WO1998016508A2 - Synthese de composes aromatiques au moyen de la reaction diels-alder sur support solide - Google Patents

Synthese de composes aromatiques au moyen de la reaction diels-alder sur support solide Download PDF

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WO1998016508A2
WO1998016508A2 PCT/US1997/017940 US9717940W WO9816508A2 WO 1998016508 A2 WO1998016508 A2 WO 1998016508A2 US 9717940 W US9717940 W US 9717940W WO 9816508 A2 WO9816508 A2 WO 9816508A2
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dienophile
diene
diels
solid support
alder
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PCT/US1997/017940
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English (en)
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James S. Panek
Bin Zhu
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Trustees Of Boston University
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Priority to AU46074/97A priority Critical patent/AU4607497A/en
Publication of WO1998016508A2 publication Critical patent/WO1998016508A2/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Aromatic compounds e.g., aromatic heterocycles, including N-bearing heterocycles, are important compounds in fields including the agrichemical and pharmaceutical industries.
  • certain substituted pyridines have herbicidal activity (see, e.g., U.S. Patents 5,438,033 and 3,495,969); histamine antagonists (see, e.g., U.S. Patent 5,432,175); fungicides (see, e.g., U.S. Patent 5,185,339); and ferroelectric liquid crystals (see, e.g., U.S. Patent 5,145,601); and as intermediates in synthesis.
  • procedures for rapidly synthesizing and screening aromatic compounds, e.g., aromatic heterocycles for activity are of considerable importance in these and other fields.
  • the invention provides methods for synthesizing aromatic compounds, preferably aromatic heterocycles, e.g., N-bearing aromatic heterocycles.
  • the methods involve reaction of a diene with a dienophile under conditions such that a Diels- Alder reaction occurs, and allowing an aromatic compound, e.g., an aromatic heterocycle, to form, wherein at least one of the diene or dienophile is immobilized to a solid support.
  • the method comprises the steps of contacting an electron- rich dienophile with a diene under conditions such that a Diels-Alder reaction occurs between the diene and the dienophile to form a Diels-Alder adduct and subjecting the Diels-Alder adduct to conditions such that said adduct decomposes to form a solid- supported aromatic heterocycle.
  • the aromatic heterocycle is bound to the solid support through a cleavable linkage, preferably an ester linkage.
  • the method includes the further step of releasing the aromatic heterocycle from the solid support by cleaving the cleavable linkage.
  • the invention provides a method for synthesizing an aromatic heterocycle such a diazine, e.g., an aromatic diazine, e.g., an aromatic 1,2-diazine; or triazine or pyridine.
  • the method includes the steps of reacting an electron-rich dienophile or a tetrazine bound to a solid support, under conditions such that a Diels-Alder reaction occurs between the dienophile and the tetrazine; and allowing the diazine to form.
  • the dienophile is selected from the group consisting of enamines, enol ethers, alkynes and ynamines.
  • the tetrazine is a 1,2,4,5-tetrazine and a 1,2,4-triazine.
  • the invention provides a method for synthesizing a substituted pyridine.
  • the method includes the steps of reacting an electron-rich dienophile and a triazine bound to a solid support under conditions such that a Diels-Alder reaction occurs between the dienophile and the triazine and allowing the pyridine to form.
  • the dienophile is selected from the group consisting of enamines, ynamines, enol ethers and alkynes.
  • the triazine is a 1 ,2,4- triazine.
  • the invention provides a method for synthesizing a library of aromatic heterocycles.
  • the method includes the steps of reacting a dienophile and a diene under conditions such that a Diels-Alder reaction occurs between the diene and the dienophile, wherein the diene comprises a heteroatom, and wherein at least one of the dienophile and the diene is provided as a variegated population; and allowing the library of aromatic heterocycles to form; wherein at least one of the diene and the dienophile is bound to a solid support.
  • the present invention relates generally to methods for synthesizing compounds and libraries of compounds, on a solid support, by use of the Diels-Alder reaction (e.g., inverse-electron demand Diels-Alder reaction) of an immobilized diene or dienophile.
  • Diels-Alder reaction e.g., inverse-electron demand Diels-Alder reaction
  • the inventive methods provide a convenient route to a variety of substituted heteroaromatic compounds.
  • the present invention required development and engineering of chemistry to effectively attach (load) the heterocyclic azadiene system onto the solid support.
  • the present inventors have prepared differentiated 1,2,4,5-tetrazines and 1 ,2,4-triazines and engineered suitable linker technologies to immobilize the diene system to a solid support.
  • solid-supported reactions can differ from the solution-phase counterparts. For example, yields and regio- or stereochemical outcomes of the reactions may differ according to whether the reaction is performed in solution or on a solid support.
