US20060167319A1 - Methods for the synthesis of unsaturated ketone intermediates useful for the synthesis of carotenoids - Google Patents

Methods for the synthesis of unsaturated ketone intermediates useful for the synthesis of carotenoids Download PDF

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US20060167319A1
US20060167319A1 US11/242,609 US24260905A US2006167319A1 US 20060167319 A1 US20060167319 A1 US 20060167319A1 US 24260905 A US24260905 A US 24260905A US 2006167319 A1 US2006167319 A1 US 2006167319A1
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compound
carotenoids
synthesis
carotenoid
solution
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Samuel Lockwood
Peng Tang
Geoff Nadolski
Henry Jackson
Zhiqiang Fang
Yishu Du
Min Yang
William Geiss
Richard Williams
David Burdick
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Cardax Pharmaceuticals Inc
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Hawaii Biotech Inc
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Definitions

  • the invention generally relates to the fields of medicinal and synthetic chemistry. More specifically, the invention relates to the synthesis and use of carotenoids, including analogs, derivatives, and intermediates.
  • Carotenoids are a group of natural pigments produced principally by plants, yeast, and microalgae. The family of related compounds now numbers greater than 700 described members, exclusive of Z and E isomers. At least fifty (50) carotenoids have been found in human sera or tissues. Humans and other animals cannot synthesize carotenoids de novo and must obtain them from their diet. All carotenoids share common chemical features, such as a polyisoprenoid structure, a long polyene chain forming the chromophore, and near symmetry around the central double bond. Tail-to-tail linkage of two C 20 geranyl diphosphate molecules produces the parent C 40 carbon skeleton.
  • Carotenoids without oxygenated functional groups are called “carotenes”, reflecting their hydrocarbon nature; oxygenated carotenes are known as “xanthophylls.” Cyclization at one or both ends of the molecule yields 7 identified end groups (illustrative structures shown in FIG. 1 ).
  • Carotenoids with chiral centers may exist either as the R (rectus) or S (sinister) configurations.
  • astaxanthin (with 2 chiral centers at the 3 and 3′ carbons) may exist as 3 possible stereoisomers: 3S, 3′S; 3R, 3′S and 3S, 3′R (identical meso forms); or 3R, 3′R.
  • the relative proportions of each of the stereoisomers may vary by natural source.
  • Haematococcus pluvialis microalgal meal is 99% 3S, 3′S astaxanthin, and is likely the predominant human evolutionary source of astaxanthin.
  • Krill (3R,3′R) and yeast sources yield different stereoisomer compositions than the microalgal source.
  • Synthetic astaxanthin produced by large manufacturers such as Hoffmann-LaRoche AG, Buckton Scott (USA), or BASF AG, are provided as defined geometric isomer mixtures of a 1:2:1 stereoisomer mixture (3S, 3′S; 3R, 3′S, (meso); 3R, 3′R) of non-esterified, free astaxanthin.
  • Natural source astaxanthin from salmonid fish is predominantly a single stereoisomer (35,3′S), but does contain a mixture of geometric isomers. Astaxanthin from the natural source Haematococcus pluvialis may contain nearly 50% Z isomers.
  • the Z conformational change may lead to a higher steric interference between the two parts of the carotenoid molecule, rendering it less stable, more reactive, and more susceptible to reactivity at low oxygen tensions.
  • the Z forms in relation to the all-E form, the Z forms: (1) may be degraded first; (2) may better suppress the attack of cells by reactive oxygen species such as superoxide anion; and (3) may preferentially slow the formation of radicals. Overall, the Z forms may initially be thermodynamically favored to protect the lipophilic portions of the cell and the cell membrane from destruction.
  • the all-E form of astaxanthin unlike ⁇ -carotene, retains significant oral bioavailability as well as antioxidant capacity in the form of its dihydroxy- and diketo-substitutions on the ⁇ -ionone rings, and has been demonstrated to have increased efficacy over ⁇ -carotene in most studies.
  • the all-E form of astaxanthin has also been postulated to have the most membrane-stabilizing effect on cells in vivo. Therefore, it is likely that the all-E form of astaxanthin in natural and synthetic mixtures of stereoisomers is also extremely important in antioxidant mechanisms, and may be the form most suitable for particular pharmaceutical preparations.
  • the antioxidant mechanism(s) of carotenoids includes singlet oxygen quenching, direct radical scavenging, and lipid peroxidation chain-breaking.
  • the polyene chain of the carotenoid absorbs the excited energy of singlet oxygen, effectively stabilizing the energy transfer by delocalization along the chain, and dissipates the energy to the local environment as heat. Transfer of energy from triplet-state chlorophyll (in plants) or other porphyrins and proto-porphyrins (in mammals) to carotenoids occurs much more readily than the alternative energy transfer to oxygen to form the highly reactive and destructive singlet oxygen ( 1 O 2 ).
  • Carotenoids may also accept the excitation energy from singlet oxygen if any should be formed in situ, and again dissipate the energy as heat to the local environment. This singlet oxygen quenching ability has significant implications in cardiac ischemia, macular degeneration, porphyria, and other disease states in which production of singlet oxygen has damaging effects. In the physical quenching mechanism, the carotenoid molecule may be regenerated (most frequently), or be lost. Carotenoids are also excellent chain-breaking antioxidants, a mechanism important in inhibiting the peroxidation of lipids. Astaxanthin can donate a hydrogen (H) to the unstable polyunsaturated fatty acid (PUFA) radical, stopping the chain reaction.
  • H hydrogen
  • PUFA unstable polyunsaturated fatty acid
  • Peroxyl radicals may also, by addition to the polyene chain of carotenoids, be the proximate cause for lipid peroxide chain termination.
  • the appropriate dose of astaxanthin has been shown to completely suppress the peroxyl radical chain reaction in liposome systems. Astaxanthin shares with vitamin E this dual antioxidant defense system of singlet oxygen quenching and direct radical scavenging, and in most instances (and particularly at low oxygen tension in vivo) is superior to vitamin E as a radical scavenger and physical quencher of singlet oxygen.
  • Carotenoids are potent direct radical scavengers and singlet oxygen quenchers and possess all the desirable qualities of such therapeutic agents for inhibition or amelioration of ischemia-reperfusion injury.
  • Synthesis of novel carotenoid derivatives with “soft-drug” properties i.e. active as antioxidants in the derivatized form), with physiologically relevant, cleavable linkages to pro-moieties, can generate significant levels of free carotenoids in both plasma and solid organs.
  • this is a particularly useful embodiment (characteristics specific to non-esterified, free astaxanthin below):
  • antioxidants which are potent singlet oxygen quenchers and direct radical scavengers, particularly of superoxide anion, should limit hepatic fibrosis and the progression to cirrhosis by affecting the activation of hepatic stellate cells early in the fibrogenetic pathway.
  • Reduction in the level of “Reactive Oxygen Species” (ROS) by the administration of a potent antioxidant can therefore be crucial in the prevention of the activation of both “hepatic stellate cells” (HSC) and Kupffer cells.
  • ROS Reactive Oxygen Species
  • Vitamin E is generally considered the reference antioxidant.
  • carotenoids are more efficient in quenching singlet oxygen in homogeneous organic solvents and in liposome systems. They are better chain-breaking antioxidants as well in liposomal systems. They have demonstrated increased efficacy and potency in vivo. They are particularly effective at low oxygen tension, and in low concentration, making them extremely effective agents in disease conditions in which ischemia is an important part of the tissue injury and pathology.
  • These carotenoids also have a natural tropism for the heart and liver after oral administration. Therefore, therapeutic administration of carotenoids should provide a greater benefit in limiting fibrosis than vitamin E.
  • Synthesis of an appropriate analog or derivative and isomer composition requires a supply of starting materials (e.g., carotenoids, carotenoid synthetic intermediates). Any new synthetic route which is more efficient to a carotenoid analog or derivative and/or synthetic intermediate would be beneficial. More efficient synthetic routes would provide a more stable source of starting materials (e.g., carotenoids) which may be difficult or expensive to extract from natural sources. Synthetic routes to natural products may facilitate the synthesis of analogs and derivatives of the natural products.
  • starting materials e.g., carotenoids, carotenoid synthetic intermediates.
  • Naturally-occurring carotenoids may include astaxanthin as well as other carotenoids including, but not limited to, zeaxanthin, carotenediol, nostoxanthin, crustaxanthin, canthaxanthin, isozeaxanthin, hydroxycanthaxanthin, tetrahydroxy-carotene-dione, lutein, lycophyll, and lycopene.
  • a method of making a compound includes: coupling a cyclohexanone derivative having the general structure where R 1 is alkyl, phenyl, aryl or silyl;
  • the metal M may be lithium, sodium or magnesium (e.g., as a Grignard reagent).
