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WO2006023720A2 - Reactions asymetriques organocatalytiques directes d'alpha-amino-aldehydes ou -cetones enolisables en vue de la formation de produits amines enantiomeriquement enrichis - Google Patents

Reactions asymetriques organocatalytiques directes d'alpha-amino-aldehydes ou -cetones enolisables en vue de la formation de produits amines enantiomeriquement enrichis Download PDF

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WO2006023720A2
WO2006023720A2 PCT/US2005/029542 US2005029542W WO2006023720A2 WO 2006023720 A2 WO2006023720 A2 WO 2006023720A2 US 2005029542 W US2005029542 W US 2005029542W WO 2006023720 A2 WO2006023720 A2 WO 2006023720A2
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aldehyde
diprotectedamino
alpha
ketone
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WO2006023720A3 (fr
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Carlos F. Barbas, Iii
Rajeswari Thayumanavan
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Scripps Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C223/00—Compounds containing amino and —CHO groups bound to the same carbon skeleton
    • C07C223/02—Compounds containing amino and —CHO groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention contemplates a method for asymmetrically forming a (diprotectedamino) - product having at least one chiral center and in which one enantiomer is in excess over the other. More particularly, the invention contemplates a method of reacting an enolizable alpha- (diprote ⁇ tedamino) -aldehyde or -ketone donor molecule with an unsaturated acceptor molecule in the presence of a chiral catalyst to provide a chiral product in which one enantiomer predominates over the other.
  • Asymmetric molecules are ubiquitous in nature, and particularly, in living organisms. That commonality, led to a change in organic chemical nomenclature from use of the terms symmetric and asymmetric, which emphasized symmetric molecules as the norm, to the terms chiral and achiral that affirmatively places emphasis on asymmetric molecules .
  • Amine-containing small molecule drugs as compared to proteinaceous pharmaceuticals, are common, due in part to their water solubility and ability to bind to anionic sites on proteins. The ability to prepare chiral amine-containing compounds would therefore be beneficial in the synthesis of pharmaceutical products.
  • the histamine H3 receptor agonist Sch 50971,1 trans-4-methyl-3-imidozoyl pyrrolidine dihydrochloride is one such compound, and analogs of that compound can be beneficial for comparative study.
  • ⁇ -hydroxy- ⁇ -amino acids are components of natural products with wide-ranging biological properties, including antibiotic, anti ⁇ cancer, and immunosuppressant activities.
  • McDonald et al. J " . Am. Chem. Soc. 2002, 124, 10260.
  • Taniguchi et al. Tetrahedron 2003, 59, 4533.
  • Ford et al. J. Am. Chem. Soc. 1999, 121, 5899;
  • Saravanan et al . J. Org. Chem. 2003, 68, 2760.
  • the present invention contemplates a method for asymmetrically forming an ⁇ - (diprotectedamino) - aldehyde or -ketone product having a chiral center and in which one enantiomer is in excess over the other.
  • This method comprises the steps of reacting an enolizable ⁇ - (diprotectedamino)aldehyde or -ketone donor molecule with an excess of an unsaturated acceptor molecule that preferably has one or no hydrogen atoms bonded to a carbon atom alpha to the carbon of the unsaturation.
  • Those donor and acceptor molecules are dissolved or dispersed in a liquid solvent and are reacted in the presence of a chiral (an optically active) amine catalyst to form an addition product reaction medium.
  • the amine catalyst contains up to about 25 carbon atoms such as D- or L-pyrrolidine.
  • the addition product reaction medium is maintained for a time sufficient to form an ⁇ - (diprotectedamino) aldehyde or -ketone product having a chiral center formed at least at the carbon atom bonded to the ⁇ - (diprotectedamino) group and preferably also at a carbon atom where the unsaturation had been in the acceptor part of the new molecule, and in which one enantiomer is in excess over the other.
  • a method of asymmetrically forming a beta- hydroxy-alpha-amino aldehyde is contemplated in one specific embodiment.
  • an alpha- (diprotectedamino)aldehyde or -ketone donor is reacted with an excess of an alpha-disubstituted (or alpha-branched) aldehyde acceptor dissolved or dispersed in a solvent and in the presence of a chiral amine catalyst to form a reaction medium. That reaction medium is maintained for a time sufficient to form a beta-hydroxy alpha- (diprotectedamino) aldehyde or -ketone.
