MX2007008974A

MX2007008974A - Synthesis of aryl pyrrolidones.

Info

Publication number: MX2007008974A
Application number: MX2007008974A
Authority: MX
Inventors: David Woodmansee; Ha-Soon Choi; Zhicheng Wang; Yun He; Baogen Wu; Truc Nguyen
Original assignee: Irm Llc
Priority date: 2005-01-28
Filing date: 2006-01-30
Publication date: 2007-09-18
Also published as: WO2006081562A3; CA2593816A1; AU2006209241A1; BRPI0607294A2; KR100890696B1; WO2006081562A2; CN101111246A; KR20070097555A; JP2008528625A; EP1841424A4; EP1841424A2; RU2007132260A; AU2006209241B2

Abstract

The invention provides methods of asymmetrically synthesizing aryl pyrrolidones with high yield and high enantionmeric excess.

Description

SYNTHESIS OF ARIL-PYRROLIDONES FIELD OF THE INVENTION The present invention relates in general to processes for the asymmetric synthesis of aryl pyrrolidones, such as the aryl pyrrolidones useful as intermediates in the production of HIV inhibitors. BACKGROUND OF THE INVENTION Aryl pyrrolidones of the type shown below are currently being studied as antiviral agents, for example HIV inhibitors, in clinical settings. Clinical trials and New Drug Application (NDA) presentations require a practical large-scale synthesis of the active drug.

Accordingly, it is desirable to find new synthetic processes for the preparation of aryl pyrrolidones. Because these pyrrolidones contain at least one chiral center, an asymmetric synthesis scheme that produces the above compound in a high yield and in a high enantiomeric excess ("ee") is preferred.

The asymmetric synthesis of aryl-piperidinones has been previously reported, Senda et al., J. Org. Chem., 66: 6852-6856 (2001) ("Path"). However, to date, the asymmetric synthesis of aryl pyrrolidones has not been reported. An asymmetric synthesis that produces a high enantiomeric excess of a desired enantiomer would represent a significant advance in this field. BRIEF DESCRIPTION OF THE INVENTION In a first aspect, the invention provides an asymmetric synthesis method. The product of this synthesis may be a heterocycle containing amide or a pharmaceutically acceptable salt thereof. The method comprises contacting an organometallic complex of rhodium (I), a chiral ligand, a heterocycle containing α, β-unsaturated amide, and a boronic ester, under conditions sufficient to form a mixture comprising a heterocycle containing amide and its enantiomer, thereby synthesizing asymmetrically the amide-containing heterocycle or the pharmaceutically acceptable salt thereof. This mixture has an enantiomeric excess of about 60 percent or greater. In a second aspect, the invention provides a mixture comprising a heterocycle containing amide and its enantiomer. In an exemplary embodiment, the heterocycle containing α, β-unsaturated amide has a structure according to the Formula wherein R1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aplo, and substituted or substituted hetero-substituted R2, R3, and R4 are each independently selected from starting from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or substituted heterocycloalkyl, substituted or substituted substituted heterolalk, substituted or unsubstituted heteroapyl, OR5a, NO2, CN, halogen, C (O) R5b, NR5aR5b, C (O) NR5aR5b and C (O) OR5b R5a is H or substituted or substituted alkyl R5b is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aplo, and substituted or unsubstituted heteroapyl An exemplified boronic ester has an unsubstituted or substituted with Formula II (ii) where R6 is aplo substituted or unsubstituted, or hetero replaced or unsubstituted. R7 and R8 are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR10, NO2 , CN, and halogen. R7 and R8, taken together with the oxygen atoms with which they are attached, can also optionally form a substituted or unsubstituted ring of 5 to 8 members. R10 is H or substituted or unsubstituted alkyl.

[0001] The present invention presents several advances in this field. An advance is the first asymmetric synthesis of a 5-member aryl-lactam. The only asymmetric synthesis previously known in this field was of the 6-member aryl-lactams, as reported in Senda. It should be noted that the reaction conditions for the 6-membered aryl-lactams are not always similar to the 5-membered aryl-lactams. For example, in Path, when a 6-membered N-benzyl-lactam substrate was reacted with an aryl fraction, yields of up to 75 percent were recorded. Surprisingly, for the 5-membered aryl-lactams, a 5-membered N-benzyl-lactam substrate only produces a 35 percent yield. When the benzyl group was replaced by a phenyl group, the reaction yield jumped from 35 percent to approximately 80 percent.

DETAILED DESCRIPTION OF THE INVENTION AND MODALITIES I. Definitions

[0002] The symbol rw ^, either used as a link, or displayed perpendicular to a link, indicates the point at which the fraction exhibited joins the rest of the link. the molecule, the solid support, etc. Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention, and are intended to be within the scope of the present invention. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. The compounds of the invention can be prepared as a single isomer (e.g., enantiomer, cis-trans, position, diastereomer), or as a mixture of isomers. In a preferred embodiment, the compounds are prepared as substantially a single isomer Methods for preparing substantially isomerically pure compounds are known in the art. For example, enantiomerically enriched mixtures and pure enantiomeric compounds can be prepared using synthetic intermediates that are enantiomerically pure in combinations with reactions that leave the stereochemistry in a chiral center unchanged, or that result in its complete inversion. Alternatively, the final product or intermediates along the synthetic route can be resolved into a single stereoisomer. Techniques for reversing or leaving unchanged a particular stereocenter, and those for solving mixtures of stereoisomers, are well known in the art, and it is well within the ability of one skilled in the art to choose an appropriate method for a particular situation. See, in general, Furniss et al., (Editors), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5A EDITION, Longman Scientific and Technical Ltd., Essex, 1991, pages 809-816; and Heller, Acc. Chem. Res. 23: 128 (1990). The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that make up these compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125l) or carbon-14 (14C). It is intended that all isotopic variations of the compounds of the present invention, whether radioactive or not, be encompassed within the scope of the present invention.