  • Oxidants which may be used to effect the oxidation/rearrangment reaction include, but are not limited to chromium oxidants (e.g., pyridinium chlorochromate), manganese oxidants, or selenium oxidants.
  • a single stereoisomer of the starting cyclohexenone derivative may be used and the resulting intermediate may be stereoselectively produced.
  • the method may be used to from the stereoisomer
  • FIG. 1 depicts a graphic representation of several examples of “parent” carotenoid structures as found in nature.
  • stereoisomer refers to a compound having one or more chiral center that, while it can exist as two or more stereoisomers, is isolated in greater than about 95% excess of one of the possible stereoisomers.
  • a compound that has one or more chiral centers is considered to be “optically active” when isolated or used as a single stereoisomer.
  • Halo refers to fluoro, chloro, bromo, or iodo.
  • Alkyl alkoxy
  • alkoxy alkoxy
  • alkyl includes, but is not limited to: methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl or pentadecyl; “alkenyl” includes but is not limited to vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hex
  • Naturally-occurring carotenoids may include astaxanthin as well as other carotenoids.
  • Some of the other carotenoids may include carotenoids such as, for example, zeaxanthin, carotenediol, nostoxanthin, crustaxanthin, canthaxanthin, isozeaxanthin, hydroxycanthaxanthin, tetrahydroxy-carotene-dione, lutein, and lycopene.
  • Carotenoids having the general formula (I) below may be synthesized using the methods described herein. Where X, Y, and Z are independently —OH or ⁇ O.
  • the compound of formula I embraces “racemic” (e.g. statistical mixture of stereoisomers), optically inactive (e.g. meso forms) and optically active (e.g. enantiomeric) compounds.
  • carotenoids may be isolated using methods described herein with an enantiomeric excess of greater than 99%. In some embodiments, carotenoids may be isolated using methods described herein with an enantiomeric excess of greater than 95%. In some embodiments, carotenoids may be isolated using methods described herein with an enantiomeric excess of greater than 90%.
  • Z is H
  • Y is —OH
  • X is ⁇ O such that the carotenoid has the general structure depicted below.
  • the carotenoid below is commonly referred to as astaxanthin.
  • Z is H
  • Y is OH
  • X is OH
  • the carotenoid below is commonly referred to as crustaxanthin.
  • Z is H.
  • Y is H, and X is ⁇ O such that the carotenoid has the general structure depicted below.
  • the carotenoid below is commonly referred to as canthaxanthin.
  • Z is H
  • Y is H
  • X is —OH
  • the carotenoid below is commonly referred to as isozeaxanthin.
  • Z is OH
  • Y is H
  • X is ⁇ O such that the carotenoid has the general structure depicted below.
  • the carotenoid below is commonly referred to as hydroxycanthaxanthin.
  • Z and Y are —OH and X is ⁇ O such that the carotenoid has the general structure depicted below.
  • the carotenoid below is commonly referred to as tetrahydroxy-carotene-dione
  • carotenoids may be synthesized using the general process shown in Scheme I below.
  • X, Y, and Z are independently —OH or ⁇ O; where R 3 is PR 4 3 , SO 2 R 4 , or M + .
  • R 4 is alkyl, phenyl, or aryl.
  • M is Li, Na, or MgBr.
  • Coupling of two “head units” with the C 10 -aldehyde yields carotenoid. Coupling may be accomplished using a Wittig coupling (R 3 is PR 4 3 ), sulphone coupling (R 3 is SO 2 R 4 ), or condensation reaction (R 3 is M + ).
  • the C 10 aldehyde is commercially available. Described herein are various methods of synthesizing the appropriate headpiece. The following U.S.
  • a headpiece useful for the synthesis of astaxanthin may be formed using the process depicted in Scheme II.
  • R 1 may include hydrogen, alkyl, or aryl.
  • R 3 may also include any alcohol protecting groups known to one skilled in the art. Protecting groups may include, but are not limited to, silyl protecting groups such as tert-butyldimethylsilane (i.e., TBDMS).
  • TBDMS tert-butyldimethylsilane
  • compound 108a may be synthesized from commercially available keto- ⁇ -isopherone 109 having a general formula of
  • Keto- ⁇ -isopherone may be selectively reduced.
  • the more sterically hindered ketone may be reduced to an alcohol.
  • the more sterically hindered ketone A may be stereoselectively reduced to an alcohol.
  • a complexing reagent may be used to react with the less sterically hindered ketone.
  • the complexing agent may protect the less sterically hindered ketone B from reacting with a reagent (e.g., a reducing agent), thereby directing the reagent to react with the more sterically hindered ketone A.
  • a complexing agent may also be optically pure or form an optically pure complex with an activating metal, either of which may react with the less sterically hindered ketone B, such that the reduction of more sterically hindered ketone A results in an optically pure product.
  • absolute terms or phrases used e.g., optically pure are understood to include at least a range typically acceptable to one skilled in the art.
  • the optically pure product referred to regarding the reduced ketone may be >90% pure.
  • the optically pure product referred to regarding the reduced ketone may be >95% pure.
  • the optically pure product referred to regarding the reduced ketone may be >99% pure.
  • the optically pure product referred to regarding the reduced ketone may be >99.9% pure.
  • a reduction catalyst may be a chiral catalyst.
  • a “chiral catalyst” a defined herein is a catalyst that includes a single stereoisomer of a chiral molecule.
  • a chiral catalyst includes a transition metal and an optically active chiral ligand. Transition metals that may be used to form a chiral catalyst for reduction of ketones include Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au.
  • a ruthenium chiral catalyst may be used to effect a stereoselective reduction of keto- ⁇ -isopherone.
  • the ruthenium chiral catalyst may be formed from a mixture of [RuX 2 ( ⁇ 6 -Ar)] 2 with an optically active amine, where X represents a halogen (e.g., F, Cl, Br, I) and Ar represents benzene or a substituted benzene (e.g., alkyl substituted benzene).
  • the optically active amine includes both (S)- and (R)-amino acids, and other optically active amines such as as H 2 N—CHPh-CHPh-OH, H 2 N—CHMe-CHPh-OH, MeHN—CHMe-CHPh-OH.
  • keto- ⁇ -isopherone with a chiral catalyst may yield the optically active hydroxy ketone 116. While hydroxy ketone 116 is depicted in the (R)-form, it should be understood that the (S)-form may be formed by using the opposite optically active compound to form a chiral catalyst. For example, forming a ruthenium catalyst using (1R, 2S)-( ⁇ )-norephedrine leads to the (R)-form of the hydroxy ketone depicted below, while forming a ruthenium catalyst using (1S, 2R)-(+)-norephedrine leads to the (S)-form of the hydroxy ketone below.
  • Compound 116 may be further reduced.
  • the remaining ketone of compound 116 may be reduced to an alcohol.
  • the resulting alcohol to which the remaining ketone of compound 116 has been reduced may be optically pure.
  • Any type of reducing agent suitable for reducing a ketone to a hydroxy group may be used.
  • the reducing agent may be a chiral reducing agent or an achiral reducing agent.
  • the stereoselectivity of the reduction at hydroxyl (D) is controlled, at least in part, by the stereochemistry of the hydroxy group (C) as depicted in 118.
  • a borohydride reducing agent may be used to reduce the ketone group of compound 116.
  • a hindered borohydride reducing agent may be used to assist in achieving an enantiomerically pure reduction of the remaining ketone of compound 116.
  • the hindered borohydride reducing agent is a lithium trialkyl borohydride. Examples of lithium trialkyl borohydrides include, but are not limited to, lithium tri-sec-butylborohydride and lithium trisiamylborohydride. Reduction of the remaining ketone of 116 results in compound 118 having a general formula of Other types of hindered reducing agents may be used such as hindered aluminum hydride reducing agents may also be used to reduce ketone 116.
  • Alcohol D of compound 118 may be selectively protected using any number of alcohol protecting groups known to one skilled in the art to produce compound 120 having the general structure of where R 1 is alkyl, phenyl, aryl or silyl.
  • protecting groups may include sterically hindered protecting groups.
  • sterically hindered protecting groups include hindered silyl protecting groups.
  • Silyl protecting groups may include, but are not limited to, trimethylsilane, triethylsilane, triisopropylsilane, tert-butyl dimethyl silane (i.e., TBDMS), and diphenyl-t-butylsilane. If R 1 is a TBDMS group, the resulting protected compound has the structure of 120a
  • oxidizing agent may include, for example, pyridinium dichromate (PDC).
  • PDC pyridinium dichromate
  • Oxidation of hydroxyl group C leads to optically active ketone 108a, where R 1 is alkyl, phenyl, aryl or silyl.