  • the beta-hydroxy alpha- (diprotectedamino) aldehyde can be converted directly into a beta-hydroxy alpha-amino acid without prior isolation or can be isolated, purified further if desired and thereafter converted into the amino acid.
  • the invention contemplates the reaction of an excess of an alpha- (diprotectedamino)aldehyde acceptor is reacted with an alpha-unsubstituted (or alpha-non-branched) aldehyde or ketone donor dissolved or dispersed in a solvent and in the presence of a chiral amine catalyst to form a reaction medium. That reaction medium is maintained for a time sufficient to form a ⁇ -hydroxy- ⁇ - (diprotectedamino)aldehyde or ketone.
  • the ⁇ -hydroxy- ⁇ - (diprotectedamino)aldehyde can be converted directly into a ⁇ -hydroxy- ⁇ - amino acid without prior isolation or can be isolated, purified further if desired and thereafter converted into the amino acid.
  • One benefit of the invention is that its method can be utilized to prepare ⁇ - (diprotectedamino)aldehyde or -ketone products such as beta-hydroxy alpha- (diprotectedamino) aldehyde products in high yields.
  • An advantage of the invention is that the ⁇ - (diprotectedamino) aldehyde or -ketone products so prepared are present in excellent diasteroselectivity and high enantioselectivity.
  • Another benefit of the invention is that the prepared ⁇ - (diprotectedamino)aldehyde products can be readily oxidized and diprotected to form the corresponding amino acid.
  • a further advantage is that the amino acids so formed retain the diastere ⁇ meric ratios and enantiomeric excesses of the ⁇ - (diprotectedamino) - aldehyde products.
  • the present invention contemplates a method for asymmetrically forming a (diprotectedamino) - product having at least one chiral center and in which one enantiomer is in excess over the other-.
  • a contemplated method comprises the steps of reacting an enolizable alpha- (diprotectedamino)aldehyde or -ketone donor molecule with an unsaturated acceptor molecule.
  • the donor and acceptor molecules are dissolved or dispersed in a solvent and are in the presence of a chiral amine catalyst to form an addition product reaction medium.
  • the reaction medium so formed is maintained for a time sufficient to form a diprotectedamino-product having at least one chiral center formed at the carbon atom bonded to the ⁇ - (diprotectedatnino) group and in which one enantiomer is in excess over the other.
  • a second chiral center is also formed at the carbon of the former acceptor molecule that is alpha to the unsaturated carbon atom.
  • the maintenance time for a given reaction can vary from about 0.5 to about 72 hours, and is more typically about one hour to about 48 hours.
  • the contemplated method can be used to form a contemplated product in which an enantiomeric excess (ee) is about 50 percent or greater. More preferably, that ee is about 75 percent or greater, and most preferably the ee is about 85 to about 100 percent.
  • an enantiomeric excess (ee) is about 50 percent or greater. More preferably, that ee is about 75 percent or greater, and most preferably the ee is about 85 to about 100 percent.
  • diastereomers are usually prepared, and the diastereomeric ratio (dr) of those isomers is also noted and can reflect the fact that an diastereomeric excess of one product over the other is formed.
  • the donor molecule contains an amino group bonded to the carbon atom that is bonded to the carbonyl carbon of the ketone or aldehyde, and that amine-containing carbon atom is referred to as the alpha-carbon.
  • the alpha-carbon also includes at least one hydrogen atom that is relatively acidic and thus can be removed to form an enolate anion at the alpha-carbon so that the donor molecule is an enolizable molecule.
  • the alpha-carbon of the donor molecule becomes at least one chiral center in the product molecule.
  • a donor molecule contains 2 to about 28 carbon atoms, excluding any carbon atoms present in the amine protecting group, "Pg".
  • a donor molecule more preferably contains 2 to about 10 carbon atoms, exclusive of those that may be in the amine protecting group.
  • the amine group of the donor molecule ⁇ -carbon is doubly blocked or doubly protected so that the two valences remaining on the amine nitrogen atom after bonding to the ⁇ -carbon atom are taken up by the blocking group or groups.
  • the amine is thus referred to as a "diprotectedamino" group.
