condensation of these Wittig salts with commercial available 2,5- dimethtylocta-2,4,6-triene-1,8-dial provided all 3 stereoisomers of zeaxanthin. Similarly, (3R)-C-Wittig and its (3S)-enantiomer were each coupled with &#x3b2;-apo-12'-carotenal.

[object Object]

The present invention relates to a process for converting lutein and/or lutein esters to (3R)-&#x3b2;-cryptoxanthin and (3R,6'R)-&#x3b1;-cryptoxanthin, suitable for human consumption as dietary supplements, by employing safe and environmentally friendly reagents. (3R)-&#x3b2;-Cryptoxanthin and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin are two rare food carotenoids that are not commercially available and the former exhibits vitamin A activity. In the first synthetic step, commercially available lutein and/or lutein esters are transformed into a mixture of dehydration products of lutein (anhydroluteins) in the presence of a catalytic amount of an acid. The resulting anhydroluteins are then converted to (3R)-&#x3b2;-cryptoxanthin (major product) and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin (minor product) by heterogeneous catalytic hydrogenation employing transition elements of group VIII (Pt, Pd, Rh supported on alumina or carbon) in a variety of organic solvents under atmospheric pressure of hydrogen and at temperatures ranging from &#x2212;15&#xb0; C. to 40&#xb0; C. Among these catalysts, Pt supported on alumina at 40&#xb0; C. in ethyl acetate provides the best yield of (3R)-&#x3b2;-cryptoxanthin and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin. Several homogeneous catalysts can also promote the regioselective hydrogenation of anhydroluteins to a mixture of (3R)-&#x3b2;-cryptoxanthin and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin in low to moderate yields. The catalysts may be transition metal complexes such as palladium acetylacetonate, Rh(PhP)Cl (Wilkinson's catalyst), [(CH)P[CH][CHN]IrPF6(Crabtree catalyst), or [CH][(MePhP)]IrPF6. Among these, Wilkinson catalyst converts anhydroluteins to (3R)-&#x3b2;-cryptoxanthin and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin in nearly quantitative yield. A novel feature of this invention is the regioselective hydrogenation of anhydroluteins while the highly conjugated polyene chain of these carotenoids remains intact.

Process for the preparation of &#x3b2;- and &#x3b1;-cryptoxanthin

(3R,3'R,6&#x2032;R)-Lutein and (3R,3&#x2032;R)-zeaxanthin are two dietary carotenoids that are present in most fruits and vegetables commonly consumed in the US and accumulate in the human plasma, major organs, and ocular tissues. Another stereoisomer of (3R,3&#x2032;R)-zeaxanthin that is not of dietary origin but is found in the human ocular tissues is (3R,3&#x2032;S;meso)-zeaxanthin. There is growing evidence that these carotenoids play an important role in the prevention of age-related macular degeneration (AMD) that is the leading cause of blindness in the U.S. and the Western World. In view of the potential therapeutic application of dietary lutein, (3R,3&#x2032;R)-zeaxanthin, and (3R,3&#x2032;S;meso)-zeaxanthin, the industrial production of these carotenoids is of considerable importance. The present invention provides a process for the partial synthesis of (3R,3&#x2032;R)-zeaxanthin and (3R,3&#x2032;S;meso)-zeaxanthin from a readily accessible dehydration product of (3R,3&#x2032;R,6&#x2032;R)-lutein, namely, (3R)-3&#x2032;,4&#x2032;-didehydro-&#x3b2;,&#x3b2;-caroten-3-ol [(3R)-3&#x2032;,4&#x2032;-anhydrolutein]. The process involves regioselective hydroboration of (3R)-3&#x2032;,4&#x2032;-anhydrolutein to a mixture of (3R,3&#x2032;R)-zeaxanthin and (3R,3&#x2032;S;meso)-zeaxanthin followed by separation of these carotenoids by enzyme-mediated acylation.

Process for synthesis of (3R,3'R)-zeaxanthin and (3R,3&#x2032;S;meso)-zeaxanthin from (3R,3&#x2032;R,6&#x2032;R)-lutein via (3R)-3&#x2032;,4&#x2032;-anhydrolutein

(3R,3'R,6&#x2032;R)-Lutein and (3R,3&#x2032;R)-zeaxanthin are two dietary carotenoids that are present in most fruits and vegetables commonly consumed in the US. These carotenoids accumulate in the human plasma, major organs, and ocular tissues. In the past decade, numerous epidemiological and experimental studies have shown that lutein and zeaxanthin play an important role in the prevention of age-related macular degeneration (AMD) that is the leading cause of blindness in the U.S. and Western World. The invention provides a process for the synthesis of (3R,3&#x2032;R,6&#x2032;R)-lutein and its stereoisomers from commercially available (rac)-&#x3b1;-ionone by a C+C+Ccoupling strategy. In addition, the present invention also provides access to the precursors of optically active carotenoids with 3-hydroxy-&#x3b5;-end group that are otherwise difficult to synthesize. The process developed for the synthesis of lutein and its stereoisomers is straightforward and has potential for commercialization.

