Enantioselective C-H amination using iron phthalocyanine and diammonium template catalysts

Abstract

Catalytic systems capable of catalyzing enantioselective C-H functionalization reactions are described, and methods of use thereof are described. These catalytic systems contain an iron complex as a host catalyst, and a diammonium guest template as a co-catalyst. The iron-based main catalyst contains a crown ether phthalocyanine ligand. The diammonium guest template is a bidentate compound with chirality. The iron-based host catalyst and the bidentate ammonium guest template can provide a complex spatial environment for stereotactic and site-selective C-H functionalization, such as C-H amination. For example, enantioselective C-H amination reactions carried out using the disclosed methods can achieve high enantiomer ratios (i.e., at least 2: 1) and optionally high yields (i.e., at least 30%).

Description

TECHNICAL FIELD

[0001] The invention disclosed herein generally falls within the field of C-H functionalization using catalytic systems containing iron-based catalysts and diammonium cocatalysts. BACKGROUND

[0002] For four decades, dirhodium paddlewheel catalysts have dominated the field of C-H functionalization via metal-carbene / nitrene intermediate. Due to sustainability and cost factors, there is a push in the catalysis community to replace noble metal catalysts with 3d transition metals, which makes iron a candidate metal. Although there have been many reports of iron-catalyzed C-H amination (E.T. Hennessey and T.A. Betley, Science, 2013, 340, 591-595; Bagh et al., J. Am. Chem. Soc. 2017, 139, 5117-5124), there are only limited examples of commercially available iron catalysts. This is mainly due to the low stability of iron catalysts supported by low-coordination ligand systems and the low valence state of the iron center, which leads to spontaneous reactions upon contact with oxygen.

[0003] Stable iron catalysts for C-H functionalization under air atmosphere are often supported by polydentate ligands (e.g., porphyrin, phthalocyanine, oligopyridine), which often lead to reduced reactivity. In addition, these polydentate ligand-supported iron catalysts are difficult to control selectivity (site selectivity, enantioselectivity, diastereoselectivity, etc.) due to the planar ligand skeleton of most of their polydentate ligands. Current solutions for improving selectivity include: (1) building three-dimensional covalent frameworks through often demanding and intensive organic synthesis (H.-H. Wang et al., Angew. Chem. Int. Ed. 2023, 62, e202218577; W.-C. Lee and X. P. Zhang, Nat. Chem. 2023, 15, 1499); and (2) introducing transition metal chemistry into genetically edited protein, DNA, and peptide biomolecules (S. Gao et al., J. Am. Chem. Soc. 2023, 145, 20196; A. Rioz-Marinez et al., Angew. Chem. Int. Ed. 2016, 55, 14136; J. Serrano-Plana et al., J. Am. Chem. Soc. 2020, 142, 10617; X. Ren et al., 30ACS Catal. 2020, 10, 2308). Both solutions are costly when it comes to large-scale production of such transition metal catalysts.

[0004] Furthermore, recent literature reports have highlighted the sensitivity of multi-binding metal ligand intermediates (metal-carbene, azene, and imide groups) to aqueous conditions, leading to reduced reactivity or pathway alteration (Y. Tan et al., Angew. Chem. Int. Ed. 2020, 58, 21706; EJ Meeus et al., Chem. Catal. 2023, 3, 100700). Therefore, there is still a need to develop catalysts that selectively catalyze CH functionalization reactions under hydrophobic conditions.

[0005] Therefore, the object of this invention is to provide a supramolecular catalytic system containing an iron-based catalyst and a chiral diammonium guest co-catalyst.

[0006] Another object of the present invention is to provide a method for using such a catalytic system in a selective CH functionalization reaction. Summary of the Invention

[0007] This application describes catalytic systems capable of selectively (e.g., enantioselectively) catalyzing CH functionalization reactions and methods of using them. These catalytic systems contain an iron complex as the host catalyst and a diammonium phosphate guest template as a co-catalyst. The iron-based host catalyst contains a crown ether phthalocyanine ligand. The diammonium phosphate guest template is a chiral bidentate compound. The iron-based host catalyst and the bidentate ammonium guest template can provide a complex steric environment for stereooriented and site-selective CH functionalization, such as CH amination. Without being bound by any theory, it is assumed that the bidentate ammonium guest template can spontaneously self-assemble with the crown ether component of the iron-based host catalyst through non-covalent interactions to form a thermally stable structure.

[0008] The catalytic system provides a method for selective iron catalysis via supramolecular catalysis. An iron-based phthalocyanine host catalyst and a chiral diammonium guest co-catalyst can self-assemble in a hydrophobic environment in a manner similar to a biocatalytic system to form a supramolecular catalytic system. Through the engineering of readily available phthalocyanine ligands, this catalytic system can catalyze CH functionalization reactions with a high level of enantioselectivity, a first among over 4000 publications.

[0009] Iron-based host catalysts can have the structure of Formula I:

[0010]

[0011] wherein: (i) each occurrence of A, together with the carbon atom to which it is attached, can form a crown ether; (ii) each occurrence of R1and R2may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, halide, hydroxyl, alkoxy, amino, amido, carbonyl, nitro, nitrile, or thiol; and (iii) the substituents can independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphanyl, phosphoryl, phosphinyl, or thiol, or combinations thereof.

[0012] In some forms, each occurrence of A, together with the carbon atom to which it is attached, can form a 12-crown-4-ether, 15-crown-5-ether, 18-crown-6-ether, dibenzo-18-crown-6-ether, 24-crown-8-ether, or azacrown ether.

[0013] In some forms, the host catalyst can have the structure of Formula II:

[0014]

[0015] In some forms, each occurrence of R1and R2may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl. In some forms, each occurrence of R1and R2may be hydrogen.

[0016] The guest template can have the structure of Formula III:

[0017]

[0018]

[0019] wherein: (i) B1and B2may independently be absent, or a carbon atom, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl; (ii) R3and R4may independently be absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl; (iii) —— can be absent or a bond (single, double, or triple bond); (iv) X1and X2may independently be absent, or an oxygen atom or NR5, and R5may be absent, or hydrogen or substituted or unsubstituted alkyl; (v) L1and L2may independently be absent or X3may be a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl, Q1and Q2may independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl; (vi) n1and n2may independently be an integer from 0 to 20; and (vii) the substituents can be as described above for Formula I.

[0020] In some versions, B1and B2may independently be a carbon atom, substituted or unsubstituted aryl, or substituted or unsubstituted polyaryl; and R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl. In some versions, the portion of the guest template may be:

[0021]

[0022] X1and X2may independently be an oxygen atom or NR5, R5may be absent or hydrogen; n4and n5may independently be an integer from 0 to 5; n6, n7, n8, and n 10 may independently be an integer from 0 to 4; n9and n 11 may independently be an integer from 0 to 2; n 12 -n 14 may independently be an integer from 1 to 6; and R7-R 14may be independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl.

[0023] In some forms, L1and L2may be independently wherein X3may be a nitrogen atom, and wherein Q1and Q2may be independently substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl. In some forms, Q1and Q2may be unsubstituted phenyl.

[0024] The disclosed catalytic system contains a host catalyst and a guest template. The host catalyst can have any of the structures described above for iron-based host catalysts; the guest template can have any of the structures described above for diammonium guest templates. Generally, the molar ratio of host catalyst to guest template in the catalytic system can be in the range of 1 : 10 to 1 : 1, 1 : 5 to 1 : 1, such as 1 : 2.

[0025] In some forms, the host catalyst and the guest template in the catalytic system can be non-covalently bound to one another, such as via the crown ether of the host catalyst and the ammonium group of the guest template being non-covalently bound to one another. The log(K) of the binding between the host catalyst and the guest template can be at least 4.0, such as in the range of 4.0 to about 8.0 or 4.0 to about 6.0.

[0026] In some forms, the host catalyst and the guest template of the catalytic system can form the following structure:

[0027]

[0028] For example, the host catalyst and the guest template of the catalytic system can form a complex having the following structure:

[0029]

[0030] The present application also discloses methods for performing enantioselective C-H amination of a substrate using the disclosed catalytic system. The enantioselective C-H amination reactions performed using the disclosed methods can achieve high enantiomeric ratios (i.e., at least 2: 1) and optionally high yields (i.e., at least 30%). For example, the amination product formed from an enantioselective C-H amination reaction catalyzed by the catalytic system disclosed herein can have an enantiomeric ratio of at least 2: 1, such as in the range of 2: 1 to 99: 1, 4: 1 to 99: 1, 9: 1 to 99: 1, or 19: 1 to 99: 1, as determined by chiral HPLC; and optionally a yield of at least 30%, at least 40%, at least 50%, in the range of about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0031] Generally, the method includes (i) maintaining a reaction mixture at room temperature for a period of time sufficient to form a product, wherein the reaction mixture contains a substrate, a nitrogen source reactant, the disclosed catalytic system, and a solvent.

[0032] In some forms, the nitrogen source reactant in the reaction mixture can be R'-NH2or R"IN-R', wherein R' can be -SO2-R'1or -SO3-R'2; R'1and R'2may independently be substituted or unsubstituted phenyl or substituted or unsubstituted alkyl (e.g., unsubstituted straight or branched C1-C10 alkyl, unsubstituted straight or branched C1-C8 alkyl, unsubstituted straight or branched C1-C6 alkyl, unsubstituted straight or branched C1-C4 alkyl, etc., such as tert-butyl, or a haloalkyl, such as -CH2CCI3, -CCl3, -CH2CH2CCl3, -CH2CCl2CCl3, etc.); R" can be substituted or unsubstituted phenyl; and when present, the substituents can independently be unsubstituted alkyl (e.g., any of those described above, such as methyl), halide (such as chloride), nitro, cyano, nitrile, or carbonyl. In some forms, the nitrogen source reactant in the reaction mixture can be R'-NH2or R"IN-R', wherein R' can be Tces, Ts, Ns, or ortho / para / meta halo-phenylsulfonyl or sulfonate (such as p-chlorophenylsulfonyl or p-chlorophenylsulfonate); and R" can be unsubstituted phenyl or phenyl substituted with alkyl or halide at any suitable position(s) on the phenyl ring (such as chlorobenzene or alkylbenzene). In some forms, the nitrogen source reactant in the reaction mixture can be PhINTces.

[0033] In some forms, the substrate in the reaction mixture can have the structure R-H, and the product formed by the enantioselective C-H amination reaction can have the structure R-NHR', where R can be a substituted or unsubstituted aryl (e.g., substituted or unsubstituted tetrahydronaphthalene, substituted or unsubstituted indane, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted chromane, substituted or unsubstituted isochromane, substituted or unsubstituted thiochromane, substituted or unsubstituted isothiochromane, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, etc.), substituted or unsubstituted cycloalkyl (mono- or polycyclic, such as a fused cycloalkyl ring), substituted or unsubstituted cycloalkenyl (mono- or polycyclic, such as a fused cycloalkenyl ring), or substituted or unsubstituted cycloalkynyl (mono- or polycyclic, such as a fused cycloalkynyl ring); the substituents can independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, siloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphonyl, phosphacyl, or thiol, or combinations thereof; and R' can be any of those described above for R'-NH2or R"IN-R', such as Tces, Ts, Ns, or ortho / para / meta halo-benzenesulfonyl or sulfonate (such as p-chlorobenzenesulfonyl or p-chlorobenzenesulfonate). In some forms, R can be a substituted or unsubstituted aryl (e.g., substituted or unsubstituted tetrahydronaphthalene, substituted or unsubstituted indane, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyl, or substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted chromane, substituted or unsubstituted isochromane, substituted or unsubstituted thiochromane, substituted or unsubstituted isothiochromane, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, etc.).

[0034] In some forms, the substrate in the reaction mixture can have the structure of Formula VI, and the product formed by the enantioselective C-H amination reaction can have the structure of Formula VII:

[0035]

[0036] wherein R 15 -R 20 may be independently hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), halide, hydroxyl, carbonyl, amino, amido, silyl, or siloxy, or R 20 and R 15 together with the carbon atom to which they are attached or R 20 and R 19 together with the carbon atom to which they are attached can form a substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings), substituted or unsubstituted cycloalkenyl (monocyclic or polycyclic, such as fused cycloalkenyl rings), substituted or unsubstituted cycloalkynyl (monocyclic or polycyclic, such as fused cycloalkynyl rings), substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxanyl, substituted or unsubstituted thianyl, substituted or unsubstituted oxolanyl, substituted or unsubstituted thiolanyl, etc.), substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteropolyaryl; when present, the substituents can be independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, siloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof, such as substituted or unsubstituted alkyl, substituted or unsubstituted aryl, carbonyl, oxo, amino, or alkoxy; and R’ can be any of those described above for R’-NH2or R”IN-R’, such as Tces, Ts, Ns, or ortho / para / meta halo-benzenesulfonyl or sulfonate (such as p-chlorobenzenesulfonyl or p-chlorobenzenesulfonate).

[0037] In some forms, R 19 may be hydrogen, R 20may be substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), or R 20 may be substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), or R 19 together with the carbon atom to which they are attached can form a substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings) or a substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxanyl, substituted or unsubstituted thianyl, substituted or unsubstituted oxolanyl, substituted or unsubstituted thiolanyl, etc.). In these forms, R 15 may be independently hydrogen, halide, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), carbonyl, or silyloxy. 18 may be independently hydrogen, halide, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), carbonyl, or silyloxy.

[0038] In some forms, the substrate in the reaction mixture can have the following structure:

[0039]

[0040]

[0041] The product formed by the enantioselective C-H amination reaction can have the following structure:

[0042]

[0043] In some forms, the molar ratio of the substrate in the reaction mixture to the nitrogen source reactant can be in the range of 10: 1 to 1: 1, or 10: 1 to 5: 1, such as 8: 1. In some forms, the loading of the host catalyst in the reaction mixture can be in the range of about 5 mol% to about 30 mol%, or about 10 mol% to about 20 mol%, such as about 15 mol%. In some forms, the solvent in which the reaction mixture is formed can be CH3CN, THF, HFIP, or C6H6, preferably, wherein the solvent can be CH3CN. In some forms, the reaction mixture further contains a molecular sieve, such as a molecular sieve, a molecular sieve, or a molecular sieve.

[0044] The enantioselective C-H amination reactions conducted using the disclosed methods can be conducted at room temperature for a period of time in the range of about 30 minutes to about 24 hours, about 1 hour to about 20 hours, or about 2 hours to about 18 hours, such as about 16 hours, to form the aminated product. Optionally, the reaction can be conducted under an inert gas environment, such as argon. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 To illustrate the guest template binding to the host catalyst Fe 18-冠-6 PC) to form a supramolecular catalytic system.

[0046] Figure 2 To illustrate the structures of exemplary guest templates grouped by base structure, chiral backbone, and alkyl linker.

[0047] Figure 3A To illustrate the UV-visible spectra of the reactions of Fe-1 with 4c, 4d, and 4e. 1 Graph of the spectra of H NMR; Figure 3B To illustrate the UV-visible spectra of the reactions of Fe-1 with 4c, 4e, and 1 in CH3CN.

[0048] Figure 4A To illustrate a schematic of the control experiments employed with Fe-1 :T2h:Ba(OTf)2 in a 1 :2:4 ratio and Fe-2:T2h in a 1 :2 ratio as catalytic systems. Figure 4B To illustrate a schematic of the principles behind the diastereoselective process.

[0049] Figures 5A-5E To illustrate a graph of the results of the titration study: H2 18-冠醚-6 PC) and T2h; 1 H-NMR signal changes Figure 5A ) of the crown ether signals of T1, T2d, T2e, T2h, and T2i relative to the amount of template Figure 5B ) of the crown ether signals of T1, T2d, T2e, T2h, and T2i relative to the amount of template 18-冠-6 PC) / (T2h)2 and Ba(OTf)2; 1 H-NMR signal changes Figure 5C ) of the crown ether signals of T1, T2d, T2e, T2h, and T2i relative to the amount of template Figure 5D ) of the crown ether signals of T1, T2d, T2e, T2h, and T2i relative to the amount of template Figure 5E ) of the UV-visible signals of the titration of Fe-1 and T2h.

[0050] Figure 6 To illustrate a schematic of the binding between the host catalyst and the guest template used to calculate the binding constant.

[0051] Figure 7A To demonstrate the supramolecular catalyst H2 ( 18-冠-6 PC) / (T2h)2 1 H- 1 Image of H NOSEY NMR. Figure 7B To demonstrate the supramolecular catalyst H2 ( 18-冠-6 PC) / (T2h)2 / (Ba(OTf)2)4 1 H- 1 Image of HNOSEY NMR. Figure 7C To demonstrate the supramolecular catalyst H2 ( 18-冠-6 PC) / (T2h)2 1 Image of HDOSY NMR.

[0052] Figure 8A To show the concentration from 4.73 x 10 -4 Up to 0.59x10 -4 The CD spectrum of T2e of M. Figure 8B To show the concentration from 4.73 x 10 -4 Up to 1.48x10 -4 The CD spectrum of M at T2d. Figure 8C The graph shows the maximum Δε change of T2h when Fe-1 and Ba(OTf)2 are added to the diluted solution of T2h. Detailed Implementation Plan DETAILED DESCRIPTION

[0054] I. Definition

[0055] It should be understood that, unless otherwise stated, the disclosed compounds, compositions, and methods are not limited to specific synthetic methods, specific analytical techniques, or specific reagents, and therefore they can vary. It should also be understood that the terminology used herein is for the purpose of describing particular forms and embodiments only and is not intended to be limiting.

[0056] "substituted" as used herein refers to all permissible substituents of the compounds or functional groups described herein. In the most general form, permissible substituents include noncyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic radical having any number of carbon atoms, preferably 1-14 carbon atoms, and optionally containing one or more heteroatoms, such as oxygen, sulfur, or nitrogen groups, in linear, branched, or cyclic structural formats. Representative substituents include substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aryloxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphino, phosphoryl, phosphono, amino acid. Such substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted phenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, halogen, hydroxyl, alkoxy, phenoxy, aryloxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphino, phosphoryl, phosphono, and amino acid can be further substituted.

