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Definitions

• This invention relates to the fields of organic synthesis, asymmetric synthesis, catalysis, combinatorial catalysis, organoboron chemistry, combinatorial chemistry and medicinal chemistry. More specifically, the invention relates to methods for preparing chiral amine or amino alcohols used to prepare chiral reagents or catalysts which can be used for the synthesis of many other molecules.
• the present invention Rather than rely on the identification of a globally effective catalyst system, the present invention allows the facile construction of stereochemically pure amine or amino alcohol ligands that are subsequently used to form chiral reagents or catalysts. These can be prepared either individually or as combinatorial libraries and can be used to easily identify the most suitable catalyst for a given transformation.
• a key feature of the present invention is the construction of amine or amino alcohol ligands in one or two steps and in high enantiomeric and diastereomeric purity.
• This invention relates to a practical and effective method for the stereocontrolled synthesis of amines or amino alcohols for the preparation of a large variety of chiral catalysts for asymmetric synthesis.
• This process involves the one-step combination of certain organoboron derivatives, including organoboronic acids, organoboronates and organoborates with primary or secondary amines and certain carbonyl derivatives, such as ⁇ -keto acids, ⁇ -hydroxy aldehydes or carbohydrates.
• This process constitutes a three-component reaction and is suitable for the rapid generation of combinatorial libraries of amine or amino alcohols.
• These products can be converted to chiral reagents or catalysts via a subsequent reaction with an appropriate reagent, which can be present as a fourth component or can be used in a follow-up step.
• An organoboron derivative as defined herein, comprises a compound having a boron atom connected to at least one alkyl, allyl, alkenyl, aryl, allenyl or alkynyl group.
• Alkyl groups of the present invention include straight-chained, branched and cyclic alkyl radicals containing up to about 20 carbons. Suitable alkyl groups may be saturated or unsaturated. Further, an alkyl may also be substituted one or more times on one or more carbons with substituents selected from the group consisting of C1-C6 alkyl, C3-C6 heterocycle, aryl, halo, hydroxy, amino, alkoxy and sulfonyl. Additionally, an alkyl group may contain up to 10 heteroatoms or heteroatom substituents. Suitable heteroatoms include nitrogen, oxygen, sulfur and phosphorous.
• Aryl groups of the present invention include aryl radicals which may contain up to 10 heteroatoms.
• An aryl group may also be optionally substituted one or more times with an aryl group or a lower alkyl group and it may be also fused to other aryl or cycloalkyl rings.
• Suitable aryl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl, pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.
• combinatorial library refers to a set of compounds that are made by the same process, by varying one or more of the reagents.
• Combinatorial libraries may be made as mixtures of compounds, or as individual pure compounds, generally depending on the methods used for identifying active compounds. Where the active compound may be easily identified and distinguished from other compounds present by physical and/or chemical characteristics, it may be preferred to provide the library as a large mixture of compounds.
• Large combinatorial libraries may also be prepared by massively parallel synthesis of individual compounds, in which case compounds are typically identified by their position within an array. Intermediate between these two strategies is “deconvolution”, in which the library is prepared as a set of sub-pools, each having a known element and a random element.
• each sub-pool might be prepared from only a single amine (where each sub-pool contains a different amine), but a mixture of different carbonyl derivatives (or organoboron reagents).
• a sub-pool is identified as having desired activity, it is resynthesized as a set of individual compounds (each compound having been present in the original active sub-pool), and tested again to identify the compounds responsible for the activity of the sub-pool.
• Metal means any metal, metal derivative, or metal substitute useful for performing the a reaction in order to synthesize a reagant or catalyst. Examples include, but are not limited to B, Li, Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce and Yb.
• the first step of this invention involves a novel synthesis of a chiral amine or amino alcohol ligand and the second step involves the conversion of this amine or amino alcohol to a chiral reagent or catalyst.
• the first step is based on the use of organoboron compounds in a C—C bond forming reaction where the electrophile is derived from a carbonyl and an amine and the product is a new substituted amine.
• organoboron compounds in a C—C bond forming reaction where the electrophile is derived from a carbonyl and an amine and the product is a new substituted amine.
• One aspect of the invention is a process for generating chiral amine derivatives of formula (1) or a combinatorial library of molecules of formula (1), by combining compounds (2), (3) and (4):
• R 1 and R 2 are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, acyl, carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, and —YR, where Y is selected from the group consisting of —O—, —NR a —, —S—, —SO—, and —SO 2 —, and R and R a are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and acyl, or R 1 and R 2 together form a methylene bridge of 2 to 20 carbon atoms; and where R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy, amino, alkylamino, dialkylamino, acylamin
• compounds of formula (1) can be subsequently easily transformed to new derivatives.