  • the protecting groups are removable and are illustrated hereinafter. Further examples of amino-protecting groups are well known in organic synthesis and the peptide art and are described by, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2 nd ed., John Wiley and Sons. New York., Chapter 7, 1991; M.
  • R 2 is selected from the group consisting of hydrido (H-), a Ci-Cig straight chain, branched chain or cyclic hydrocarbyl group, an aryl group such as a phenyl, a naphthyl, pyridyl, pyrimidyl, furanyl, thiofuranyl or pyrazinyl group, or an aryl group substituted with a substituent selected from the group consisting of Ci-Cg straight chain, branched chain or cyclic hydrocarbyl group, halogen, cyano, trifluoromethyl, nitro, hydroxyl, and a -CC> 2 R a group, wherein R a is a Ci-Cg straight chain, branched chain or cyclic hydrocarbyl group.
  • a contemplated acceptor molecule is unsaturated and thus contains a double bond, with a carbon atom that participates in the unsaturation being the site of a new carbon-to-carbon bond that is formed and is usually a site of a newly formed chiral center except where formaldehyde is the acceptor.
  • the second atom of the unsaturated bond, W can be an oxygen atom where the acceptor is an aldehyde or ketone and the reaction is an aldol reaction, a protected nitrogen atom as is present in an imine where the reaction is a Mannich reaction, and a substituted carbon atom where the reaction is a Michael addition reaction.
  • Illustrative acceptor compounds are shown below in Table 2, where the wavy line indicates the position of the bond between the alpha-carbon of the substituent group and the adjacent ( ⁇ -) unsaturated carbon of the acceptor molecule.
  • the acceptor molecule contains one, and preferably two, carbon atoms and can contain up to about 30 carbons.
  • An acceptor more preferably contains 2 to about 12 carbons, exclusive of any carbons that may be present in an amine protecting group as where the group "W" contains a substituted nitrogen atom of an imine.
  • the R. 3 substituent can be hydrido.
  • the R- 3 group can include an alpha-carbon that is bonded to one or no hydrogen atoms, and contains up to 29 carbon atoms.
  • Such an R 3 group comprises a substituent selected from the group consisting of: a branched chain hydrocarbyl, a cyclic hydrocarbyl, a cyclic group containing 1 to 3 heteroatoms in the ring, wherein the heteroatoms are oxygen, sulfur and trisubstituted nitrogen atoms, or two of the three heteroatoms, an aryl group such as a phenyl group, a naphthyl group, as well as a single ring or two ring heterocyclic group containing one to four heteroatoms that are oxygen, sulfur and trisubstituted nitrogen atoms such as a pyridyl, pyrimidyl, furanyl, thiofuranyl, pyrazinyl, an N-blocked imidazolyl,
  • C 1 -C 8 ] group a substituted aryl group as discussed above wherein the substituent is selected from the group consisting of C 1 -Cg straight chain, branched chain or cyclic hydrocarbyl group, halogen, cyano, trifluoromethyl, nitro, C 1 -Cg-hydrocarbyloxy and hydroxyl, and a straight chain hydrocarbyl group substituted with 1, 2 or 3 substituents selected from the group consisting of (a) a halogen, (b) a Ci-Cs- hydrocarbyloxy group, (c) an aryl group as above, or (d) a substituted aryl group as above.
  • the alpha-carbon that is part of the R 3 group contain no hydrogen atoms, as where R 3 is an aryl group. If one hydrogen atom is present bonded to the alpha-carbon, the remaining R 3 substituent is preferably bulky and contains at least four carbon atoms so that the R 3 group can sterically hinder the approach of the amine catalyst to that alpha-carbon-bonded hydrogen.
  • Formaldehyde is the simplest acceptor molecule and R 3 is hydrido where formaldehyde is the acceptor.
  • the R 4 group can be the same as or different from an R 3 group. However, when R 4 is other than hydrido, the sum of the carbon atoms in R 3 and R 4 can be a total of 29 atoms, the number of carbon atoms in each of R 3 and R 4 is adjusted accordingly so that the sum of carbon atoms in the acceptor molecule is about 30 or fewer. It is preferred that the R 4 group be hydrido for an acceptor utilized in each of an aldol reaction, a Mannich reaction and a Michael addition reaction.
  • hydrocarbyl is used herein as a short hand term to include aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen.