[0057] Heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valence state of the heteroatom. It should be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence states of the substituted atoms and the substituents, and that the substitution results in a stable compound, i.e. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0058] As used herein, "alkyl" refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, and cyclic alkyl (alicyclic) groups. In some forms, straight- chain or branched-chain alkyl groups have 30 or fewer carbon atoms in their backbone (e.g., C1-C30 alkyl groups). Unless otherwise specified, alkyl groups can be substituted or unsubstituted. Alkyl groups that are substituted with substituents other than halogen, hydroxyl, alkoxy, phenoxy, aryloxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphino, phosphoryl, phosphono, and amino acid are referred to herein as "substituted alkyl." 30 , branched-chain C3-C30 alkyl groups. Unless otherwise specified, alkyl groups can be substituted or unsubstituted. Alkyl groups that are substituted with substituents other than halogen, hydroxyl, alkoxy, phenoxy, aryloxy, silyl, thiol, alkylthio, substituted alkylthio, phenylthio, arylthio, cyano, isocyano, nitro, substituted or unsubstituted carbonyl, carboxyl, amino, amido, oxo, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphino, phosphoryl, phosphono, and amino acid are referred to herein as "substituted alkyl." 30alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Likewise, cycloalkyl is a non-aromatic carbon-based ring consisting of at least three carbon atoms, such as a non-aromatic monocyclic or non-aromatic polycyclic ring containing 3-30 carbon atoms, 3-20 carbon atoms, or 3-10 carbon atoms in its ring structure, and having 5, 6, or 7 carbon atoms in the ring structure. Cycloalkyl groups containing polycyclic ring systems can have two or more non-aromatic rings, with two or more carbons being shared by two adjacent rings (i.e., a "fused cycloalkyl ring"). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0059] "Substituted alkyl" refers to an alkyl moiety having one or more substituents for the hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents can be any of the substituents described above, for example, halogen (such as fluorine, chlorine, bromine, or iodine), hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), aryl, alkoxyl, aralkyl, phosphine, phosphineoxy, phosphineyl, phosphoryl, phosphate, phosphonate, phosphinite, amino, amido, amidine, imine, cyano, nitro, azido, oxo, thiol, alkylthio, silyl, sulfinyl, sulfate, sulfonate, sulfamoyl, sulfamide, sulfonyl, heterocyclyl, aromatic, or heteroaromatic moieties. -NRR', where R and R' are independently hydrogen, alkyl, or aryl, and where the nitrogen atom is optionally quaternized; -SR, where R is phosphinyl, sulfinyl, silyl, hydrogen, alkyl, or aryl; -CN; -NO2; -COOH; carboxylate; -COR, -COOR, or CON(R)2, where R is hydrogen, alkyl, or aryl; imine, silyl, ether, haloalkyl (such as -CF3, -CH2CF3, -CCl3); -CN; -NCOCOCH2CH2; -NCOCOCHCH; and -NCS; and combinations thereof.

[0060] It will be understood by those skilled in the art that, if appropriate, the substituted moieties on the hydrocarbon chain can themselves be substituted. For example, the substituents of a substituted alkyl group can include halogen, hydroxyl, nitro, thiol, amino, aralkyl, azido, imine, amido, phosphine, phosphineoxy, phosphineyl, phosphoryl (including phosphonate and phosphinite), oxo, sulfonyl (including sulfate, sulfamide, sulfamoyl, and sulfonate), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketone, aldehyde, carboxylate, and ester), haloalkyl, -CN, and the like. Cycloalkyl groups can be substituted in the same manner.

[0061] "Lower alkyl" as used herein, unless the number of carbons is otherwise specified, refers to an alkyl radical as defined above but having from 1 to 10 carbon atoms in the main chain structure, more preferably 1 to 6 carbon atoms. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0062] "Heteroalkyl" as used herein refers to a straight or branched chain or cyclic carbon-containing alkyl group or combinations thereof containing at least one heteroatom in the carbon backbone. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkyl group" refers to a cycloalkyl group as defined above wherein at least one carbon atom in the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0063] The term "alkenyl" as used herein is a hydrocarbon group of 2 to 24 carbon atoms and the structural formula contains at least one carbon-carbon double bond. Alkenyl groups include straight chain alkenyl groups, branched chain alkenyl groups, and cyclic alkenyl groups. Cyclic alkenyl groups are non-aromatic carbon-based rings composed of at least three carbon atoms and at least one carbon-carbon double bond, such as non-aromatic monocyclic or non-aromatic polycyclic rings containing 3-30 carbon atoms and at least one carbon-carbon double bond, 3-20 carbon atoms and at least one carbon-carbon double bond, or 3-10 carbon atoms and at least one carbon-carbon double bond in the ring structure, and having 5, 6, or 7 carbon atoms and at least one carbon-carbon double bond in the ring structure. Cyclic alkenyl groups containing polycyclic systems can have two or more non-aromatic rings, wherein two or more carbons are shared by two adjacent rings (i.e., "fused ring alkenyl rings") and contain at least one carbon-carbon double bond. Asymmetric structures such as (AB)C=C(C'D) are intended to encompass both the E and Z isomers. This can be inferred in the structural formulae herein where asymmetric alkenes are present, or can be explicitly indicated with the bond symbol C. The term "alkenyl" as used throughout the specification, examples and claims is intended to encompass both "unsubstituted alkenyl" and "substituted alkenyl", where the latter refers to alkenyl moieties having one or more substituents on one or more carbons of the substituted hydrocarbon backbone. The term "alkenyl" also includes "heteroalkenyl".

[0064] The term "substituted alkenyl" refers to an alkenyl moiety having one or more substituents that replace a hydrogen atom on one or more carbons of the hydrocarbon backbone. Such substituents can be any of the substituents described above, for example halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphion, phosphine, phospho, phosphinate, phosphonate, phosphite, amine (such as quaternized amines), amide, amidine, imine, cyano, nitro, azido, oxo, thia, alkylthio, sulfate, sulfonate, sulfamide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0065] As used herein, "heteroalkenyl" refers to a straight, branched, or cyclic carbon-containing alkenyl group or combinations thereof containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkenyl group" refers to a cycloalkenyl group in which at least one carbon atom in the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0066] As used herein, the term "alkynyl group" is a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups include straight chain alkynyl groups, branched chain alkynyl groups, and cycloalkynyl groups. Cycloalkynyl groups are non-aromatic carbon-based rings composed of at least three carbon atoms and at least one carbon-carbon triple bond, such as non-aromatic monocyclic or non-aromatic polycyclic rings containing 3-30 carbon atoms and at least one carbon-carbon triple bond, 3-20 carbon atoms and at least one carbon-carbon triple bond, or 3-10 carbon atoms and at least one carbon-carbon triple bond, and having 5, 6, or 7 carbons and at least one carbon-carbon triple bond in the ring structure. Cycloalkynyl groups containing polycyclic systems can have two or more non-aromatic rings with two or more carbons common to two adjacent rings (i.e., "fused ring cycloalkynyl rings") and containing at least one carbon-carbon triple bond. Asymmetric structures such as (AB)C≡C(C"D) are intended to include both the E and Z isomers. This can be inferred in structural formulae herein where there is an asymmetric alkynol, or it can be explicitly indicated with the bond symbol C. The term "alkynyl" as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," where the latter refers to an alkynyl moiety having one or more substituents that replace a hydrogen on one or more carbons of the hydrocarbon backbone. The term "alkynyl" also includes "heteroalkynyl."

[0067] The term "substituted alkynyl" refers to an alkynyl moiety having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can be any substituents described above, for example halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphonyl, phospho, phosphinate, phosphonate, phosphite, amido (such as a quaternized amido), amide, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, -CC13), -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0068] "Heteroalkynyl" as used herein refers to a straight or branched or cyclic carbon-containing alkynyl group containing at least one heteroatom or combinations thereof. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, wherein the nitrogen, phosphorus and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. For example, the term "heterocycloalkynyl group" is a cycloalkynyl group in which at least one carbon atom in the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.

[0069] "Aryl" as used herein refers to a C4-C 26 A meta-aryl group is an aryl group having one or more non- aromatic rings fused to one or more aromatic rings. Examples of meta-aryl groups are indenyl, indanyl, benzocyclopentadiene, benzocyclohexadiene, and the like.

[0070] The term "substituted aryl" refers to an aryl group in which one or more hydrogen atoms on one or more aromatic rings are replaced by one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, carbonyl (such as ketone, aldehyde, carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphonyl, phospho, phosphinate, phosphonate, phosphite, amido (or quaternized amido), amide, amidine, imine, cyano, nitro, azido, thiol, imino, alkylthio, sulfate, sulfonate, sulfamide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, -CC13), -CN, aryl, heteroaryl, and combinations thereof.

[0071] "Heterocycle" and "heterocyclyl" are used interchangeably and refer to cyclic groups attached via a ring carbon or nitrogen atom of a monocyclic or polycyclic ring system containing 3-30 ring atoms, 3-20 ring atoms, 3-10 ring atoms, or 5-6 ring atoms, wherein the polycyclic ring system contains one or more non-aromatic rings and optionally one or more aromatic rings, wherein at least one non-aromatic ring contains carbon and 1 to 4 heteroatoms each selected from non-peroxidic oxygen, sulfur, and N(Y), wherein Y is absent or H, O, C1-C6alkyl, or phenyl or benzyl, and optionally contains 1-3 double bonds, and is optionally substituted with one or more substituents. By definition, heterocyclyl is not the same as heteroaryl. Heterocycles can be heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, and the like, such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl. Heterocyclyl groups can be optionally substituted with one or more substituents as defined above for alkyl and aryl. 10 alkyl, phenyl, or benzyl, and optionally contains 1-3 double bonds, and is optionally substituted with one or more substituents. By definition, heterocyclyl is not the same as heteroaryl. Heterocycles can be heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, and the like, such as piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, dihydrofuro[2,3-b]tetrahydrofuran, morpholinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyranyl, 2H-pyrrolyl, 4H-quinolizinyl, quinuclidinyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl. Heterocyclyl groups can be optionally substituted with one or more substituents as defined above for alkyl and aryl.

[0072] The term "heteroaryl" refers to C3-C 26heteroatom. Suitable heteroatoms include, but are not limited to, oxygen, sulfur, and nitrogen. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Examples of heteroaryl rings include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indoleninyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinoaxazole, pyridinoimidazole, pyridinothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, and xanthenyl. One or more rings can be substituted as defined below for "substituted heteroaryl."

[0073] The term "substituted heteroaryl" refers to a heteroaryl group in which one or more of the hydrogen atoms on one or more of the heteroaryl rings are replaced by one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, carbonyl (such as ketone, aldehyde, carboxyl, carboalkoxy, formyl or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, thiol, imino, alkylthio, sulfate, sulfonate, sulfamido, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl (such as CF3, -CH2-CF3, -CC13), -CN, aryl, heteroaryl, and combinations thereof.

[0074] The term "polyaryl" refers to a fused ring system comprising two or more aromatic rings and optionally one or more non-aromatic rings. Examples of polyaryl groups are naphthalene, anthracene, phenanthrene, pyrene, chrysene, coronene, and the like. When the fused ring system contains two or more aromatic rings and optionally one or more non-aromatic rings, wherein one or more of the carbon atoms in the structure of one or more of the aromatic rings is replaced by a heteroatom, the fused ring system can be referred to as a "polyheteroaryl." When the fused ring system contains two or more aromatic rings and optionally one or more non-aromatic rings, wherein one or more of the carbon atoms in the fused ring system is replaced by a heteroatom, the fused ring system can be referred to as a "heteropolyaryl." The term "substituted polyaryl" refers to a polyaryl group in which one or more of the aryl groups is substituted by one or more substituents including, but not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, carboalkoxy, formyl or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (or quaternized amino), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamido, sulfoxide, sulfonamido, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. When referring to a polyheteroaryl, the chemical moiety can be referred to as a "substituted polyheteroaryl."

[0075] The term "ring" or "cyclic group" refers to a substituted or unsubstituted monocyclic ring or a substituted or unsubstituted polycyclic ring (such as those formed from a monocyclic ring system or a fused ring system), such as a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, or substituted or unsubstituted heterocyclyl, having from 3 to 30 carbon atoms where the geometry permits. Substituted cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl groups are substituted as defined above for alkyl, alkenyl, alkynyl, and heterocyclyl, respectively.

[0076] The term "aralkyl" as used herein refers to an aryl group or a heteroaryl group having an alkyl, alkenyl or alkynyl group as defined above attached to an aromatic group such as aryl, heteroaryl, polyaryl or polyheteroaryl. An example of an aralkyl group is a benzyl group.

[0077] The terms "alkoxyl" or "alkoxy", "aroxy" or "aryloxy" generally describe a compound of the formula -OR v where R v include, but are not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted carbonyl, phosphonium, phosphinyl, phosphonyl, sulfinyl, silyl, thiol, amido, and amino. Exemplary alkoxyl groups include methoxyl, ethoxyl, propoxyl, t-butoxyl, and the like. A "lower alkoxyl" group is an alkoxyl group containing one to six carbon atoms. An "ether" is two functional groups covalently linked by an oxygen as defined below. Thus, an alkyl substituent that makes an alkyl into an ether is an alkoxyl or similar alkoxyl such as can be represented by -O-alkyl, -O-alkenyl, -O-alkynyl, -O-aralkyl, -O-aryl, -O-heteroaryl, -O-polyaryl, -O-polyheteroaryl, -O-heterocyclyl, and the like.

[0078] The term "substituted alkoxyl" refers to an alkoxyl group having one or more substituents that replace one or more hydrogen atoms on one or more carbons of the alkoxyl backbone. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl such as carboxyl, alkoxycarbonyl, formyl, or acyl, silyl, ether, ester, thiocarbonyl such as thioester, thioacetate, or thioformate, alkoxyl, phosphonium, phosphinyl, phosphoryl, phosphate, phosphonate, phosphinate, amino (for example, ammonium, quaternized amines), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, oxy, sulfate, sulfonate, sulfamidate, sulfamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof.

[0079] The term "ether" as used herein is represented by the formula A 2 OA 1 where A2 and A 1 may independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphinyl, phosphonyl, sulfinyl, silyl, thiol, substituted or unsubstituted carbonyl, alkoxy, amido, or amino.

[0080] The term "polyether" as used herein is represented by the following formula:

[0081]

[0082] where A 3 may independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, phosphonium, phosphinyl, substituted or unsubstituted carbonyl, alkoxy, amido, or amino; g can be a positive integer from 1 to 30.

[0083] The term "phenoxy" is art-recognized and refers to a compound of the formula -OR v where R v is C6H5 (i.e., -O-C6H5). One of skill in the art recognizes that phenoxy is a type of aryloxy.

[0084] The term "substituted phenoxy" refers to a phenoxy group as defined above having one or more substituents replacing one or more hydrogen atoms on one or more carbons of the phenyl ring. Such substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl such as carboxyl, alkoxycarbonyl, formyl, or acyl; silyl; ether; ester; thiocarbonyl such as thioester, thioacetate, or thioformate; alkoxyl; phosphiono; phosphonyl; phospho; phosphinate; amino; quaternized amino; amido; amidine; imine; cyano; nitro; azido; thiol; alkylthio; sulfate; sulfonate; sulfamido; sulfamide; sulfonyl; heterocyclyl; alkylaryl; haloalkyl; -CN; aryl; heteroaryl; and combinations thereof.

[0085] The terms "aroxy" and "aryloxy" are used interchangeably herein and are represented by -O-aryl or -O-heteroaryl, where aryl and heteroaryl are as defined herein.

[0086] The terms "substituted aroxy" and "substituted aryloxy," used interchangeably herein, represent -O-aryl or -O-heteroaryl having one or more substituents substituting one or more hydrogen atoms on one or more ring atoms of the aryl and heteroaryl groups, as defined herein. Such substituents can be any substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphion, phosphine, phosphonyl, phosphate, phosphinate, phosphonate, phosphinite, amino (such as quaternized amino), amido, amidine, imine, cyano, nitro, azo, thiol, alkylthio, sulfate, sulfonate, sulfamide, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof.

[0087] The term "amino" as used herein includes the following groups

[0088]

[0089] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein R x , R xi and R xii each independently represent substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (such as substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxy, alkoxy, phosphion, phosphine, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH2) m R'" represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphion group, an amido group, or an amino group; m is zero or an integer from 1 to 8. The term "quaternary amino" also includes where the nitrogen, Rx R xi and R xii and the N + to which they are attached form a heterocyclyl or heteroaryl group having 3 to 14 atoms in the ring structure. Those skilled in the art will appreciate that the above recited E groups are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0090] The terms "amide" or "amido" are used interchangeably and refer to "unsubstituted amido" and "substituted amido" and are represented by the following general formula:

[0091]

[0092] wherein E is absent or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, or substituted or unsubstituted heterocyclyl, wherein R and R' each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH2) m R" or R and R' together with the N atom to which they are attached form a heterocycle having 3 to 14 atoms in the ring structure; R" represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, phosphonium, phosphinyl, amido, or amino; and m is 0 or an integer from 1 to 8. In some forms, when E is oxygen, a carbamate is formed. Those skilled in the art will appreciate that the above recited E groups are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0093] "Carbonyl" as used herein is art-recognized and includes such moieties that can be represented by the general formula:

[0094]

[0095] wherein X is a bond, or represents oxygen or sulfur, and R represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, amido, amino, or -(CH2) m or a pharmaceutically acceptable salt; E" is absent, or E" is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl; R' represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, amido, amino, or -(CH2) mR"; R" represents a hydroxyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphine group, an amide group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphonium, phosphine, phosphonyl, phosphate, phosphinate, sulfhydryl, alkylthio, sulfate, sulfamate, sulfamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the above-listed E" groups are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl). When X is oxygen and R is as defined above, the moiety is also referred to as a carboxyl group. When X is oxygen and R is hydrogen, the formula represents a "carboxylic acid." When X is oxygen and R' is hydrogen, the formula represents a "formate." When X is oxygen and R or R' is other than hydrogen, the formula represents an "ester." In general, when the oxygen atom in the above formula is replaced with a sulfur atom, the formula represents a "thiocarbonyl" group. When X is sulfur and R or R' is other than hydrogen, the formula represents a "thioester." When X is sulfur and R is hydrogen, the formula represents a "thiocarboxylic acid." When X is sulfur and R' is hydrogen, the formula represents a "thioformate." When X is a bond and R is other than hydrogen, the above formula represents a "ketone." When X is a bond and R is hydrogen, the above formula represents an "aldehyde."