• removing groups R 1 and R 2 can provide primary amines, while joining two or more groups will result in the formation of cyclic or polycyclic amines.
• the multicomponent nature of the process described in this invention allows the direct and rapid generation of combinatorial libraries of individual products or mixtures of products, by varying the desired substituents.
• Such libraries can be generated either in solution or in the solid phase, upon attachment of one substituent onto a solid support.
• one may couple the amine component (2) to a substrate through either R 1 or R 2 , and react the immobilized amine to a mixture of different organoboron compounds (3), where R 5 is a variety of different groups) and individual or mixed carbonyl compounds (4) to produce a mixture of bound products (1).
• the carbonyl compound may be immobilized, and a mixture of organoboron compounds and diverse amines added.
• Combinatorial libraries may be generated either as individual compounds or as mixtures of compounds.
• an organoboron compound of formula (8) is combined with a preformed iminium derivative (5), aminol (6), or aminal (7), prepared by the combination of an amine (2) and a carbonyl compound (3), or by other methods:
• R 5 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl
• R 6 , R 7 and R 8 are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and heteroaryl, or together form a methylene bridge of 3 to 7 atoms
• X is a positive counter ion
• n is 0 or 1.
• the reaction may be promoted by the addition of a silyl derivative SiR 9 R 10 R 11 R 12 , where R 9 is selected from the groups consisting of: chloro, bromo, iodo, alcoxy, acyloxy, triflate, alkylsulfonate or arylsulfonate, while substituents R 10 , R 11 and R 12 are selected from the groups consisting of: alkyl, cycloalkyl, aryl, alkoxy, aryloxy or chloro.
• a preferred R 5 is an alkenyl or aryl group leading to the formation of geometrically and isomerically pure allylamines or benzylamines (2), respectively.
• reaction can proceed directly in a variety of solvents, including water, alcohols, ethers, hydrocarbons, chlorinated hydrocarbons and acetonitrile.
• the stereochemistry of the product in these reactions can be controlled by the use of a chiral amine, a chiral carbonyl compound or a chiral organoboron derivative (L. Deloux et al., Chem. Rev. (1993) 93:763).
• the use of chiral amines or similar amino alcohol or amino acid derivatives can give products with a high degree of diastereocontrol (up to 99.5% de). Removal of the chiral group substituent can give the free amino acid with a high enantiomeric excess (up to 99.5% ee).
• organoboron compounds that can be used in this manner include compounds (4) that have R 5 selected from the group consisting of alkyl, allyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl, including substituted and isomerically pure derivatives.
• the boron substituents R 6 and R 7 which do not appear in the product (10), are selected from the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted and isomerically pure derivatives.
• Groups R 6 and R 7 may be connected together to form a bridge of 3 to 7 atoms.
• Substituents R 3 in compound (9) are selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, hydroxyamino, alkyl, cycloalkyl, aryl, hetero aryl, including substituted and isomerically pure derivatives.
• Substituents R 4 in compound (9) are selected from the group consisting of hydrogen, carboxy, alkyl, cycloalkyl, aryl., hetero aryl, including substituted and isomerically pure derivatives.
• Substituents R 1 and R 2 in amine (2) are selected from the groups consisting of: alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkylthio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted and isomerically pure derivatives.
• Groups R 1 and R 2 may be connected together to form a bridge of 2 to 20 atoms.
• the reactants are combined in approximately equimolar amounts in the solvent, and maintained at a temperature between about 0° C. and the reflux temperature of the solvent, preferably between about 25° C. and about 65° C., until the reaction is complete.
• the course of the reaction may be followed by any standard method, including thin-layer chromatography, GC and HPLC. In general, the reaction is conducted for about 1 to about 72 hours, preferably about 12 to about 24 hours.
• Product isolation usually gives fairly pure products without the need for chromatography or distillation.
• the products (10) of the invention can be subsequently transformed to produce new derivatives.
• R 3 is hydroxyl
• removing groups R 1 and R 2 can provide primary amino acids, while joining two or more groups will result in the formation of cyclic or polycyclic derivatives.
• a number of amine components (2) can be used which include R 1 and R 2 groups that can be easily removed in subsequent reactions.
• benzylamine derivatives can be cleaved by hydrogenation, while others, such as the di(p-anisyl)methylamino group or the trityl group, can be removed under acidic conditions which prevent facile racemization.
• the multicomponent nature of the process described in this invention allows the direct and rapid generation of combinatorial libraries of the products, by varying the desired substituents.
• Such libraries can be generated either in solution or in the solid phase, upon attachment of one substituent onto a solid support.