  • R 1 may include a protecting group (e.g., TBDMS) such that 108a has a general structure of 108b
  • an enantiomeric excess of compound 108a may be determined. Enantiomeric excess may be determined by first removing any protecting groups, then measuring the optical purity using circular dichroism (CD) spectroscopy.
  • CD circular dichroism
  • hydroxy ketone 108 may be used to synthesize astaxanthin, as well as other carotenoid derivatives, as described herein.
  • ketone 108 is reacted with a nucleophilic acetylenic derivative to form an addition product 112 depicted below where R 1 is alkyl, phenyl, aryl or silyl.
  • Compound 112 may be formed by reacting ketone 108 with a nucleophile.
  • the nucleophile may selectively react with the carbonyl group of compound 108, transforming the carbonyl to an alcohol, as well as forming a new substituent at the 2 position of the carbonyl.
  • compound 108 may be alkynylated.
  • Alkyne may be reacted with compound 108 in an inert solvent (e.g., tetrahydrofuran (“THF”)).
  • THF tetrahydrofuran
  • Alkynes may include compounds having the general formula H—C ⁇ C—R 2 where R 2 includes: and where R 1 is alkyl, phenyl, aryl or silyl.
  • R 2 may include other substituents known to one skilled in the art (e.g., H, silane substituents, alkynes, alkenes, alkyls, aryl substituents, heteroaryl substituents).
  • Addition of alkyne H—C ⁇ C—R 2 to ketone may be accomplished by forming a metal anion of the acetylene, to form the reactive nucleophilic acetylenic compound M + ⁇ C ⁇ C—R 2 , where M + may be, but is not limited to, Li, Na, MgBr, Cd, or Zn.
  • a lithium salt of alkyne H—C ⁇ C—R 2 may be formed by reacting the alkyne with, for example, BuLi.
  • Other metal salts of alkynes may be made using methods known to one or ordinary skill in the art.
  • the nucleophilic acetylenic compound M + ⁇ C ⁇ C—R 2 may be reacted with ketone 108 to form a coupling product 112 as depicted below: where R 2 includes: and where R's alkyl, phenyl, aryl or silyl.
  • Compound 112 may be subjected to rearrangement conditions and oxidized to be converted into unsaturated ketone 114, as depicted below.
  • R 2 includes: and where R 1 is alkyl, phenyl, aryl or silyl.
  • Unsaturated ketone 114 may be formed by a two step process or in a novel one step rearrangement oxidation.
  • compound 112 is subjected to rearrangement conditions (e.g., treatment with aqueous acid) to effect rearrangement of the alcohol to an allylic alcohol (not shown). Subsequent oxidation of the allylic alcohol leads to the unsaturated ketone 114. This two step procedure reduces the efficiency of the process.
  • treatment of compound 112 with an oxidant affords the unsaturated ketone 114.
  • This ketone is formed by simultaneous rearrangement and oxidation of the alcohol.
  • the oxidizing agent used in a one-step process may include, for example, chromium oxidant (e.g., pyridinium dichlorochromate (PDC)), selenium oxidant, or manganese oxidant.
  • Unsaturated ketone 114 may be reduced to olefin 104 as depicted below.
  • Compound 114 may be used to synthesize compound 104.
  • Treatment of compound 114 with an appropriate reducing agent may reduce the alkyne substituent to give an E-olefin as depicted above.
  • Reducing metal reductions are particularly suited for forming E-olefins from alkynes. Reducing metal reductions may be accomplished using reagents such as Li/NH 3 , Na/NH 3 and Zn/acid.
  • zinc and an acid may be used to reduce the alkyne to an alkene.
  • the acid may include, for example, glacial acetic acid, ammonium acetate and/or ammonium chloride. The reduction yields the E-isomer predominantly.
  • one or more protecting groups e.g., alcohol protecting groups (R 1 ) may be removed before partially reducing the alkyne to an alkene.
  • conjugated alkene 104 Upon formation of conjugated alkene 104, the intermediate may be converted into compound 102 having a functional group capable of reacting with an aldehyde to form a double bond.
  • Examples of functionalities that may be reacted with an aldehyde include PR 4 3 , SO 2 R 4 , or M + where R 4 is alkyl, phenyl, or aryl and M is Li, Na, or MgBr.
  • Coupling of two “head units” with a C 10 -aldehyde yields a carotenoid. Coupling may be accomplished using a Wittig coupling (R 3 is PR 4 3 ), sulphone coupling (R 3 is SO 2 R 4 ), or condensation reaction (R 3 is M + ).
  • a phosphonium salt may be synthesized from compound 104. Phosphines and acid may be used to synthesize the phosphonium salt.
  • Phosphines may have the general structure —PR 5 3 or —CH 2 —P( ⁇ O)(OR 5 ) 2 where R 5 is alkyl, phenyl, or aryl.
  • Acids may include any of a number of acids known to one skilled in the art.
  • One example of an acid which may be used is hydrogen bromide (“HBr”).
  • Compound 102 may be reacted with a molecule containing an aldehyde functionality.
  • the functional group e.g., the phosphonium salt
  • the functional group may react with an aldehyde functionality under appropriate conditions to couple compound 102 to the dialdehyde.
  • Compound 102 may be reacted with a dialdehyde in order to perform a double coupling as depicted below.
  • a method may include analyzing the distribution of stereoisomers of a carotenoid (e.g., astaxanthin).
  • a method allowing analysis of the distribution of possible stereoisomers of a carotenoid may be used to determine the outcome of a synthetic method for preparing a carotenoid. The method may also be useful for checking the purity of carotenoid materials provided by chemical manufacturers.
  • a chiral HPLC column may be used to determine the stereoisomeric distribution of a carotenoid.
  • coupling of the headpiece unit with a coupling agent may be accomplished by forming pendant aldehyde groups on the headpiece and reacting them with a coupling agent as depicted below.
  • a carotenoid may be synthesized by condensing a compound of the general formula with a compound of the general formula
  • Condensation reactions using compounds such as those pictured above may, in some embodiments, be coupled under what are commonly known as Wittig condensation conditions.
  • the condensation may be carried out in the presence of an alkali metal alcoholate (e.g., sodium methylate, lithium carbonate, or sodium carbonate).
  • the condensation may be carried out in the presence of an alkyl substituted alkylene oxide (e.g., ethylene oxide, 1,2-butylene oxide).
  • Appropriate solvents may be used, such as alkanols (e.g., methanol, ethanol, isopropanol).
  • the condensation may be carried out over a range of temperatures. In some embodiments, the condensation may be carried out below room temperature (e.g., 0° C.).
  • intermediates used to synthesize astaxanthin may also be used to synthesize other carotenoids such as lutein and zeaxanthin.
  • lutein may be synthesized using the scheme depicted below:
  • intermediates used to synthesize astaxanthin may also be used to synthesize other carotenoids such as zeaxanthin.
  • zeaxanthin may be synthesized using the scheme depicted below:
  • the synthesis of the intermediate 150 is based on a modified synthesis of the intermediate 102 used to make astaxanthin. As shown above, the final coupling of intermediate 150 with a dialdehyde yields zeaxanthin in an analogous manner to astaxanthin. Synthesis of intermediate 150 may be accomplished using the scheme depicted below.
  • synthesis of the intermediate 150 may be accomplished using the same synthetic techniques as have been described above for astaxanthin to obtain intermediate 120.
  • Intermediate 120 may be converted into saturated ketone 160 using a procedure that is modified from the process used in the synthesis of astaxanthin.
  • a saturated ketone 160 may be formed by a two step procedure by oxidizing the hydroxyl group and reducing the double bond. Alternatively, the reduction of the double bond may be performed prior to oxidation of the hydroxyl group.
  • the scheme for converting compound 120 to 150 is shown below.
  • the more sterically hindered alcohol of compound 120 may be oxidized to a ketone.
  • Oxidation of the hydroxyl group may be accomplished using a variety of oxidizing reagents such as chromium oxidants, manganese oxidants, and selenium oxidants.
  • the oxidizing agent may include, for example, pyridinium dichromate (PDC). Oxidation of the hydroxyl group leads to an optically active ketone 108a, where R 1 is alkyl, phenyl, aryl or silyl.
  • Hydrogenation of the double bond using catalytic hydrogenation gives the intermediate 150.
  • hydrogenation may be performed to reduce the double bond followed by oxidation of the hydroxyl group to the ketone to form intermediate 150.
  • intermediate 102 used to make astaxanthin may be formed using an alternate method.
  • An alternate method for making intermediate 120 is depicted below:
  • the method includes an initial step of oxidizing ketoisopherone to hydroxylated ketoisopherone as depicted below:
  • Suitable oxidants include chromium oxidants, manganese oxidants and peroxide oxidants.