  • alkyl, ' alkenyl and alkynyl groups are contemplated as are aralkyl groups such as benzyl and phenethyl, whereas aromatic hydrocarbons such as phenyl and naphthyl groups, which strictly speaking could also be included as hydrocarbyl groups, are referred to herein as aryl groups, substituents or radicals.
  • aryl groups, substituents or radicals where a specific aliphatic hydrocarbyl substituent group is intended, that group is recited; i.e., C ⁇ -C 4 alkyl, methyl or dodecenyl.
  • hydrocarbyl groups contain a chain of 1 to 18 carbon atoms, and preferably one to about 8 carbon atoms.
  • a hydrocarbyloxy group is an ether containing a hydrocarbyl group linked to an oxygen atom.
  • a chiral (optically active) amine containing up to about 25 carbon atoms such as a D- or L-pyrrolidine catalyst is utilized in a contemplated method.
  • the catalyst should be one or the other of the racemates. More usually, that chiral amine catalyst contains about 5 to about 10 carbon atoms.
  • a catalyst is utilized in an amount of about 1 to about 50 mole percent of the amount of the donor aldehyde or ketone, and preferably at about 10 to about 30 mole percent of that reagent.
  • a contemplated catalyst can be utilized with or without an acid co-catalyst.
  • Exemplary acid co-catalysts include 2,4-dinitrobenzenesulfonic acid, acetic acid, (S) - (+) -camphorsulfonic acid and trifluoroacetic acid (TFA) .
  • An excess of the acceptor over the donor molecule is preferably utilized in a contemplated method.
  • the excess utilized can be a minor amount such as about 5 to about 10 mole percent, but is preferably about 1- to about 20-fold over the donor molecule, and more preferably about 5- to about 10- fold of the acceptor over the donor molecule on a molar basis.
  • a synthetic method contemplated herein is carried out in a liquid solvent, and substantially any solvent that is a liquid at a temperature of about -50° C to about 150° C, and more preferably is liquid at a temperature of about zero 0 C to about 50° C, and most preferably is liquid at a temperature of about zero 0 C to about 40° C.
  • Ambient room temperature about 20-25° C is a particularly preferred temperature for carrying out a contemplated method.
  • a contemplated solvent is free of aldehydic, ketonic, acidic or ester carbonyl groups, and can dissolve or disperse the donor, acceptor and catalyst.
  • Illustrative solvents include dimethyl sulfoxide (DMSO) , dimethyl formamide (DMF) , N-methyl pyrrolidinone (MNP), acetonitrile, methanol, iso- propanol, ethanol, diethyl ether, dioxane, methylene chloride, chloroform, poly(ethylene glycol) having an average molecular weight of about 200 to about 1450 and preferably about 200 to about 600, an ionic liquid, water and a combination of one of the above solvents and water.
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • MNP N-methyl pyrrolidinone
  • acetonitrile acetonitrile
  • methanol iso- propanol
  • ethanol diethyl ether
  • a contemplated ionic liquid is molten at a temperature of about -50° C to about 150° C. More preferably, a contemplated ionic liquid is liquid (molten) at or below a temperature of about 120° C and above a temperature of minus 44° C (-44 C) . Most preferably, a contemplated ionic liquid is liquid (molten) at a temperature of about -10° to about 100° C.
  • An ionic liquid is comprised of a cation and an anion.
  • a cation of an ionic liquid is preferably cyclic and corresponds in structure to a formula selected from the group consisting of
  • R 1 and R 2 are independently a C ] _-Cg alkyl group or a C ⁇ -Cg alkoxyalkyl group, and R 3 , R 4 ,
  • R 5 , R 6 , R 7 , R 8 and R 9 when present, are independently a hydrido, a C ⁇ -Cg alkyl, a C ] _-Cg alkoxyalkyl group or a C]--Cg alkoxy group.
  • the "R" groups of the ionic liquids are different from those utilized with donor or acceptor molecules discussed elsewhere herein.
  • the anions of the ionic liquid are those monovalent anions well known to those skilled in chemistry. Illustrative anions include trifluoro- methanesulfonate, trifluoroacetate, tetrafluoroborate
  • hexafluorophosphate PFg "
  • halogen halogen
  • pseudohalogen halogen
  • Preferred anions include tetrafluoroborate and hexafluorophosphate. It is to be noted that there are two iosmeric 1,2, 3-triazoles. It is preferred that all R groups not required for cation formation be hydrido.