• at least one of the, groups R 1 through R 7 is a polymeric material.
• the dicarbonyl compound may be immobilized, and a mixture of organoboron compounds and diverse amines added.
• Combinatorial libraries may be generated either as individual compounds or as mixtures of compounds.
• Substituents R 1 and R 2 in the amino acid component (13) are selected from the group consisting of alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted and isomerically pure derivatives.
• Groups R 1 and R 2 may also be connected to other amino acid units (peptides) or may be connected together to form a bridge of 2 to 20 atoms.
• Groups R 8 and R 9 are selected from the group consisting of alkyl, cycloalkyl, aryl, hetero aryl, acyl and carboxy, including substituted and isomerically pure derivatives.
• Groups R 8 and R 9 may be connected together or with other groups in (13), (9), or (4) to form a bridge of 3 to 7 atoms.
• Substituents R 3 and R 4 in compound (9) are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and heteroaryl.
• the boron substitutent R 5 in (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl.
• the boron substituents R 6 and R 7 which do not appear in the products, are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and heteroaryl, including substituted and isomerically pure derivatives.
• Groups R 1 and R 2 in the amine component (2) are selected from the groups consisting of: alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted and isomerically pure derivatives.
• Groups R 1 and R 2 may be connected together to form a bridge of 2 to 20 atoms.
• Groups R 3 in compound (18) are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl.
• Groups R 3 in compound (18) have at least one carbon atom and are attached to a group XH, where X is selected from a group consisting of —O—, —NR a —, —S—, and R a is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, and acylamino.
• the boron substitutent R 5 in compound (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl.
• the boron substituents R 6 and R 7 which do not appear in the products, are selected from the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted and isomerically pure derivatives.
• Groups R 6 and R 7 may be connected together to form a bridge of 3 to 7 atoms.
• an amine (2) and an organoboron compound (4) are reacted with 1-amino carbonyl derivatives (20) to give directly 1,2-diamines (21).
• Groups R 1 and R 2 in the amine component (2) are selected from the groups consisting of: alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted and isomerically pure derivatives.
• Groups R 1 and R 2 may be connected together to form a bridge of 2 to 20 atoms.
• Groups R 3 , R 4 and R 8 in compound (20) are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl.
• Groups R 9 and R 10 in compound (20) are selected from the group consisting of alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted and isomerically pure derivatives.
• Groups R 9 and R 10 may be connected with other groups in compounds (2), (20) or (4) to form a bridge of 2 to 20 atoms.
• the boron substitutent R 5 in compound (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl.
• the boron substituents R 6 and R 7 which do not appear in the products, are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and heteroaryl, including substituted and isomerically pure derivatives.
• Groups R 6 and R 7 may be connected together to form a bridge of 3 to 7 atoms.
• the products (21) of the invention can be subsequently transformed to produce new derivatives.
• removing groups R 1 and R 2 can provide primary amines, while joining two or more groups will result in the formation of cyclic or polycyclic derivatives.
• a number of amine components (2) can be used which include R 1 and R 2 groups that can be easily removed in subsequent reactions.
• benzylamine derivatives can be cleaved by hydrogenation, while others, such as the di(p-anisyl)methylamino group or the trityl group, can be removed under acidic conditions which prevent facile racemization.
• an amine (2) and an organoboron compound are reacted with an ⁇ -hydroxy carbonyl derivative (22) to give 1,2-amino alcohols (23).
• Compounds (22) can also exist in a hemiacetal form, and can include carbohydrate derivatives.
• the use of chiral derivatives (22) can form products (23) with a very high degree of diastereocontrol (up to greater than 99.5% de) and enantiocontrol diastereocontrol (up to greater than 99.5% ee).
• Groups R 1 and R 2 in the amine component (2) are selected from the group consisting of alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted and isomerically pure derivatives.
• Groups R 1 and R 2 may be connected with other groups in compounds (2), (22) or (4) to form a bridge of 2 to 20 atoms.
• Groups R 3 , R 4 and R 8 in compound (22) are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl.
• the boron substitutent R 5 in compound (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl.
• the boron substituents R 6 and R 7 which do not appear in the products, are selected from the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted and isomerically pure derivatives.
• Groups R 6 and R 7 may be connected together to form a bridge of 3 to 7 atoms.
• the products (23) of the invention can be subsequently transformed to produce new derivatives.
• removing groups R 1 and R 2 can provide primary amines, while joining two or more groups will result in the formation of cyclic or polycyclic derivatives.
• a number of amine components (2) can be used which include R 1 and R 2 groups that can be easily removed in subsequent reactions.