  • the present inventors have found conditions suitable for performing versatile Diels-Alder reactions in good yield in solid-supported formats. The successful implementation of this reaction methodology provides new and efficient ways to generate libraries of N-bearing heterocycles in a combinational format.
  • Diels-Alder reaction is art-recognized and refers to a [4+2] cycloaddition reaction between a diene (generally a compound having two conjugated double bonds) and a dienophile (generally a compound having at least one double or triple bond) (for a review, see, e.g., Brieger and Bennett, Chem. Rev. 80, 63-97 (1980)).
  • a Diels-Alder reaction produces a product having a newly-formed six- membered ring, although the product may spontaneously decompose or rearrange to produce a new compound, e.g., by extrusion of nitrogen, elimination and aromatization, and the like.
  • inverse-electron demand Diels-Alder reaction is art recognized and as used herein refers to a Diels-Alder reaction in which the diene partner is electron poor, and the dienophile partner electron rich.
  • Preferred Diels-Alder reactions for use in the invention are inverse-electron demand Diels-Alder reactions.
  • heteroatom is art-recognized and, as used herein, refers to atoms other than carbon and hydrogen. Preferred heteroatoms include, but are not limited to, N, O, P, and S.
  • diene In general, the invention features reaction of a diene with a dienophile.
  • Diels-Alder reactions are known in the art, and/or can be selected by the ordinarily skilled artisan.
  • a diene suitable for use in the methods of the invention can be represented by the one of the structures:
  • R3-R8 are each independently substituent groups.
  • Suitable substitutent groups include hydrogen or a substituted or unsubstituted group such as alkyl (which as used herein includes cycloalkyl), alkenyl, alkynyl, aryl, (including heteroaryl), alkoxyl, amino (including alkylamino, dialkylamino (including cyclic groups such as pyrrolidino), arylamino, and diarylamino), acylamino (including alkylcarbonylamino, alkoxycarbonylamino, arylcarbonylamino, and aryloxycarbonylamino), carboxyl, alkoxycarbonyl, aminocarbonyl, arylcarbonyl, heterocyclyl, cyano, halogen, alkylsulfonyl, arylsulfonyl, and the like.
  • R4 and R 5 taken together with the 4-atom dienyl moiety to which they are attached, can join to form a carbocycle or heterocycle, thereby forming a cyclic diene, which can be aromatic. It will be understood that any of the groups R3-R8 can represent a bond or a linker to a solid support.
  • a diene will be selected according to criteria such as: 1) the reactivity of the dienophile; 2) the reactivity of the diene; 3) the desired structure of the Diels- Alder product; and 4) the availability of the diene (e.g., commercial availability or synthetic accessibility).
  • the diene is selected to be an electron-deficient diene, e.g., at least one of R 3 -R 8 is an electron-withdrawing moiety, i.e., a group which withdraws electron density relative to a hydrogen atom.
  • Electron-withdrawing groups are known in the art and include alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl, arylsulfonyl, cyano, and the like. Dienes having at least one electron-withdrawing group are preferred for inverse-electron demand Diels-Alder reactions.
  • substituents e.g., R3-R8, can be derivatized with removable groups, e.g., protecting groups, to "tune" the electronic characteristics of the diene.
  • the diene is a cyclic compound, e.g., a heterocyclic compound, e.g., a diazine, a triazine, or a tetrazine.
  • the diene is an aromatic compound.
  • the diene is selected such that Diels- Alder reaction of the diene with a dienophile will result in a compound capable of spontaneous extrusion of dinitrogen; accordingly, for example, in certain embodiments, the diene is a 1,2-diazine, a 1,2,4-triazine, or a 1,2,4,5-tetrazine.
  • the diene is selected such that Diels-Alder reaction of the diene with a dienophile will result in a compound capable of spontaneous extrusion of another moiety, e.g., sulfur dioxide, carbon dioxide, or carbon monoxide.
  • a diene can be, e.g., a 1,1-thiophene dioxide, a 2-pyrone, or a cyclopentadienone, respectively. Dienophiles
  • a dienophile suitable for use in the Diels-Alder reactions are known in the art and/or can be selected by the ordinarily skilled artisan.
  • a dienophile can have the structure:
  • each of R9-R12 is independently either a hydrogen or a substituted or unsubstituted group such as alkyl, alkoxy, alkenyl, alkynyl, aryl, (including heteroaryl), alkoxyl, amino (including alkylamino, dialkylamino (including cyclic groups such as pyrrolidino, arylamino, and diarylamino), acylamino (including alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, and aryloxycarbonyl), carboxyl, alkoxycarbonyl, aminocarbonyl, arylcarbonyl, heterocyclyl, cyano, halogen, and the like.