[0096] The term "phosphine" is represented by the formula

[0097]

[0098] wherein E is absent or E is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted heterocyclyl group, wherein R vi and R viieach independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH2) m -R”’, or R vi and R vii together with the P atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R”’ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (such as quaternary vi , R vii and R viii together with the P atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R”’ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (such as quaternary

[0099] The term “phosphonium” is represented by the formula

[0100]

[0101] wherein E is absent or E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, wherein independently of E, R vi , R vii and R viii together with the P atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R”’ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (such as quaternaryeach independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH2) m -R”’, or R vi , R vii , and R viii together with the P + atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R”’ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphinate, phosphonate, phosphide, amino (such as quaternary

[0102] The term "phosphonyl" is represented by the formula

[0103]

[0104] wherein E is absent or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, oxygen, alkoxy, aryloxy, or substituted alkoxy or substituted aryloxy, wherein, independent of E, R vi and R vii are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, phosphonyl, sulfinyl, silyl, thiol, amido, amino, or -(CH2) m -R”’, or R vi and R vii together with the P atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R”’ represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the above-described substituents, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (such as, for example, quaternary amines), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamoyl, sulfamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations of such groups. It is understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0105] The term "phosphoryl" defines a phosphonyl group wherein E is absent, or is oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above, and independent of E, R viand R vii independently hydroxyl, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above. As understood by one of ordinary skill in the art, when E is oxygen, the phosphoroyl group cannot be attached to another chemical species, such as to form an oxygen-oxygen bond or other unstable bond. When E, R vi and R vii When substituted, substituent groups include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphonyl, phosphoester, phosphinate, amino (for example, a quaternized amino group), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonamide, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. As will be understood by one of ordinary skill in the art, the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0106] The term "sulfinyl" is represented by the formula

[0107]

[0108] where E is absent, or E is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, where R, independently of E, represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted heterocyclyl, hydroxyl, alkoxy, phosphonium, phosphinyl, phosphonyl, silyl, thiol, amido, amino, or -(CH2) m- R", or E and R together with the S atom to which they are attached form a heterocycle having 3 to 14 atoms in the ring structure; R" represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino (such as, for example, quaternary

[0109] The term "sulfonyl" is represented by the formula

[0110]

[0111] where E is absent, or E is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group (e.g., a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted aralkyl group, etc.), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, where, independently of E, R represents hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aralkyl group (e.g., a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted aralkyl group), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted heterocyclyl group, a hydroxyl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, an amino group, or -(CH2) m- R", or E and R together with the S atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R" represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium group, a phosphinyl group, an amido group, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphinate, phosphonate, phosphinate, amino (such as, for example, quaternary amines), amido (such as, for example, ketone imines, aldehyde imines, imine imines, and enamines), amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamidate, sulfamidite, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl groups, and combinations thereof. It will be understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0112] The term "sulfonic acid" refers to a sulfonyl group as defined above, where R is a hydroxyl group, and E is absent, or E is a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, or a substituted or unsubstituted heteroaryl group. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphinate, phosphonate, phosphinate, amino (such as, for example, quaternary amines), amido (such as, for example, ketone imines, aldehyde imines, imine imines, and enamines), amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonate, sulfamidate, sulfamidite, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl groups, and combinations thereof. It will be understood by those skilled in the art that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0113] The term "sulfate" refers to a sulfonyl group as defined above, where E is absent, or is oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above, and R is independently hydroxy, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above. When E is oxygen, the sulfate cannot be linked to another chemical species, such as to form an oxygen-oxygen bond or other unstable bond, as would be understood by one of ordinary skill in the art. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphoester, phosphinoester, phosphine, amino (for example, a quaternized amino group), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonamide, sulfamoyl, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (for example, methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0114] The term "sulfate" refers to a sulfonyl group as defined above, where E is absent, or is oxygen, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above, and R is independently hydroxy, alkoxy, aryloxy, substituted alkoxy, or substituted aryloxy, as defined above. When E is oxygen, the sulfate cannot be linked to another chemical species, such as to form an oxygen-oxygen bond or other unstable bond, as would be understood by one of ordinary skill in the art. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphoester, phosphinoester, phosphine, amino (for example, a quaternized amino group), amido, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonamide, sulfamoyl, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (for example, methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl). mR", R" represents a hydroxyl group, a substituted or unsubstituted carbonyl group, an aryl group, a cycloalkyl ring, a cycloalkenyl ring, a heterocyclic ring, an amide group, an amino group, or a polycyclic ring; and m is zero or an integer from 1 to 8. When E is oxygen, the sulfonate ester cannot be attached to another chemical species, such as to form an oxygen-oxygen bond or other unstable bond, as would be understood by one of ordinary skill in the art. Such substituents can be any of the substituents described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphoester, phosphinoester, phosphinothioester, amino (such as, for example, a quaternized amino group), amide, amidine, imine, cyano, nitro, azido, thiol, alkylthio, sulfate, sulfonamide, sulfamoyl, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations thereof. It will be understood by those of ordinary skill in the art that the E groups listed above are divalent (e.g., methylene, ethane- 1,2-diyl, ethene- 1,2-diyl, 1,4-phenylene, cyclohexane- 1,2-diyl).

[0115] The term "sulfamoyl" refers to a sulfonamide or a sulfonamide represented by the formula

[0116]

[0117] where E is absent or E is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aralkyl group (e.g., a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted aralkyl group, etc.), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted heterocyclyl group, where, independently of E, R and R' each independently represent hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aralkyl group (e.g., a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted aralkyl group, etc.), a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted heterocyclyl group, a hydroxyl group, an alkoxyl group, a phosphonium group, a phosphino group, an amide group, an amino group, or -(CH2) m- R", or R and R' together with the N atom to which they are attached form a heterocyclic ring having 3 to 14 atoms in the ring structure; R" represents a hydroxyl group, a substituted or unsubstituted carbonyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, an alkoxy group, a phosphonium, a phosphinyl, an amido, or an amino group; and m is zero or an integer from 1 to 8. Such substituents can be any of the substituents described above, for example halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphinate, phosphonate, phosphinate, amino (such as, for example, quaternized

[0118] As used herein, the term "silyl group" is represented by the formula -SiRR'R", where R, R', and R" can independently be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group (such as, for example, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted aralkyl group, and the like), a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted carbonyl group, a phosphonium, a phosphinyl, a phosphonyl, a sulfinyl, a thiol, an amido, an amino group, an alkoxy group, or an oxo group, as described above. Such substituents can be any of the substituents described above, for example halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphinate, phosphonate, phosphinate, amino (such as, for example, quaternized

[0119] The term "thiol" is used interchangeably and is represented by -SR, where R can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl (e.g., substituted or unsubstituted alkylaryl, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted carbonyl, phosphonium, phosphinyl, amido, amino, alkoxy, oxo, phosphono, sulfinyl, or silyl, as described above. Such substituents can be any of the substituents described above for "substituted" groups, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), silyl, ether, ester, thio carbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, sulfonate, sulfamidate, sulfamidate, sulfanyl, sulfate, sulfonate ester, sulfonamide, sulfonyl, heterocyclyl, alkylaryl, haloalkyl, -CN, aryl, heteroaryl, polyaryl, polyheteroaryl, and combinations of such groups.

[0120] The disclosed compounds and substituents can independently have two or more of the above-listed groups. For example, if a compound or substituent is a straight-chain alkyl group, one hydrogen atom of the alkyl group can be replaced with a hydroxyl group, an alkoxy group, etc. Depending on the groups selected, the first group can be incorporated within the second group, or alternatively, the first group can be pendant (i.e., attached) to the second group. For example, for the phrase "alkyl group comprising an ester group," the ester group can be incorporated within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the selected group(s) will determine whether the first group is embedded in or attached to the second group.

[0121] The compounds and substituents can be independently substituted with the substituents described in the definition of "substituted" above.

[0122] Numerical ranges recited herein are inclusive of the entire range of values between the recited minimum and maximum values. When numerical ranges are recited herein, these include all the smaller sub-ranges falling within the recited ranges. For instance, a range from about 1 to 10 also discloses the sub-ranges from 1 to 6.1 to 2.2 to 4 or 3.5 to 10, etc.

[0123] The use of the term“about” is intended to describe values that are near to the stated value of the term so modified, but are not necessarily exactly thereto. Unless otherwise stated, when the term“about” is used in reference to a numerical range (i.e., about 1-5) or a series of numbers (i.e., about 1, 2, 3, 4, etc.), it is intended to modify the two end values of the numerical range and / or each number recited in the series.

[0124] The disclosed compounds and substituents can independently have two or more of the above-listed groups. For example, if a compound or substituent is a straight-chain alkyl group, one hydrogen atom of the alkyl group can be replaced by a hydroxyl group, an alkoxy group, etc. Depending on the group chosen, the first group can be embedded within the second group, or alternatively, the first group can be pendant (i.e., attached) to the second group. For example, for the phrase“an alkyl group comprising an ester group,” the ester group can be embedded within the backbone of the alkyl group. Alternatively, the ester can be attached to the backbone of the alkyl group. The nature of the selected group(s) will determine whether the first group is embedded or attached to the second group.

[0125] The compounds and substituents can be independently substituted with the substituents described in the definition of“substituted” above.

[0126] II. Compositions

[0127] Catalytic systems have been developed that are capable of catalyzing C-H functionalization reactions such as C-H amination with enantioselectivity. These catalytic systems comprise an iron complex as a host catalyst and a diammonium guest template as a co-catalyst. The iron-based host catalyst comprises a crown ether phthalocyanine as a supporting ligand. The diammonium guest template is a bidentate compound with chirality. The structure of the iron-based host catalyst and the bidentate ammonium guest template of the catalytic system enables them to interact, providing a complex spatial environment that enables stereodirected and site-selective C-H functionalization such as enantioselective C-H amination. The terms “enantioselective C-H amination” and “asymmetric C-H amination” are used interchangeably herein. For example, the disclosed catalytic systems can catalyze C-H amination with high enantioselectivity (i.e., at least 2: 1) and optionally high yield (i.e., > 30%) under mild reaction conditions such as room temperature.

[0128] Without being bound by any theory, it is believed that the bidentate ammonium guest template can spontaneously self-assemble with the iron-based host catalyst to form a supramolecular structure through non-covalent interactions between the ammonium groups and the crown ether component of the host catalyst. The strong binding affinity (i.e., log(K) of at least 4.0) of the bidentate ammonium guest template to the crown ether-containing host catalyst stabilizes the overall supramolecular structure and provides thermal stability to the catalytic system. Such thermally stable supramolecular structures can provide a favorable spatial environment for stereodirected and site-selective C-H functionalization such as enantioselective C-H amination.

[0129] A. Iron-based host catalyst

[0130] The disclosed catalytic systems contain an iron-based host catalyst (also referred to herein as “host catalyst”). The host catalyst comprises a crown ether phthalocyanine as a supporting ligand. The pi-accepting phthalocyanine backbone of the ligand can provide the iron-based host catalyst with improved reactivity and stability. The inclusion of a crown ether substituent on the core phthalocyanine backbone can provide supramolecular chemistry properties for creating structural complexity. For example, the crown ether component of the supporting ligand enables non-covalent interactions (such as ionic interactions, hydrogen bonding, van der Waals forces, pi effects, hydrophobic / hydrophilic effects, etc.) with various functional groups (such as ammonium, e.g., the ammonium groups of the bidentate ammonium guest templates described herein) to create a complex spatial environment for stereodirected and site-selective reactions such as enantioselective C-H amination.

[0131] The disclosed iron-based host catalysts can have the structure of Formula I:

[0132]

[0133] wherein: (i) each occurrence of A, together with the carbon atom to which it is attached, can form a crown ether; (ii) each occurrence of R1and R2may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, halide, hydroxyl, alkoxy, amino, amido, carbonyl, nitro, nitrile, or thiol; and (iii) the substituents can independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof.

[0134] In some versions of Formula I, each occurrence of A, together with the carbon atom to which it is attached, can form a 12-crown-4-ether, 15-crown-5-ether, 18-crown-6-ether, dibenzo-18-crown-6-ether, 24-crown-8-ether, or azacrown ether.

[0135] In some versions, the host catalyst can have the structure of Formula II:

[0136]

[0137] wherein R1and R2are as defined above for Formula I.

[0138] For either of Formula I and Formula II, each occurrence of R1and R2may independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl. For example, in some versions, each occurrence of R1and R2in Formula I and / or Formula II is hydrogen.

[0139] In some versions, the host catalyst can have the following structure:

[0140]

[0141] B. Diammonium Guest Templates

[0142] The disclosed catalytic system also includes as a co-catalyst a bidentate ammonium guest template (also referred to herein as a "guest template" or "diammonium template"). The guest template includes a chiral backbone and at least two terminal ammonium groups that can bind to the crown ether component of the host catalyst via non-covalent interactions, such as through hydrogen bonding.

[0143] The disclosed guest template can have the structure of Formula III:

[0144]

[0145] wherein: (i) B1and B2may independently be absent, or a carbon atom, a substituted or unsubstituted aryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyaryl group, or a substituted or unsubstituted heterocyclic group; (ii) R3and R4may independently be absent, or hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyaryl group, or a substituted or unsubstituted heterocyclic group; (iii) —— can be absent or a bond (single, double, or triple bond); (iv) X1and X2may independently be absent, or an oxygen atom or NR5, and R5is absent, or hydrogen, or a substituted or unsubstituted alkyl group; (v) L1and L2may independently be absent, or a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyaryl group, or a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, or a substituted or unsubstituted cycloalkynyl group; (vi) n1and n2may independently be an integer from 0 to 20; and (vii) the substituents can independently be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted aralkyl group, a carbonyl group, a halide, a hydroxyl group, a phenoxy group, an aryloxy group, an alkylthio group, a phenylthio group, an arylthio group, a cyano group, an isocyano group, an alkoxy group, a nitro group, a carboxyl group, an amino group, an amide group, an oxo group, a silyl group, a sulfinyl group, a sulfonyl group, a sulfonic acid, a phosphonium, a phosphine group, a phosphoryl group, a phosphonate group, or a thiol, or a combination thereof. X3may be a nitrogen atom or CR6, R6is hydrogen or a substituted or unsubstituted alkyl group, Q1and Q2may independently be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyaryl group, or a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, or a substituted or unsubstituted cycloalkynyl group; (vi) n1and n2may independently be an integer from 0 to 20; and (vii) the substituents can independently be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted aralkyl group, a carbonyl group, a halide, a hydroxyl group, a phenoxy group, an aryloxy group, an alkylthio group, a phenylthio group, an arylthio group, a cyano group, an isocyano group, an alkoxy group, a nitro group, a carboxyl group, an amino group, an amide group, an oxo group, a silyl group, a sulfinyl group, a sulfonyl group, a sulfonic acid, a phosphonium, a phosphine group, a phosphoryl group, a phosphonate group, or a thiol, or a combination thereof.

[0146] In some versions of Formula III, B1and B2may independently be a carbon atom, a substituted or unsubstituted aryl group, or a substituted or unsubstituted polyaryl group; and R3and R4are independently absent, hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aralkyl group.

[0147] Typically, Formula III is contains one or more chiral centers. For example, in some versions of Formula III, may be one of the following:

[0148]

[0149] where X1and X2may independently be an oxygen atom or NR5, R5may be absent or hydrogen; n4and n5may independently be an integer from 0 to 5; n6, n7, n8, and n 10 may independently be an integer from 0 to 4; n9and n 11 may independently be an integer from 0 to 2; n 12 - n 14 may independently be an integer from 1 to 6; and R7-R 14 may independently be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyaryl group, or a substituted or unsubstituted heterocyclic ring.

[0150] In some versions of Formula III, L1and L2may independently be where X3may be a nitrogen atom, and where Q1and Q2may independently be a substituted or unsubstituted aryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, or a substituted or unsubstituted cycloalkynyl group. For example, Q1and Q2are unsubstituted phenyl groups.

[0151] In some forms, the guest template is a salt form of the structure of Formula III. In these forms, the guest template comprises a cationic component having the structure of Formula III and an anion. Any suitable anion can be used to form the guest template, such as tetrafluoroborate, acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / dihydrogen phosphate / bisodium phosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate. In some forms, the guest template contains a cationic component having the structure of Formula III and a tetrafluoroborate anion.

[0152] In some forms, the guest template can have any one of the following structures:

[0153]

[0154]

[0155] C. Catalytic system

[0156] The catalytic system disclosed herein comprises an iron-based host catalyst and a bidentate ammonium guest template, such as any of the host catalysts and any of the guest templates described above. Generally, the molar ratio of the host catalyst to the guest template of the catalytic system can be in the range of 1 : 10 to 1 : 1, 1 : 5 to 1 : 1, such as 1 : 2.

[0157] The structures of the host catalyst and the guest template enable them to interact with each other, such as through non-covalent interactions, to provide a complex spatial environment suitable for stereodirecting and site-selective C-H functionalization, such as C-H amination. For example, without being bound by any theory, it is believed that the bidentate ammonium guest template can spontaneously self-assemble with the iron-based host catalyst through non-covalent interactions between the ammonium group and the crown ether component of the host catalyst to form a supramolecular structure, such as the structure of Formula IV shown below. The supramolecular structure formed by the host catalyst and the guest template can be examined using spectroscopic methods, such as by using NMR, UV-visible, and / or CD spectroscopy.

[0158]

[0159] The supramolecular structure can provide a spatial environment for stereodirecting and site-selective C-H functionalization such as C-H amination. For example, the disclosed catalytic system can catalyze C-H amination with high enantioselectivity (i.e., at least 2: 1).

[0160] Further, the bidentate ammonium guest template can bind to the crown ether-containing host catalyst with strong binding affinity (i.e., a log(K) of at least 4.0). For example, the binding between the host catalyst and the guest template has a log(K) of at least 4.0, such as in a range of 4.0 to about 8.0 or 4.0 to about 6.0. Such binding affinity can stabilize the overall supramolecular structure, thereby providing thermal stability to the catalytic system. This enables enantioselective chemical reactions such as enantioselective C-H amination at room temperature, in contrast to enantioselective C-H amination using rhodium catalysts known in the art, which requires low temperature (typically -10 °C to -35 °C) (e.g., see C. Liang et al., Angew. Chem. Int. Ed. 2006, 45, 4641-4644; C. Liang et al., J. Am. Chem. Soc. 2008, 130, 343-350). For example, the disclosed catalytic system can catalyze C-H amination with high enantioselectivity (i.e., at least 2: 1) and optionally high yield (i.e., > 30%) under mild reaction conditions such as at room temperature.

[0161] In some forms, the host catalyst and the guest template can form any of the following supramolecular structures:

[0162]

[0163] In some forms, for any of Formulae I-V above, when present, the substituent groups can independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted alkylaryl (e.g., benzyl), carbonyl (e.g., carboxyl, ester, etc.), alkoxy (e.g., methoxy, ethoxy, aryloxy, benzoate, etc.), halide, hydroxyl, or haloalkyl, or combinations thereof.

[0164] For any of Formulae I-V above, the alkyl group can be a straight chain alkyl, a branched chain alkyl, or a cyclic alkyl (mono- or polycyclic). The terms "cyclic alkyl" and "cycloalkyl" are used interchangeably herein. Exemplary alkyl groups include straight chain C1-C 30 alkyl, branched C4-C 30 alkyl, cyclic C3-C 30 alkyl, straight chain C1-C 20 alkyl, branched C4-C 20 alkyl, cyclic C3-C20 alkyl, straight chain C1-C 10 alkyl, branched C4-C 10 alkyl, cyclic C3-C 10 alkyl, straight chain C1-C6alkyl, branched C4-C6alkyl, cyclic C3-C6alkyl, straight chain C1-C4alkyl, cyclic C3-C4alkyl, such as straight chain C1-C 10 , C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2alkyl group, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4alkyl group, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C 3-6 , C3-C5, or C3-C4alkyl group. Cyclic alkyl groups can be monocyclic or polycyclic alkyl groups, such as C4-C 30 , C4-C 25 , C4-C 20 , C4-C 18 , C4-C 16 , C4-C 15 , C4-C 14 , C4-C 13 , C4-C 12 , C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5monocyclic or polycyclic alkyl group.