Where substituent groups are specified by their conventional chemical formulas, written from left to right, they also encompass the chemically identical substituents, which would result from writing the structure from right to left, for example, -CH2O- also means -OCH2-. The term "alkyl," by itself or as part of another substituent, means, unless otherwise mentioned, a straight or branched chain, or cyclic hydrocarbon radical, or a combination thereof, which may be fully saturated, mono- or poly-unsaturated, and may include di- and multi-valent radicals, with the designated carbon atom number (ie, C -? - C10 means from one to ten carbon atoms). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, normal butyl, tertiary butyl, isobutyl, secondary butyl, cyclohexyl, (cyclohexyl) -methyl, cyclopropyl-methyl, homologs and isomers of, for example, normal pentyl, normal hexyl, normal heptyl, normal octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of the unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl , 1- and 3-propynyl, 3-butynyl, and homologs and higher isomers. The term "alkyl," unless otherwise noted, is also intended to include the alkyl derivatives defined in greater detail below, such as "heteroalkyl" Alkyl groups that are limited to hydrocarbon groups are referred to as "hoalkyl". The term "alkylene", by itself or as part of another substituent, means a divalent radical derived from an alkane, as exemplified, but not limited, by -CH2CH2CH2CH2-, and further includes the groups described below as "hetero-alkylene." Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, which generally has eight or fewer carbon atoms. The terms "alkoxy" "alkylamino" and "thioalkyl" (or thioalkoxy) are used in their conventional sense, and refer to the alkyl groups attached to the rest of the molecule by means of a carbon atom, an amino group, or a sulfur atom, respectively.

The term "heteroalkyl", by itself or in combination with another term, means, unless otherwise mentioned, a straight or branched chain, or cyclic, stable hydrocarbon radical, or combinations thereof, which consists of the number of carbon atoms mentioned, and at least one heteroatom selected from the group consisting of O, N, Si, and S, and wherein the nitrogen or sulfur atoms may optionally be oxidized, and the nitrogen heteroatom optionally can be quaternized. The heteroatoms O, N, S, and Si can be placing in any internal position of the hetero-alkyl group, or in the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3 > -CH2-S-CH2-CH3, -CH2-CH2, -S (O) -CH3, -CH2-CH2-S (O) 2 -CH3, -CH = CH-O-CH3, Si (CH3) 3, -CH2-CH = N-OCH3, and -CH = CH-N (CH3) -CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3. In a similar manner, the term "hetero-alkylene", by itself or as part of another substituent, means a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CH2-CH2-S- CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For the hetero-alkylene groups, the heteroatoms may also occupy either or both of the chain terms (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for the alkylene and hetero-alkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (O) 2R'- represents both -C (O) 2R'- and -R'C (O) 2-. The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise mentioned, the cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle joins the rest of the molecule. The examples of Cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydro-pyridyl), 1-piperidinyl, 2-piperidinyl, 3-pipe ridinyl, 4-morpholinyl, 3-morpholinyl. , tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "halo" or "halogen", by themselves or as part of another substituent, mean, unless otherwise mentioned, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "haloalkyl (1-4 carbon atoms)" is intended to include, but is not limited to,, trifluoro-methyl, 2,2,2-trifluoro-ethyl, 4-chloro-butyl, 3-bromo-propyl, and the like. The term "aryl" means, unless otherwise mentioned, a polyunsaturated aromatic substituent, which may be single-ring or multi-ring (preferably 1 to 3 rings), which are fused together or they are linked in a covalent way. The term "hetero-aryl" refers to aryl groups (or rings) containing one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the Nitrogen atoms are optionally quaternized. A hetero-aryl group can be attached to the rest of the molecule through a heteroatom. The non-limiting examples of the aplo and hetero-aplo groups include phenyl, benzyl, 1-naphthyl, 2-naphthyl, 4-b? phenol, 1-pyrrolidone, 2-pyrrolidone, 3-pyrrolyl, 3-pyrolyl, 2-? M? Dazolyl, 4-? M? Dazol ?, pyrazinyl, 2-oxazole, 4-oxazole, 2-phenyl? -4 -oxazole, 5-oxazole, 3-? soxazole, 4? -soxazole, 5? -soxazole, 2-t-azole, 4-t-azole, 5- t? azollo, 2-furlo, 3-fu rilo, 2-t? in? lo, 3-t? in? lo, 2-p? r? d? lo, 3-p? r? d It, 4-p? r? d ?, 2-pipmidilo, 4-p? r? m? d ?, 5-benzot? aolol, pupnilo, 2-benc? m? dazololo, 5 -? ndol? lo, 1 -isoqumohlo, 5-? soqu? nol? lo, 2-qu? noxal? n? lo, 5-qumoxa nilo, 3-qu? nol? lo, and 6-qu? nollo The substituents for each of the aforementioned a-ring and hetero-aplo ring systems are selected from the group of acceptable substituents described below. For brevity, the term "aplo", when used in combination with other terms ( for example, aploxil, thioa ploxil, apl-alkyl) includes the rings of both aplo and hetero As defined above, therefore, the term "apl-alkyl" is intended to include radicals wherein an aplo group is attached to an alkyl group (eg, benzyl, phenethyl, pipdyl-methyl, and the like) including alkyl groups wherein a carbon atom (e.g., a methylene group) has been replaced, for example, by an oxygen atom (e.g., phenoxy-methyl, 2-pipdoyloxy-ethyl, 3- (1-naphthalox? ) -prop? lo, and the like) Each of the foregoing terms (for example, "alkyl", "hetero-alkyl", "aplo", and "hetero-aplo") are intended to include both substituted and unsubstituted forms of the radical indicated The Preferred substituents for each type of radical are provided below. Substituents for the alkyl and heteroalkyl radicals (including the groups often referred to as alkylene, alkenyl, hetero-alkylene, hetero-alkenyl, alkynyl, cycloalkyl, hetero-cycloalkyl, cycloalkenyl, and hetero-cycloalkenyl) are generically referred to as "alkyl group substituents", and may be one or more of a variety of groups selected from, but not limited to: -OR ', = O, = NR', = N-OR ', -NR'R " , -SR ", -halogen, -SiR'R" R "', -OC (O) R', -C (O) R \ -CO2R ', -CONR'R", -OC (O) NR'R ", -NR" C (O) R \ -NR'-C (O) NR "R" \ -NR "C (O) 2R ', -NR-C (NR'R" R' ") = NR" ", -NR-C (NR'R") = NR '", -S (O) R', -S (O) 2R ', -S (O) 2NR'R ", -NRSO2R ', -CN and -NO2 in a number in the range from zero to (2m' + 1), where m 'is the total number of carbon atoms in this radical R ', R ", R"' and R "" each independently preferably refer to hydrogen, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted aryl, for example aryl substituted with 1 to 3 halogens, alkyl groups, alkoxy or substituted or unsubstituted thioalkoxy, or aryl-alkyl groups When a compound of the invention includes more than one group R, for example, each of the groups R is independently selected, as well as each of the groups R ', R ", R" 'and R "", when there is more than one of these groups present When R' and R "are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a ring of 5,6. , or 7 members. For example, -NR'R "is intended to include, but is not limited to, 1-pyrrolidinium and 4-morpholinyl.From the foregoing discussion of substituents, one skilled in the art will understand that the term" alkyl " it is intended to include groups that include carbon atoms bonded to different groups of hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C (O) CH3, -C (O ) CF3, -C (O) CH2OCH3, and the like.) In a manner similar to the substituents described for the alkyl radical, the substituents for the aryl and hetero-aryl groups are generically referred to as "aryl group substituents". substituents are selected from, for example: halogen, -OR ', = O, = NR', = N-OR ', -NR'R ", -SR', -halogen, -SiR'R" R "' , -OC (O) R ", -C (O) R \ -CO2R ', -CONR'R", -OC (O) NR'R ", -NR" C (O) R', -NR'- C (O) NR "R" ', -NR "C (O) 2R', -NR-C (NR'R" R '") = NR" ", -NR-C (NR'R") = NR "\ -S (O) R ', -S (O) 2R', -S (O) 2NR'R", -NRSO2R ', -CN and -NO2, -R', -N3, -CH (Ph) 2, fl uoro-alkoxy (of 1 to 4 carbon atoms), and fluoro-alkyl (of 1 to 4 carbon atoms), in a number in the range from zero to the total number of open valencies on the aromatic ring system; and wherein R ', R ", R"' and R "" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected, as well as each of the groups R ', R ", R'" and R "" when more than one of these groups are present. Two of the substituents on the adjacent atoms of the aryl or hetero-aryl ring may be optionally replaced with a substituent of the formula -TC (O) - (CRR ') qU-, wherein T and U are independently -NR-, -O-, -CRR'- or an individual bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on the adjacent atoms of the aryl or hetero-aryl ring can be optionally replaced with a substituent of the formula -A- (CH2) rB-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S (O) -, -S (O) 2- , -S (O) 2NR'- or an individual link, and r is an integer from 1 to 4. One of the individual links of the new ring thus formed can optionally be replaced with a double bond. Alternatively, two of the substituents on the adjacent atoms of the aryl or hetero-aryl ring can be optionally replaced with a substituent of the formula - (CRR ') sX- (CR "R'") d-, wherein syd are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S (O) -, -S (O) 2-, or -S (O) 2NR'-. The substituents R, R "and R" "are preferably independently selected from hydrogen or substituted or unsubstituted alkyl (1 to 6 carbon atoms). As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