  • a substituted or unsubstituted group such as alkyl, alkoxy, alkenyl, alkynyl, aryl, (including heteroaryl), alkoxyl, amino (including alkylamino, dialkylamino (including cyclic groups such as pyr
  • RjO and R12 taken together with the ethylene moiety to which they are attached, can join to form a carbocycle or heterocycle (preferably having from 4 to 8 atoms in the cyclic moiety), thereby forming a cyclic dienophile.
  • a dienophile can be represented by one of the structures:
  • R9-R1 ] are as defined above (preferably alkyl or aryl) and R13 and R' 53 are independently alkyl, alkenyl, alkynyl, aryl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, and aryloxycarbonyl. It will be understood that any of the groups R9-R13 (in any of the embodiments described above) can represent a bond or a linker to a solid support.
  • a dienophile will be selected according to criteria such as: 1) the reactivity of the dienophile; 2) the reactivity of the diene; 3) the desired structure of the Diels-Alder product; and 4) the availability of the dienophile (e.g., commercial availability or synthetic accessibility).
  • at least one of R9-R12 is an electron-donating group, i.e., a group which releases electron density relative toa hydrogen atom. Examples of electron-donating groups include amino, acylamino, alkoxy, thioalkyl, and the like. Dienophiles having at least one electron- donating group are preferred for inverse-electron demand Diels-Alder reactions.
  • substituents e.g., R 8 -R13
  • R 8 -R13 can be derivatized with removable groups, e.g., protecting groups, to "tune" the electronic characteristics of the dienophile.
  • the groups R9-R12 can be selected such that at least one of the moieties R 9 -R12 can be eliminated (preferably spontaneously under the conditions of the Diels-Alder reaction) from the Diels-Alder product to produce a new product.
  • the initial Diels- Alder reaction is accompanied by extrusion of dinitrogen to produce an initial, non- aromatic heterocycle having a substituent such as a dialkylamino group (e.g., Table 1, entries 8a, b, d, e, and f) an acylamino group (e.g., Table 1, entry 8c), an alkoxy group (e.g., Table 1, entries 8g and h), and the like.
  • a dialkylamino group e.g., Table 1, entries 8a, b, d, e, and f
  • an acylamino group e.g., Table 1, entry 8c
  • an alkoxy group e.g., Table 1, entries 8g and h
  • a dienophile can be a vinylstannane, a vinylsilane, a vinylphosphonate, and the like.
  • the methods of the invention involve the Diels-Alder reaction of a diene with a dienophile, wherein at least one of the diene and the dienophile is immobilized on a solid support.
  • the Diels-Alder adduct i.e., the immediate product of the Diels-Alder reaction
  • the Diels-Alder adduct can have at least two possible structures, depending upon the regioselectivity of the Diels-Alder reaction (if any).
  • the regiochemistry of a Diels-Alder reaction can be affected by such factors as the steric bulk of the diene and the dienophile, and the stereoelectronic nature of the diene and the dienophile.
  • alteration of the steric bulk and/or the stereoelectronic nature of either reaction partner can have an effect on the regiochemical outcome of the Diels- Alder reaction, and may also have an effect on the reaction rate.
  • product (Table 1) 8e with product (Table 2) lOe - the regiochemistry obtained is opposite, presumably due to the differing electronic nature of the dienes and dienophiles employed (i.e., enamine vs. alkyne, and thiomethyl diene vs. sulfonyl diene).
  • Appropriate choice of diene and dienophile can thus affect the product of the reaction, and should be chosen to favor the desired product.
  • the Diels-Alder reaction produces an initial product (or adduct) which is generally not aromatic, but can preferably be aromatized to produce an aromatic compound, e.g., by elimination as described herein.
  • the intermediate Diels-Alder adduct can be aromatized spontaneously under the conditions of the Diels-Alder reaction or conventional workup.
  • the initial Diels-Alder adduct can be manipulated, e.g., further processed, derivatized, or reacted, to produce an aromatic compound.
  • the aromatic products produced according to the methods of the invention are unsubstituted or substituted compounds which include a six-membered aromatic ring.
  • the aromatic compound is a substituted heterocyclic aromatic compound, e.g., a 1,2-diazine, a pyridine, a quinoline, and the like.
  • the aromatic product can be a carbocycle, e.g., a substituted benzene, naphthalene, or the like.
  • the aromatic product can be substituted with any of the groups R3-R13 as defined herein.
  • the nature of the aromatic compound produced by the methods of the invention is determined largely by the diene and dienophile used for the Diels-Alder reaction, together with the reaction conditions employed for the Diels-Alder reaction and aromatization steps.