[0165] For any of Formulae I-V above, alkenyl groups can be straight chain alkenyl, branched alkenyl, or cyclic alkenyl (monocyclic or polycyclic). The terms "cyclic alkenyl" and "cycloalkenyl" are used interchangeably herein. Exemplary alkenyl groups include straight chain C2-C 30 alkenyl, branched C4-C 30 alkenyl, cyclic C3-C 30 alkenyl, straight chain C2-C 20 alkenyl, branched C4-C 20 alkenyl, cyclic C3-C 20 alkenyl, straight chain C2-C 10 alkenyl, branched C4-C 10 alkenyl, cyclic C3-C 10 alkenyl, straight chain C2-C6alkenyl, branched C4-C6alkenyl, cyclic C3-C6alkenyl, straight chain C2-C4alkenyl, cyclic C3-C4alkenyl, such as straight chain C2-C 10C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkenyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups. Cyclic alkenyl groups can be monocyclic or polycyclic alkenyl groups, such as C4-C 30 C4-C 25 C4-C 20 C4-C 18 C4-C 16 C4-C 15 C4-C 14 C4-C 13 C4-C 12 C4-C 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 monocyclic or polycyclic alkenyl groups.

[0166] For any of Formulae I-V above, alkynyl groups can be linear alkynyl, branched alkynyl, or cyclic alkynyl (monocyclic or polycyclic). The terms “cyclic alkynyl” and “cycloalkynyl” are used interchangeably herein. Exemplary alkynyl groups include linear C2-C 30 branched C4-C 30 cyclic C3-C 30 linear C2-C 20 branched C4-C 20 cyclic C3-C 20 linear C2-C 10 branched C4-C 10 cyclic C3-C 10 linear C2-C6 alkynyl, branched C4-C6 alkynyl, cyclic C3-C6 alkynyl, linear C2-C4 alkynyl, cyclic C3-C4 alkynyl, such as linear C2-C 10 C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkynyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkynyl groups. Cyclic alkynyl groups can be monocyclic or polycyclic alkynyl groups, such as C4-C 30 C4-C 25 C4-C 20 C4-C 18 C4-C 16C4-C 15 C4-C 14 C4-C 13 C4-C 12 C4-C 10 C4-C9, C4-C8, C4-C7, C4-C6 or C4-C5 monocyclic or polycyclic alkynyl groups.

[0167] It should be understood that any exemplary alkyl, alkenyl, and ynyl groups can be heteroalkyl, heteroalkenyl, and heteroynyl, respectively.

[0168] For any of the above formulas IV, the aryl group can be C5-C. 30 Aryl, C5-C 20 Aryl, C5-C 12 Aryl, C5-C 11 Aryl, C5-C9 aryl, C6-C 20 Aryl, C6-C 12 Aryl, C6-C 11 Aryl or C6-C9 aryl. It should be understood that aryl can be heteroaryl, such as C5-C9. 30 heteroaryl, C5-C 20 heteroaryl, C5-C 12 heteroaryl, C5-C 11 heteroaryl, C5-C9 heteroaryl, C6-C 30 heteroaryl, C6-C 20 heteroaryl, C6-C 12 heteroaryl, C6-C 11 Heteroaryl or C6-C9 heteroaryl. For any of formulas I, Ia, II, III, and IV, the polyaryl group can be C 10 -C 30 Polyaryl, C 10 -C 20 Polyaryl, C 10 -C 12 Polyaryl, C 10 -C 11 Polyaryl or C 12 -C 20 Polyaryl. It should be understood that aryl groups can be polyheteroaryl, such as C... 10 -C 30 Polyarylene, C 10 -C 20 Polyarylene, C 10 -C 12 Polyarylene, C 10 -C 11 Polyarylene or C 12 -C 20 Multi-aryl aromatics.

[0169] III. Methods of Preparation and Reagents Thereof

[0170] The iron-based host catalysts, ligands forming the host catalysts, and diammonium templates described herein can be synthesized using methods known in the art of organic chemical synthesis.

[0171] The target host catalysts can be synthesized by reacting the corresponding crown ether phthalocyanine ligand with an iron precursor in a suitable solvent. The corresponding ligand(s) can be prepared using methods known in the art, such as those described in the Examples. The reaction solution containing the corresponding crown ether phthalocyanine ligand and the iron precursor can be stirred at room temperature, and optionally under an inert gas atmosphere, such as a nitrogen atmosphere, for an appropriate time to form a product containing the target iron-based host catalyst. The product containing the target iron-based host catalyst can be purified, and optionally recrystallized, to provide the target iron-based host catalyst.

[0172] The diammonium templates can be prepared using methods known in the art, such as those described in the Examples.

[0173] More specific reagents, reaction conditions, and the resulting iron-based host catalysts and diammonium templates are described in the Examples.

[0174] IV. Methods of Use

[0175] The catalytic systems described herein are thermally stable and provide a spatial environment for chemical reactions. For example, the supramolecular structure formed from the non-covalent interactions between the host catalyst and the guest template can provide a spatial environment for stereodirecting and site-selective C-H functionalization, such as C-H amination. In addition, the bidentate ammonium guest template is capable of binding the crown ether-containing host catalyst with a strong binding affinity (i.e., a log(K) of at least 4.0), thereby providing thermal stability to the catalytic system. This enables enantioselective chemical reactions, such as enantioselective C-H amination, at room temperature, in contrast to enantioselective C-H amination using rhodium catalysts known in the art, which require low temperatures (typically -10 °C to -35 °C) (see, e.g., C. Liang et al., Angew. Chem. Int. Ed. 2006, 45, 4641-4644; C. Liang et al., J. Am. Chem. Soc. 2008, 130, 343-350). Thus, the catalytic systems disclosed herein are particularly suitable for use in enantioselective reactions, such as enantioselective C-H functionalization reactions, under mild reaction conditions, such as at room temperature (i.e., 1 atmosphere, 20-22 °C). For example, the disclosed catalytic systems can catalyze C-H amination of various substrates at room temperature with high enantioselectivity (i.e., at least 2: 1) and optionally high yield (i.e., > 30%) to produce aminated products.

[0176] Generally, the method of catalyzing an enantioselective C-H amination of a substrate using the catalytic system disclosed herein comprises: (i) maintaining a reaction mixture at room temperature for a period of time sufficient to form an aminated product, wherein the reaction mixture comprises the substrate, a nitrogen source reactant, the catalytic system described herein, and a solvent.

[0177] Generally, the loading of the host catalyst of the catalytic system used in the method of catalyzing an enantioselective C-H amination reaction in the reaction mixture is in the range of about 5 mol% to about 30 mol% or about 10 mol% to about 20 mol%, such as about 15 mol%. The loading of the host catalyst in the reaction mixture can be calculated using the following formula: mol% of host catalyst = [(moles of host catalyst) / (moles of limiting reagent)] x 100%. For example, if 1 equivalent of PhINTces is the limiting reagent, then 0.15 equivalents of Fe catalyst can be used.

[0178] The nitrogen source reactant in the reaction mixture of the disclosed method can be any suitable compound capable of providing a nitrogen atom(s) or a nitrogen atom(s)-containing functional group that displaces a hydrogen of the substrate to form the aminated product. In some forms, the nitrogen source reactant in the reaction mixture can be R’-NH2or R”IN-R’, wherein R’ can be -SO2-R’1or -SO3-R’2; R’1and R’2may independently be a substituted or unsubstituted phenyl or a substituted or unsubstituted alkyl (e.g., an unsubstituted straight or branched C1-C10 alkyl, an unsubstituted straight or branched C1-C8 alkyl, an unsubstituted straight or branched C1-C6 alkyl, an unsubstituted straight or branched C1-C4 alkyl, etc., such as tert-butyl, or a haloalkyl, such as -CH2CCl3, -CCl3, -CH2CH2CCl3, -CH2CCl2CCl3, etc.); R” can be a substituted or unsubstituted phenyl; and when present, the substituents can independently be an unsubstituted alkyl (e.g., any of those described above, such as methyl), a halide (such as chloride), a nitro group, a cyano group, a nitrile, or a carbonyl group. In some forms, the nitrogen source reactant in the reaction mixture can be R’-NH2or R”IN-R’, wherein R’ can be Tces, Ts, Ns, or an ortho / para / meta halo-phenylsulfonyl or sulfonate (such as p-chlorophenylsulfonyl or p-chlorophenylsulfonate); and R” can be an unsubstituted phenyl or a phenyl substituted with an alkyl or halide at any suitable position(s) on the phenyl ring (such as chlorobenzene or alkylbenzene). In some forms, the nitrogen source reactant in the reaction mixture can be PhINTces.

[0179] In some forms of the method, the substrate used in the reaction mixture for the enantioselective C-H amination reaction can have the structure R-H, and the aminated product formed by the enantioselective C-H amination reaction can have the structure R-NHR’, where R can be a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted tetrahydronaphthalene, a substituted or unsubstituted indane, a substituted or unsubstituted aralkyl group, etc.), a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyl group, a substituted or unsubstituted heterocyclic group (e.g., a substituted or unsubstituted chromane, a substituted or unsubstituted isochromane, a substituted or unsubstituted thiochromane, a substituted or unsubstituted isothiochromane, a dihydrobenzofuran, a dihydroisobenzofuran, a dihydrobenzothiophene, a dihydroisobenzothiophene, etc.), a substituted or unsubstituted cycloalkyl group (a monocyclic or polycyclic, such as a fused cycloalkyl ring), a substituted or unsubstituted cycloalkenyl group (a monocyclic or polycyclic, such as a fused cycloalkenyl ring), or a substituted or unsubstituted cycloalkynyl group (a monocyclic or polycyclic, such as a fused cycloalkynyl ring); the substituents can independently be a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted polyaryl group, a substituted or unsubstituted polyheteroaryl group, a substituted or unsubstituted aralkyl group, a carbonyl group, a halide, a hydroxyl group, a phenoxy group, an aryloxy group, an alkylthio group, a phenylthio group, an arylthio group, a cyano group, an isocyano group, an alkoxy group, a nitro group, a carboxyl group, an amino group, an amide group, an oxo group, a silyl group, a siloxy group, a sulfinyl group, a sulfonyl group, a sulfonic acid, a phosphonium, a phosphine group, a phosphoryl group, a phosphonate group, or a thiol, or a combination thereof; and R’ can be any of those described above for R’-NH2or R”IN-R’, such as Tces, Ts, Ns, or an ortho / para / meta halobenzenesulfonyl group or sulfonate (such as a p-chlorobenzenesulfonyl group or p-chlorobenzenesulfonate). In some forms, R can be a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted tetrahydronaphthalene, a substituted or unsubstituted indane, a substituted or unsubstituted aralkyl group, etc.), a substituted or unsubstituted polyaryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteropolyl group, or a substituted or unsubstituted heterocyclic group (e.g., a substituted or unsubstituted chromane, a substituted or unsubstituted isochromane, a substituted or unsubstituted thiochromane, a substituted or unsubstituted isothiochromane, a dihydrobenzofuran, a dihydroisobenzofuran, a dihydrobenzothiophene, a dihydroisobenzothiophene, etc.).

[0180] In some forms of the method, the substrate used in the reaction mixture for the enantioselective C-H amination reaction can have the structure of Formula VI, and the aminated product formed by the enantioselective C-H amination reaction can have the structure of Formula VII:

[0181]

[0182] wherein R 15 -R 20 may independently be hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), halide, hydroxyl, carbonyl, amino, amido, silyl, or silyloxy, or R 20 and R 15 together with the carbon atom to which they are attached or R 20 and R 19 together with the carbon atom to which they are attached can form a substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings), substituted or unsubstituted cycloalkenyl (monocyclic or polycyclic, such as fused cycloalkenyl rings), substituted or unsubstituted cycloalkynyl (monocyclic or polycyclic, such as fused cycloalkynyl rings), substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxacyclohexyl, substituted or unsubstituted thiacyclohexyl, substituted or unsubstituted oxacyclopentyl, substituted or unsubstituted thiacyclopentyl, etc.), substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteropolyaryl; when present, the substituents can independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, silyloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphonyl, phosphide, thiol, or combinations thereof, such as substituted or unsubstituted alkyl, substituted or unsubstituted aryl, carbonyl, oxo, amino, or alkoxy; R’ can be any of those described above for R’-NH2or R”IN-R’, such as Tces, Ts, Ns, or ortho / para / meta halo-benzenesulfonyl or sulfonate (such as p-chlorobenzenesulfonyl or p-chlorobenzenesulfonate).

[0183] In some forms, R 19 may be hydrogen, and R 20It can be a substituted or unsubstituted alkyl group (e.g., substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C1-C8 straight-chain or branched alkyl groups, substituted or unsubstituted C1-C6 straight-chain or branched alkyl groups, etc.), or R 20 and R 19 Together with the carbon atoms they are attached to, they can form substituted or unsubstituted cycloalkyl groups (including monocyclic groups such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic groups such as substituted or unsubstituted fused cycloalkyl rings), or substituted or unsubstituted heterocyclic groups (e.g., substituted or unsubstituted oxetyl, substituted or unsubstituted thiohexyl, substituted or unsubstituted oxetyl, substituted or unsubstituted thiohexetyl, etc.). In these forms, R 15 -R 18 It can be independently hydrogen, a halide, a substituted or unsubstituted alkyl group (e.g., substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C1-C8 straight-chain or branched alkyl groups, substituted or unsubstituted C1-C6 straight-chain or branched alkyl groups, etc.), a substituted or unsubstituted aryl group (e.g., substituted or unsubstituted phenyl or benzyl), an alkoxy group (e.g., methoxy, ethoxy, etc.), a carbonyl group, or a silyloxy group. For example, R 15 R 16 and R 18 For hydrogen, R 17 Independently, it is hydrogen, a halide, a substituted or unsubstituted alkyl group (e.g., substituted or unsubstituted C1-C10 straight-chain or branched alkyl groups, substituted or unsubstituted C1-C8 straight-chain or branched alkyl groups, substituted or unsubstituted C1-C6 straight-chain or branched alkyl groups, etc.), a substituted or unsubstituted aryl group (e.g., substituted or unsubstituted phenyl or benzyl), an alkoxy group (e.g., methoxy, ethoxy, etc.), a carbonyl group, or a silyloxy group.

[0184] In some forms of equations VI and VII, R 17 and R 20 It can be hydrogen, substituted or unsubstituted alkyl (e.g., unsubstituted C1-C) independently. 10 R is a C1-C8 or C1-C6 straight-chain or branched alkyl group, carbonyl group, alkoxy group (e.g., methoxy, ethoxy, aryloxy, benzo[a] ether, etc.), substituted or unsubstituted alkylaryl group (e.g., benzyl), haloalkyl group, or halide (e.g., fluoride, chloride, bromide, or iodide). In some forms of formulas VI and VII, R 20 and R 15 Together with the carbon atoms they are attached to or R 20 and R 19together with the carbon atom to which they are attached can form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, such as unsubstituted C3-C6 cycloalkyl or unsubstituted C3-C6 heterocycloalkyl, e.g., piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, or thiomorpholine.

[0185] In some forms, for any of R-H, R-NHR’, Formula VI, and Formula VII, the substituents can independently be substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted alkylaryl (e.g., benzyl), carbonyl (e.g., carboxyl, ester, etc.), alkoxy (e.g., methoxy, ethoxy, aryloxy, benzyloxy, etc.), oxo, amino, halide, hydroxyl, or haloalkyl, or combinations thereof.

[0186] For any of R-H, R-NHR’, Formula VI, and Formula VII, the alkyl can be a linear alkyl, branched alkyl, or cyclic alkyl (mono- or polycyclic). The terms “cyclic alkyl” and “cycloalkyl” are used interchangeably herein. Exemplary alkyl groups include linear C1-C 30 alkyl, branched C4-C 30 alkyl, cyclic C3-C 30 alkyl, linear C1-C 20 alkyl, branched C4-C 20 alkyl, cyclic C3-C 20 alkyl, linear C1-C 10 alkyl, branched C4-C 10 alkyl, cyclic C3-C 10 alkyl, linear C1-C6 alkyl, branched C4-C6 alkyl, cyclic C3-C6 alkyl, linear C1-C4 alkyl, cyclic C3-C4 alkyl, such as linear C1-C 10 , C1-C9, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, or C1-C2 alkyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 alkyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, or C3-C4 alkyl groups. The cyclic alkyl can be a monocyclic or polycyclic alkyl, such as C4-C 30 , C4-C 25 , C4-C 20 , C4-C 18 , C4-C 16C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 15 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 14 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 13 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 12 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group.

[0187] For any of R-H, R-NHR’, Formula VI, and Formula VII, the alkenyl group can be a linear alkenyl group, a branched alkenyl group, or a cyclic alkenyl group (mono- or polycyclic). The terms “cyclic alkenyl” and “cycloalkenyl” are used interchangeably herein. Exemplary alkenyl groups include linear C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2 alkenyl groups, branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups, or cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4 alkenyl groups. The cyclic alkenyl group can be a monocyclic or polycyclic alkenyl group, such as C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkenyl group. 30 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 30 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 30 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 20 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 20 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 20 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 30 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 25 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 20 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 18 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 16 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 15 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 14 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 13 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 12 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group. 10 C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5 mono- or polycyclic alkyl group.

[0188] For any of R-H, R-NHR', Formula VI, and Formula VII, the alkynyl group can be a linear alkynyl group, a branched alkynyl group, or a cyclic alkynyl group (mono- or polycyclic). The terms "cyclic alkynyl" and "cycloalkynyl" are used interchangeably herein. Exemplary alkynyl groups include linear C2-C 30 alkynyl, branched C4-C 30 alkynyl, cyclic C3-C 30 alkynyl, linear C2-C 20 alkynyl, branched C4-C 20 alkynyl, cyclic C3-C 20 alkynyl, linear C2-C 10 alkynyl, branched C4-C 10 alkynyl, cyclic C3-C 10 alkynyl, linear C2-C6alkynyl, branched C4-C6alkynyl, cyclic C3-C6alkynyl, linear C2-C4alkynyl, cyclic C3-C4alkynyl, such as linear C2-C 10 , C2-C9, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C2alkynyl group, a branched C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4alkynyl group, or a cyclic C3-C9, C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4alkynyl group. The cyclic alkynyl group can be a monocyclic or polycyclic alkynyl group, such as C4-C 30 , C4-C 25 , C4-C 20 , C4-C 18 , C4-C 16 , C4-C 15 , C4-C 14 , C4-C 13 , C4-C 12 , C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6, or C4-C5monocyclic or polycyclic alkynyl group.

[0189] It should be understood that any of the exemplary alkyl, alkenyl, and alkynyl groups can be heteroalkyl, heteroalkenyl, and heteroalkynyl, respectively.