  • a cyclohexene derivative may be hydroxylated using hydrogen peroxide. After the compound has been oxidized, the hydroxylated product is reduced to form a dihydroxylated compound having the general structure
  • the method may also include protecting the dihydroxylated compound.
  • a dihydroxylate may be protected by reacting the dihydroxylated compound with a ketone (e.g., acetone).
  • a ketone may be reacted with the dihydroxylated compound to form a protected dihydroxylated compound having the general structure
  • R 1 may be alkyl (e.g., methyl), aryl or each R 1 together forms a cyclic ring.
  • the method may include coupling an alkyne to the protected dihydroxylate to form an intermediate coupled product.
  • the intermediate coupled product may not be isolated. Instead the intermediate product may be directly subjected to the next reduction process to give a product having the structure:
  • the intermediate coupled product may be transformed into a phosphonium salt product.
  • R 5 may be alkyl or aryl.
  • a method may include transforming a hydroxylated product into a phosphonium salt product. Transforming the hydroxylated product into a phosphonium salt product may include reducing the hydroxylated product to form a dihydroxylated compound having the general structure In some embodiments, the hydroxylated compound may be reduced stereoselectively.
  • stereoselective reduction may be generally defined as stereochemical reduction by which one of a pair of enantiomers, each having at least one asymmetric carbon atom, is produced selectively, i.e., in an amount larger than that of the other enantiomer.
  • the stereo-differentiating reduction is classified into enantioface- and diastereo-differentiating reductions, by which optical isomers having one asymmetric carbon atom and those having two asymmetric carbon atoms are produced, respectively.
  • the present reduction may be said to pertain to stereo-differentiating hydrogenation of carbonyl compounds.
  • a carbonyl may be stereoselectively reduced such that the resulting chiral center comprises a stereochemistry of R or S comprising a stereoselectivity of greater than 50%.
  • a stereoselectivity of a reduction may be greater than 75%.
  • a stereoselectivity of a reduction may be greater than 90%.
  • a stereoselectivity of a reduction may be greater than 95%.
  • a stereoselectivity of a reduction may be greater than 99%.
  • KIP ketoisophorone
  • compound 108c S-phorenol
  • carotenoids e.g., zeaxanthin or astaxanthin
  • KIP KIP
  • 108c Direct asymmetric reduction of KIP to 108c may save several steps relative to syntheses previously reported.
  • Use of catalytic reagents for stereoselective reduction avoids expensive reagents used in stoichiometric amounts for reduction.
  • Compound 108c may be useful for synthesis of carotenoids such as astaxanthin via derivative 108b.
  • KIP is known and commercially available and therefore a prime candidate for beginning a synthesis of some carotenoids with.
  • ketoisophorone can occur at C—I and/or C-4 and/or at the double bond, thus problems of regioselectivity and stereoselectivity must be solved.
  • 1,2-reduction at C-4 has been achieved with a stoichiometric amount of the reagents sodium borohydride/cerium chloride (JOC, 1986, 491, incorporated herein by reference) to give racemic product.
  • 1,2-reduction at C-4 has been achieved with 2-propanol in the presence of zirconium oxide catalyst to give racemic product (Bull Chem Soc Jap, 1988, 3283, incorporated herein by reference).
  • Compound 108c has been obtained by bioprocesses. Typical are product mixtures from non-selective reduction and over-reduction. See for example Agr Biol Chem, 1988, 2929 with Aspergillus niger , incorporated herein by reference, the product was the undesired 4 R enantiomer. 108c has been obtained in up to 99% enantiomeric excess by esterase hydrolysis of the racemic chloroacetate ester. The maximum yield reported was 30%. The maximum theoretical yield is 50% (Tetr Assy. 1999, 3811, incorporated herein by reference). 108c has been obtained in homochiral form by asymmetric catalytic reduction of the enol acetate of KIP (U.S. Pat. No. 5,543,559 to Broger et al., incorporated herein by reference). This requires preparation of the enol acetate and hydrolysis of the product acetate to obtain 108c.
  • Stereoselective reductions may be carried out using catalytic reagents (e.g., chemical, biological).
  • Biological catalysts may include for example living organisms (e.g., yeast) capable of facilitating a reduction of a carbonyl.
  • Catalytic reagents may be used due to their efficiency. Efficiency may be related to more than just a yield of a reaction or turnover, but also may include cost of the reagent as well as total cost of running the reaction (e.g., cost of catalyst, mole percentage of catalyst required, ease of reclaiming catalyst). Catalysts may be more attractive as possible reducing agents on an industrial scale due to a reduction in related expenses.
  • direct stereoselective reduction of KIP (including derivatives and analogs of KIP) to the alcohol product (including protected alcohols, such as ethers) may include the use of reagents such as boranes.
  • Boranes may include at least one B—H bond (e.g., diborane, borane-THF complex, borane-methyl sulfide complex, phenoxyboranes (such as catechol borane), amine-borane complexes, or alkoxyboranes).
  • borane reagents may include chiral substituents.
  • Chiral catalysts may include chiral derivatives which form weak complexes with the borane reductant.
  • Chiral catalysts which form weak complexes with borane reductants may include amine derivatives.
  • chiral oxazaborolidine catalysts with borane-THF may be used to stereoselectively reduce KIP and its analogs and derivatives (as described by Prof E J Corey in U.S. Pat. No. 4,943,635 and reviewed in Angew Chem Intl Engl, 1998, 37, 1986, both of which are incorporated herein by reference).
  • oxazaborolidine catalysts may include a compound having a general structure Using oxazaborolidine catalyst 202 with borane-THF as reductant, complete conversion may be achieved with 100% regioselectivity of reduction of the carbonyl at C-4 and a minimum of 25% enantiomeric excess.
  • Enantiomeric excesses of over 55% may be achieved using compound 202.
  • regioselectivity and enatiomeric excess may vary with temperature, the B—H source, and/or the structure of the catalyst.
  • Enantiomeric excesses may be improved with purification techniques known to one skilled in the art.
  • a chiral product may be purified via crystallization.
  • Compound 108c is a crystalline solid whereas the racemate is typically obtained as non-crystalline. Therefore crystallization of product to chiral purity may be a useful means of achieving this end.
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • Compound 1 (R 3 ⁇ H) is a known substance, found naturally and prepared synthetically.
  • the only other known example of structure 204 is the methyl ether (R 3 ⁇ CH 3 ) which was prepared as an analytical derivative for characterization of natural product 204 (R ⁇ H).
  • 206 (R 3 ⁇ H) and 208 are known substances (racemic and enantiomers) and demonstrated useful intermediates for the synthesis of racemic or homochiral astaxanthins (Helv Chim Acta, 1981, 240, 2447, 2463, incorporated by reference herein).
  • Derivatives and analogs of 206 (R 3 ⁇ H) and 208 provide useful intermediates for the synthesis of racemic or homochiral carotenoids, as well as, other natural products and their derivatives and analogs.
  • Desirable is direct asymmetric reduction of 204 to 206 and conversion to homochiral 208 for use in the synthesis of homochiral carotenoids (e.g., astaxanthin).
  • This sequence avoids the need for problematic oxidation steps which are required when the 3-hydroxy or 3-alkoxy substituents are absent.
  • the presence of a C-3 substituent may facilitate the asymmetric reduction of the carbonyl at C-4.
  • the only prior asymmetric reduction of 204 reported is a bioreduction of 204 (R 3 ⁇ H) reported to give the 4S isomer of 206a (R 3 ⁇ H) in 65% enantiomeric excess (Helv Chim Acta, 1981, 240, 2447, incorporated by reference herein).
  • a method may include preparation of epoxyketoisophorone from ketoisophorone.
  • An epoxide of ketoisophorone may be prepared using reagents including, but not limited to, peroxides (e.g., hydrogen peroxide).
  • peroxides e.g., hydrogen peroxide
  • peroxides e.g., m-ClC 6 H 4 CO 3 H
  • peroxides e.g., m-ClC 6 H 4 CO 3 H.
  • peroxides e.g., m-ClC 6 H 4 CO 3 H
  • There are other epoxidation reagents described in references such as “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” Larock, R. C. VCH Publishers, Inc. pages 456-461, which is incorporated herein by reference.
  • a method may include preparation of 3-hydroxyketoisophorone from epoxyketoisophorone.
  • a hydroxide anion e.g., sodium hydroxide
  • acidification of the solution may be employed to convert the epoxide to the hydroxide.
  • a method may include preparation of 3-methoxyketoisophorone from 3-hydroxyketoisophorone.
  • a base e.g., sodium hydroxide, sodium carbonate
  • a solvent e.g., dimethyl formamide, methanol
  • a methylating reagent e.g., dimethylsulfate
  • the methyl group may act as a protecting group masking the hydroxy group from reagents used in later transformations.