  • the invention provides methods for synthesizing a variety of unsubstituted or substituted heterocycles, including pyridines, quinolines, diazines, quinazolines, and the like.
  • At least one member of each diene/dienophile pair will be immobilized on a solid support. Accordingly, a diene or dienophile can be immobilized on a solid support through a direct bond to the support, or through a linker or spacer arm to the support.
  • a linker arm where employed, can conveniently be attached to, and/or cleaved from, the diene or dienophile and/or the solid support (i.e., is a cleavable linker), preferably under mild conditions, to permit the immobilization of a diene or dienophile on the solid support, and the ready detachment of a product from the solid support, without causing undesirable side reactions of, e.g., the diene, dienophile, product, or solid support.
  • linkers which may find use in the invention are known in the art, e.g., for the solid-phase synthesis of peptides or the combinatorial synthesis of non-peptide organic molecules.
  • reaction temperature influences the speed of the reaction, as well as the stability of the reactants and catalyst.
  • the reactions will usually be run at temperatures in the range of -78°C to 100°C, more preferably in the range -20°C to 50°C and still more preferably in the range -20°C to 25°C.
  • the reactions according to the invention will be performed in a solvent, e.g., in solution or suspension.
  • the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, optionally including the polymeric support, are substantially soluble.
  • Suitable solvents include ethers such as diethyl ether, 1 ,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or
  • a solvent that is not inert to the substrate under the conditions employed, e.g., use of ethanol as a solvent when ethanol is desired as a reactant.
  • the reactions can be conducted under anhydrous conditions.
  • ethereal solvents e.g., diethyl ether, tetrahydrofuran (THF), dioxane, dimethoxyethane, and the like.
  • the reaction conditions are selected to permit isolation or purification of the Diels-Alder product, or a product resulting from rearrangement of the Diels-Alder adduct.
  • a soluble polymeric support conjugated to a Diels- Alder product can be precipitated by the addition of an inert nonsolvent, and the precipitate washed with an inert nonsolvent to remove, or reduce the amount of, impurities and unreacted materials.
  • an insoluble polymeric support conjugated to a Diels-Alder product can be separated from a reaction mixture by, e.g., filtration, and washed to remove, or reduce the amount of, impurities and unreacted materials (see, e.g., Example 1).
  • the purified polymeric-support-bound product can then be further reacted or processed, if desired.
  • catalysts such as Lewis acid catalysts, including, e.g., boron trifluoride etherate, aluminum chloride, SnCl 4 , and the like. Accordingly, the invention contemplates the use of catalysts in the Diels-Alder reaction, where appropriate.
  • solid support refers to a solid or insoluble moiety suitable for immobilization of a compound, and further reaction or purification of the immobilized compound.
  • Immobilization of a compound (e.g., a diene or a dienophile) to a solid support can be covalent or non-covalent (e.g., ionic, hydrophobic, magnetic, etc.).
  • the compound is immobilized to a solid support through a covalent bond.
  • the solid support is a polymeric support.
  • the solid support is in the form of discrete particles, e.g., polymer beads, although, as described herein, methods for attachment of a library of compounds to a spatial array on a surface or on supports such as polystyrene pins are known in the art and are contemplated for use in the methods and compositions of the invention.
  • Polymeric supports with appropriate functional groups are known in the art and can be prepared by known techniques.
  • polymers including the carboxylic acid chloride functionality e.g., -COC1 are known (see, e.g., P. Hodge and D.C. Sherrington, "Polymer-supported Reactions in Organic Synthesis", Chapter 1, (1980)) and can be prepared by treatment of conventional polymer-supported carboxylic acids (e.g., polyacrylic acids) with, e.g., thionyl chloride, oxalyl chloride, and the like.
  • Polymeric supports including sulfonyl chloride functionalities can be obtained by the reaction of a polymer including sulfonic acid moieties (e.g., -SO3H) with, e.g., thionyl chloride, or by other known methods, for example, the method described in U.S. Patent 5,118,766.
  • Benzyl halide-containing polymers are well known and include chloromethylated polystyrene (e.g., Merrifield resin).
  • the polymeric support be easily recyclable.
  • the polymeric support can be regenerated and reused.
  • Soluble polymeric supports include functionalized polymers based on polyvinyl alcohol or polyethylene glycol (PEG).
  • a soluble support can be made insoluble (e.g., can be made to precipitate) by addition of a suitable inert nonsolvent.
  • One advantage of reactions performed using soluble polymeric supports according to the invention is that reactions in solution can be more rapid, higher yielding, and/or more complete than reactions that are performed on insoluble polymeric supports.
  • Insoluble polymeric supports include functionalized polymers based on polystyrene, polystyrene/divinylbenzene copolymers, and other polymers known to the skilled artisan.