[0190] For any of R-H, R-NHR', Formula VI, and Formula VII, the aryl group can be a C5-C 30 aryl, C5-C 20 aryl, C5-C 12 aryl, C5-C 11 aryl, C5-C9aryl, C6-C 20 aryl, C6-C 12 aryl, C6-C11 aryl or C6-C9 aryl. It should be understood that aryl can be heteroaryl, such as C5-C 30 heteroaryl, C5-C 20 heteroaryl, C5-C 12 heteroaryl, C5-C 11 heteroaryl, C5-C9 heteroaryl, C6-C 30 heteroaryl, C6-C 20 heteroaryl, C6-C 12 heteroaryl, C6-C 11 heteroaryl or C6-C9 heteroaryl. For any of Formula I, Ia, II, III, and IV, the polyaryl group can be C 10 -C 30 polyaryl, C 10 -C 20 polyaryl, C 10 -C 12 polyaryl, C 10 -C 11 polyaryl or C 12 -C 20 polyaryl. It should be understood that aryl can be polyheteroaryl, such as C 10 -C 30 polyheteroaryl, C 10 -C 20 polyheteroaryl, C 10 -C 12 polyheteroaryl, C 10 -C 11 polyheteroaryl or C 12 -C 20 polyheteroaryl.

[0191] In some forms of the method, the substrate used in the enantioselective C-H amination reaction can have any of the following structures:

[0192]

[0193]

[0194] The amination product can have any of the following structures:

[0195]

[0196] Generally, the molar ratio of substrate to nitrogen source reactant in the reaction mixture of the disclosed method can range from 10: 1 to 1 : 1 or 10: 1 to 5: 1, such as 8: 1.

[0197] Exemplary solvents suitable for forming a reaction mixture comprising a substrate, a nitrogen source reactant, a catalytic system disclosed herein, and a solvent include, but are not limited to, CH3CN, THF, HFIP, and C6H6. For example, the solvent in which the reaction mixture is formed is CH3CN.

[0198] In some forms, the reaction mixture of the disclosed methods further comprises a drying agent such as MgO or a molecular sieve such as a molecular sieve, a molecular sieve or a molecular sieve, or a combination thereof. The use of a drying agent and / or a molecular sieve in the reaction mixture can remove residual moisture in the reaction mixture.

[0199] Reaction conditions, such as reaction time, gaseous environment, stirring, etc., for performing the enantioselective C-H amination reaction depend on the specific reactants and desired reaction product. For example, the C-H amination catalyzed by the catalytic system disclosed herein is optionally performed at room temperature for a period of time ranging from about 30 minutes to about 24 hours, about 1 hour to about 20 hours, or about 2 hours to about 18 hours, such as about 16 hours, and optionally under an inert gaseous environment (such as under nitrogen, helium, and / or argon) and / or under stirring.

[0200] Optionally, the methods disclosed herein for catalyzing enantioselective C-H amination further comprise a step of mixing the substrate, the nitrogen source reactant, the disclosed catalytic system, and the solvent to form a reaction mixture prior to step (i), and / or a step of purifying the amination product after step (i), optionally by column chromatography.

[0201] In some forms, the amination product formed by the enantioselective C-H amination reaction catalyzed by the catalytic system disclosed herein can have a yield of at least 30%, at least 40%, at least 50%, ranging from about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0202] In some forms, the amination product formed by the enantioselective C-H amination reaction catalyzed by the catalytic system disclosed herein can have an enantiomeric ratio of at least 2: 1, such as ranging from 2: 1 to 99: 1, 4: 1 to 99: 1, 9: 1 to 99: 1, or 19: 1 to 99: 1, as determined by chiral HPLC.

[0203] In some forms, the aminated product formed by the enantioselective C-H amination reaction catalyzed by the catalytic system disclosed herein can have a yield of at least 30%, at least 40%, at least 50%, in a range of about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%; and can have an enantiomer ratio of at least 2: 1, such as in a range of 2: 1 to 99: 1, 4: 1 to 99: 1, 9: 1 to 99: 1, or 19: 1 to 99: 1, as determined by chiral HPLC.

[0204] The following examples describe specific exemplary substrates, nitrogen source reactants, and their corresponding yields and enantiomer ratios.

[0205] The disclosed compositions and methods can be further understood by the following numbered paragraphs.

[0206] 1. A host catalyst having the following structure:

[0207]

[0208] wherein:

[0209] (i) each occurrence of A, together with the carbon atom to which it is attached, forms a crown ether;

[0210] (ii) each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, halide, hydroxyl, alkoxy, amino, amido, carbonyl, nitro, nitrile, or thiol; and

[0211] (iii) the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof.

[0212] 2. The host catalyst of paragraph 1, wherein each occurrence of A, together with the carbon atom to which it is attached, forms a 12-crown-4-ether, 15-crown-5-ether, 18-crown-6-ether, dibenzo-18-crown-6-ether, 24-crown-8-ether, or azacrown ether.

[0213] 3. The host catalyst of paragraph 1 or 2, wherein the host catalyst has the structure:

[0214]

[0215] 4. The host catalyst of any one of paragraphs 1-3, wherein each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl.

[0216] 5. The host catalyst of any one of paragraphs 1-4, wherein each occurrence of R1and R2is hydrogen.

[0217] 6. A guest template having the structure:

[0218]

[0219] wherein:

[0220] (i) B1and B2are independently absent, or a carbon atom, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl;

[0221] (ii) R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl;

[0222] (iii) is absent or a bond (single, double, or triple bond);

[0223] (iv) X1and X2are independently absent, or an oxygen atom or NR5, and R5is absent, or hydrogen, or substituted or unsubstituted alkyl;

[0224] (v) L1and L2are independently absent, or

[0225] X3is a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl,

[0226] Qi and Q2 are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl;

[0227] (vi) n1 and n2 are independently integers from 0 to 20; and

[0228] (vii) the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof.

[0229] 7. The guest template of paragraph 6, wherein B1 and B2 are independently carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted polyaryl; and R3 and R4 are independently absent, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.

[0230] 8. The guest template of paragraph 6 or 7, wherein, is:

[0231]

[0232]

[0233] X1 and X2 are independently oxygen atoms or NR5, R5 is absent or hydrogen;

[0234] n4 and n5 are independently integers from 0 to 5;

[0235] n6, n7, n8, and n 10 are independently integers from 0 to 4;

[0236] n9 and n 11 are independently integers from 0 to 2;

[0237] n 12 -n 14 are independently integers from 1 to 6; and

[0238] R7-R 14 independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl.

[0239] 9. The guest template of any of paragraphs 6-8, wherein L1and L2are independently wherein X3is a nitrogen atom, and wherein Q1and Q2are independently substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl.

[0240] 10. The guest template of any of paragraphs 6-9, wherein Q1and Q2are unsubstituted phenyl.

[0241] 11. A catalytic system comprising:

[0242] a host catalyst; and

[0243] a guest template,

[0244] wherein the host catalyst has the structure:

[0245]

[0246] wherein:

[0247] (i) each occurrence of A, together with the carbon atom to which it is attached, forms a crown ether;

[0248] (ii) each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, halide, hydroxyl, alkoxy, amino, amido, carbonyl, nitro, nitrile, or thiol; and

[0249] wherein the guest template has the structure:

[0250]

[0251] wherein:

[0252] (i) B1and B2are independently absent, or a carbon atom, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl;

[0253] (ii) R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl;

[0254] (iii) — is absent or a bond (single, double, or triple bond);

[0255] (iv) X1and X2are independently absent, or an oxygen atom or NR5, and R5is absent, or hydrogen, or substituted or unsubstituted alkyl;

[0256] (v) L1and L2are independently absent, or

[0257] X3is a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl,

[0258] Q1and Q2are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl;

[0259] (vi) n1and n2are independently integers from 0 to 20; and

[0260] wherein the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof.

[0261] 12. The catalytic system of paragraph 11, wherein the molar ratio of the host catalyst to the guest template is in the range of 1 : 10 to 1 : 1, 1 : 5 to 1 : 1, such as 1 : 2.

[0262] 13. The catalytic system of paragraph 11 or 12, wherein the host catalyst and the guest template are optionally non-covalently bound to one another via a crown ether of the host catalyst and an ammonium group of the guest template.

[0263] 14. The catalytic system of paragraph 13, wherein the binding between the host catalyst and the guest template has a log(K) of at least 4.0, such as in the range of 4.0 to about 8.0 or 4.0 to about 6.0.

[0264] 15. The catalytic system of paragraph 13 or 14, wherein the host catalyst and the guest template form the following structure:

[0265]

[0266] 16. The catalytic system of any one of paragraphs 11-15, wherein the host catalyst has the following structure:

[0267]

[0268] 17. The catalytic system of any one of paragraphs 11-16, wherein each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl.

[0269] 18. The catalytic system of any one of paragraphs 11-17, wherein each occurrence of R1and R2is hydrogen.

[0270] 19. The catalytic system of any one of paragraphs 11-18, wherein B1and B2are independently a carbon atom, substituted or unsubstituted aryl, or substituted or unsubstituted polyaryl; and R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl.

[0271] 20. The catalytic system of any one of paragraphs 11-19, wherein is:

[0272]

[0273] X1and X2are independently an oxygen atom or NR5, R5is absent or hydrogen;

[0274] n4and n5are independently integers from 0 to 5;

[0275] n6, n7, n8, and n 10 are independently integers from 0 to 4;

[0276] n9and n 11is independently an integer from 0 to 2;

[0277] n 12 -n 14 is independently an integer from 1 to 6; and

[0278] R7-R 14 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl.

[0279] 21. The catalytic system of any one of paragraphs 11-20, wherein L1and L2are independently wherein X3is a nitrogen atom, and wherein Q1and Q2are independently substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl.

[0280] 22. The catalytic system of any one of paragraphs 11-21, wherein Q1and Q2are unsubstituted phenyl.

[0281] 23. The catalytic system of any one of paragraphs 13-22, wherein the host catalyst and the guest template form a complex having the structure:

[0282]

[0283] 24. A method for asymmetric C-H amination of a substrate, comprising:

[0284] (i) maintaining the reaction mixture at room temperature for a period of time sufficient to form a product,

[0285] wherein the reaction mixture comprises a substrate, a nitrogen source reactant, the catalytic system of any one of paragraphs 11-23, and a solvent.

[0286] 25. The method of paragraph 24, wherein the nitrogen source reactant is R'-NH2 or R"IN-R', wherein R' is -SO2-R'1 or -SO3-R'2; R'1 and R'2 are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl (e.g., unsubstituted straight or branched C1-C10 alkyl, unsubstituted straight or branched C1-C8 alkyl, unsubstituted straight or branched C1-C6 alkyl, unsubstituted straight or branched C1-C4 alkyl, etc., such as t-butyl, or a haloalkyl such as -CH2CCI3, -CCl3, -CH2CH2CCl3, -CH2CCl2CCl3, etc.); R" is substituted or unsubstituted phenyl; when present, the substituents are independently unsubstituted alkyl (e.g., any of those described above, such as methyl), halide (e.g., fluoride, chloride, bromide, iodide, etc.), nitro, cyano, nitrile, or carbonyl.

[0287] 26. The method of paragraph 24 or 25, wherein:

[0288] the substrate has the structure R-H, and

[0289] the product has the structure R-NHR',

[0290] R is substituted or unsubstituted aryl (e.g., substituted or unsubstituted tetrahydronaphthalene, substituted or unsubstituted indane, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted chromane, substituted or unsubstituted isochromane, substituted or unsubstituted thiochromane, substituted or unsubstituted isothiochromane, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, etc.), substituted or unsubstituted cycloalkyl (mono- or polycyclic, such as a fused cycloalkyl ring), substituted or unsubstituted cycloalkenyl (mono- or polycyclic, such as a fused cycloalkenyl ring), or substituted or unsubstituted cycloalkynyl (mono- or polycyclic, such as a fused cycloalkynyl ring); and

[0291] the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, siloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or a combination thereof.

[0292] 27. The method of paragraph 26, wherein:

[0293] The substrate has the following structure:

[0294] and

[0295] The product has the following structure:

[0296]

[0297] R 15 -R 20 independently hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), halide, hydroxyl, carbonyl, amino, amido, silyl, or siloxy, or R 20 and R 15 together with the carbon atom to which they are attached, or R 20 and R 19 together with the carbon atom to which they are attached, can form a substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings), substituted or unsubstituted cycloalkenyl (monocyclic or polycyclic, such as fused cycloalkenyl rings), substituted or unsubstituted cycloalkynyl (monocyclic or polycyclic, such as fused cycloalkynyl rings), substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxacyclohexyl, substituted or unsubstituted thiacyclohexyl, substituted or unsubstituted oxacyclopentyl, substituted or unsubstituted thiacyclopentyl, etc.), substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteropolyaryl; when present, the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, siloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof, such as substituted or unsubstituted alkyl, substituted or unsubstituted aryl, carbonyl, oxo, amino, or alkoxy.

[0298] 28. The method of paragraph 27, wherein R 19 is hydrogen, and R 20 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), or R 20 and R 19 together with the carbon atom to which they are attached form substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings), or substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxanyl, substituted or unsubstituted thianyl, substituted or unsubstituted oxolanyl, substituted or unsubstituted thiolanyl, etc.).

[0299] 29. The method of paragraph 27 or 28, wherein R 15 -R 18 is independently hydrogen, halide, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), carbonyl, or silyloxy.

[0300] 30. The method of any one of paragraphs 27-29, wherein R 15 , R 16 , and R 18 are hydrogen, and R 17 is hydrogen, halide, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), carbonyl, or silyloxy.

[0301] 31. The method of any one of paragraphs 25-30, wherein R’ is Tces, Ts, Ns, halobenzenesulfonyl, or halobenzenesulfonate (e.g., p-chlorobenzenesulfonyl or p-chlorobenzenesulfonate); and R” is unsubstituted phenyl or phenyl substituted with alkyl or halide (e.g., chlorobenzene or alkylbenzene).

[0302] 32. The method of any one of paragraphs 24-31, wherein the nitrogen source reactant in the reaction mixture is PhINTces.

[0303] 33. The method of any one of paragraphs 24-32, wherein the substrate has the following structure:

[0304]

[0305]

[0306] The product has the following structure:

[0307]

[0308]

[0309] 34. The method of any one of paragraphs 24 to 33, wherein the molar ratio of the substrate to the nitrogen source reactant is in the range of 10: 1 to 1: 1 or 10: 1 to 5: 1, such as 8: 1.

[0310] 35. The method of any one of paragraphs 24 to 34, wherein the host catalyst has a loading in the range of about 5 mole% to about 30 mole% or about 10 mole% to about 20 mole%, such as about 15 mole%.

[0311] 36. The method of any one of paragraphs 24 to 35, wherein the solvent is CH3CN, THF, HFIP, or C6H6, preferably wherein the solvent is CH3CN.

[0312] 37. The method of any one of paragraphs 24-36, wherein the reaction mixture further comprises a desiccant or molecular sieves, such as molecular sieves, molecular sieves or molecular sieves.

[0313] 38. The method of any one of paragraphs 24-37, wherein the reaction is performed under an inert gas environment, optionally wherein the inert gas is argon.

[0314] 39. The method of any one of paragraphs 24-38, wherein the reaction mixture is maintained in the range of about 30 minutes to about 24 hours, about 1 hour to about 20 hours, or about 2 hours to about 18 hours, such as about 16 hours.

[0315] 40. The method of any one of paragraphs 24-39, wherein the product has a yield of at least 30%, at least 40%, at least 50%, in the range of about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0316] 41. The method of any one of paragraphs 24-40, wherein the product has an enantiomeric ratio of at least 2: 1, such as in the range of 2: 1 to 99: 1, 4: 1 to 99: 1, 9: 1 to 99: 1, or 19: 1 to 99: 1, as determined by chiral HPLC.

[0317] Examples

[0318] Example 1: Exemplary supramolecular catalytic system for asymmetric C-H amination of various substrates

[0319] Materials and methods

[0320] Commercially available reagents from Sigma-Aldrich, Diekmann Chemical, Bide Pharmatech Ltd., and J & K Chemicals were used as received. All catalytic amination reactions were performed under argon using deoxygenated anhydrous solvents and 3 A molecular sieves for the removal of moisture. Unless otherwise stated, all other reactions were performed under a stream of argon using deoxygenated solvents.

[0321] Chromatography (HPLC) analysis was performed using an Agilent Technologies 1260 Infinite II series instrument equipped with a DAD detector and an OD-H, AD-H, or OD-3 column. Thin layer chromatography (TLC) was performed using Merck silica gel 60 F254 pre-coated plates (0.25 mm) and visualized with UV light, potassium permanganate, cerium ammonium molybdate, or vanillin staining. Flash column chromatography was performed using silica gel (230-400 mesh) according to the method described by Still et al. (Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923) unless otherwise stated.

[0322] 1H-NMR spectra were recorded on a Bruker 400 MHz or 500 MHz spectrometer and reported in ppm using the solvent (TMS at 0 ppm) as an internal standard. Data reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, b = broad, app = apparent; coupling constant(s) in Hz; integration. Proton-decoupled13C-NMR spectra were recorded on a Bruker 400 MHz or 500 MHz spectrometer and reported in ppm using the solvent (CDCI3) at 77.0 ppm as an internal standard.

[0323] ​Low resolution electrospray ionization mass spectrometry (ESI-MS) was recorded on a Finnigan LCQ quadrupole ion trap mass spectrometer (Thermo Fisher Scientific), and high resolution ESI-MS was measured on a Waters Corporation Micromass Q-TOF Premier quadrupole time-of-flight tandem mass spectrometer. MALDI-mass spectra were recorded on a Bruker ultrafleXtreme instrument equipped with the built-in Flex control software, calibrated using the porphyrinoid substance, sinapinic acid or a-cyano-4-hydroxycinnamic acid matrix.

[0324] Circular dichroism (CD) spectra were recorded on a Mattson Galaxy Series FTIR 5000 and reported in terms of absorption frequency (cm). UV spectra were recorded on an Agilent Technologies Cary 8454 and reported in terms of absorbance and wavelength (nm); kinetic mode was applied for the detection of Fe---N intermediates.

[0325] Results

[0326] Design and synthesis of supramolecular catalytic systems

[0327] Supramolecular catalytic systems are formed by the self-assembly of 18-crown-6 substituted phthalocyanine host catalysts and diammonium guest templates Figure 1 ). The ligand H2( 18-冠-6 PC) of the host catalyst was synthesized according to literature procedures and characterized by 1 H, 13 C NMR, MALDI-TOF and UV-visible spectroscopy. The Fe II (PC) complex, Fe-1 and Fe-2 were prepared according to a synthetic route similar to that reported in the literature. Fe-1 was formed from 18-冠-6 PC bearing an 18-crown-6 substituent on the phthalocyanine moiety, and Fe-2 was formed from t BuPC bearing a tert-butyl substituent on the phthalocyanine moiety. The complexes of Fe-1 and Fe-2 were characterized by 1 H-NMR, MALDI-TOF and UV-visible spectroscopy, which were similar to those reported in the literature. Fe-1 could be prepared in gram scale. Chiral diammonium templates bearing a hexanoic acid linker to (R)-(+)-2,2’-diamino-1,1’- binaphthyl (T1) and a series of Trost ligand derived templates (T2a-T2i) were designed, synthesized and characterized by 1 H, 13 C NMR and ESI-MS.

[0328] Catalytic studies

[0329] The performance of chiral diammonium templates (30 mol%) for the catalytic C-H amination of tetralin (1 equiv) was investigated in anhydrous CH3CN with 15 mol% of Fe-1 as catalyst and PhINTces1 (3 equiv) as nitrogen source (Scheme 1). The yields and enantiomeric ratios are summarized in Table 1.