  • protecting groups for hydroxy groups known to one skilled in the art (e.g., silyl protecting groups).
  • the hydroxy substituent of 3-hydroxyketoisophorone may be methylated using diazomethane.
  • Other alkylation methods may include going through an intermediate (e.g., a mesylate) which is subsequently subtituted with a methoxy substitutent.
  • An alkylation e.g., methylation
  • the alkylation step may be circumvented by opening the epoxy group of, for example, epoxyketoisophorone with a methoxide salt (e.g., sodium methoxide) along with simultaneous dehydration.
  • a methoxide salt e.g., sodium methoxide
  • a method may include preparation of 4-(S)-hydroxy-ketoisophorone from 3-methoxyketoisophorone.
  • a hydrogen source e.g., H 2
  • a catalyst may be used to catalyze the reduction.
  • an enantiomeric excess of a particular enantiomer may be achieved without the use of stereoselective reagents.
  • stereoselective reagents e.g., chiral catalysts
  • reagents which are not typically stereoselective reagents may be used to reduce a carbonyl to a hydroxy group.
  • the reaction may not be stereoselective.
  • the reaction may be stereoselective, but may be stereoselective due to the inherent nature of the molecule.
  • sodium borohydride may be used to reduce the carbonyl to the hydroxy compound.
  • a method may include preparation of 4-hydroyxketoisophorone acetone ketal from 4-(S)-hydroxy-ketoisophorone.
  • a diol may be converted to an acetal using a ketone (e.g., acetone) and an acid (e.g., p-toluenesulfonic acid hydrate).
  • the acetal group may act as a protecting group masking the diol from reagents used in later transformations. There are other protecting groups for diols known to one skilled in the art.
  • one or more of the synthetic steps of a method for preparing 4-hydroyxketoisophorone acetone ketal may be combined into a “one-pot reaction” and/or an intermediate may not be isolated and/or purified before exposing it to another set of reagents.
  • a method may include stereoselectively reducing a carybonyl 1 of a compound 210 having the general structure to form a chiral center 2 of a compound 212 having the general structure
  • R 1 may be H or OR 3 .
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be H, alkyl, or aryl.
  • R 3 and/or R 5 of compound 1 may include alkyl, substituted alkyl, aryl.
  • Alkyl may include alkyl substituents, where alkyl comprises two or more carbons.
  • R 3 may include other substituents not listed known to one skilled in the art, even substituents typically unstable during reductive conditions may be used if protected properly using known functional protection methodology.
  • salts formed from compound 1 (R 3 ⁇ H) may include metals of period I or II or transition metals compatible with the reductants, ammonia, or amines (e.g., alkyl, substituted alkyl, aryl, heteroaryl, primary, secondary, or tertiary), or phosphines (e.g., alkyl, substituted alkyl, aryl, heteroaryl, primary, secondary, or tertiary). Salts formed from compound 1 (R 3 ⁇ H) may contain chirality in their structures or as associated ligands.
  • R 3 may be any alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group compatible with the reduction conditions. Any of the R groups may contain chiral centers or associated chiral ligands. In certain embodiments, R 3 may be an alkyl group comprising from one to eight carbons.
  • a reductant may be selected from among the classes of: hydrogen, a non-gaseous hydrogen source (e.g., reduction with an alcohol, formic acid, etc.), a nucleophilic metal hydride (e.g., NaBH 4 etc.), a covalent metal hydride (e.g., Dibal), a non-metal hydride (e.g., boranes or silanes) or metal catalyzed transfer of hydride from alcohols (e.g., Meerwein-Pondorf-Verley reduction).
  • the reductant may be chiral.
  • reductants may include hydrogen, formic acid, isopropanol, or sec-butanol.
  • Catalysts for hydrogenation or transfer hydrogenation may be chosen from among transition metals or metal ions (e.g., such as nickel, cobalt, platinum, palladium, iridium, rhodium, and ruthenium, modified with chiral ligands or surface modifiers) capable of facilitating reduction of ketones selectively over reduction of other moieties (e.g., esters).
  • transition metals or metal ions e.g., such as nickel, cobalt, platinum, palladium, iridium, rhodium, and ruthenium, modified with chiral ligands or surface modifiers
  • catalysts for hydrogenation or transfer hydrogenation may be complexes of rhodium (I) or Ruthenium (II) with C 2 -symmetric ligands or platinum metal modified with chiral cinchona alkaloids. Examples of ligands are known to one skilled in the art.
  • Compound 1 may be prepared from commercially available ketoisophorone by several means:
  • a carbonyl may be stereoselectively reduced, as for example:
  • R 1 may be R 5 , OSiR 5 3 , or OR 5 .
  • R 3 may be SiR 5 3 , aryl, or alkyl. Alkyl may comprise two or more carbons.
  • R 5 may be H, alkyl, or aryl. In some embodiments, R 5 may be methyl. R 3 may be methyl or hydrogen.
  • a carbonyl may be stereoselectively reduced as below
  • a method for reducing a carbonyl may include selectively reducing a first carbonyl in the presence of a second carbonyl.
  • the second carbonyl may be chemically distinguishable from the first carbonyl.
  • the first carbonyl may be electronically distinguishable from the second carbonyl.
  • the second carbonyl may not be reduced using the described method for reducing the first carbonyl.
  • the second carbonyl may be described as a vinylic ester and/or and ester.
  • the second carbonyl may be sterically hindered. For reasons such as these, a first carbonyl may be regioselectively reduced.
  • a reduction catalyst may be a chiral catalyst.
  • a chiral catalyst includes a transition metal and an optically active chiral ligand. Transition metals that may be used to form a chiral catalyst for reduction of ketones include Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, and Au.
  • a ruthenium chiral catalyst may be used to effect a stereoselective reduction of keto-az-isopherone.
  • the ruthenium chiral catalyst may be formed from a mixture of [RuX 2 ( ⁇ 6 -Ar)] 2 with an optically active amine, where X represents a halogen (e.g., F, Cl, Br, I) and Ar represents benzene or a substituted benzene (e.g., alkyl substituted benzene).
  • the optically active amine includes both (S)- and (R)-amino acids, and other optically active amines such as as H 2 N—CHPh-CHPh-OH, H 2 N—CHMe-CHPh-OH, MeHN—CHMe-CHPh-OH, and TsNH—CHPh-CHPh-NH 2 .
  • a chiral catalyst may include a catalyst having the structure
  • a method may include a stereoselective reduction such as
  • a solution of (1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine may be added to dichloro(p-cymene)ruthenium(II)dimer.
  • the suspension may be heated as necessary during which time the solids may go into solution.
  • the reaction may be cooled to room temperature, a solution of 204b may be added followed by KOH.
  • the method may include protecting the dihydroxylated compound.
  • a dihydroxylate may be protected by reacting the dihydroxylate with a ketone (e.g., acetone).
  • a ketone may be reacted with the dihydroxylate compound to form a protected dihydroxylate compound having the general structure
  • R 5 may be alkyl (e.g., methyl) or aryl.
  • the method may include coupling the protected diol to form an intermediate coupled product.
  • the intermediate coupled product may not be isolated.
  • the intermediate coupled product may include a compound having the general structure
  • the intermediate coupled product may be transformed into a phosphonium salt product having the general structure
  • a synthetic sequence may include:
  • an alkyne may be formed via the following synthetic sequence
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be alkyl (e.g., methyl) or aryl.
  • R 3 may include a protecting group, such as the described silyl protecting group.
  • protecting groups There are many protecting groups known to one skilled in the art for masking or protecting hydroxy functionalities. Different protecting groups may be used depending upon what conditions one wants to protect the hydroxy group under and/or what conditions one desires to deprotect and “unmask” the hydroxy group.
  • the above synthetic sequence may embody other types of optically active and/or non optically active endproducts.
  • at least some of the synthetic steps may be carried out in a similar manner to similar chemical reactions as described in other synthetic schemes as described herein above and/or in the Examples section.
  • an isomer of the alkyne coupled to the protected diol as described above may be employed to couple to the protected diol.
  • the isomer of the alkyne may include a compound having the general structure
  • the isomer of the alkyne may be synthesized by coupling acetylene and methyl vinyl ketone.
  • the acetylene may be added to the methyl vinyl ketone via 1,2 addition. Due to the instability of methyl vinyl ketone other synthetic routes my be employed to provide the desired product.
  • stable chemical equivalents of methyl vinyl ketone may be used. Stable equivalents may include 2-(beta-bromoethyl)-2-methyl-1,3-dioxolane.
  • carotenoids which may be synthesized using methods described herein may include carotenoids based on a chemical intermediate having the general structure
  • the compound depicted above embraces racemic, optically active stereoisomers and optically inactive stereoisomers.
  • R 3 may be OR 5 , OSiR 5 3 , H, alkyl, or aryl.