  • Non-resin-based solid supports include silica, functionalized silica, and the like; many silica-derived supports are commercially available.
  • the invention provides methods for synthesizing aromatic compounds, preferably aromatic heterocycles, e.g., N-bearing aromatic heterocycles.
  • the methods involve reaction of a diene with a dienophile under conditions such that a Diels-Alder reaction occurs, and allowing an aromatic compound, e.g., an aromatic heterocycle, to form, wherein at least one of the diene and dienophile is immobilized to a solid support.
  • the diene is immobilized on the solid support.
  • the diene comprises a heteroatom; in certain embodiments, the diene is a heterocycle.
  • the method comprises the steps of contacting an electron-rich dienophile with a diene under conditions such that a Diels-Alder reaction occurs between the diene and the dienophile to form a Diels-Alder adduct and subjecting the Diels-Alder adduct to conditions such that said adduct decomposes to form a solid- supported aromatic heterocycle.
  • the diene comprises a heteroatom; in preferred embodiments, at least one of the diene and the dienophile is bound to a solid support.
  • the step of decomposing the Diels- Alder adduct comprises heating the Diels-Alder adduct.
  • the decomposing step comprises eliminating from the Diels-Alder adduct a leaving group selected from the group consisting of alcohols and amines.
  • the aromatic heterocycle is bound to the solid support through a cleavable linkage, preferably an ester linkage.
  • the method includes the further step of releasing the aromatic heterocycle from the solid support by cleaving the cleavable linkage.
  • the invention provides a method for synthesizing a substituted pyridine.
  • the method includes the steps of reacting an electron-rich dienophile and a triazine bound to a solid support under conditions such that a Diels-Alder reaction occurs between the dienophile and the triazine and allowing the pyridine to form.
  • the dienophile is selected from the group consisting of enamines, ynamines, enol ethers and alkynes.
  • the triazine is a 1,2,4- triazine.
  • the invention provides a method for synthesizing a diazine, e.g., an aromatic diazine, e.g., an aromatic 1,2-diazine.
  • the method includes the steps of reacting an electron-rich dienophile and a tetrazine, wherein either the dienophile or the tetrazine is bound to a solid support, under conditions such that a Diels-Alder reaction occurs between the dienophile and the tetrazine; and allowing the diazine to form.
  • the dienophile is selected from the group consisting of enamines, enol ethers and alkynes.
  • the tetrazine is a 1,2,4,5-tetrazine.
  • the invention provides a method for synthesizing a library of aromatic heterocycles.
  • the method includes the steps of reacting a dienophile and a diene under conditions such that a Diels-Alder reaction occurs between the diene and the dienophile, wherein the diene comprises a heteroatom, and wherein at least one of the dienophile and the diene is provided as a variegated population; and allowing the library of aromatic heterocycles to form; wherein at least one of the diene and the dienophile is bound to a solid support.
  • variant population refers to a population including at least two different chemical entities, e.g., of different chemical structure.
  • a "variegated population" of dienophiles would comprise at least two different dienophiles.
  • a variegated population of dienes comprises at least two different dienes.
  • a "variegated population” can be employed in the combinatorial synthesis methods described above, e.g., as a mixture of compounds undergoing reaction in a single vessels, or as individual compounds employed in a plurality of reactions in a plurality of vessels.
  • the Diels-Alder adduct, and, preferably, the aromatic product are synthesized while immobilized on a solid support.
  • the Diels-Alder adduct and/or the aromatic product can be readily processed, e.g., washed, purified, filtered, and the like, by methods known in the art, e.g., filtration and other physical separations.
  • This has the advantage of easily providing purified compounds with expensive and time-consuming steps such as chromatography, crystallization, and the like (although, of course, such techniques can be used to purify compounds which have been cleaved from the solid support).
  • the invention features substituted aromatic compounds (e.g., N-bearing heteroaromatic compounds); libraries of substituted aromatic compounds (e.g., N-bearing heteroaromatic compounds); methods for synthesizing aromatic compounds (e.g., N-bearing heteroaromatic compounds); and methods of synthesizing libraries of substituted aromatic compounds (e.g., N-bearing heteroaromatic compounds).
  • substituted aromatic compounds e.g., N-bearing heteroaromatic compounds
  • libraries of substituted aromatic compounds e.g., N-bearing heteroaromatic compounds
  • methods for synthesizing aromatic compounds e.g., N-bearing heteroaromatic compounds
  • methods for synthesizing aromatic compounds e.g., N-bearing heteroaromatic compounds
  • methods of synthesizing aromatic compounds e.g., N-bearing heteroaromatic compounds
  • synthesizing libraries of substituted aromatic compounds e.g., N-bearing heteroaromatic compounds
  • the invention provides a library of aromatic heterocycles represented by the formula S-L-A, in which S is a solid support; L is absent or, if present, is a linking moiety; A is an aromatic heterocyclyl moiety.