"Protective group", as used herein, refers to a portion of a substrate that is substantially stable under a particular reaction condition, but which dissociates from the substrate under a different reaction condition. A protecting group may also be selected such that it participates in the direct oxidation of the aromatic ring component of the compounds of the invention. For examples of the useful protecting groups, see, for example, Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York, 1991. "Enantiomeric excess" or "ee", as used herein, is an expression for the extra amount of one enantiomer over another in a mixture of enantiomers. The "ee" is usually mentioned as a percentage. Algebraically, R-S \ e.e. X 100% R + S For more information on the "ee", see, for example, Wade, L.G., ORGANIC CHEMISTRY, 5th Edition, Prentice Hall, New Jersey, 2003, pages 167-207. "Disorder associated with HIV infection" or "disease associated with HIV infection" means in the present a disease state marked by HIV infection. These disorders associated with HIV infection include, but are not limited to, AIDS; Kaposi's sarcoma; opportunistic infections such as those caused by Pneumocystis carinii and Mycobacterium tuberculosis; oral lesions, including thrush, hairy leukoplakia, and aphthous ulcers; generalized lymphadenopathy; grain; thrombocytopenia; aseptic meningitis; neurological disease such as toxoplasmosis, cryptococcosis, CMV infection, primary lymphoma of the central nervous system, and dementia associated with HIV; peripheral neuropathies, attacks; and myopathy. As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of the nucleoside reverse transcriptase inhibitors include, but are not limited to, AZT, ddC, ddl, d4T, and 3TC. Examples of non-nucleoside reverse transcriptase inhibitors include, but are not limited to, delavirdine (Pharmacia and Upjohn U90152S), efavirenz (DuPont), nevirapine (Boehringer Ingelheim), Ro 18,893 (Roche), trovirdine (Lilly). , MKC-442 (Triangle), HBY 097 (Hoechst), ACT (Korean Research Institute), UC-781 (Rega Institute), UC-782 (Rega Institute), RD4-2025 (Tosoh Co. Ltd.), and MEN 10979 (Menarini Farmaceutici). As used herein, "HIV protease inhibitor" is intended to refer to compounds that inhibit HIV protease. The examples include, but are not limited to, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), amprenavir (Vertex / Glaxo Wellcome), nelfinavir (Agouron, AG-1343) , palinavir (Boehringer Ingelheim), BMS-232623 (Bristol-Myers Squibb), GS3333 (Gilead Sciences), KNI-413 (Japan Energy), KNI-272 (Japan Energy), LG-71350 (LG Chemical), CGP-61755 (Ciba-Geigy), PD 173606 (Parke Davis), PD 177298 (Parke Davis), PD 178390 (Parke Davis), PD 178392 (Parke Davis), U-140690 (Pharmacia and Upjohn), and ABT-378. Additional examples include the cyclic protease inhibitors disclosed in International Publications Nos. WO93 / 07128, WO 94/19329, and WO 94/22840, and in the TCP Application Number US96 / 03426. "Therapeutically effective dose" means in the present a dose that produces effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by a person skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992), Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999) and Pickar, Dosage Calculations (1999)). "Reactive functional group", as used herein, refers to groups that include, but are not limited to, olefins, acetylenes, alcohols, phenols, ethers, oxides, halides, aldehydes, ketones, carboxylic acids, esters, amides, cyanates, isocyanates, thiocyanates, isothiocyanates, amines, hydrazines, hydrazones, hydrazides, diazo, diazonium, nitro, nitriles, mercaptans, sulphides, disulfides, sulfoxides, sulfones, sulphonic acids, sulfinic acids, acetals, ketals, anhydrides, sulphates, sulfenic acids, isonitriles, amidines, imides, imidates, nitrones, hydroxyl amines, oximes, hydroxamic acids, thiohydroxamic acids, alenes, orro-esters, sulfites, enamines, inamines, ureas, pseudo-ureas, semicarbazides, carbodi-amides, carbamates, imines, azides, azo compounds, Azo compounds, and nitroso compounds. Reactive functional groups also include those used for the preparation of bioconjugates, for example, N-hydroxy-succinimide esters, maleimides, and the like. Methods for the preparation of each of these functional groups are well known in the art, and their application or modification for a particular purpose is within the capacity of an expert in this field (see, for example, Sandier and Karo, Editors ORGANIC FUNCTIONAL GROUP PREPARATIONS, Academic Press, San Diego, 1989). "Non-covalent protein binding groups" are those fractions that interact with an intact or denatured polypeptide in an associative manner. The interaction can be reversible or irreversible in a biological environment. The incorporation of a "non-covalent protein binding group" into a chelating agent or complex of the invention, provides the agent or complex with the ability to interact with a polypeptide in a non-covalent manner. Exemplary non-covalent interactions include hydrophobic-hydrophobic and electrostatic interactions. "Non-covalent protein binding groups" include the anionic groups, for example, phosphate, thiophosphate, phosphonate, carboxylate, boronate, sulfate, sulfone, thiosulfate, and thiosulfonate. As used herein, "link member" refers to a covalent chemical linkage that includes at least one hetero atom. The example link members include -C (O) NH-, -C (O) O-, -NH-, -S-, -O-, and the like.