  • R 5 may be H, alkyl, or aryl.
  • R 7 may include C—R 3 or C ⁇ O.
  • a method of synthesizing such a compound may include transforming a halogenated derivative having the general structure into a phosphorous compound having the general structure
  • R 5 may be alkyl or aryl.
  • X may be a halogen (e.g., Br, Cl).
  • the method may include reacting the phosphorous compound with an aldehyde or an aldehyde equivalent having a general structure to form a alcohol coupling product having the general structure The method may include transforming the alcohol coupling product into a halogenated coupling product having the general structure
  • R 5 may be alkyl or aryl.
  • X may be a halogen (e.g., Br, Cl).
  • a method may include transforming the halogenated coupling product into a phosphonium salt product having the general structure
  • R 5 may be alkyl or aryl.
  • X may be a halogen (e.g., Br, Cl).
  • a method may include reacting the phosphonium salt product with a dialdehyde having the general structure to form a carotenoid chemical intermediate having the general structure
  • R 3 may be OR 5 , OSiR 5 3 , H, alkyl, or aryl.
  • R 5 may be H, alkyl, or aryl.
  • R 7 may include C—R 3 or C ⁇ O.
  • a carotenoid chemical intermediate may include a compound having the general structure
  • a synthetic sequence may include:
  • carotenoid chemical intermediates may be used to synthesize naturally occurring carotenoids as well as carotenoid analogs and carotenoid derivatives.
  • Carotenoid chemical intermediates may be used to synthesize naturally occurring carotenoids such as lycopene and lycophyll, and lycopene/lycophyll analogs and lycopene/lycophyll derivatives.
  • the chemical intermediate pictured above having the general structure may be coupled with a phosphonium salt product having the general structure to form lycopene having the general structure
  • Y may include —CH 2 —PR 5 3 or —CH 2 —P( ⁇ O)(OR 5 ) 2 .
  • R 5 may be alkyl or aryl.
  • methodologies as described herein may be used to prepare acyclic carotenoids, as well as, derivatives and/or analogs of acyclic carotenoids.
  • acyclic carotenoids as well as, derivatives and/or analogs of acyclic carotenoids.
  • the intermediates used to synthesize acyclic carotenoids are also useful in the preparation of carotenoids containing cyclic rings (referred to herein sometimes as cyclic carotenoids, e.g., astaxanthin).
  • a compound prepared by the method described herein may include an enantiomeric excess of at least one of the possible stereoisomers of the compound.
  • a compound prepared by the method described herein may include an excess of a stereoisomer relative to the stereoisomer's statistical abundance.
  • carotenoids, carotenoid derivatives, or carotenoid analogs which may be synthesized using methods described herein may include carotenoids based on a chemical intermediate having the general structure Compound 214 may be coupled to a phosphonium salt product 216 having the general structure to form protected carotenoid 218 having the general structure
  • Y may be PR 5 3 or P( ⁇ O)(OR 5 ) 2 .
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be alkyl or aryl.
  • a solution of LiOMe e.g., in methanol
  • Y may be PR 5 3
  • R 5 may be phenyl, and such that phosphonium salt product 216 has the general structure
  • X may be F, Cl, Br, or I.
  • R 3 may be methyl and X may be Br.
  • a method may include reducing protected carotenoid 218 to form carotenoid 220 having the structure
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be alkyl or aryl.
  • R 3 may be H when protected carotenoid 218 is reduced to an alcohol forming carotenoid 2H.
  • Reducing agents e.g., DIBAL or Diisobutylaluminium hydride
  • Other reducing agents known to one skilled in the art may be used.
  • carotenoid derivatives and analogs may be synthesized from naturally occurring carotenoids. These carotenoids may be synthetically produced and/or isolated from natural sources.
  • a method may include condensing carotenoid 220 with succinic anhydride to prepare compound 222 having the general structure 222.
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be alkyl or aryl.
  • R3 may include a co-antioxidant (e.g., Vitamin C, Vitamin C analogs and derivatives) and/or other substituents described herein.
  • a base e.g., N,N-diisopropylethylamine in a solvent such as CH 2 Cl 2
  • a non-nucleophilic base may be used.
  • the method may include forming a salt 224 of compound 222 having a general structure 224.
  • X is a counterion.
  • X may be a counterion.
  • X may include inorganic salts and/or organic salts.
  • X may include, but is not limited to, Li, Na, or K.
  • NaOMe may be used to convert the acid to the salt.
  • Other reagents such as LiOMe, NaOEt, as well as other based may be used to prepare the salt.
  • a method may include phosphorylating carotenoid 220 to form compound 226 having the general structure 221.
  • Y may be PR 5 3 or P( ⁇ O)(OR 5 ) 2 .
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be H, alkyl, benzyl, or aryl.
  • the method may include forming a salt 223 of compound 226 having a general structure 223.
  • X may be a counterion.
  • X may include inorganic salts and/or organic salts. X may include, but is not limited to, Li, Na, or K. NaOMe may be used to convert the acid to the salt. Other reagents such as LiOMe, NaOEt, as well as other bases may be used to prepare the salt.
  • a method may include preparing phosphonium salt product 216 by oxidizing ester 228 having the general structure to form aldehyde 230 having the general structure
  • Selective oxidizing agents e.g., SeO 2 in a solution of for example 95% ethanol
  • the method may include oxidizing aldehyde 230 to form oxidized product 232 having the general structure
  • Selective oxidizing agents e.g., NaClO 2 , Na 2 HPO 4 , Me 2 C ⁇ CHMe, t-BuOH/H 2 O
  • Oxidized product 232 may be selectively deprotected to form product 234 having the general structure
  • Selective bases e.g., K 2 CO 3 , MeOH/H 2 O
  • Conversion of product 232 to product 234 may be viewed as more of a deprotection of an alcohol.
  • the method may include halogenating product 234 to form halogenated product 236 having the general structure
  • halogenation of alcohols may be accomplished by a variety of methods (e.g., CBr 4 /Ph 3 P in a polar solvent such as THF).
  • Halogenated product 236 may be converted to the phosphonium salt product 216. Conversion of the halogen to the phosphonium salt may include using Ph 3 P in a solvent such as EtOAc.
  • X may be a counterion. X may include inorganic salts and/or organic salts. X may include F, Cl, Br, or I.
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be alkyl, benzyl, or aryl.
  • a multi-gram scale total synthesis of lycophyll (16,16′-dihydroxy-lycopene; ⁇ , ⁇ -carotene-16,16′-diol) may be based on a 2 (C10)+C20 synthetic methodology using the commercially available materials geraniol (C10) and crocetindialdehyde (C20).
  • C10 commercially available materials geraniol
  • C20 crocetindialdehyde
  • a late-stage double Wittig olefination of crocetindialdehyde may be used to form the lycophyll scaffold.
  • the double Wittig may generate a mixture of polyenic geometric isomers that may be separated (e.g., using HPLC).
  • the all-trans lycophyll may be achieved in >95% purity using about 8 linear synthetic steps.
  • the disuccinate and diphosphate sodium salts of the rare carotenoid may then be prepared.
  • Carotenoid derivatives and analogs e.g., disuccinate and diphosphate sodium salts
  • Retrometabolic in design, these novel derivatives could find utility in those applications where parenteral delivery of therapeutically relevant forms of lycophyll are desired.
  • lycopene 2F the primary carotenoid in tomatoes
  • other antioxidants e.g. vitamin E
  • ADME absorption-distribution-metabolism-excretion
  • a method of treating disease in a human subject may include administering to the human subject a pharmaceutical or nutraceutical composition including a predetermined ratio of two or more geometric and/or stereoisomers of a structural analog or derivative or synthetic intermediate of a carotenoid.
  • a method of treating disease in a human subject may include administering to the human subject a pharmaceutical or nutraceutical composition including a predetermined ratio of two or more structural analogs or derivatives or synthetic intermediates of a carotenoid.
  • a pharmaceutical or nutraceutical composition including a predetermined ratio of two or more structural analogs or derivatives or synthetic intermediates of a carotenoid.
  • Prospective, randomized clinical trials in humans also demonstrate improved indices of proliferation and oxidative stress across a range of oral doses in cancer patients. Delivery of a highly potent radical scavenger to prostatic tissue may restore or augment endogenous antioxidant levels.
  • Lycoxanthin 2G and lycophyll 2H which can be isolated from the red, ripe berries of Solanum dulcamara , as well as tomatoes and watermelon, are C40 lycopene-like xanthophylls functionalized with primary hydroxyl groups.
  • the originally proposed chemical structures of the xanthophylls however lacked complete assignment and required further studies that were realized in the early 1970's. Utilizing high-resolution mass spectroscopy and NMR, the regiochemistry of the hydroxyl groups was characterized.