  • a cation that contains a single five- membered ring that is free of fusion to other ring structures is a more preferred cation.
  • an imidazolium cation that corresponds in structure to Formula A is particularly preferred, wherein R 1 , R 2 , and R 3 -R 5 , are as defined before.
  • a 1,3-di- (C 1 -C 6 alkyl) -substituted- imidazolium ion is a more particularly preferred cation; i.e., an imidazolium cation wherein R 3 -R ⁇ of
  • Formula A are each hydrido, and R ⁇ and R 2 are independently each a C ] _-Cg-alkyl group or a C 1 -Cg alkoxyalkyl group.
  • R ⁇ and R 2 are independently each a C ] _-Cg-alkyl group or a C 1 -Cg alkoxyalkyl group.
  • a 1- (Ci-Cg-alkyl) -3- (methyl) - imidazolium [C n -mim, where n 1-6] cation is most preferred, and a tetrafluoroborate is a preferred anion.
  • a most preferred cation is illustrated by a compound that corresponds in structure to Formula B, below, wherein R 3 -R 5 of Formula A are each hydrido and R 1 is a C 1 -Cg-alkyl group or a C 1 -Cg alkoxyalkyl group.
  • Exemplary C 1 -Cg alkyl groups and C 1 -C4 alkyl groups include methyl, ethyl, propyl, iso- propyl, butyl, sec-butyl, iso-butyl, pentyl, iso- pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl and the like.
  • Corresponding C 1 -Cg alkoxy groups contain the above Ci-Cg alkyl group bonded to an oxygen atom that is also bonded to the cation ring.
  • An alkoxyalkyl group thus contains an ether group bonded to an alkyl group, and here contains a total of up to six carbon atoms.
  • An anion for a contemplated ionic liquid cation is preferably tetrafluoroborate or hexafluorophosphate ion, although other ions such as a trifluoromethanesulfonate or trifluoroacetate anion, as well as a halogen ion (chloride, bromide, or iodide) , perchlorate, a pseudohalogen ion such as thiocyanate and cyanate or C]--Cg carboxylate.
  • halogen ion chloride, bromide, or iodide
  • Pseudohalides are monovalent and have properties similar to those of halides [Schriver et al. , Inorganic Chemistry, W.H. Freeman & Co., New York (1990) 406-407] .
  • Pseudohalides include the cyanide (CN “1 ) , thiocyanate (SCN “1 ) , cyanate (OCN “1 ) , fulminate (CNO “1 ) and azide (N3 "1 ) anions.
  • Carboxylate anions that contain 1-6 carbon atoms are illustrated by formate, acetate, propionate, butyrate, hexanoate, maleate, fumarate, oxalate, lactate, pyruvate and the like.
  • Contemplated donor and acceptor molecules can be used in the relative amounts dissolved or dispersed in a previously discussed solvent with a chiral amine catalyst as also discussed before.
  • the present invention contemplates a method for asymmetrically forming a beta-hydroxy-alpha- (diprotectedamino)aldehyde or -ketone using an aldol reaction.
  • an alpha- (dipr ⁇ tectedamino) - aldehyde or -ketone donor is reacted with an excess of an alpha-disubstituted (or alpha-branched) aldehyde acceptor dissolved or dispersed in a solvent and in the presence of a chiral amine catalyst such as a D- or L-pyrrolidine to form a reaction medium. That reaction medium is maintained for a time sufficient to form a beta-hydroxy-alpha- (diprotectedamino)aldehyde or -ketone.
  • the protecting groups can be removed once the product is formed, or can be left in place for subsequent steps.
  • the acceptor aldehyde other than formaldehyde is referred to as being "alpha- disubstituted” or “alpha-branched” or ⁇ ⁇ , ⁇ -disubstituted” . That nomenclature is used to indicate that the usually present alpha-carbon of the acceptor molecule is itself bonded to at least two atoms other than hydrogen, which also means that the alpha-carbon is bonded to no more than one hydrogen atom. Thus, acetaldehyde and aldehyde are not acceptor molecules in a reaction contemplated by this embodiment as each as at least two hydrogen atoms bonded to the alpha-carbon.