[0003] The term "steering group" is intended to mean a moiety that: (1) is capable of actively directing the entity with which it is attached (eg, a contrast agent) to a target region, eg, a tumor; or (2) is preferably passively absorbed by, or introduced into, a target tissue, e.g., a tumor. The targeting group may be a small molecule, which is intended to include both non-peptides and peptides. The targeting group can also be a macromolecule, which includes, but is not limited to, saccharides, lectins, receptors, ligands for receptors, proteins such as bovine serum albumin, antibodies, poly- (ethers), dendrimers, polymers. (amino acids), etc. The term "dissociable group" is intended to mean a fraction that allows the release of the chelate from the remainder of the conjugate, by dissociating a link that is linking to the chelate (or to the construction of the chelating linker arm) with the rest of the conjugate. This dissociation is of a chemical nature, or is enzymatically mediated. Exemplary enzymatically dissociable groups include natural amino acids or peptide sequences that terminate with a natural amino acid. In addition to the enzymatically dissociable sites, it is within the scope of the present invention to include one or more sites that dissociate by the action of an agent other than an enzyme. The example non-enzymatic dissociation agents include, but they are not limited to, acids, bases, light (for example, nitrobenzyl derivatives, phenacyl groups, benzoin esters), and heat. Many dissociable groups are known in the art. See, for example, Jung et al., Biochem. Biophys. Acta, 761: 152-162 (1983); Joshi et al., J. Biol. Chem., 265: 14518-14525 (1990); Zarling et al., J. Immunol., 124: 913-920 (1980); Bouizar et al., Eur. J. Biochem., 155: 141-147 (1986); Park et al., J. Biol. Chem., 261: 205-210 (1986); Browning et al., J. Immunol., 143: 1859-1867 (1989). Moreover, a large number of bifunctional (both homo- and hetero-bifunctional) spacer groups are commercially available with suppliers such as Pierce. II. The Methods In a first aspect, the invention provides a method of synthesis. The product of this synthesis may be a heterocycle containing amide or a pharmaceutically acceptable salt thereof. The method comprises: a) contacting an organometallic complex of rhodium (I), a chiral ligand, a heterocycle containing α, β-unsaturated amide, and a boronic ester, under conditions sufficient to form a product comprising a heterocycle contains amide, thereby synthesizing the amide containing heterocycle or the pharmaceutically acceptable salt thereof. In an exemplary embodiment, the heterocycle containing α, β-unsaturated amide has a structure according to Formula I: wherein R1 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R2, R3, and R4 are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR5a, NO2, CN, halogen, C (O) R5b, NR5aR5b, C (O) NR5aR5 and C (O) OR5b. R5a is H or substituted or unsubstituted alkyl. R5b is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. An exemplary boronic ester has a formula according to Formula II: wherein R is substituted or unsubstituted aryl, or heteroaryl replaced or unsubstituted. R7 and R8 are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR10, NO2 , CN, and halogen. R7 and R8, taken together with the oxygen atoms with which they are attached, can also optionally form a substituted or unsubstituted ring of 5 to 8 members. R10 is H or substituted or unsubstituted alkyl. The amide containing heterocycle may have a formula according to Formula III: In an example embodiment, the synthesis is asymmetric. In an exemplary embodiment, the product is enantiomerically pure, and has a formula according to Formula III. In another exemplary embodiment, the synthesis produces an enantiomer of the amide-containing heterocycle according to Formula III. In another exemplary embodiment, the product further comprises an amide-containing heterocycle having a formula according to Formula Illa: In an exemplary embodiment, the product has an enantiomeric excess of about 10 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 30 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 50 percent or greater. In another example mode, the product has an enantiomeric excess of about 60 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 70 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 80 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 90 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 95 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 97 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 98 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 990 percent or greater In another example embodiment, the product has an enantiomeric excess of about 992 percent or greater In another example embodiment, the product has an excess enantiomeric of about 994 percent or greater In another example embodiment, the product has an enantiomeric excess of about 996 percent or greater. In another example embodiment, the product has an enantiomeric excess of about 998 percent or greater. an example embodiment, the method has a throughput of about 20 percent or greater In an example embodiment, the method has a throughput of about 30 percent or greater In an example mode, the method has a throughput of about 40 percent or greater In an example mode, the method has a yield of approximately 50 percent or greater In an example mode, the method has a performance of approximately 60 percent or greater In an example mode, the method has a performance of approximately 70 percent or greater In an example mode, the method has a yield of approximately 80 percent or greater In an example embodiment, the method has a yield of approximately 90 percent or greater In an example embodiment, the method has a yield of approximately 95 percent or greater In an exemplary embodiment, the method is conducted at a temperature between 40 ° C and 150 ° C. In another example embodiment, the method is conducted at a temperature between 50 ° C and 130 ° C. In an exemplary embodiment, the method is conducted at a temperature between 60 ° C and 110 ° C. In an exemplary embodiment, the method is conducted for a time between 2 hours and 8 hours. In another example embodiment, the method is conducted for a time between 3 hours and 7 hours. In another exemplary embodiment, the organometallic complex of rhodium (1) includes a chiral ligand selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In another exemplary embodiment, the chiral ligand comprises a phosphine substituted by aryl. In another exemplary embodiment, the chiral ligand is (R) -BINAP or (S) -BINAP. In another exemplary embodiment, R6 is a member selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, benzofuranyl. substituted or unsubstituted, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted benzoimidazolyl, substituted or unsubstituted quinazolinyl, and substituted or unsubstituted quinoxalinyl. In an exemplary embodiment, R1 is a member selected from substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl. In an exemplary embodiment, R1 is substituted phenyl or unsubstituted In an exemplary embodiment, the product may have an enantiomeric excess of about 80 percent or greater. In an exemplary embodiment, the method may further comprise: b) purifying the mixture from step a), thereby producing a product with an enantiomeric excess that is greater than the enantiomeric excess after step a). In an exemplary embodiment, the purification may comprise subjecting the mixture to a recovery method comprising column chromatography and recrystallization. In a second aspect, the invention provides a mixture of a heterocycle containing amide and its enantiomer. This mixture may comprise a compound according to Formula IV: and a compound according to Formula IVa: wherein R 11 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R12, R13, and R14 are each independently selected from H, alkyl substituted or unsubstituted, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR15, NO2, CN, halogen, C (O) R15, NR15R16, C (O) NR15R16 and C (O) OR15. R15 is a member selected from H and substituted or unsubstituted alkyl. R16 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R17 is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, the mixture has an enantiomeric excess of about 60 percent or greater. In an example embodiment, the mixture can be produced according to a process. This process involves contacting an organometallic rhodium complex (I), a chiral ligand, and an unsubstituted, β-unsaturated heterocycle according to Formula V, under conditions sufficient to form a mixture. The N-substituted a, β-unsaturated heterocycle has a formula according to Formula V: (V) wherein R 11 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR15 , NO2, CN, halogen, C (O) R15, NR15R16, C (O) NR15R16 and C (O) OR15. R15 is a member selected from H and substituted or unsubstituted alkyl. R16 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The boronic ester may have a formula according to Formula II: wherein R6 is substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R7 and R8 are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR10, NO2, CN, and halogen. R7 and R8, taken together with the atoms of oxygen with which they are attached, they can also optionally form a substituted or unsubstituted ring of 5 to 8 members. R10 is H and substituted or unsubstituted alkyl. In another exemplary embodiment, R 11 is a member selected from substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl. In another exemplary embodiment, R 11 is substituted or unsubstituted phenyl. In a third aspect, the invention provides a method for the production of a compound and its enantiomer. The compound may have a structure according to Formula VI: wherein R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR15 , NO2, CN, halogen, C (O) R15, NR15R16, C (O) NR15R16 and C (O) OR15. R15 is a member selected from H and substituted or unsubstituted alkyl. R16 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted hetero-cycloalkyl or unsubstituted, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R30, R32, R33, and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR19 , NO2, CN, halogen, C (O) R19, NR19R20, C (O) NR19R20 and C (O) OR19. R33 and R34 or R33 and R32 or R32 and Z1, together with the atoms with which they are attached, form at least one 5-membered ring selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl , and substituted or unsubstituted heteroaryl. R19 is a member selected from H, substituted or unsubstituted aryl, and substituted or unsubstituted alkyl. R20 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. Z is a fraction according to the Formula VII: wherein R40 and R are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR44, NO2, CN, and halogen. R44 is a member selected from H and substituted or unsubstituted alkyl. R43 is halogen. Z2 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. The method comprises: a) contacting an organometallic complex of rhodium (I), a chiral ligand, a heterocycle containing α, β-unsaturated amide, and a boronic ester, under conditions sufficient to form a mixture comprising a heterocycle contains amide according to Formula IX and its enantiomer, wherein the mixture has an enantiomeric excess of about 60 percent or greater. The N-substituted a, β-unsaturated heterocycle according to Formula VIII: where X * is a protective group. R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR25 , NO2, CN, and halogen. The boronic ester may have a formula according to Formula IX: R30, R32, R33, and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR19, NO2, CN, and halogen. Y * is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR19, NO2, CN , and halogen. R17 and R18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R17 and R 8, taken together with the oxygen atoms with which they are attached, optionally form a substituted or unsubstituted ring of 4 to 8 members. R19 is a member selected from H, substituted or unsubstituted aryl, and substituted or unsubstituted alkyl. The amide containing heterocycle has a formula according to Formula X: The method further comprises: b) subjecting the product of step a) to a deprotection reaction, removing X *, and producing a compound according to Formula XI: and its enantiomer. The method further comprises: c) subjecting the product of step b) to a deprotection reaction, stirring Y *, and producing a compound according to Formula XII: and its enantiomer. The method also includes: d) submitting to the product of step c) to an apposition reaction, yielding a compound according to Formula XIII and its enantiomer Z1 is a fraction according to Formula XIV wherein R40, R41, R42, R43, and R44 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aplo, substituted or unsubstituted heteroample, OR46, NO2, CN, halogen, C (O) R46, NR46R47, C (O) NR46R47 and C (O) OR46 R46 is a member selected from H and substituted or unsubstituted alkyl R47 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, hetero-cycloalkyl substituted or unsubstituted, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The method further comprises: e) arylating the lactam nitrogen of the product of step d), yielding a compound according to Formula VI: and its enantiomer. Z2 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, thereby producing a compound having the formula according to Formula VI. In an exemplary embodiment, Z2 is a fraction according to Formula XV: R50, R51, R52, R53 and R54 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR55, SO2NR55R56, CONR55R56, NR55R56, NO2, CN, and halogen; and any two of R50, R51, R52, R53 and R54, taken together with the atoms to which they are attached, optionally form a substituted or unsubstituted ring of 5 to 8 members. R55 is a member selected from H and substituted or unsubstituted alkyl. R56 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In another example embodiment, R32 is halogen. In another example embodiment, R30, R33, and R34 are H. In another example embodiment, R40, R41, and R42 are H. In another example embodiment, R51 and R52, taken together with the atoms to which they are attached , they can optionally form a substituted or unsubstituted 6-membered ring. In another exemplary embodiment, Z2 is a member selected from a fraction according to Formula XVI and a fraction according to Formula XVII: (XVI) wherein R60 and R61 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR62, NO2, CN, NR62R63S (O) 2NR62R63, NR62S (O) 2R63, C (O) NR62R63, S (O) 2R62 and halogen. R62 is a member selected from H and substituted or unsubstituted alkyl. R63 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In an exemplary embodiment, Z2 is a fraction according to Formula XVIII: (XVIII).