[0330] Scheme 1. Chiral diammonium templates for asymmetric C-H amination of tetralin.

[0331]

[0332] *Reaction conditions: 1 (0.75 mmol), 2a (0.25 mmol), Fe-1 (15 mol%) or Fe-2 (15 mol%), template co-catalyst T1 and T2a-i (30 mol%), CH3CN (2 mL), PhINTces1 (3 equiv), molecular sieves (100 mg) under argon. Isolated yield is calculated based on the conversion of 2a to product 3a; the endure yield of the reaction is the remaining starting material 2a. The enantiomeric ratio (e.r.) was determined by chiral HPLC analysis.

[0333] Table 1. Results of asymmetric C-H amination of tetralin with chiral diammonium templates.

[0334] Item Substrate Host Catalyst Guest Template Yield of 3a RSM Enantiomeric Ratio 1 Tetralin 2a Fe-1 T1 53％ 47％ Racemic 2 Tetralin 2a Fe-1 T2a 40％ 60％ 75:25 3 Tetralin 2a Fe-1 T2b 43％ 57％ 87:13 4 Tetralin 2a Fe-1 T2c 44％ 56％ 70:30 5 Tetralin 2a Fe-1 T2d 45％ 55％ 94:6 6 Tetralin 2a Fe-1 T2e 38％ 62％ 74:26 7 Tetralin 2a Fe-1 T2f 40％ 60％ 72:28 8 Tetralin 2a Fe-1 T2g 33％ 67％ 95:5 9 Tetralin 2a Fe-1 T2h 50％ 50％ 95:5 10 Tetralin 2a Fe-1 T2i 48％ 52％ 98:2

[0335] The following three features of the chiral diammonium templates can influence the catalytic enantioselectivity: (1) the linker of the template, (2) the chiral environment of the backbone, and (3) the hydrogen bonding motif. Regarding the linker of the template, although the same 1,1-binaphthalene-2,2’-diamine chiral backbone was installed on templates T1 and T2e Figure 2 ), only T2e, which is derivatized with a Trost ligand, could achieve enantioselective C-H amination Figure 2 , enantiomeric ratio = 74:26). Regarding the chiral environment of the backbone, for example, it was found that the modification of the 1,1’-diaminocyclohexane chiral backbone in T2a Figure 2 , enantiomeric ratio = 75:25) to 1,2-diphenyl-1,2-ethanediamine in T2b Figure 2 , enantiomeric ratio = 87:13) had a significant impact on enantioselectivity. Regarding the hydrogen bonding motif, templates T2d and T2e have similar structures, only with a slight difference in the availability of the hydrogen bonding motif adjacent to the chiral backbone (i.e., carboxylate in T2d and amide in T2e). The lack of hydrogen bond donor in T2d Figure 2 , enantiomeric ratio = 94:6) can lead to its inferior performance compared to T2e​Figure 2 The higher level of enantioselectivity compared to T2g in Table 1.

[0336] For reactivity, if the size of the reaction cavity is too small, the di-ammonium template affects the product yield (e.g. Figure 2 T2g in Table 1), the product yield is more than 10% lower than T2d, T2h, and T2i. T2h was chosen for further catalytic study because of its high product yield (Table 1, product yield = 50%) while maintaining a high level of enantioselectivity (enantioselectivity = 95:5).

[0337] The study of Fe-1 / T2h / 1 catalytic system is shown in Scheme 1 and the results are summarized in Table 2. The ratio of substrate:nitrogen source was varied (Table 2, entries 1-3, product yield = 50-60%, enantioselectivity = 95:5-98:2), which indicates that a suitable substrate:nitrogen source ratio is 8:1. The effect of solvent was investigated (CH2Cl2, HFIP, and THF, Table 2, entries 4-6, product yield = 11-32%, enantioselectivity = 99:1-95:5). In addition to the solvent, the reaction conditions of entry 3 were used. The highest enantioselective product yield was obtained with CH3CN as the solvent (Table 2, entry 3), which is comparable to the intermolecular C-H non- enantioselective amination using the known catalyst Mn(Cl8PC)Cl (Table 2, entry 9).

[0338] Table 2. Results of Fe-1 / T2h / 1 catalytic system for asymmetric C-H amination of tetralin.

[0339]

[0340]

[0341] a Isolated yield was calculated based on the ratio of the amount of conversion to product 3a:2a; the tolerated yield of the reaction is the remaining starting material 2a. b The enantiomeric ratio (e.r.) was determined by chiral HPLC analysis. c Data taken from the literature, no co-catalyst template T2h was used [Nat. Chem. 2018, 10, 583-591].

[0342] Two control experiments were conducted to investigate the effect of the host-guest interaction between the 18-crown-6 substituent and the diammonium template on asymmetric catalysis (Table 2, entries 7-8). First, the addition of a more strongly bound Ba(Otf)2 additive to the Fe-1-T2h / 1 catalytic system yielded the CH amination product 3a in a higher yield but in a non-stereoselective manner. Second, the substitution of Fe-1 with a non-18-crown-6 substituted Fe-2 produced the non-stereoselective CH amination product 3a. Both results indicate that the host-guest interaction between the 18-crown-6 substituent of Fe-1 and the diammonium template participates in enantioselective catalysis.

[0343] Amination of benzyl CH-bonded substrates using the Fe-1-T2h / 1 catalytic system is shown in Scheme 2, and the results are summarized in Table 3. First, para-substituted ethylbenzene 2b-f (8 equivalents) was treated in CH3CN at 25 °C with the Fe-1 (15 mol%) / T2h (30 mol%) / 1 (1 equivalent) catalytic system to give CH-amination products 3b-f in yields of 55-70% with enantiomeric ratios of 92:8 to 96:4 (Table 3, entries 2-6). This Fe-1 / T2h / 1 method yielded higher product yields for substrates containing electron-donating groups (Table 3, entry 6, 2f) and was tolerant to other organofunctional groups (Table 3, entries 2-5, 2b-e), with results similar to those for tetrahydronaphthalene 2a. The Fe-1 / T2h / 1 methodology was performed at room temperature and yielded CH-amination products with a relatively high level of enantioselectivity. In contrast, existing asymmetric CH amination schemes using Rh2(COOR)4 as a catalyst typically require reaction temperatures of -10 to -35 °C to achieve similar levels of enantioselectivity.

[0344] Scheme 2. A Fe-1 / T2h / 1 catalytic system for asymmetric CH amination of various substrates.

[0345]

[0346] *Reaction conditions: 1 (0.25 mmol), 2a-l (2 mmol), Fe-1 (15 mol%), template co-catalyst T2h (30 mol%), CH3CN (2 mL), Molecular sieve (100 mg), under argon atmosphere.

[0347] Table 3. Results of asymmetric CH amination of various substrates in the Fe-1 / T2h / 1 catalytic system.

[0348]

[0349]

[0350]

[0351] a Isolated yields are calculated based on the amount of conversion of the product 3a-3l; the durable yield of the reaction is the remaining starting material 2a-2l. b The enantiomeric ratio (e.r.) was determined by chiral HPLC analysis.

[0352] The Fe-1 / T2h / 1 catalytic system can also catalyze the amination of other cyclic C-H bond substrates, such as indane 2g and isochroman 2h, with 65-68% yield and 96:4 enantioselectivity (Table 3, entries 7-8, 3g-3h). For substrates containing multiple C-H bonds, such as 2i-2l, the Fe-1 / T2h / 1 catalytic system can selectively generate the benzylic C-H amination products 3i-3p with 50-64% yield and 82:18-96:4 enantioselectivity (Table 3, entries 9-12). In contrast, literature reports on similar C-H functionalization via metal carbene intermediates reported mixtures of regioisomers for similar diverse substrates.

[0353] Mechanism study of C-H functionalization

[0354] Competitive amination of equimolar mixture of 2b and 2b-d catalyzed by Fe-1, Fe-1 / T2h or Rh2(esp)2 10 The KIE for the amination of ethylbenzene 2b with PhINTces 1 was investigated (Scheme 3). The reactions catalyzed by Fe-1 and Fe-1 / T2h gave k H / k D values of 2.6-3.0 (Table 4). This is greater than the k H / k D value obtained with Rh2(esp)2 catalysis (k H / k D = 1.22, Table 4).

[0355] Scheme 3. Kinetic isotope experiment

[0356]

[0357] Table 4. Results of kinetic isotope experiment

[0358]

[0359] (S)-1-phenylethanol 4a protected as a tert-butyldimethylsilyl ether was synthesized according to literature procedures. This chiral tertiary C-H bond substrate was used in the catalytic amination with Fe-1 or Rh2(esp)2 as catalyst in CH3CN3 at room temperature to give 4b (Scheme 4). HPLC analysis of the product 4b obtained with Fe-1 as catalyst indicated racemization at the chiral C-H bond center (Table 5). The use of Rh2(esp)2 as catalyst was able to preserve the chirality of 4b (Table 5). This phenomenon is most likely due to the generation of short-lived organic radicals during the catalytic cycle of Fe-1, which are not present in Rh2(esp)2.

[0360] Scheme 4. Stereocenter racemization experiments

[0361]

[0362] Table 5. Stereocenter racemization experiment results

[0363]

[0364] NMR spectra of the reaction mixture of Fe-1 / NH2Tces 4c with 2,4,6- trimethylpyridine 4d or PhI(OPiv)2 4e were examined Figure 3A ). The initial mixture of Fe-1 / 4c had no detectable paramagnetism. After the addition of 4d or 4e, high field chemical shifts and line broadening of the proton resonances of Fe-1 were observed in the NMR spectra. Since no residual magnetic moments were detected for Fe-1 / 4c / 4d or Fe-1 / 4c / 4e, it is likely that the Fe-1(NTces) species has a closed shell character.

[0365] The reactions of Fe-1 with 4c, 4d or 1 were monitored by UV-visible spectroscopy Figure 3B ). Treatment of Fe-1 with 4c and 4d in CH3CN at room temperature resulted in no significant UV-visible spectral changes. Addition of 1 to a CH3CN solution of Fe-1 resulted in a significant change in the isosbestic point. The Soret and Q bands of Fe-1 gradually blue shifted from 418 nm to 384 nm and from 704 nm to 561 nm, respectively.

[0366] Mechanistic studies on the supramolecular aspects

[0367] Control experiments for the catalytic C-H amination of 2a with 1 as nitrogen source were performed. These experiments used a 1 :2:4 ratio of Fe-1 :T2h:Ba(OTf)2 and a 1 :2 ratio of Fe-2:T2h as catalytic system Figure 4ABoth reactions resulted in the formation of amination product 3a with an enantiomeric ratio of 50:50, accompanied by increased product yield. The underlying mechanism of these diastereoselective processes is attributed to two factors: (i) the exchange mechanism between barium cations and the ammonium template, thereby replacing the chiral supramolecular structure; and (ii) the lack of cation acceptors after the crown ether group in the iron catalyst Fe-1 is replaced by the tert-butyl group substituted in Fe-2. Figure 4B ).

[0368] H2( 18-冠-6 The reaction between PC and template T (i.e., T1, T2d, T2e, T2h, and T2i) is mediated by 1 H NMR spectral monitoring ( Figure 5A and 5B H2 was titrated with template T2d at room temperature. 18-冠-6 The solution of PC in CD3CN resulted in a low-field shift (approximately 3.4–4.5 ppm) in the signal of 18-crown-6. Figure 5A ). 1 The offset of the H NMR signal stops when the equivalent is greater than 2.0 ( Figure 5B ), indicating that H2 ( is used to form supramolecular systems) 18-冠-6 The ratio of PC) / T2d is H2( 18-冠-6 PC:T2d=1:2. Under the same conditions, H2 was titrated with T1, T2e, T2h and T2i respectively. 18-冠-6 Similar phenomena were observed in PC. Titration of templates T1 and T2h in CD3CN with benzo-18-crown-6 also resulted in a low-field shift (approximately 3.4–4.5 ppm) in the 18-crown-6 signal, and this change ceased when the titration equivalent was greater than 2.0. Figure 5B ).

[0369] Figure 5C The supramolecular system H2 ( 18-冠-6 The reaction between PC) / T2h and Ba(OTf)2 (which has a stronger binding affinity than ammonium) 1 ¹H NMR spectrum. Titration of H₂ with Ba(OTf)₂ ( 18-冠-6 The solution of PC) / T2h in CD3CN results in: (1) NH ammonium units 1 High-field shift of H NMR signal, (2) crown-ether unit 1 Further low-field shift of the H NMR signal, (3) and disappearance of the aromatic signal due to reduced interaction of aromatic groups. These changes are not significant when the titration equivalent is greater than 4.0. Titration data for supramolecular systems T1, T2d, T2e, T2h and T2i are in Figure 5D As shown in the image.

[0370] The titration of Fe-1 in CH3CN using templates T1 or T2d at room temperature was monitored by UV-Vis spectroscopy. Figure 5E The addition of the template led to increased absorbance at 300, 350, and 620 nm, and decreased absorbance at 430 and 715 nm. The UV-Vis spectra remained unchanged when the equivalent was greater than 2.0. The UV-Vis spectra of Fe-1 / T1 and Fe-1 / T2d in CH3CN were also detected at different temperatures (25–80 °C), and no changes were observed. This indicates that temperature has no significant effect on the overall supramolecular structure.

[0371] Regarding supramolecular equilibrium, with a host:guest ratio of 1:2, BindFit was used to analyze the template T1 / T2h and the crown ether acceptor (benzo-18-crown-6, H2). 18-冠-6 Titration data of the combination between PC and Fe-1 Figure 6 The binding constant is based on the change in mole fraction (which depends on...). 1 The offset of the H NMR signal was calculated. The Gibbs free energy is shown in Table 6. The log(K1) and log(K2) binding constants of benzo-18-crown-6 and T1 / T2h were calculated to be 3.65 / 3.41 and 2.39 / 2.01, respectively (Table 6, entries 1-2). H2 was found to... 18-冠-6 The binding affinity (log(K1)) and log(K2)) of the self-assembly process between PC or Fe-1 and diammonium template T1 / T2h were significantly greater (Table 6, entries 3-6, log(K1) = 4.49-5.09 and log(K2) = 4.28-5.90).

[0372] Table 6. Binding constants between host catalyst and guest template.

[0373] Item Host Guest [log(K1)] G K1 (kJ / mol) c ]]> [log(K2)] G K2 (kJ / mol) c ]]> 1 T1 Benzene-18-crown-6 3.65 -20.81 2.39 -13.63 2 T2h Benzene-18-crown-6 3.41 -19.44 2.01 -11.46 3 Fe-1 T1 4.70 -26.80 4.28 -24.40 4 H2 18冠6 PC T1 5.09 -29.02 4.89 -27.88 5 Fe-1 T2h 4.99 -28.45 5.90 -33.64 6 H2 18冠6 PC T2h 4.49 -25.60 5.52 -31.48

[0374] a pass 1 Determined by H-NMR titration. b Determined by UV-visible titration. c The calculation is based on ΔG = -RTlnK, where T = 298K.

[0375] Compared to the reported host-guest catalytic systems, Fe-1 / T2h2 and H2 ( 18冠6 The log(K) of PC) / T2h2 is the combination of monoammonium / 18-crown-6 (logK) a =3.56), hydrogen bonding between two carboxylic acid groups (logK) a =3.51) and the binding of anionic / cyclodextrin (logK) a=3.06) is 1.2-1.9 times that of the original template. Compared with the literature template, the use of diammonium template has led to a significant improvement in binding constant. The significant binding affinity of diammonium template may facilitate selective asymmetric catalysis, as the release of chiral diammonium template leads to a non-stereoselective pathway.

[0376] Given the non-covalent interactions in supramolecular catalysts, 2D-NMR spectroscopy was used ( 1 H- 1 H NOSEY and 1 HDOSY) checked H2 ( 18-冠-6 PC) / T12 and H2( 18-冠-6 Titration of PC) / T2h2. H2( 18-冠-6 PC) / T12 and H2( 18-冠-6 PC) / T2h2 in CD3CN 1 H- 1 H NOSEY spectra indicate that H2 ( 18-冠-6 crown-ether components of PC 1 The strong interaction between H resonance and the alkyl / aryl signals in the aromatic region at T1 / T2h ( Figure 7A Add Ba(OTf)2 to H2( 18-冠-6 PC) / T12 and H2( 18-冠-6 The CD3CN solution of PC / T2h2 leads to aromatic / crown-ether regions 1 H- 1 The H NOSEY NMR signal was significantly reduced ( Figure 7B ).

[0377] H2 was performed in CD3CN at 298K. 18-冠-6 PC) / T2h2 and Fe-1 / T2h2 1 H DOSYNMR showed the same diffusion coefficient of 1.097 × 10⁻⁶. -5 cm 2 / s( Figure 7C The radius of the reaction chamber was calculated using the Stoke-Einstein equation.

[0378] The CD spectra of T2e and T2h at different concentrations were examined. Figure 8A and 8B For the T2e spectrum, as the T2e concentration increases, the signals at 300 nm and 385 nm gradually increase, while the signal shape does not change significantly. Figure 8A Adding Fe-1 (1 equivalent) to a solution of T2e resulted in a new peak at 300 nm, while λ 最大The peak remained unchanged. Further addition of Ba(OTf)2to the solution of Fe-1 / T2e resulted in a spectrum similar to the initial spectrum of T2e(without Fe-1). Similarly, the CD spectrum of T2hwas recorded at the same concentration as T2e( Figure 8B ). By gradually diluting the solution of T2h, the recorded λ 最大 peak shifted within ±50 nm. Addition of Fe-1and Ba(OTf)2to the diluted solution of T2hresulted in insignificant changes of the maximum Δε peak, and a spectrum similar to the initial spectrum of T2h( Figure 8C ). The difference in the recorded CD spectra of T2eand T2his likely due to the more pre-organized hydrogen-bonded T2ebackbone, which leads to a more rigid secondary structure. The flexibility of the template T2hmight contribute to the high enantioselectivity of the amination.

[0379] Synthesis of 4,5-dibromo-benzo-18-crown-6

[0380] Scheme 5. Synthesis of 4,5-dibromo-benzo-18-crown-6

[0381]

[0382] A 500 mL round bottom flask was charged with 2.89 g (8 mmol) of 4,5-dicyano-benzo-18-crown-6, 0.25 g of iron powder, and anhydrous dichloromethane using a stir bar. A catalytic amount of solid iodine was added at 0 °C, followed by the slow addition of 3.5 mL (68.5 mmol) of bromine over a period of 2 hours. The reaction mixture was stirred at room temperature for 48 hours, then filtered into another 500 mL round bottom flask. The resulting orange-red mixture was quenched with 100 mL of 10% aqueous sodium hydroxide solution. The organic layer was separated, washed with deionized water (3 x 200 mL), dried over magnesium sulfate, concentrated under vacuum to give a yellow-brown oil. The oil was extracted with anhydrous hexanes (3 x 200 mL). The combined hexane extracts were concentrated and cooled to 0 °C to give 8 g of colorless solid in 53% isolated yield.