Process for synthesis of (3R,3'R,6'R)-lutein and its stereoisomers

A method of isolating, purifying and recrystallizing substantially pure lutein, preferably from saponified marigold oleoresin in its pure free form, apart from chemical impurities and other carotenoids. Lutein may be used as an analytical standard or in cancer prevention trials and as a safe and effective color additive for human food.

Process for isolation, purification, and recrystallization of lutein from saponified marigold oleoresin and uses thereof

A process for extracting and isolating carotenoid esters or carotenoids in high purity from plants without the use of harmful organic solvents. Zeaxanthin esters were isolated and purified from the berries of Lycium Chinese Mill (LCM berries). The esters isolated according to the invention contain substantially no isomerized double bonds. The purified carotenoid esters or carotenoids isolated by this process are free from impurities and serve as a safe source of nutritional supplement for human consumption as well as providing a suitable and effective color additive for human foods.

Process for extraction and purification of lutein, zeaxanthin and rare carotenoids from marigold flowers and plants

Disclosed is a process for purification of a mixture of carotenoids from palm oil concentrate to produce a crystalline mixture of a &#x3b1;-carotene, &#x3b2;-carotene, &#x3b3;-carotene, and &#x3b5;,&#x3b5;-carotene as well as a product enriched in geometrical isomers of a &#x3b2;-carotene (9-cis-&#x3b2;-carotene, 13-cis-&#x3b2;-carotene) and &#x3b1;-carotene as well as &#x3b5;,&#x3b5;-carotene and &#x3b3;-carotene.

Process for purification and crystallization of palm oil carotenoids

The present invention relates to a method of reacting (3R,3'R,6&#x2032;R)-lutein with a catalytic amount of an acid to obtain a mixture of anhydroluteins, rich in anhydrolutein III, with substantially no Z-isomers being formed. The mixture is converted to (3R)-&#x3b2;-cryptoxanthin (major product) and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin (minor product) by reacting the anhydroluteins with borane-amine complexes (e.g. MeN.BH) or other hydride donors and an acid in a chlorinated solvent, preferably dichloromethane, at ambient temperature to produce (3R)-&#x3b2;-cryptoxanthin and (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin.

Method for production of &#x3b2;-cryptoxanthin and &#x3b1;-cryptoxanthin from commercially available lutein

Disclosed are processes for conversion of (3R,3'R,6&#x2032;R)-lutein to (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin, (3R)-&#x3b2;-cryptoxanthin, anhydroluteins I, II, and III (dehydration products of lutein), and a method for separating and purifying the individual carotenoids including the unreacted (3R,3&#x2032;R)-zeaxanthin. The invention also includes two methods that transform (3R,3&#x2032;R,6&#x2032;R)-lutein into (3R,6&#x2032;R)-&#x3b1;-cryptoxanthin in excellent yields.

Method for production of rare carotenoids from commercially available lutein

A process for the conversion of (3R,3&prime;R,6&prime;R)-lutein to 3&prime;-epilutein, a carotenoid precursor for industrial production of naturally occurring (3R,3&prime;R)-zeaxanthin, is disclosed.

Process for making a (3R,3&prime;R)-zeaxanthin precursor

A process for simultaneously extracting, saponifying, and isolating lutein and zeaxanthin, and a mixture of several rare carotenoids in high purity from plants without the use of harmful organic solvents. Lutein crystals containing 5% zeaxanthin were obtained from the dried petals of Marigold flowers,while zeaxanthin was isolated and purified from the berries of,(LCM berries). Similarly, this process has been employed to isolate and purify a mixture of lutein, beta-carotene, neoxanthin, violaxanthin, and lutein epoxide from green plants, preferably, kale, collard green, and spinach. These plants, to a lesser extent, also serve as a source of several rare carotenoids such as alpha-cryptoxanthin (Marigolds) and beta-cryptoxanthin (LCM berries). The purified carotenoids isolated by this process are free from impurities and serve as a safe source of nutritional supplement for human consumption as well as providing a suitable and effective color additive for human foods.

Growing community of inventors

Rockville, MD, United States of America

Frederick Khachik