In another example embodiment, Z2 is a fraction according to Formula XIX: lll. Reaction Conditions for the Methods The following discussion is offered to illustrate some of the various methods available for use in the assembly of the compounds and mixtures of the invention, and is not intended to define the extent of reaction or reaction sequences that are useful in the preparation of the compounds of the invention. The compounds used in this invention are synthesized in accordance with Scheme 1. Scheme 1 Reagents and conditions: a) CH3CN, 0.4 N HCl, room temperature, 1 hour; b) Rh (cat), (R) -BINAP, K2C03, Dioxane / H20, 80 ° C, 6 hours; c) CAN, CH3CN / H20 OC 4 hours In the first step of Scheme 1, compounds 1 and 2 can be reacted under the conditions of step a in order to form compound 3. Compound 4 can be synthesized by mixing a aryl and borate fraction with a palladium catalyst. Compounds 3 and 4 can be reacted under the conditions of step b in order to form compound 5. Finally, the pyrrolidone nitrogen can be deprotected under the conditions of step c in order to form compound 6. Another reaction involved in the methods of the invention is a deprotection reaction. In an example embodiment, a protective group is removed as shown in Scheme 2. Scheme 2 In Scheme 2, compound 6 is reacted with a palladium catalyst in order to remove the benzyl protecting group, and to produce compound 7. Another reaction involved in the methods of the invention is an arylation reaction. In an example embodiment, an aryl fraction is added as shown in Scheme 3.