  • Lycophyll was prepared by total synthesis at multiple gram scale for the current testing and derivatization to novel water-soluble, water-dispersible compounds. Isolation from natural sources demonstrates high cost, significant manpower, and generally low yields. Retrosynthetic analysis of the target xanthophyll revealed an efficient methodology utilizing at least some commercially available materials. In cases where commercial material was not available, these intermediates were synthesized in appropriate amounts. In some embodiments, commercially available materials may include geranyl acetate, a protected form of geraniol (C10), and/or crocetindialdehyde (C20). A method may include a total synthesis of acyclic carotenoids (e.g., lycophyll).
  • acyclic carotenoids e.g., lycophyll
  • a synthesis of, for example, lycophyll may be realized in about 8 synthetic steps (Schemes 1 and 2).
  • Synthetic steps may include an “endgame” double-Wittig olefination that successfully forms the target C40 scaffold while generating a mixture of geometric isomers (Scheme 2).
  • the isomeric mixture may be deconvoluted to yield the target all-trans lycophyll.
  • Deconvolution may include, but is not limited to, thermal or liquid chromatographic methods.
  • the methodology shown in Schemes 1 and 2 for synthesizing lycophyll may be used to synthesize other acyclic carotenoids, carotenoid derivatives, and carotenoid analogs.
  • a phosphonium salt product having the general structure may be coupled with an aldehyde product having the general structure to form lycopene having the general structure
  • Y may include —CH 2 —PR 5 3 or —CH 2 —P( ⁇ O)(OR 5 ) 2 .
  • R 5 may be alkyl or aryl.
  • a lycopene analog or a lycopene derivative may include one or more substituents. At least one of the substituents may include hydrophilic substituents. In some embodiments, substituents may include chemically reactive substituents which serve as chemical intermediates.
  • carotenoid chemical intermediates may be used to synthesize naturally occurring carotenoids such as xanthophylls.
  • a method may include coupling a phosphonium salt product having the general structure with a dialdehyde having the general structure to form a carotenoid having the general structure
  • R 1 and R 2 may be H or OR 3 .
  • R 3 may be SiR 5 3 , H, alkyl, or aryl.
  • R 5 may be alkyl or aryl.
  • Y may include —CH 2 —PR 5 3 or —CH 2 —P( ⁇ O)(OR 5 ) 2 .
  • R 7 may include C—OR 3 or C ⁇ O. Examples of xanthophyll carotenoids than may be synthesized using this methodology include, but are not limited to, astaxanthin, lutein, zeaxanthin, and canthaxanthin.
  • one or more of the conversions and/or reactions discussed herein may be carried out within one reaction vessel increasing the overall efficiency of the synthesis of the final product.
  • a product of one reaction during a total synthesis may not be isolated and/or purified before continuing on with the following reaction.
  • a reaction may instead only partially be worked up. For example, solid impurities which fall out of solution during the course of a reaction may be filtered off and the filtrate washed with solvent to ensure all of the resulting product is washed through and collected. In such a case the resulting collected product still in solution may not be isolated, but may then be combined with another reagent and further transformed.
  • multiple transformations may be carried out in a single reaction flask simply by adding reagents one at a time without working up intermediate products.
  • These types of “shortcuts” will improve the overall efficiency of a synthesis, especially when dealing with large scale reactions (e.g., along the lines of pilot plant scale and/or plant scale).
  • An example of increasing the overall efficiency of a synthesis may include reducing the alkyne of compound 114 to an alkene forming compound 104.
  • zinc and an acid may be used to reduce the alkyne to an alkene.
  • the acid may include, for example, glacial acetic acid.
  • the resulting zinc acetate may then be filtered off, and the filter cake washed with an organic solvent (e.g., methylene chloride) to ensure collection of as much of the resulting product compound 104 as possible.
  • an organic solvent e.g., methylene chloride
  • the resulting product compound 104 may then be added dropwise over a period of time (e.g., 30 minutes) to an aqueous solution of acid (e.g., HBr) and the resulting mixture stirred (e.g., for 10 minutes).
  • the organic phase may be separated from the aqueous phase and triphenylphosphine added to the organic phase without isolating the previous product from solution.
  • the addition of triphenylphosphine may result in compound 102.
  • Dialdehyde compound 112 may be added to the resulting solution of compound 102 and cooled down (e.g., to about 0° C.).
  • a base in solution may be added to the solution (e.g., sodium methoxide in methanol) dropwise. After stirring (e.g., about 5 hours), the solution may be finally fully worked up to acquire the purified isolated compound 104.
  • the compound of formula 100 embraces racemic and optically active and optically inactive stereoisomers.
  • a specific example of may include the synthesis of astaxanthin having a general formula of
  • carotenoid derivatives may be synthesized from naturally-occurring carotenoids.
  • the carotenoids may include structures 2A-2F depicted in FIG. 1 .
  • the carotenoid derivatives may be synthesized from a naturally-occurring carotenoid including one or more alcohol substituents.
  • the carotenoid derivatives may be synthesized from a derivative of a naturally-occurring carotenoid including one or more alcohol substituents.
  • the synthesis may result in a single stereoisomer.
  • the synthesis may result in a single geometric isomer of the carotenoid derivative.
  • the synthesis/synthetic sequence may include any prior purification or isolation steps carried out on the parent carotenoid. Synthesis of carotenoid derivatives can be found in U.S. Published Patent Application Nos. 2004-0162329 and 2005-0113372, both of which are incorporated herein by reference.
  • Quantity Raw Materials FW Used Moles 2,6,11,15-Tetramethyl-hexadeca-2,4,6,8,10,12,14- 384.51 200 g 0.52 mol heptaenedioic acid diethyl ester Methylene chloride 3000 mL Diisobutylaluminum hydride-(1.5 M, Toluene) 142.22 1533 mL 2.30 mol
  • a buffer may be substituted for the controlled base feed and the pH controller as described here.
  • TLC e.g., ethyl acetate; heptane 30:70 v/v, silica, iodine visualization, ketoisophorone Rf 0.70, epoxyketoisophorone Rf 0.7
  • the mixture was allowed to separate, the organic phase retained and the aqueous extracted three times, each time with 100 ml dichloromethane.
  • the combined organic and dichloromethane phases were then washed with 50 ml 5 wt % sodium bisulfite solution then with 50 ml 20 wt % sodium chloride solution and the solution dried over anhydrous sodium sulfate.
  • the epoxyketoisophorone product was converted to 3-hydroxyketoisophrone.
  • To a 500 ml round bottom flask equipped with an addition funnel, a thermometer, and a magnetic stirrer were charged 30 ml water and 19.6 g epoxyketoisophorone and the mixture stirred while adding dropwise over one hour 18 ml 28 wt % sodium hydroxide solution while keeping the temperature between 30 and 35° C. with a water ice cooling bath.
  • the yellow mixture was stirred another two hours, cooled to room temperature then acidified by dropwise addition to pH 1 with 37% hydrochloric acid during which a solid precipitated.
  • the slurry was stirred for one hour, then filtered over paper, washed to neutrality with water, then dried at 50° C. and 26 inches vacuum with a nitrogen purge to furnish 17.6 g 3-hydroxyketoisophorone as a yellowish solid.
  • the yield is estimated at 90%. mp 137-139 (lit. 141-143).
  • reaction mixture was neutralized by adding a solution of 35 mg citric acid in 1 ml water, the mixture filtered through a small pad of silica gel, them stripped to dryness on a rotovac. The residue was chromatographed over 40 g silica gel using a gradient of ethyl acetate-hexanes 20:80 to 40:60 v/v. On concentration of fractions and stripping in vacuo was obtained 589 mg 4-hydroxyketoisophorone as a white crystalline solid. Yield was estimated at 87%.
  • 1H NMR 1.10 (s, 3H), 1.22 (s, 3H), 1.75 (s, 3H), 1.9 (m, 1H), 2.2 (d,d, 1H) 4.0 (s, 3H), 4.7 (m, 1H).
  • the column bed was formed using the dynamic axial compression of the RamPak unit.
  • the packing solvent was flushed from the column bed for 50 min at a flow rate of 150 mL/min using the preparative HPLC mobile phase consisting of 95% toluene and 5% methyl ethyl ketone (MEK).
  • the preparative HPLC system consisted of a Waters Prep 4000 solvent delivery system and a Waters model 486 variable UV detector fitted with a prep cell (3 mm path length).
  • sample solution was injected directly through the pump, detection was at 580 nm, and the chromatogram was recorded on a strip chart recorder. At the preparative flow rate of 280 mL/min, the system backpressure was 840 psi. The laboratory was equipped with yellow lights, and the windows were covered to avoid any effects of light on the sample.