  • the solid support can be a polymer resin.
  • the aromatic heterocyclyl moiety is selected from the group consisting of pyridyl, 1 ,2-diazinyl, 1,3-diazinyl, and 1,4- diazinyl.
  • combinatorial libraries are well known in the art and has been reviewed (see, e.g., E.M. Gordon et al., J. Med. Chem. 37:1385-1401 (1994)).
  • the subject invention contemplates methods for synthesis of combinatorial libraries of compounds (e.g., aromatic compounds, e.g., N-bearing aromatic heterocycles).
  • Such libraries can be synthesized according to a variety of methods.
  • a "split- pool" strategy can be implemented in the following way: beads of a functionalized polymeric support are placed in a plurality of reaction vessels. To each aliquot of beads is added a solution of a different diene (or dienophile), appropriately functionalized
  • a "diversomer library” is created by the method of Hobbs DeWitt et al. (Proc. Natl. Acad. Sci. U.S.A. 90:6909 (1993)).
  • Aliquots of functionalized polymeric support beads are placed in an array of reaction vessels, and one of a plurality of dienes (or dienophiles), having a reactive group suitable for reaction with, and immobilization to, the solid support, is introduced into each vessel. After reaction, the beads are washed to yield an array vessels containing polymer- supported dienes (or dienophiles). Each vessel in the array is then reacted with one of a plurality of dienophiles (or dienes). After Diels-Alder reaction, purification and workup yields a soluble library of substituted Diels-Alder products.
  • synthesis methods including the "tea-bag” technique of Houghten (see, e.g., Houghten et al., Nature 354:84-86 (1991)) can also be used to synthesize libraries of compounds according to the subject invention.
  • Combinatorial libraries can be screened to determine whether any members of the library have a desired activity, and, if so, to identify the active species. Methods of screening combinatorial libraries have been described (see, e.g., Gordon et al., J Med. Chem., op. cit.).
  • Soluble compound libraries can be screened by affinity chromatography with an appropriate receptor to isolate ligands for the receptor, followed by identification of the isolated ligands by conventional techniques (e.g., mass spectrometry, NMR, and the like).
  • Immobilized compounds can be screened by contacting the compounds with a soluble receptor; preferably, the soluble receptor is conjugated to a label (e.g., fluorophores, colorimetric enzymes, radioisotopes, luminescent compounds, and the like) that can be detected to indicate ligand binding.
  • a label e.g., fluorophores, colorimetric enzymes, radioisotopes, luminescent compounds, and the like
  • immobilized compounds can be selectively released and allowed to diffuse through a membrane to interact with a receptor.
  • Combinatorial libraries of compounds can also be synthesized with "tags" to encode the identity of each member of the library (see, e.g., W.C. Still et al., PCT Publication No. WO 94/08051).
  • this method features the use of inert, but readily detectable, tags, that are attached to the solid support or to the compounds.
  • the identity of the compound is determined by identification of the unique accompanying tag.
  • This tagging method permits the synthesis of large libraries of compounds which can be identified at very low levels.
  • the libraries of aromatic e.g., heteroaromatic, e.g.,
  • N-bearing heteroaromatic) compounds of the invention contain at least 30 compounds, more preferably at least 100 compounds, and still more preferably at least 500 compounds.
  • the libraries of N-bearing aromatic compounds of the invention contain fewer than 10 ⁇ compounds, more preferably fewer than 10 ⁇ compounds, and still more preferably fewer than 10? compounds. The invention is further illustrated by the following non-limiting examples.
  • This reaction constructs functionalized 1 ,2-diazines which can display a high degree of a functional group diversity.
  • the process should be readily adaptable to the preparation of small molecule libraries of N-bearing heterocycles that project functional group diversity displayed in an array of 180°, i.e., at four consecutive positions on the aromatic ring.
  • Scheme 1 The preparation of immobilized dienes is summarized in Scheme 1 , and utilized the readily available 3,6-bis(thiomethyl)-l,2,4,5-tetrazine 2 (see, e.g., Boger, D.L.; Sakya, S.M. J.Org. Chem. 1988, 53, 1415-1423).
  • the tetrazine 2 was selected, at least in part, based on its easily replaceable thiomethyl groups, which provide easy access to suitable linkers as well as other functional groups at the C-3 and C-6 positions (see, e.g., Barlin, G.B.; Brown, W.V. J. Chem. Soc. (C) 1967, 2473-2476).