Scheme 3 In Scheme 3, the compound 7 is reacted with an aryl and base fraction, in order to produce the compound 8. Another reaction involved in the methods of the invention is the binding of an aryl fraction to the lactam nitrogen. In an example embodiment, an aryl fraction is added as shown in Scheme 4. Scheme 4 In Scheme 4, compound 8 is reacted with an aryl fraction 9 under the aforementioned reaction conditions for the purpose of producing compound 10. The compounds of the invention are synthesized by an appropriate combination of synthetic methods generally well known. Useful techniques for synthesizing the compounds of the invention are both readily apparent and accessible to those skilled in the relevant art.

Although this invention has been disclosed with reference to the specific embodiments, it can be seen that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. EXAMPLES General In the following examples, unless otherwise mentioned, temperatures are given in degrees Celsius (° C); the operations were carried out at room temperature, "rt," or "RT," (typically a range of about 18CC to 25 ° C), the evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (typically, 4.5 to 30 mm Hg) with a bath temperature of up to 60 ° C, the course of the reactions was typically followed by thin layer chromatography (TLC), and the reaction times are given for illustration only, the melting points are not are corrected, products exhibited satisfactory 1H-NMR and / or microanalytical data, yields are provided for illustration only, and the following conventional abbreviations are also used: mp (melting point), L (liter (s)), mL (milliliters), mmol (millimoles), g (grams), mg (milligrams), min (minutes), and h (hours) Unless otherwise specified, all solvents (HPLC grade) and reagents were purchased with the suppliers and used without further purification. The reactions are They drove under a blanket of argon, unless otherwise mentioned. Analytical TLC was carried out on Whatman Inc. silica gel plates 60 (thickness 0.25 millimeters). The compounds were visualized under an ultraviolet lamp (254 nanometers), or revealed with KMnO / KOH, ninhydrin, or Hanessian solution. Flash chromatography was done using Selectro Scientific silica gel (particle size 32-63). The spectra of 1 H NMR, 19 F NMR and 13 C NMR were recorded on a machine Variar 300 to 300 MHz, 282 MHz and 75.7 MHz, respectively. The melting points were recorded on an Electrothermal IA9100 device and were not corrected.

EXAMPLE 1 Preparation of 6 1.1 Synthesis of 3 To a solution of p-anisidine 2 (18.48 grams, 0.15 moles, 1 equivalent) and 2,5-dimethoxy-2,5-dihydrofuran 1 (39.04 grams, 0.3 moles, 2 equivalents) in acetonitrile (750 milliliters), a solution of 0.4N aqueous HCl (600 milliliters) was added. The reaction mixture was stirred at room temperature for 1 hour, quenched with NaHCO3 (40.32 grams, 0.48 moles, 2 equivalents of HCl), concentrated under reduced pressure at 27 ° C and partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine, dried over Na2SO, and concentrated. The crude residue was purified by chromatography on column with hexanes: EtOAc (1: 1), to give 1- (4-methoxy-phenyl) -1,5-dihydro-pyrrol-2-one 3 (10.85 grams, 38 percent). 1.2 Results The analytical data for structure 3 are provided below. 7.2.a 1- (4-Methoxy-phenyl) -1,5-dihydro-pyrrol-2-one 1 H NMR (CDCl 3): d 7.57 (2 H, d, J = 9.2 Hz), 7.14 (1H, dt, J = 0.8, 6.0 Hz), .6.92 (2 H, d, J = 9.2 Hz), 6.26 (1 H, dt, J = 0.8, 6.0), 4.40 (2 H, t, J = 1.6), 3.80 ( 3 H, s) ppm. 1-3 Synthesis of 4 A mixture of 2-benzyloxy-4-bromo-1-chloro-benzene (120 grams, 0.4 moles), diborate (107.5 grams, 0.42 moles), KOAc (117.8 grams, 3 equivalents), Pd (dppf) 2Cl2 (1 mole percent) and 500 milliliters of N, N-dimethylformamide was degassed, with stirring, and recharged with nitrogen. The mixture was heated at 80 ° C for 3 hours. The N, N-dimethyl formamide was removed in vacuo, resulting in the formation of a residue. The residue was mixed with ethyl acetate and then filtered. After filtration, the solid was washed with ethyl acetate (20 milliliters, 3 times), and recrystallized from ethyl acetate to give 97 grams of the pure product.