  • R 1 , R 2 and R 4 all preferably hydrido (H-)
  • the R ⁇ substituent in addition to including the ⁇ -carbon that itself contains one or no hydrogen atoms, further contains one to 29 carbon atoms and is a substituent selected from the group consisting of: a branched chain hydrocarbyl, a cyclic hydrocarbyl, a cyclic hydrocarbyl containing 1 to 3 heteroatoms in the ring, wherein the heteroatoms are oxygen, sulfur and trisubstituted nitrogen atoms, or two of the three heteroatoms, an aryl group as discussed previously, a substituted aryl group wherein the substituent is selected from the group consisting of C ⁇ -Cg straight chain, branched chain or cyclic hydrocarbyl group, halogen, cyano, trifluoromethyl, nitro, C ⁇ -Cg-hydrocarbyloxy and hydroxyl, and a straight chain hydrocarbyl substituted with 1, 2 or
  • (diprotectedamino) aldehyde product can be converted directly into a beta-hydroxy alpha-amino acid without prior isolation or can be isolated (recovered) , purified further if desired and thereafter converted into the amino acid. That conversion can take place by oxidation of the aldehyde to a carboxylic acid using a common oxidation reagent such as NaClC>2/ and deprotection of the amine using a usual reagent for that purpose such as hydrazine for phthalimides, succinimides and maleimides, or acid in the case of t-BOC group. These methods of oxidation and deprotection are well known in this art.
  • the invention contemplates the reaction of an excess of an alpha- (diprotectedamino)aldehyde acceptor is reacted with an alpha-unsubstituted (or alpha-non- branched) aldehyde or ketone donor dissolved or dispersed in a solvent and in the presence of an optically active amine catalyst that contains up to about 25 carbon atoms such as D- or L-pyrrolidine to form a reaction medium. That reaction medium is maintained for a time sufficient to form a ⁇ -hydroxy- ⁇ - (diprotectedamino)aldehyde or -ketone.
  • the ⁇ -hydroxy- ⁇ - (diprotectedamino)aldehyde can be converted directly into a ⁇ -hydroxy- ⁇ -amino acid without prior isolation or can be isolated, purified further if desired and thereafter converted into the amino acid.
  • the acceptor aldehyde molecule can be the same as the donor aldehyde molecule used in the method of preparing a beta- hydroxy-alpha- (diprotectedamino) aldehyde, and the acceptor molecule here can be a ketone or aldehyde that contains at least two hydrogen atoms on a carbon alpha to the carbonyl group.
  • Structural formulas for the acceptor molecules in this embodiment are those discussed for a donor molecule in a before-discussed aldol reaction embodiment, whereas the donor molecules have structural formulas that correspond to those shown below in Table 4.
  • a donor contemplated in this embodiment can contain up to about 18 carbon atoms, preferably 2 to about 6 carbon atoms, and is preferably an aldehyde so that substituent R ⁇ is preferably a hydrido group.
  • a donor here can also be a ketone in which case the donor's R ⁇ substituent can be the same as those shown for R ⁇ below.
  • the R 6 substituent when a donor is a ketone, it is preferred that the R 6 substituent contain no more than one alpha-hydrogen atom; i.e., be ⁇ , ⁇ -disubstituted, and have structure such as those shown f or the R 3 group of an acceptor used in the f irst embodiment as is shown in Table 2 .
  • Another more specific aspect of the present invention contemplates a Mannich reaction using a before-described donor molecule and an unsaturated acceptor molecule that is present as an imine and the product is an ⁇ , ⁇ - (protected-diamino)aldehyde or - ketone.
  • the generalized reaction scheme is illustrated in the Scheme 4 below, wherein Pg and Pg 2 are nitrogen protecting groups that are usually different .
  • R 1 , R 2 and R 4 groups are as described before. However, it is again preferred that R 1 , R 2 and R 4 groups each be hydrido (H-) .
  • C 1 -C 8 ] group a substituted aryl group wherein the substituent is selected from the group consisting of C ⁇ -Cs straight chain, branched chain or cyclic hydrocarbyl group, halogen, cyano, trifluoromethyl, nitro, C ⁇ -Cg hydrocarbyloxy and hydroxyl, and a straight chain hydrocarbyl substituted with 1, 2 or 3 substituents selected from the group consisting of (a) a halogen, (b) a C ⁇ -C 8 - hydrocarbyloxy group, (c) an aryl group as above, or (d) a substituted aryl group as above.