[0383] Appearance: white solid.1H NMR: (400 MHz, CDCl3) 6.92 (s, 2H), 4.20-3.65 (m, 20H). HRMS: (ESI-TOF MS ES+) m / z [C 16 H 22 Br2O6+Na] + Calculated: 490.96808, found 490.96810.

[0384] Synthesis of 4,5-dicyano-benzo-18-crown-6

[0385] Scheme 6. Synthesis of 4,5-dicyano-benzo-18-crown-6

[0386]

[0387] A 500 mL round bottom flask was equipped with a stir bar and charged with 2.52 g (5.25 mmol) of 4,5-dibromo-benzo-18-crown-6, 1.43 g (16 mmol) of copper(I) cyanide and anhydrous DMF (25 mL) under an argon atmosphere. The reaction mixture was heated to 150 °C for 20 h. Subsequently, the reaction was cooled to room temperature and quenched with 100 mL of 25% aqueous ammonia. The crude product was extracted with chloroform (3 x 200 mL). The combined organic phases were washed with deionized water (3 x 200 mL), dried over magnesium sulfate and concentrated in vacuo to give a brown oil. The oil was purified via column chromatography (230 mesh neutral alumina as stationary phase, CHCI3as eluent) to give 1.21 g of a white solid in 63% yield.

[0388] Appearance: white solid. 1 H NMR: (300 MHz, CDCI3) δ 7.14 (s, 2H), 4.26-3.65 (m, 20H). HRMS: (ESI-TOF MS ES+) m / z [C 18 H 22 N2O6+Na] + Calculated: 362.1478, found 362.1477.

[0389] Fe( 18-冠-6 PC) of the synthesis

[0390] Scheme 7. Synthesis of Fe( 18-冠-6 PC) of the synthesis

[0391]

[0392] A 250 mL round bottom flask was equipped with a stir bar and charged with 0.72 g (2 mmol) of 4,5-dicyano-benzo-18-crown-6, 0.39 g of iron pentacarbonyl (2 mmol) and 100 mL of ethylene glycol. The reaction mixture was stirred at 220 °C for 20 h, filtered into a 500 mL round bottom flask after returning to room temperature and the ethylene glycol was removed under vacuum. The resulting mixture was purified via column chromatography (neutral alumina as stationary phase, CHCI3as eluent) to give a dark green solid in 53% isolated yield.

[0393] Appearance: dark green solid. MS: (MALDI-TOF MS+) m / z [C 72 H 88 FeN8O 24 ]+ Calculated: 1504.5261, found 1504.5442. UV: (UV-visible) λ 最大 (ACN) / nm 227 (ε / dm 3 mol -1 cm -1 293 67347), 292 (21836735), 349 (1584694), 417 (10239796), 653 (8469389), 705.7 (12540816).

[0394] Synthesis of N,N'-([1,1'-binaphthalene]-2,2'-diyl)bis(6-bromohexanamide)

[0395] Scheme 8. Synthesis of N,N'-([1,1'-binaphthalene]-2,2'-diyl)bis(6-bromohexanamide)

[0396]

[0397] In a 250 mL round bottom flask equipped with a stir bar, 2 g (7.04 mmol) of (R)-(+)-1,1'-binaphthalene-2,2'diamine, 2.93 g (15 mmol) of 6-bromohexanoic acid, 85 mg (0.70 mmol) of 4-dimethylaminopyridine and anhydrous dichloromethane (100 mL) were combined. Under an argon atmosphere, 3.71 g of solid N,N'-dicyclohexylcarbodiimide (18 mmol) was added in one portion at 0 °C. The reaction mixture was stirred at room temperature for 24 hours, then filtered. The solid residue was washed with dichloromethane and the resulting colorless solution was concentrated under vacuum. The resulting yellow solid was purified using column chromatography to give 3.22 g of white solid with an isolated yield of 72%.

[0398] Appearance: white solid. 1 H NMR: (300 MHz, CDC13) δ 8.10 (d, J = 9 Hz, 2H), 7.92 (d, J = 6 Hz, 2H), 7.83 (d, J = 9 Hz, 2H), 7.35 (t, J = 9 Hz, 2H), 7.13 (m, 2H), 6.96 (d, J = 9 Hz, 2H), 2.96 (t, J = 6 Hz, 4H), 1.88 (m, 4H), 1.16 (m, 8H), 0.91 (m, 4H). 13 C NMR: (95 MHz, CDC13) δ 179.91., 141.3, 133.5, 127.5, 127.2, 126.9, 125.7, 121.7, 117.7, 115.8, 38.6, 33.8, 27.2, 25.0. HRMS: (ESI-TOF MS ES+) m / z [C 32H 34 Br2N2O2] + Calculated: 636.0987, found 636.0980.

[0399] Synthesis of N,N'-([1,1'-binaphthalene]-2,2'-diyl)bis(6-azidohexanamide)

[0400] Scheme 9. Synthesis of N,N'-([1,1'-binaphthalene]-2,2'-diyl)bis(6-azidohexanamide)

[0401]

[0402] In a 100 mL round bottom flask equipped with a stir bar, 1 g (1.57 mmol) of N,N'-([1,1'-binaphthalene]-2,2'-diyl)bis(6-bromohexanamide), 110 mg of sodium azide (1.65 mmol) and dimethyl sulfoxide (25 mL) were combined. The reaction mixture was stirred at 80 °C for 24 hours. After cooling to room temperature, the organic phase was extracted with ethyl acetate (3 x 25 mL) and the combined organic phases were washed with distilled water, dried over magnesium sulfate and concentrated in vacuo. This procedure gave 750 mg of a white solid with an isolated yield of 85%.

[0403] Appearance: white solid. 1 H NMR: (400 MHz, CDC13) δ 8.20 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz, 2H), 7.95 (d, J = 2 Hz, 2H), 7.46 (t, J = 4, 8 Hz, 2H), 7.26 (t, J = 4, 8 Hz, 2H), 7.07 (d, J = 4 Hz, 2H), 3.07 (t, J = 4, 8 Hz, 4H), 1.99 (t, J = 4, 8 Hz, 4H), 1.33 (m, 4H), 1.23 (m, 4H), 1.01 (m, 4H). 13 CNMR: (126 MHz, CDC13) δ 179.7, 141.4, 133.3, 127.6, 127.2, 126.9, 125.5, 121.6, 117.7, 115.8, 50.1, 34.2, 27.2, 25.0. HRMS: (ESI-TOF MS ES+) m / z [C 32 H 34 N8O2] + Calculated: 562.2805, found 562.2812.

[0404] Synthesis of N,N'-([1,1'-binaphthalene]-2,2'-diyl)bis(6-aminohexanamide)

[0405] Scheme 10. Synthesis of N,N'-([1,1 '-binaphthalene]-2,2'-diyl)bis(6- aminohexanamide)

[0406]

[0407] A 100 mL three-necked round bottom flask was equipped with a stir bar and charged with 500 mg (0.617 mmol) of N,N'-([1,1 '-binaphthalene]-2,2'-diyl)bis(6-azidohexanamide) and 40 mL of ethyl acetate and 20 mL of methanol. The solution was degassed with argon for 20 minutes. To the reaction mixture was added 50 mg of Pt / C under argon atmosphere. The reaction mixture was then degassed with hydrogen and sealed with a balloon of hydrogen. After stirring for 16 hours, the mixture was filtered through a short pad of celite and concentrated under reduced pressure. The reaction mixture was purified using flash column chromatography with hexanes: ethyl acetate as eluent to give 332 mg of white solid product (yield = 71 %).

[0408] 1 H NMR: (400 MHz, CDC13): δ 8.31 (m, 2H), 8.06 (d, J = 4 Hz, 2H), 7.96 (d, J = 4 Hz, 2H), 7.47 (t, J = 4 Hz, 2H), 7.28 (m, 2H), 7.08 (d, J = 8 Hz, 2H), 2.53 (t, J = 4 Hz, 4H), 2.02 (t, J = 4 Hz, 4H), 1.28 (m, 8H), 1.03 (m, 4H). 13 C NMR: (126 MHz, CDC13) δ 179.5, 141.3, 133.2, 127.7, 127.2, 127.0, 125.5, 121.3, 117.7, 115.5, 42.5, 34.3, 27.0, 25.2. HRMS: (ESI-TOF MS ES+) m / z [C 32 H 40 N4O2] + Calculated: 512.3151, found 512.3142.

[0409] Synthesis of N-(2'-(6-(14-azidohexanamido)-[1,1 '-binaphthalene]-2-yl)-6- aminohexanamide ditetrafluoroborate

[0410] Scheme 11. Synthesis of N-(2'-(6-(14-azidohexanamido)-[1,1 '-binaphthalene]-2-yl)-6- aminohexanamide ditetrafluoroborate

[0411]

[0412] A 20 mL round bottom flask was charged with 100 mg (0.195 mmol) of N,N’-([1,1’- binaphthalene]-2,2’-diyl)bis(6-aminohexanamide), 4 mL of diethyl ether, and 4 mL of anhydrous dichloromethane using a stir bar. The solution was cooled and stirred vigorously at 0 °C. A solution of HBF4(0.505 mmol) in diethyl ether was added dropwise. After 30 minutes, the mixture was concentrated to about 1 mL, then filtered. The resulting off-white solid was washed with diethyl ether to give 55 mg of product (41% yield).

[0413] 1H NMR: (400 MHz, CDC13) δ 8.12 (d, J = 16 Hz, 2H), 8.04 (d, J = 8 Hz, 2H). 7.95 (d, J = 8 Hz, 2H), 7.52 (t, J = 8 Hz, 2H), 7.32 (t, J = 8 Hz, 2H), 7.02 (d, J = 16 Hz, 2H), 6.42 (m, 2H), 2.00 (m, J = 8 Hz, 8H), 1.39 (quin, J = 8 Hz, 4H), 1.21 (m, 4H), 0.92 (m, 4H).13C NMR: (126 MHz, CDC13) δ 179.8, 141.3, 133.2, 127.7, 127.2, 127.0, 125.5, 121.5, 117.5, 115.5, 42.3, 34.3, 27.0, 25.2. HRMS: (ESI-TOF MS ES+) m / z [C 32 H 40 N4O2] + Calculated: 512.3151, found 512.3156.

[0414] Synthesis of ethyl 2-benzamidobenzoate

[0415] Scheme 12. Synthesis of ethyl 2-benzamidobenzoate

[0416]

[0417] A 500 mL two-necked round bottom flask was charged with 10 g (60.6 mmol) of ethyl 2- aminobenzoate and anhydrous dichloromethane (200 mL) using a stir bar. Under an argon atmosphere, 25.8 mL of triethylamine (182 mmol) was added in one portion at 0 °C, followed by dropwise addition of 7.01 mL of benzoyl chloride (60.6 mmol). The reaction mixture was refluxed at 50 °C for 16 hours. The reaction mixture was concentrated to about 100 mL, the white solid was collected by filtration and washed with diethyl ether to give 13.37 g of product (yield = 82%).

[0418] 1H NMR: (400 MHz, CDC13) δ 8.29 (s, 1H), 8.04 (t, J = 8, 16 Hz, 1H), 7.38 (m, 6H), 6.70 (m, 2H), 4.39 (q, J = 8 Hz, 2H), 1.45 (t, J = 8 Hz, 3H). 13 CNMR: (126 MHz, CDC13) δ 168.76, 151.03, 138.97, 134.56, 131.69, 128.73, 127.19, 114.90, 111.72, 110.56, 60.33, 14.43. HRMS: (ESI-TOF MS ES+) m / z [C 16 H 15 NO3] + Calculated: 269.1052, found 269.1058.

[0419] Synthesis of ethyl 2-(N-(6-bromohexyl)benzamido)benzoate

[0420] Scheme 13. Synthesis of ethyl 2-(N-(6-bromohexyl)benzamido)benzoate

[0421]

[0422] A 100 mL round bottom flask was equipped with a stir bar and charged with 2 g (7.44 mmol) of ethyl 2-benzamidobenzoate and anhydrous dimethylformamide in a 100 mL round bottom flask. Under an argon atmosphere, 715 mg of 50% sodium hydride (14.88 mmol) was added in one portion at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. A solution of 1,6-dibromohexane (14.88 mmol) in anhydrous dimethylformamide (20 mL) was slowly added to the reaction mixture at 0 °C. The resulting yellow mixture was stirred overnight (16 hours). The reaction was quenched by pouring the mixture into a 1 L beaker containing ice water. The organic phase was then extracted with ethyl acetate (200 mL x 3) and the combined organic phase was washed with deionized water (200 mL x 5). The solution was then dried over magnesium sulfate and concentrated under reduced pressure. The product was obtained as a pale yellow oil (yield = 1.35 g, 42%) by flash column chromatography using hexanes: ethyl acetate as eluent.

[0423] 1H NMR: (400 MHz, CDC13) δ 7.78 (dd, J = 8 Hz, 1H), 7.40 (t, J = 8 Hz, 1H), 7.24 (m, 3H), 7.13 (m, 4H), 4.32 (q, J = 8 Hz, 2H), 3.38 (t, J = 8 Hz, 2H), 1.84 (m, 3H), 1.69 (m, 3H), 1.46 (m, 4H), 1.36 (t, J = 8 Hz, 3H). 13 C NMR: (126 MHz, CDC13) δ 170.02, 165.64, 143.33, 136.20, 132.65, 131.66, 130.54, 129.41, 128.28, 127.56, 127.24, 61.54, 50.82, 33.83, 32.64, 27.88, 27.42, 26.24. HRMS: (ESI-TOF MS ES+) m / z [C 22 H 25 BrNO3] + Calculated: 430.1018, found 430.1026.

[0424] Synthesis of ethyl 2-(N-(6-azidohexyl)benzamido)benzoate

[0425] Scheme 14. Synthesis of ethyl 2-(N-(6-azidohexyl)benzamido)benzoate

[0426]

[0427] In a 100 mL round bottom flask, equipped with a stirring bar, 500 mg (1.15 mmol) of ethyl 2-(N-(6-bromohexyl)benzamido)benzoate, 90 mg of sodium azide (1.39 mmol) and dimethyl sulfoxide (25 mL) were combined. The reaction mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the organic phase was extracted with ethyl acetate (3 x 25 mL) and the combined organic phases were washed with distilled water, dried over magnesium sulfate and concentrated in vacuo. This procedure gave 408 mg of a white solid with an isolated yield of 90%.

[0428] 1 1H NMR: (400 MHz, CDC13) δ 7.85 (d, J = 8 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 7.30 (m, 4H), 7.21 (m, 1H), 7.15 (t, J = 8, 16 Hz, 2H), 3.51 (q, J = 8 Hz, 3H), 3.29 (t, J = 8 Hz, 2H), 1.72 (m, 2H), 1.61 (m, 4H), 1.42 (t, 4H), 1.20 (t, J = 8 Hz, 3H).13 C NMR: (126 MHz, CDC13) δ 171.35, 168.86, 143.00, 136.31, 132.60, 130.79, 129.15, 127.77, 127.41, 127.30, 61.41, 56.92, 50.96, 32.09, 28.38, 26.12, 25.10, 14.04. HRMS: (ESI-TOF MS ES+) m / z [C 22 H 26 N4O3] + Calculated: 394.2005, found 394.2011.

[0429] Synthesis of 2-(N-(6-azidohexyl)benzamido)benzoic acid

[0430] Scheme 15. Synthesis of 2-(N-(6-azidohexyl)benzamido)benzoic acid

[0431]

[0432] A 100 mL round bottom flask was equipped with a stir bar and charged with 400 mg (1.02 mmol) of 2-(N-(6-azidohexyl)benzamido)benzoic acid ethyl ester, 121 mg of sodium hydroxide (3.06 mmol), 30 mL of ethanol and 15 mL of deionized water. The reaction mixture was refluxed at 80 °C for 3 hours. After cooling to room temperature, 1 M HC1 was added to the reaction mixture to neutralize the solution to pH = 6. The organic phase was extracted with ethyl acetate (3 x 25 mL) and the combined organic phase was washed with distilled water, dried over sodium sulfate and concentrated under vacuum to give 268 mg of colorless oil with an isolated yield of 72%.

[0433] 1 H NMR: (400 MHz, CD3OD) δ 7.85 (d, J = 8 Hz, 1H), 7.48 (t, J = 8 Hz, 1H), 7.29 (m, 4H), 7.17 (m, 3H), 3.28 (t, J = 8 Hz, 2H), 1.71 (m, 2H), 1.59 (m, 3H), 1.41 (m, 5H). 13 C NMR: (126 MHz, CDC13) δ 171.35, 168.86, 143.00, 136.31, 132.60, 130.79, 129.15, 127.77, 127.41, 127.30, 61.41, 56.92, 50.96, 32.09, 28.38, 26.12, 25.10, 14.04. HRMS: (ESI-TOF MS ES+) m / z [C 20 H21 N4O3 + Na + Calculated: 388.1511, found 388.1514.

[0434] Synthesis of N,N'-((((((lS)-cyclohexane-l,2-diyl)bis(azanediyl))bis(carbonyl))bis(2, 1- phenylene))bis(N-(6-azidohexyl)benzamide)

[0435] Synthesis of N,N'-((((((lS)-cyclohexane-l,2-diyl)bis(azanediyl))bis(carbonyl))bis(2, 1- phenylene))bis(N-(6-azidohexyl)benzamide)

[0436]

[0437] A 100 mL round bottom flask was equipped with a stir bar and charged with 1 g (2.73 mmol) of 2-(N-(6-azidohexyl)benzamido)benzoic acid, 140 mg (1S,2S)-(-)-1,2- diaminocyclohexane (1.23 mmol), 166 mg 4-dimethylaminopyridine, and anhydrous dichloromethane (50 mL). Under an argon atmosphere, 0.5 g of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (3.28 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 16 hours. The solution was evaporated and the product was purified using column chromatography to give 1.77 g of a light yellow oil with an isolated yield of 80%.

[0438] 1 H NMR: (400 MHz, CDC13) δ 7.54 (s, 1H), 7.45 (m, 5H), 7.35 (m, 2H), 7.29 (s, 1H), 7.16 (d, J = 8 Hz, 2H), 7.09 (t, J = 4, 8 Hz, 4H), 6.99 (m, 1H), 6.84 (d, J = 8 Hz, 2H), 6.74 (d, J = 4 Hz, 0.5H), 6.33 (d, J = 8 Hz, 0.5H), 4.36 (q, J = 4, 8 Hz, 1H), 4.25 (m, 1H), 4.05 (br s, 1H), 3.90 (m, 2H), 3.32 (br s, 1H), 3.25 (m, 6H), 2.21 (m, 1H), 2.02 (m, 1H), 1.84 (m, 2H), 1.70 (m, 2H), 1.56 (m, 6H), 1.37 (m, 12H). 13C NMR: (126 MHz, CDC13) δ 170.2, 167.6, 142.2, 141.4, 136.4, 135.9, 134.5, 132.9, 131.3, 130.9, 129.5, 128.7, 128.5, 127.6, 127.5, 126.9, 126.0, 54.4, 45.6, 42.0, 33.5, 32.3, 31.6, 29.7, 27.4, 26.8, 26.0, 25.0, 24.8, 22.7, 17.0, 14.1. HRMS: (ESI-TOF MS ES+) m / z [C 46 H 54 N 10 O4] + Calculated: 810.4330, found 810.4336.