  • Carboxylated polystyrene resin 1 was prepared from Polystyrene-CO2H (commercially available from Advanced ChemTech) with excess of (COCl)2 (4.0 equiv) refluxing in dry benzene for 12 h. The resulting resin was washed with dry benzene under argon and dried in vacuo to afford the acid chloride 1 as a light brown colored solid (PS indicates the polymeric support).
  • the tetrazine nucleus was next covalently linked to carboxylated polystyrene 1 through its acid chloride (cat. 4-dimethylaminopyridine (DMAP), Et 3 N, CH 2 C1 2 , rt, 48 h) to afford the immobilized amino tetrazine 4.
  • DMAP 4-dimethylaminopyridine
  • Et 3 N CH 2 C1 2 , rt, 48 h
  • This material was made more electron deficient by the acylation of the secondary amine with (Boc) 2 O (4 equiv, cat.
  • Cyclic ketone the pyrrolidino enamines were prepared in benzene with the aid of azeotropic removal of water (cf. Stork, G.; Brizzolara, A.; Austinman, H.; Szmuszkovic, J.; Terrel, R. J.Am. Chem. Soc. 1963, 85, 207-222),
  • Acyclic ketone the enamines were prepared in ethyl ether with the aid of 4- A molecular sieves, (cf. Taguchi, K.; Westheimer, F.H. J. Org. Chem.
  • Table 2 illustrates the variety of 3-amino-6-sulfonylmethyl-l,2-pyridazines that were synthesized in this reaction.
  • Regioselectivity was achieved in the reactions of both 5 and 6, which was resulted from the difference of the electron withdrawing ability between the tetrazines two substituted groups.
  • the more electron-rich end of the dienophile tends to attach to the more electron-deficient carbon of the tetrazine.
  • the electron withdrawing ability is -SO 2 Me > -NBoc > -SMe
  • the conversion of SMe to SO 2 Me inverts the electron deficiency at carbons in 5 and 6 (from C-3 in 5 to C-6 in 6), turning over the regiochemical course of the reactions of 5 and 6.
  • the preparation of the immobilized triazine 15 is summarized in Scheme 4, and utilized the readily available dimethyl l,2,4-triazine-3-thiomethyl-5,6-carboxylate 12 (Benson, S.C.; Lee, L.; Snyder, J.K. Tetrahedron Lett. 1996, 37, 5061-5064).
  • the choice of triazine 12 is based on its easily replaceable thiomethyl group which provides easy access to other functional groups at the C-3 position. Nucleophilic aromatic substitution of the thiomethyl group with amino-ethanol (1.2 equiv., EtOH, rt, 12 h) afforded triazine 13 in 90% yield bearing the four-atom tether.
  • Carboxylated resin 11 was prepared from polystyrene-CO 2 H (commercially available from Advanced ChemTech) with excess of (COCl) 2 (4.0 equiv) refluxing in dry benzene for 12 h. The resulting resin was washed with dry benzene under argon and dried in vacuo to afford the acid chloride 11 as a light brown colored solid. The triazine nucleus was covalently linked to resin 11 through its acid chloride (cat. DMAP, Et 3 N, CH 2 C1 2 , rt, 48 h) to afford the immobilized amino triazine 14.
  • This material was made more electron deficient by the acylation of the secondary amine with (Boc) 2 O(4 equiv, cat, DMAP, THF, rt, 16 h) producing the fully elaborated, immobilized triazine complex 15 as a yellow solid.
  • azadiene complex 15 was reacted with various electron-rich olefins in dioxane at room or elevated temperature to give the resin-bound cycloaddition-aromatization product 16.
  • the Boc group of 16 was removed with 25% TFA in CH 2 C1 2 before the product 17 was cleaved from the solid support by base hydrolysis (K 2 CO 3 , 1 :2 MeOH-THF) (Scheme 5).
  • Example 3 An exemplary procedure for Diels-Alder reaction of a diene (e.g., a triazine) immobilized on solid support is as follows: the reactions of 15 were performed with 50 mg of resin using 10-20 equivalent of dienophile in 4.0 mL dioxane or chloroform for 24 h (r.t. or reflux). The resin was washed with CH2CI2 (3 x 5.0 mL) to afford 16 which was then stirred slowlyin 4 mL 1 :3 CF3CO2H-CH2CL2 for 1.5 h at room temperature.
  • a diene e.g., a triazine
  • An exemplary procedure for Diels-Alder reaction of an immobilized tetrazine is as follows: a solid supported 3-amino-6-thiomethyl-l,2,4,5-tetrazine (50 mg diene- functionalized resin, 0.077 mmol) was reacted with 10 equivalents of dienophile in a suitable solvent (e.g., dioxane) (4.0 mL) for 24 hours. Temperature for the reaction ranged from room temperature to reflux temperature, depending on the reactivity of the diene and dienophile). The resin was then washed with dioxane (3 x 5.0 mL) and methylene chloride (3 x 5.0 mL), to remove impurities.