  • R 3 group is an N-protected imidazolyl group
  • a chiral pyrrolidine aldehyde analogue or pyrrolidone aldehyde analogue of Sch 50971,1 can be prepared by reaction of N-phthalimidoglycine aldehyde with an acceptor in which the R 3 group is N-protected imidazolyl (as in an N-trityl-imidazoyl group) and the R ⁇ group is hydrido, followed by removal of the two nitrogen blocking groups and reaction with formaldehyde or dimethyl carbonate to close the pyrrolidine or pyrrolidone ring, respectively.
  • a further specific embodiment of the invention contemplates a Michael addition reaction.
  • a before-describe donor molecule is used and an addition reaction occurs across the double bond of the ethylenically unsaturated acceptor molecule to form an ⁇ -(diprotectedamino) aldehyde or -ketone.
  • the number of carbon atoms in each of the donor and acceptor, exclusive of those in protecting groups, is as before discussed, but the can be arrayed differently here because of the two additional "R” groups. This reaction is illustrated in Scheme 5, below.
  • the R 1 , R 2 and R 4 groups are as described before, and each is again preferably hydrido.
  • the R 3 substituent can be hydrido, but preferably contains 1 about 29, and more preferably 1 to about 20 carbon atoms, and is a substituent selected from the group consisting of: a branched chain hydrocarbyl, a cyclic hydrocarbyl, a cyclic group containing 1 to 3 heteroatoms in the ring, wherein the heteroatoms are oxygen, sulfur and trisubstituted nitrogen atoms, or two of the three heteroatoms, an aryl group as discussed before, a substituted aryl group wherein the substituent is selected from the group consisting of C ⁇ -Cg straight chain, branched chain or cyclic hydrocarbyl group, halogen, cyano, trifluoromethyl, nitro, C]_-C ⁇ hydrocarbyloxy and hydroxyl, and a straight chain hydrocarbyl substituted with 1, 2 or 3 substituents selected from
  • R 3 substituent be an aryl or substituted aryl group in many embodiments, particularly where one of R 7 and R ⁇ is a nitro group.
  • R 7 or R 8 group that is not an electron withdrawing group can be a hydrido group, a substituent containing one to about 20 carbon atoms that is selected from the group consisting of: a branched chain hydrocarbyl, a cyclic hydrocarbyl, a cyclic group containing 1 to 3 heteroatoms in the ring, wherein the heteroatoms are oxygen, sulfur and trisubstituted nitrogen atoms, or two of the three heteroatoms, an aryl group as described before, a substituted aryl group as discussed above wherein the substituent is selected from the group consisting of C ⁇ -Cg straight chain, branched chain or cyclic hydrocarbyl group, halogen, cyano, trifluoromethyl, nitro, C ⁇ -Cg hydrocarbyloxy and hydroxyl, and a straight chain hydrocarbyl substituted with 1, 2 or 3 substituents selected from the group consisting of (a) a halogen, (b) a C ⁇ -Cg hydrocar
  • R 7 and R 8 are not electron withdrawing substituent, it is preferred that the non-electron withdrawing substituent be hydrido.
  • R 3 substituent be an aryl or substituted aryl group, particularly where one of R 7 and R 8 is a nitro group.
  • preferred Michael addition acceptor molecules are cis- and trans- ⁇ -nitro-styrene and their derivatives and analogues.
  • a ⁇ -nitro-styrene derivative has one, two or three substituent groups on the phenyl ring, whereas an analogue compound contains an aryl group as discussed previously herein instead of a phenyl group.
  • trans- ⁇ -Nitro-styrene, some illustrative derivatives and analogues are shown in Table 5, below, wherein "Trt” is trityl and the wavy line indicates the position of the bond.
  • the derivatives can be substituted with one through three substituents selected from the group consisting of Ci-Cs-hydrocarbyl, Ci-Cg-hydrocarbyloxy, trifluoromethyl and halo.
  • NMP N-methylpyrrolidone
  • Aldehyde Compound 1 can be synthesized in large scale in two steps,- reaction of allylamine with phthalic anhydride [See (1) hereinbefore] followed by ozonolysis provides a crystalline product that is stable for at least several months at room temperature.