The mother solution was also concentrated. The residue was purified by column chromatography (10 percent ethyl acetate / hexane) to give the crude product, which was recrystallized from ethyl acetate. The product was 2- (4-chloro-3-benzyloxy-phenyl) -4,4,5,5, -tetramethyl- [1,2,2] -dioxaborolane 4. 1. 4 Results The analytical data for structure 4 are given below. 1.4.a (4-Chloro-3-benzyloxy-phenyl) -4.4.5.5. -tetramethyl- [1.3.21- dioxaborolane 1H NMR (CDCI3): d 7.35 (2 H, d, J = 7.6 Hz), 7.28 (1 H, brs), 7.17-7.26 (5 H, m), 7.11 (1 H, s), 5.02 (2 H, s), 1.20 (12 H, s) ppm. 1.5 Synthesis of 5 A solution of 3 (9 grams, 47.57 millimoles, 1 equivalent), 4 (32.8 grams, 95.14 millimoles, 2 equivalents), chloro- (1, 5-cyclo-octadiene) -rodio (l) dimer (352 milligrams, 0.7136 millimoles, 0. 015 equivalents), (R) -BINAP (1.04 grams, 1,665 millimoles, 0.035 equivalents), and K2CO3 (3.3 grams, 23.8 millimoles, 0.5 equivalents) in dioxane: water (10: 1), purged with nitrogen, and heated in an oil bath at 80 ° C for 26 hours. The reaction mixture was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined EtOAc extracts were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (5: 4, hexanes.EtOAc) to give a solid product. Recrystallization from EtOAc and hexanes gave the product of (R) -4- (3-benzyloxy-4-chloro-phenyl) -1- (4-methoxy-phenyl) -pyrrolidin-2-one, 5. 1.6 Results The data Analytics for structure 5 are provided below. 1. 6.a (R) -4- (3-Benzyloxy-4-chloro-phenyl) -1- (4-methoxy-phenyl) -pyrrolidin-2-one 1 H NMR (CDCl 3): d 7.48 (2 H, d, J = 9.2 Hz), 7.44 (2 H, m), 7.32-7.39 (4 H, m), 6.92 (2 H, d, J = 9.2 Hz), 6.86 (1 H, d, J = 1.6 Hz), 6.83 (1 H, dd, J = 0.8, 8.0 Hz), 5.16 (2 H, s), 4.12 (1 H, dd, J = 8.0, 9.6 Hz), 3.81 (3 H, s), 3.75 (1 H , dd, J = 6.8, 9.6 Hz), 3.63 (1 H, dddd, J = 8 Hz), 2.98 (1 H, dd, J = 8.8, 16. 8 Hz), 2.68 (1 H, dd, J = 16.8, 8.4 Hz) ppm. 1.7 Synthesis of 6 To a solution of 5 (16.5 grams, 40 millimoles, 1 equivalent) in CH3CN (1400 milliliters), a solution of ammonium nitrate and cerium (CAN) (65.8 grams, 0.12 moles, 3) was added dropwise. equivalents) in 50% aqueous CH3CN at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour Na2S2O3 (45.4 grams, 0.36 moles, 9 equivalents) was added. The reaction mixture was stirred at 0 ° C for another hour, and filtered through Celite to remove the precipitate. The filtrate was concentrated under reduced pressure and the residue was partitioned between 5 percent MeOH in EtOAc and H2O. The aqueous phase was extracted with 5 percent MeOH in EtOAc, and the combined extracts were washed with brine, dried over Na2SO, and evaporated. Purification through column chromatography (40: 1 CH2Cl2: MeOH) yielded the product of (R) -4- (3-benzyloxy-4-chloro-phenyl) -pyrrolidin-2-one, 6. 1.8 Results The data analytics for structure 6 are provided in followed. 1.8.a (R) -4- (3-Benzyloxy-4-chloro-phenyl) -pyrrolidin-2-one 1 H NMR (CDCl 3): d 7.41 (d, 2H, J = 7.6 Hz), 7.35 (t, 2H , J = 6.8 Hz), 7.29 (d, 2H, J = 8.0 Hz), 6.78 (d, 1H, J = 2.0 Hz), 6.75 (dd, 1H, J = 2.0, 8.0 Hz), 5.58 (brs, 1H), 5.11 ( s, 2H), 3.70 (t, 1H, J = 8.4 Hz), 3. 62-3.56 (m, 1H), 2.27 (dd, 1H, J = 6.8, 9.2 Hz), 2.66 (dd, 1H, J = 8. 8, 16.8 Hz), 2.36 (dd, 1H, J = 9.2, 17.2 Hz); LCMS m / z 302.20 [M + H] +.

EXAMPLE 2 Determination of the effectiveness of the substituents R1 A study of pyrrolidones with different substituents on the endocyclic nitrogen was undertaken. The general reaction scheme is shown in Scheme 5. The different substituents R1 are also listed. The results of these tests are as follows: Scheme 5 Surprisingly, the percent recovery for these reactions increased from 35 percent to approximately 80 percent when a phenyl group was replaced by a benzyl group in the Z position. This contrasts with the asymmetric synthesis reactions described in Senda , where yields of up to 75 percent were recorded for piperidinones with benzyl groups in the equivalent of the Z-position.

EXAMPLE 3 Determination of the efficiency of the boronic ester Y substituents A study of boronic esters with different Y substituents was undertaken. The general reaction scheme is shown in Scheme 6. The different boronic ester substituents are also listed. The results of these experiments are as follows: Scheme 6 13 14 15 EXAMPLE 4 Determination of the effectiveness of the bases in the reaction conditions A study was undertaken that varied the types of bases used. The general reaction scheme is shown in Scheme 7. The different bases are also listed. The results of these experiments are as follows: Scheme 7 All patents, patent applications, and other publications cited in this application are incorporated by reference in their entirety.