  • a sample solution for preparative HPLC was prepared by dissolving 30 g of ASTA-DCE in 90 mL of methylene chloride and diluting the solution with 210 mL of toluene. A portion of the resulting solution (272 mL) was further diluted with 688 mL of preparative HPLC mobile phase to generate the sample solution that was subsequently injected onto the preparative HPLC system.
  • the preparative HPLC injection consisted of pumping 120 mL of this ASTA-DCE sample solution (3.4 g of ASTA-DCE) through the pump and onto the preparative column.
  • the preparative loading was selected to optimize sample throughput, and the resulting chromatogram consisted of three slightly overlapping peaks with the 3R,3′R ester eluting at 14 min, the meso-(3R,3′S) ester at 16.5 min, and the 3S,3′S ester at 21.5 min.
  • subsequent injections were made 20 min into the previous run at the valley between the meso and 3S,3′S peaks.
  • Heart cuts of each of the three peaks were collected in addition to the mixed fractions at the overlap of the 3R,3′R/meso and the meso/3S,3′S peaks.
  • a total of 40 preparative injections were processed using 84 L of mobile phase. Thirty-six (36) L of effluent were collected among the five fractions.
  • the preparative system was flushed with 100 mL of methylene chloride approximately every 6-8 injections or whenever the chromatographic separation deteriorated due to effects from mixing with mobile phase in the pump heads during the injection process. Purified materials were recovered by removing the solvents in a rotary evaporator protected from light to afford 25.4 g of 3R,3′R ester, 47.8 g of meso-(3R,3′S) ester, and 24.9 g of 3S,3′S ester.
  • the purified astaxanthin dicamphanate esters were saponified to afford 8.5 g (79.8% purity by HPLC) of 3R,3′R-astaxanthin, 18.2 g (90.1% purity by HPLC) of meso-astaxanthin, and 9.4 g (82.0% purity by HPLC) of 3S,3′S-astaxanthin.
  • the major impurities of the saponification reaction were the 13- and 9-cis isomers of astaxanthin, identified by HPLC.
  • the cis-isomers were thermally isomerized to all-trans by refluxing in heptane to afford 8.5 g (87.3% purity by HPLC) of 3R,3′R-astaxanthin, 18.2 g (92.5% purity by HPLC) of meso-astaxanthin, and 9.4 g (86.8% purity by HPLC) of 3S,3′S-astaxanthin.
  • Crocetindialdehyde (238) was obtained from SynChem, Inc. (Des Plaines, Ill.) as a brick-red solid and was used without further purification.
  • Lycopene was obtained from ChromaDex (Santa Ana, Calif.) as a red solid and was used without further purification.
  • Acetic acid 3,7-dimethyl-8-oxo-octa-2,6-dienyl ester (230a) (Liu and Prestwich 2002) was synthesized by literature procedures from commercially available geranyl acetate (228a). All other reagents and solvents used were purchased from Acros Organics (Morris Plains, N.J.) and Sigma-Aldrich (St.
  • Gradient program for intermediates 230a-236a and 216a: 70% A/30% B (start), step gradient to 50% B over 5 minutes, step gradient to 100% B over 1.3 minutes, hold at 100% B over 4.9 minutes.
  • Gradient program for intermediates 218a, 2H: 70% A/30% B (start), step gradient to 50% B over 5 minutes, step gradient to 98% B over 3.3 minutes, hold at 98% B over 16.9 minutes.
  • a catalytic amount of trifluoroacetic acid is used in the eluents to improve chromatographic resolution.
  • LRMS +mode
  • ESI electrospray chemical ionization, ion collection using quadrapole
  • APCI atmospheric pressure chemical ionization, ion collection using quadrapole.
  • diphosphate salt 223a (approximately 50% pure; 0.018 g, 43%) as a red hygroscopic solid; LC/MS (ESI): 9.26 min (9.34%), ⁇ max 295 nm (28%), 362 nm (18%), 447 nm (81%), 472 nm (100%), 503 nm (87%), m/z 897 (8%), 392 (100%), 381 (10%); 9.48 min (46.98%), ⁇ max 295 nm (29%), 362 nm (15%), 447 nm (80%), 472 nm (100%), 503 nm (91%), m/z 911 (10%), 849 (15%), 399 (87%), 368 (100%); 9.56 min (43.68%), ⁇ max 295 nm (28%), 362 nm (12%), 447 nm (77%), 472 nm (100%), 503 nm (90%),
  • Racemic astaxanthin (e.g., 3S,3′S, meso (3R,3′S), and 3R,3′R in a 1:2:1 ratio) was run through the chiral HPLC column and the retention time for 3S,3′S(“S,S”)-astaxanthin was 32.763 min, meso-astaxanthin was 31.165, and 3R,3′R (“R,R”)-astaxanthin was 29.937. The total run time was 60 minutes.

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US11/242,643 Active US7247752B2 (en) 2004-10-01 2005-10-03 Methods for the synthesis of astaxanthin
US11/242,627 Abandoned US20060111580A1 (en) 2004-10-01 2005-10-03 Methods for the synthesis of chiral dihydroxy ketone intermediates useful for the chiral synthesis of carotenoids
US11/242,591 Abandoned US20060088904A1 (en) 2004-10-01 2005-10-03 Methods for the synthesis of astaxanthin
US11/242,641 Abandoned US20060178538A1 (en) 2004-10-01 2005-10-03 Methods for the synthesis of chiral dihydroxy intermediates useful for the chiral synthesis of carotenoids

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US20050009930A1 (en) * 2002-07-29 2005-01-13 Lockwood Samuel Fournier Carotenoid analogs or derivatives for controlling connexin 43 expression
US20050037995A1 (en) * 2002-07-29 2005-02-17 Lockwood Samuel Fournier Carotenoid ester analogs or derivatives for the inhibition and amelioration of ischemic reperfusion injury
US20050065096A1 (en) * 2002-07-29 2005-03-24 Lockwood Samuel Fournier Pharmaceutical compositions including carotenoid ether analogs or derivatives for the inhibition and amelioration of disease
US20050090469A1 (en) * 2002-07-29 2005-04-28 Lockwood Samuel F. Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease
US20050113372A1 (en) * 2002-07-29 2005-05-26 Lockwood Samuel F. Carotenoid analogs or derivatives for the inhibition and amelioration of disease
US7763649B2 (en) 2002-07-29 2010-07-27 Cardax Pharmaceuticals, Inc. Carotenoid analogs or derivatives for controlling connexin 43 expression
US7723327B2 (en) 2002-07-29 2010-05-25 Cardax Pharmaceuticals, Inc. Carotenoid ester analogs or derivatives for the inhibition and amelioration of liver disease
US20060155150A1 (en) * 2004-10-01 2006-07-13 Lockwood Samuel F Methods for the synthesis of lutein
US20060111580A1 (en) * 2004-10-01 2006-05-25 Lockwood Samuel F Methods for the synthesis of chiral dihydroxy ketone intermediates useful for the chiral synthesis of carotenoids
US20060178538A1 (en) * 2004-10-01 2006-08-10 Lockwood Samuel F Methods for the synthesis of chiral dihydroxy intermediates useful for the chiral synthesis of carotenoids
US20060183947A1 (en) * 2004-10-01 2006-08-17 Lockwood Samuel F Methods for the synthesis of astaxanthin
US20060183185A1 (en) * 2004-10-01 2006-08-17 Lockwood Samuel F Method for the synthesis of astaxanthin
US7247752B2 (en) 2004-10-01 2007-07-24 Cardax Pharmaceuticals, Inc. Methods for the synthesis of astaxanthin
US20060088904A1 (en) * 2004-10-01 2006-04-27 Lockwood Samuel F Methods for the synthesis of astaxanthin
US20060088905A1 (en) * 2004-10-01 2006-04-27 Lockwood Samuel F Methods for the synthesis of zeazanthin
US20090099061A1 (en) * 2006-01-27 2009-04-16 Foss Bente J Synthesis of carotenoid analogs or derivatives with improved antioxidant characteristics
US20090124574A1 (en) * 2007-03-23 2009-05-14 Lockwood Samuel F Carotenoid analogs and derivatives for the prevention of platelet aggregation
US8063101B2 (en) 2007-03-23 2011-11-22 Cardax Pharmaceuticals, Inc. Carotenoid analogs and derivatives for the prevention of platelet aggregation
CN101906445A (zh) * 2010-06-18 2010-12-08 西南大学 2h-1-苯并吡喃-2-酮衍生物的合成方法

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WO2006039685A3 (en) 2007-01-04
US20060088904A1 (en) 2006-04-27
US7247752B2 (en) 2007-07-24
US20060088905A1 (en) 2006-04-27
US20060155150A1 (en) 2006-07-13
US20060183947A1 (en) 2006-08-17

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