  • t-Butyloxy- carbonyl- (Boc) and benzoyl-protected glycine aldehyde derivatives were less optimal as donors in this reaction as compared to phthalimidoacetaldehyde
  • Succinimido or maleimido derivatives are similar to the phthalimido derivatives.
  • aldol product Compound 2a was transformed into 3-hydroxyleucine (Compound 5) via oxidation of the aldehyde with NaClO 2 and deprotection of the phthalimide with hydrazine.
  • Aldol product 2a obtained from the L-proline- catalyzed reaction afforded (2S,3S) -Compound 5, t(2) (c) Laib, et al. , J " . Org. Chem. 1998, 63, 1709.
  • Aldehyde reaction partner selection was key in order to assign donor and acceptor roles to aldehydes in the previously discussed aldol reaction.
  • Aldol reactions between Compound 1 and oc-non-branched aldehydes such as isovaleraldehyde and hexanal afforded ⁇ -hydroxy- ⁇ - (diprotected) amino aldehydes Compounds 6 under identical conditions to those used in Table 5 (see, Scheme 10, hereinbelow, wherein R is a non-branched substituent containing at least two hydrogen atoms) . No formation of ⁇ -hydroxy- ⁇ -amino aldehydes was detected. In these instances, aldehyde Compound 1 acted as the acceptor. Slow addition of aldehyde Compound 1 to isovaleraldehyde in the presence of the catalyst did not change the outcome of the reaction.
  • a ⁇ -hydroxy- ⁇ - (diprotected) amino aldehyde of Scheme 10 can be deprotected and oxidized as discussed elsewhere herein to form the corresponding ⁇ -hydroxy- ⁇ -amino acid as is shown in Scheme 10a, below.

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Abstract

L'invention concerne un procédé destiné à former, de manière asymétrique, un produit amino diprotégé qui comprend un centre chiral et dans lequel un énantiomère est présent en excès par rapport à l'autre. Ce procédé consiste à faire réagir une molécule donneuse d'alpha-(amino diprotégé)-aldéhyde ou cétone présentant un excès d'une molécule receveuse insaturée comprenant au maximum un atome d'hydrogène lié à un atome de carbone en position alpha par rapport au carbone de l'insaturation. Les molécules donneuses et receveuses sont dissoutes ou dispersées dans un solvant liquide et sont en présence d'un catalyseur aminé chiral en vue de la formation d'un milieu de réaction de produit d'addition. Le milieu de réaction est conservé pendant une durée suffisante pour former un produit d'α-(amino diprotégé)-aldéhyde ou cétone comprenant un centre chiral formé au niveau d'un atome de carbone lié au groupe α-(amino diprotégé) et dans lequel un énantiomère est présent en excès par rapport à l'autre.
PCT/US2005/029542 2004-08-20 2005-08-19 Reactions asymetriques organocatalytiques directes d'alpha-amino-aldehydes ou -cetones enolisables en vue de la formation de produits amines enantiomeriquement enrichis Ceased WO2006023720A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008115116A (ja) * 2006-11-06 2008-05-22 Nagoya Institute Of Technology α−ヒドロキシ−α−トリフルオロメチル−γ−ラクタム誘導体の製造方法
WO2009039181A3 (fr) * 2007-09-17 2009-07-16 State Of Oregon Acting By & Th Organocatalyseurs à base de sulfonamide et procédé pour leur utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THAYUMANAVAN R. ET AL.: 'Direct Organocatalytic Asymmetric Aldol Reactions of alpha-Amino Aldehydes: Expedient Syntheses of Highly Enantiomerically Enriched anti-beta-Hydroxy-alpha-amino Acids' ORGANIC LETTERS vol. 6, no. 20, 2004, pages 3541 - 3544, XP003006244 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008115116A (ja) * 2006-11-06 2008-05-22 Nagoya Institute Of Technology α−ヒドロキシ−α−トリフルオロメチル−γ−ラクタム誘導体の製造方法
WO2009039181A3 (fr) * 2007-09-17 2009-07-16 State Of Oregon Acting By & Th Organocatalyseurs à base de sulfonamide et procédé pour leur utilisation

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