• benzylamine derivatives can be cleaved by hydrogenation, while others, such as the di(p-anisyl)methylamino group or the trityl group, can be removed under acidic conditions which prevent facile racemization.
• R 5 in the organoboron component, such as alkenyl or activated aryl or heteroaryl, followed by oxidative cleavage gives new products where the R 5 is a carbonyl group (aldehyde, ketone or carboxylic acid).
• carbonyl components (22) having a group R 4 or R 8 consisting of a carbon atom attached to a hydroxyl group, as with many carbohydrate derivatives, followed by oxidative diol cleavage can produce new variations of compounds of the general formula (10).
• the second step of this invention involves the reaction of a ligand derived from the first step, for example a compound of formula (1), (10), (11), (12), (14), (15), (16), (17), (19), (21), or (23) with a compound (24) of the general formula M(L)n to give a new chiral reagent or catalyst that contains one or more bonds among M and a heteroatom of the ligand.
• a ligand derived from the first step for example a compound of formula (1), (10), (11), (12), (14), (15), (16), (17), (19), (21), or (23) with a compound (24) of the general formula M(L)n to give a new chiral reagent or catalyst that contains one or more bonds among M and a heteroatom of the ligand.
• the atom M in formula (24) is selected from a group consisting of Li, Mg, B, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce, Yb;
• L is a ligand selected from a group consisting of chloro, bromo, iodo, fluoro, oxo, hydroxy, hydroperoxy, alkoxy, aryloxy, acyloxy, acetoacetyl, carboxy, nitro, amino, alkylamino, dialkylamino, azido, carbonyl, alkyl, alkenyl, dienyl, aryl, triflate, arylsulfonyl; where n is a number selected from 0-6; and where all ligands L are the same or different.
• Typical reagents of formula (24) include, but are not limited to: ZnBr 2 , Ti(OR 4 ), Zr(OR) 4 , YbCl 3 , CrCl 2 , WOCl 4 , FeCl 2 , RuCl 2 , CoCl 2 , NiCl 2 , PdCl 2 , CuCl 2 , ZnCl 2 , AgOTf, BCl 3 , AlCl 3 etc.
• the chiral reagents or catalysts derived during the second step of this invention can be used in a large number of synthetic processes for the preparation of a large variety chiral products. These include: alkylations, aldol reactions, additions of nucleophiles to aldehydes or ketones, additions of nucleophiles to imine derivatives, Diels-Alder reactions, cycloadditions, cyclopropanations, aziridinations, carbonyl reductions, alkene hydrogenations, epoxidations, epoxide opening, etc.
• Combinatorial catalysis The facile synthesis of chiral ligands and chiral catalysts with this invention, allows the rapid preparation of large numbers of variants in the form of combinatorial libraries of catalysts. Such libraries can then be used to identify the optimum catalyst for any particular synthetic transformation. Following the screening of the library of catalysts, the most effective one can be easily prepared in large quantities for scale-up.
• organoboron compounds particularly boronic acids and boronates
• nucleophilic components for amino acid and amine synthesis is a new concept which offers a number of distinct features, including the following:
• Organoboronic acids are often crystalline, easy to prepare and easy to handle compounds that are stable in air and water. They are also non toxic and non hazardous. Although the synthesis and reactivity of these molecules has been studied extensively, the present method is the first successful example of their utilization in the synthesis of amines and amino acids.
• the present method is highly versatile, allowing a high degree of structural variation in all of the reacting components.
• the process is also a multi-component reaction, allowing the one-pot construction of amine derivatives from several readily available building blocks. For these reasons, this method is easily applicable to the solid or liquid phase combinatorial synthesis.
• the stereochemical control of the reaction can be accomplished not only with the use of chiral amine and carbonyl components but also with chiral organoboron derivatives.
• An advantage of boron-based auxiliaries is that they can be easily introduced and can be efficiently recycled after the reaction, thus making this method especially attractive for large scale applications.
• the present invention involving a one-step stereocontrolled synthesis of amino alcohols from readily available starting materials, opens the way for the development of a practical combinatorial catalyst synthesis involving these well-established ligands.
• the invention allows the preparation of potentially large libraries of chiral catalysts with novel structures that may be used to identify the most effective system for a particular asymmetric transformation.

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• 1999
  • 1999-10-22 US US09/425,498 patent/US6602817B1/en not_active Expired - Lifetime
  • 1999-10-22 WO PCT/US1999/024967 patent/WO2000024510A1/en active Application Filing
  • 1999-10-22 AU AU13217/00A patent/AU1321700A/en not_active Abandoned
• 2003
  • 2003-08-04 US US10/633,760 patent/US20040053775A1/en not_active Abandoned

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