  • a suitable solvent e.g., dioxane
  • the resin-bound heterocyclic product was then stirred in 2.5. mL of 1 :4 trifluoroacetic acid:methylene chloride for 1 hour at room temperature, to remove the Boc protecting group.
  • the resin was then washed with methylene chloride (3 x 5.0 mL) and 1 :2 MeOH:THF (2 x 5.0 mL), and then gently stirred in 3.0 mL of MeOH:THF of potassium carbonate for 12 hours to cleave the product from the resin.
  • the mixture was filtered and the filtrate extracted with ethyl acetate.
  • the organic phase was concentrated to dryness to afford the heterocyclic product.

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Abstract

L'invention se rapporte à des méthodes de synthèse de composés aromatiques, par exemple d'hétérocycles aromatiques, au moyen de la réaction Diels-Alder sur un support solide. L'invention concerne également des composés immobilisés sur des supports solides et des bibliothèques de composés.
PCT/US1997/017940 1996-10-02 1997-10-01 Synthese de composes aromatiques au moyen de la reaction diels-alder sur support solide WO1998016508A2 (fr)

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WO2001023887A1 (fr) * 1999-09-29 2001-04-05 Lion Bioscience Ag Derives de 2-aminopyridine et bibliotheques combinatoires
US7172905B2 (en) 2001-08-07 2007-02-06 The University Of Chicago Polypeptide immobilization
EP1867638A1 (fr) * 2006-06-16 2007-12-19 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Procédé pour le lien de deux molécules par une réaction Diels-Alder avec une demande d'électron inverse
JP2008528447A (ja) * 2004-12-31 2008-07-31 レディ ユーエス セラピューティックス， インコーポレイテッド Ｃｅｔｐインヒビターとしての新規ベンジルアミン誘導体
US7592451B2 (en) 2005-06-23 2009-09-22 New York University Treatment for diabetes and obesity as well as method of screening compounds useful for such treatments
US7718655B2 (en) 2001-10-12 2010-05-18 New York University Trisubstituted triazine compounds, and methods for making and using the compounds, which have antitubulin activity
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US6458789B1 (en) 1999-09-29 2002-10-01 Lion Bioscience Ag 2-aminopyridine derivatives and combinatorial libraries thereof
WO2001023887A1 (fr) * 1999-09-29 2001-04-05 Lion Bioscience Ag Derives de 2-aminopyridine et bibliotheques combinatoires
US7172905B2 (en) 2001-08-07 2007-02-06 The University Of Chicago Polypeptide immobilization
US9074300B2 (en) 2001-08-07 2015-07-07 The University Of Chicago Polypeptide immobilization
US7888055B2 (en) 2001-08-07 2011-02-15 The University Of Chicago Polypeptide immobilization
US7718655B2 (en) 2001-10-12 2010-05-18 New York University Trisubstituted triazine compounds, and methods for making and using the compounds, which have antitubulin activity
JP2008528447A (ja) * 2004-12-31 2008-07-31 レディ ユーエス セラピューティックス， インコーポレイテッド Ｃｅｔｐインヒビターとしての新規ベンジルアミン誘導体
US7592451B2 (en) 2005-06-23 2009-09-22 New York University Treatment for diabetes and obesity as well as method of screening compounds useful for such treatments
JP2009539911A (ja) * 2006-06-16 2009-11-19 ドイチェス クレープスフォルシュングスツェントルム 逆電子要求性ディールズ・アルダー反応を伴う２つの分子の共有結合方法
WO2007144200A1 (fr) * 2006-06-16 2007-12-21 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Procédé de liaison covalente de deux molécules par réaction de diels-alder avec demande inverse d'électrons
US8552183B2 (en) 2006-06-16 2013-10-08 Deutsches Krebsforschungszentrum Stiftung Des Offentlichen Rechts Process for the covalent coupling of two molecules by means of a diels-alder reaction with inverse electron requirement
EP1867638A1 (fr) * 2006-06-16 2007-12-19 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Procédé pour le lien de deux molécules par une réaction Diels-Alder avec une demande d'électron inverse
WO2021007101A1 (fr) * 2019-07-05 2021-01-14 Medimmune, Llc Procédé et molécules
CN114127033A (zh) * 2019-07-05 2022-03-01 免疫医疗有限责任公司 方法和分子
CN110563663A (zh) * 2019-10-28 2019-12-13 南京红杉生物科技有限公司 一种伐地考昔及其合成方法

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