Claims

CLAIMS 1. A method for synthesizing a heterocycle containing amide, or a pharmaceutically acceptable salt thereof, the method comprising: a) contacting an organometallic complex of rhodium (I), a chiral ligand, a heterocycle containing amide a, β-unsaturated according to Formula I: wherein: R1 is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R2, R3, and R4 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR5a, NO2 , CN, halogen, C (O) R, 53bD, NRsaRSD, C (O) NR5aRSD and C (O) ORS, wherein: R is a member selected from H and substituted or unsubstituted alkyl; R5b is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and a boronic ester according to Formula II: wherein: R6 is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R7 and R8 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl wherein R7 and R8, taken together with the oxygen atoms with which they are attached, they optionally form a substituted or unsubstituted 5 to 8 membered ring, wherein: R10 is a member selected from H and substituted or unsubstituted alkyl, under conditions sufficient to form a product which comprises a heterocycle containing amide according to the Formula lll: thus synthesizing the amide containing heterocycle, or the pharmaceutically acceptable salt thereof. 2. The method according to claim 1, wherein this product further comprises a heterocycle containing amide according to Formula Illa: 3. The method according to claim 2, wherein this product has an enantiomeric excess of about 60 percent or greater. 4. The method according to claim 1, wherein the rhodium organometallic complex (I) comprises a chiral ligand selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 5. The method according to claim 1, wherein the chiral ligand comprises a phosphine substituted by aryl. 6. The method according to claim 1, wherein R6 is a member selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzofuranyl, substituted benzothiophenyl. or unsubstituted, substituted or unsubstituted benzoimidazolyl, substituted or unsubstituted quinazolinyl, and substituted or unsubstituted quinoxalinyl. The method according to claim 1, wherein R1 is a member selected from substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl. 8. The method according to claim 1, wherein R1 is substituted or unsubstituted phenyl. 9. The method according to claim 2, wherein this product has an enantiomeric excess of about 80 percent or more. The method according to claim 3, which further comprises: b) purifying the mixture from step a), thereby producing a product with an enantiomeric excess which is greater than the enantiomeric excess after step a). The method according to claim 10, wherein said purification comprises subjecting the mixture to a recovery method comprising column chromatography and recrystallization. 12. A mixture comprising a compound according to Formula IV: and a compound according to Formula IVa: wherein: R is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR15, NO2 , CN, halogen, C (O) R15, NR15R16, C (O) NR15R16 and C (O) OR15, wherein: R15 is a member selected from H and alkyl replaced or unsubstituted; R16 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, wherein: 17 is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The mixture of claim 12, wherein this mixture has an enantiomeric excess of about 60 percent or greater. The mixture of claim 12, produced by a process comprising: a) contacting an organometallic complex of rhodium (I), a chiral ligand, an N-substituted, β-unsaturated heterocycle in accordance with Formula V : wherein: R is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR15, NO2 , CN, halogen, C (O) R15, NR15R16, C (O) NR15R16 and C (O) OR15, wherein: R15 is a member selected from H and substituted or unsubstituted alkyl; R16 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and a boronic ester according to Formula II: wherein: R6 is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R7 and R8 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl wherein R7 and R8, taken together with the oxygen atoms with which they are attached, optionally form a 5- to 8-membered ring, under conditions sufficient to form this mixture. 15. The mixture of claim 12, wherein R11 is a member selected from substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl. 16. The mixture of claim 12, wherein R11 is substituted or unsubstituted phenyl. 17. A method for producing a compound having the formula according to Formula VI: and its enantiomer, wherein: R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, heteroaryl replaced or unsubstituted, OR15, NO2, CN, halogen, C (O) R15, NR15R16, C (O) NR15R16 and C (O) OR15, wherein: R15 is a member selected from H and substituted or unsubstituted alkyl; R16 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R30, R32, R33, and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR19 , NO2, CN, halogen, C (O) R19, NR19R20, C (O) NR19R20 and C (O) OR19, where: R33 and R34 or R33 and R32 or R32 and Z1 together with the atoms with which they are attached , form at least one 5-membered ring selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; R19 is a member selected from H, substituted or unsubstituted aryl, and substituted or unsubstituted alkyl; R20 is a member selected from H, substituted or unsubstituted alkyl, hetero-substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Z1 is a fraction according to the Formula VII: wherein: R40, R41, and R42 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR44, NO2, CN, and halogen, wherein: R44 is a member selected from H and substituted or unsubstituted alkyl; and R43 is halogen; Z2 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; this method comprising: a) contacting an organometallic complex of rhodium (1), a chiral ligand, an N-substituted a, β-unsaturated heterocycle in accordance with Formula VIII: wherein: X * is a protecting group; R12, R13, and R14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR25, NO2 , CN; and a boronic ester according to Formula IX: wherein: R30, R32, R33, and R34 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted heteroaryl or unsubstituted, OR19, NO2, CN, and halogen; Y * is a member selected from H, alkyl substituted or unsubstituted, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR19, NO2, CN, and halogen; R17 and R18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and R17 and R18, taken together with the oxygen atoms with which they are attached, optionally form a substituted or unsubstituted 4- to 8-membered ring, wherein: R19 is a member selected from H, substituted or unsubstituted aryl, and substituted or unsubstituted alkyl; under conditions sufficient to form a mixture comprising a heterocycle containing amide according to Formula X: and its enantiomer, wherein this mixture has an enantiomeric excess of about 60 percent or greater; b) subjecting the product of step a) to a deprotection reaction, removing X *, and producing a compound according to Formula XI: and its enantiomer; c) subjecting the product of step b) to a deprotection reaction, removing Y *, and producing a compound according to Formula XII: and its enantiomer; d) subjecting the product of step c) to an arylation reaction, yielding a compound according to Formula XIII: and its enantiomer, wherein: Z1 is a fraction according to Formula XIV: wherein: R40, R41, R42, R43, and R44 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted hetero-alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetero-cycloalkyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, OR46, NO2, CN, halogen, C (O) R46, NR46R47, C (O) NR46R47 and C (O) OR46, wherein: R46 is a member selected from H and substituted alkyl or unsubstituted R47 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; e) arylating the lactam nitrogen of the product of step d), yielding a compound according to Formula VI: ) and its enantiomer, wherein: Z2 is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; thereby producing the compound having the formula according to Formula VI. 18. The method according to claim 17, wherein Z2 is a fraction according to Formula XV: (XV) R50, R51, R52, R53 and R54 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR55, SO2NR55R56, CONR55R56, NR55R56, NO2, CN, and halogen; and any two of R50, R51, R52, R53 and R54, taken together with the atoms with which they are attached, optionally form a substituted or unsubstituted 5 to 8 membered ring, wherein: R55 is a member selected from H and substituted or unsubstituted alkyl; R56 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. 19. The method according to claim 17, wherein R32 is halogen. 20. The method according to claim 18, wherein R30, R33, and R34 are H. The method according to claim 17, wherein R40, R41, and R42 are H. 22. The method of agreement with claim 18, wherein R51 and R52, taken together with the atoms with which they are attached, they form a 6-membered ring substituted or unsubstituted. The method according to claim 17, wherein Z2 is a member selected from a fraction according to Formula XVI and a fraction according to Formula XVII: wherein: R60 and R61 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR62, NO2 , CN, NR62R63 s (O) 2NR62R63, NR62S (O) 2R63, C (O) NR62R63, S (O) 2R62 and halogen, wherein: R62 is a member selected from H and substituted or unsubstituted alkyl; R63 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. The method according to claim 23, wherein Z2 is a fraction according to Formula XVIII: (XVIII). 25. The method according to claim 17, wherein Z2 is a fraction according to Formula XIX: (XIX).