[0439] Synthesis of N,N’-(((((1R)-cyclohexane-1,2-diyl)bis(azanediyl))bis(carbonyl))bis(2,1- phenylene))bis(N-(6-aminohexyl)benzamide)

[0440] Scheme 17. Synthesis of N,N’-(((((1R)-cyclohexane-1,2-diyl)bis(azanediyl))bis(carbonyl))bis(2,1- phenylene))bis(N-(6-aminohexyl)benzamide)

[0441]

[0442] A 100 mL three-necked round-bottom flask was equipped with a stir bar and charged with 500 mg (0.617 mmol) of N,N’-(((((1S)-cyclohexane-1,2-diyl)bis(azanediyl))bis(carbonyl))bis(2,1- phenylene))bis(N-(6-azidohexyl)benzamide) and 40 mL of ethyl acetate and 20 mL of methanol. The solution was degassed with argon for 20 minutes. To the reaction mixture was added 50 mg of Pt / C under an argon atmosphere. The reaction mixture was then degassed with hydrogen and sealed with a balloon of hydrogen. After stirring for 16 hours, the mixture was filtered through a short pad of celite and concentrated under reduced pressure. The reaction mixture was purified using flash column chromatography with hexanes: ethyl acetate as eluent to yield 332 mg of white solid product (yield = 71%).

[0443] 1H NMR: (400 MHz, CDC13) δ 7.45 (m, 8H), 7.12 (m, 8H), 6.84 (m, 2H), 4.39 (m, 2H), 4.22 (t, J = 9 Hz, 2H), 3.91 (m, 4H), 3.56 (s, 4H), 3.19 (m, 2H), 2.61 (t, J = 6 Hz, 4H), 2.30 (t, J = 9 Hz, 4H), 1.88 (m, 12H), 1.67 (m, 4H). 13 CNMR: (126 MHz, CDC13) δ 170.4, 167.2, 142.1, 141.6, 136.8, 136.0, 134.6, 133.0, 131.5, 130.9, 129.6, 128.9, 128.4, 127.5, 127.3, 126.8, 126.1, 45.8, 42.5, 42.3, 33.6, 32.1, 32.0, 29.6, 27.3, 26.9, 25.9, 24.9, 24.5, 22.5, 17.3, 14.5. HRMS: (ESI-TOF MS ES+) m / z [C 46 H 58 N6O4] + Calculated: 758.4520, found 758.4526.

[0444] Synthesis of 6,6’-((((((1R)-cyclohexane-1,2-diyl)bis(azanediyl))bis(carbonyl))bis(2,1- phenylene))bis(benzoyl azanediyl))bis(hexan-1-aminium) ditetrafluoroborate

[0445] Synthesis of 6,6’-((((((1R)-cyclohexane-1,2-diyl)bis(azanediyl))bis(carbonyl))bis(2,1- phenylene))bis(benzoyl azanediyl))bis(hexan-1-aminium) ditetrafluoroborate

[0446]

[0447] A 20 mL round bottom flask was charged with 200 mg (0.263 mmol) of N,N’-(((((1R)-cyclohexane-1,2-diyl)bis(azanediyl))bis(carbonyl))bis(2,1- phenylene))bis(N-(6-aminohexyl)benzamide), 4 mL of ether, and 4 mL of anhydrous dichloromethane using a stir bar. The solution was cooled and stirred vigorously at 0 °C. A solution of HBF4(0.605 mmol) in ether was added dropwise. After 30 minutes, the mixture was concentrated to about 1 mL, then filtered. The resulting off-white solid was washed with ether to give 61 mg of product (25% yield).

[0448] 1H NMR: (400 MHz, CDC13) δ 7.17 (m, 6H), 7.00 (m, 2H), 6.87 (m, 2H), 6.59 (m, 2H), 6.04 (br s, 2H), 3.99 (m, 1H), 3.84 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 2.91 (m, 2H), 2.62 (m, 4H), 2.33 (t, J = 4 Hz, 2H), 2.04 (m, 2H), 1.76 (m, 2H), 1.51 (m, 2H), 1.13 (m, 16H). HRMS: (ESI-TOF MS ES+) m / z [C 46 H 60 N6O4] + Calculated: 760.4676, found 760.4670.

[0449] Fe-1 or H2( 18冠6 Self-assembly of PC) / T supramolecular catalysts

[0450] The following components were charged into a 25 mL polytetrafluoroethylene-capped Schlenk tube: complex Fe-1 or H2 18冠6 PC) (15 mg, 0.01 mmol), template T (0.01 to 0.02 mmol, 0 to 2 equivalents) and CD3CN (3 mL). The tube was placed on a stirring plate and stirred vigorously at room temperature under an argon atmosphere for 30 minutes.

[0451] Recordings 1 H NMR, CD and UV-visible spectra were recorded to determine the binding constant and the secondary supramolecular structure.

[0452] Self-assembly of PC) / T supramolecular catalysts

[0453] The following were charged into a 25 mL polytetrafluoroethylene-capped Schlenk tube: complex Fe-1 (0.0375 mmol, 15 mol%), chiral template T2h (0.075 mmol, 30 mol%), substrate (0.25 mmol, 1 equivalent), CH3CN (2 mL, 0.03125 M), MS (100 mg) and a magnetic stirrer bar. The tube was placed on a stirring plate and stirred vigorously at room temperature under an argon atmosphere. PhINTces (0.25 mmol, 1 equivalent) was added in one portion and the reaction turned purple within a minute. Notably, the reaction had to be carried out under an argon atmosphere, otherwise a significant drop in yield was observed. After 16 hours, the solution was concentrated and the product was purified by flash column chromatography. The isolated organic product was characterized by 1 HNMR, 13 C NMR, ESI-MS and chiral HPLC.

[0454] Evaluation of enantiomeric effects of chiral templates

[0455] The following components were charged into a 25 mL polytetrafluoroethylene-capped Schlenk tube: complex Fe-1 (0.0375 mmol, 15 mol%), chiral template T2h (0.075 mmol, 30 mol%), substrate (0.25 mmol, 1 equiv), CH3CN (2 mL, 0.03125 M), and MS (100 mg), and a magnetic stir bar. The tube was placed on a stirring plate and vigorously stirred at room temperature under an argon atmosphere. PhINTces (0.75 mmol, 3 equiv) was added in one portion and the reaction turned purple within a minute. It is important that the reaction must be carried out under an argon atmosphere as not doing so results in a significant decrease in yield. After 16 hours, the solution was concentrated and the product was purified via flash column chromatography.

[0456] The isolated organic product was characterized using 1 H NMR, 13 C NMR, ESI-MS, and chiral HPLC. The data presented in Table 1 and Figure 2 The data presented in Table 1 and

[0457] Optimization of the conditions for tetralone amination

[0458] The following components were charged into a 25 mL polytetrafluoroethylene-capped Schlenk tube: complex Fe-1 (0.0375 mmol, 15 mol%), chiral template T2h (0.075 mmol, 30 mol%), tetralone 2a (0.25 to 2 mmol, 1 to 8 equiv), THF or HFIP or CH2Cl2or CH3CN (2 mL, 0.03125 M), and MS (100 mg), and a magnetic stir bar. The tube was placed on a stirring plate and vigorously stirred at room temperature under an argon atmosphere. PhINTces (0.25 mmol, 1 equiv) was added in one portion and the reaction turned purple within a minute. It is important that the reaction must be carried out under an argon atmosphere as not doing so results in a significant decrease in yield. After 16 hours, the solution was concentrated and the product was purified via flash column chromatography.

[0459] The isolated organic product was characterized using 1 H NMR, 13 C NMR, ESI-MS, and chiral HPLC. The data presented in Table 2 represent the isolated yield and enantiomeric values determined by HPLC.

[0460] Controlled experiments for tetralone amination

[0461] A 25 mL polytetrafluoroethylene-capped Schlenk tube was charged with complex Fe-1 (0.0375 mmol, 15 mol%), chiral template T2h (0.075 mmol, 30 mol%), tetralone 2a (0.25 to 2 mmol, 1 to 8 equiv), THF or HFIP or CH2CI2 or CH3CN (2 mL, 0.03125 M), and MS (100 mg), and a magnetic stir bar. The tube was placed on a stirring plate and stirred vigorously at room temperature under an argon atmosphere. PhINTces (0.25 mmol, 1 equiv) was added in one portion and the reaction turned purple within a minute. It is important that the reaction be run under an argon atmosphere as not doing so results in a significant decrease in yield. After 16 hours, the solution was concentrated and the product was purified via flash column chromatography. The isolated organic product was characterized by 1 H NMR, 13 CNMR, ESI-MS, and chiral HPLC. The data presented in Table 2 represent isolated yield and enantiomeric values determined by HPLC.

[0462] benzyl sp 3 Evaluation of functional group compatibility and substrate scope in C-H bond amination

[0463] A 25 mL polytetrafluoroethylene-capped Schlenk tube was charged with complex Fe-1 (0.0375 mmol, 15 mol%), chiral template T1-T2h (0.075 mmol, 30 mol%), substrate (2 mmol, 8 equiv), CH3CN (2 mL, 0.03125 M), and MS (100 mg), and a magnetic stir bar. The tube was placed on a stirring plate and stirred vigorously at room temperature under an argon atmosphere. PhINTces (0.25 mmol, 1 equiv) was added in one portion and the reaction turned purple within a minute. It is important that the reaction be run under an argon atmosphere as not doing so results in a significant decrease in yield. After 16 hours, the solution was concentrated and the product was purified via flash column chromatography.

[0464] The isolated organic product was characterized by 1 H NMR, 13 CNMR, ESI-MS, and chiral HPLC. The data presented in Table 3 represent isolated yield and enantiomeric values determined by HPLC.

[0465] Conclusion

[0466] Secondary coordination spheres as synthetic catalysts are rare. An exemplary supramolecular (host catalyst-guest template) catalytic system was prepared with Fe-1 as the host catalyst and chiral diammonium template as the guest template, and was applied to asymmetric C-H amination of various substrates. The Fe-1 / T2h catalytic system was suitable for benzyl C-H bond substrates with high enantioselectivity level and moderate product yield. The asymmetric catalysis was attributed to the strong binding affinity of the diammonium template to the 18-crown-6 receptor, which stabilized the entire supramolecular structure. The synthetic method was suitable for C-H functionalization and amination reactions of various substrates.

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[0511] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. The publications cited herein and their citations are hereby specifically incorporated by reference. Furthermore, unless otherwise noted, the use of the expression "weight percent" means "weight / weight %".

[0512] One skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A host catalyst having the structure: wherein: (i) each occurrence of A, together with the carbon atom to which it is attached, forms a crown ether; (ii) each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, halide, hydroxyl, alkoxy, amino, amido, carbonyl, nitro, nitrile, or thiol; and (iii) the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof. each occurrence of A, together with the carbon atom to which it is attached, forms a 12-crown-4-ether, 15-crown-5-ether, 18-crown-6-ether, dibenzo-18-crown-6-ether, 24-crown-8-ether, or azacrown ether. the host catalyst has the structure: each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl, optionally wherein each occurrence of R1and R2is hydrogen.

5. A guest template having the structure: wherein: (i) B1and B2are independently absent, or a carbon atom, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally B1and B2are independently a carbon atom, substituted or unsubstituted aryl, or substituted or unsubstituted polyaryl; (ii) R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; (iii) the is absent or a bond (single, double, or triple bond); (iv) X1and X2are independently absent, or an oxygen atom or NR5, and R5is absent, or hydrogen, or substituted or unsubstituted alkyl; (v) X3is a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl, (vi) R7is absent, or a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally R7is absent, or a substituted or unsubstituted alkyl, and (vii) R8is absent, or a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally R8is absent, or a substituted or unsubstituted alkyl.

2. The procatalyst of claim 1, wherein, each occurrence of A, together with the carbon atom to which it is attached, forms a 12-crown-4-ether, 15-crown-5-ether, 18-crown-6-ether, dibenzo-18-crown-6-ether, 24-crown-8-ether, or azacrown ether.

3. The procatalyst of claim 1, wherein, the host catalyst has the structure:

4. The procatalyst of claim 1, wherein, each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl, optionally wherein each occurrence of R1and R2is hydrogen.

5. A guest template having the structure: wherein: (i) B1and B2are independently absent, or a carbon atom, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally B1and B2are independently a carbon atom, substituted or unsubstituted aryl, or substituted or unsubstituted polyaryl; (ii) R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally R3and R4are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; (iii) the is absent or a bond (single, double, or triple bond); (iv) X1and X2are independently absent, or an oxygen atom or NR5, and R5is absent, or hydrogen, or substituted or unsubstituted alkyl; (v) X3is a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl, (vi) R7is absent, or a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally R7is absent, or a substituted or unsubstituted alkyl, and (vii) R8is absent, or a substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclic group, optionally R8is absent, or a substituted or unsubstituted alkyl. X3is a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl, ​ ​ ​ ​ (v) L1and L2are independently absent, or are ​ Q1and Q2are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl; (vi) n1and n2are independently integers from 0 to 20; and (vii) the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxyl, aryloxyl, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof.

6. The guest template of claim 5, wherein: (a) is X1and X2are independently an oxygen atom or NR5, R5is absent or hydrogen; n4and n5are independently integers from 0 to 5; n6, n7, n8, and n 10 are independently integers from 0 to 4; n9 and n 11 are independently integers from 0 to 2; n 12 -n 14 are independently integers from 1 to 6; and R7-R 14 independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero polyaryl, or substituted or unsubstituted heterocyclyl, or (b) L1and L2are independently wherein X3is a nitrogen atom, and wherein Q1and Q2are independently substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl, optionally Q1and Q2are unsubstituted phenyl, or (c) combinations thereof.

7. A catalytic system comprising: Host catalysts; and a guest template, wherein, the host catalyst has the following structure: wherein: (i) each occurrence of A, together with the carbon atom to which it is attached, forms a crown ether; (ii) each occurrence of R1and R2is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, halide, hydroxyl, alkoxy, amino, amido, carbonyl, nitro, nitrile, or thiol; and wherein, the guest template has the following structure: wherein: (i) B1and B2are independently absent, a carbon atom, substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl; (ii) R3and R4are independently absent, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl; (iii) is absent or a bond (single, double, or triple bond); (iv) X1and X2are independently absent, an oxygen atom, or NR5, and R5is absent, hydrogen, or substituted or unsubstituted alkyl; (v) L1and L2are independently absent, or are X3is a nitrogen atom or CR6, R6is hydrogen or substituted or unsubstituted alkyl, Qi and Q2 are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyaryl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl; (vi) n1 and n2 are independently integers from 0 to 20; and wherein, the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic group, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof.

8. The catalytic system of claim 7, wherein: (a) the molar ratio of the host catalyst to the guest template is in the range of 1 : 10 to 1 : 1, 1 :5 to 1 : 1, such as 1 :2; or (b) the host catalyst and the guest template are non-covalently bound to one another, optionally via a crown ether of the host catalyst and an ammonium group of the guest template, and optionally wherein the log(K) of the binding between the host catalyst and the guest template is at least 4.0, such as in the range of 4.0 to about 8.0 or 4.0 to about 6.0; or (c) combinations thereof.

9. The catalytic system of claim 7, wherein, the host catalyst and the guest template form the following structure:

10. The catalytic system of claim 7, wherein: (a) each occurrence of R1 and R2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxyl, alkoxy, or carbonyl, optionally each occurrence of R1 and R2 is hydrogen; or (b) B1 and B2 are independently carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted polyaryl; and R3 and R4 are independently absent, or hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; or (c) combinations thereof.

11. The catalytic system of claim 7, wherein: (a) is: X1 and X2 are independently oxygen atoms or NR5, R5 is absent or hydrogen; n4 and n5 are independently integers from 0 to 5; n6, n7, n8, and n 10 are independently integers from 0 to 4; n9 and n 11 are independently integers from 0 to 2; n 12 -n 14 are independently integers from 1 to 6; and R7-R 14 independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hetero polyaryl, or substituted or unsubstituted heterocyclyl, or (b) L1and L2are independently wherein X3is a nitrogen atom, and wherein Q1and Q2are independently substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted cycloalkynyl, optionally Q1and Q2are unsubstituted phenyl, or (c) combinations thereof.

12. The catalytic system of claim 7, wherein, the host catalyst and the guest template form a complex having the following structure:

13. A method for asymmetric C-H amination of a substrate, comprising: (i) maintaining a reaction mixture at room temperature for a period of time sufficient to form a product, wherein the reaction mixture comprises a substrate, a nitrogen source reactant, the catalytic system of claim 7, and a solvent.

14. The method of claim 13, wherein, The nitrogen source reactant is R'-NH2or R"IN-R', wherein R' is -SO2-R'1or -SO3-R'2; R'1and R'2are independently substituted or unsubstituted phenyl or substituted or unsubstituted alkyl (e.g., unsubstituted straight or branched C1-C10 alkyl, unsubstituted straight or branched C1-C8 alkyl, unsubstituted straight or branched C1-C6 alkyl, unsubstituted straight or branched C1-C4 alkyl, etc., such as t-butyl, or haloalkyl such as -CH2CCI3, -CCl3, -CH2CH2CCl3, -CH2CCl2CCl3, etc.); R" is substituted or unsubstituted phenyl; when present, the substituents are independently unsubstituted alkyl (e.g., any of those described above, such as methyl), halide (e.g., fluoride, chloride, bromide, iodide, etc.), nitro, cyano, nitrile, or carbonyl.

15. The method of claim 13, wherein: the structure of the substrate is R-H, and the structure of the product is R-NHR', R is substituted or unsubstituted aryl (e.g., substituted or unsubstituted tetrahydronaphthalene, substituted or unsubstituted indane, substituted or unsubstituted aralkyl, etc.), substituted or unsubstituted polyaryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteropolyl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted chromane, substituted or unsubstituted isochromane, substituted or unsubstituted thiochromane, substituted or unsubstituted isothiochromane, dihydrobenzofuran, dihydroisobenzofuran, dihydrobenzothiophene, dihydroisobenzothiophene, etc.), substituted or unsubstituted cycloalkyl (mono- or polycyclic, such as a fused cycloalkyl ring), substituted or unsubstituted cycloalkenyl (mono- or polycyclic, such as a fused cycloalkenyl ring), or substituted or unsubstituted cycloalkynyl (mono- or polycyclic, such as a fused cycloalkynyl ring); and the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, siloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or a combination thereof.

16. The method of claim 13, wherein: the substrate has the structure: and the product has the structure: R 15 -R 20 independently hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), halide, hydroxyl, carbonyl, amino, amido, silyl, or siloxy, or R 20 and R 15 together with the carbon atom to which they are attached, or R 20 and R 19 together with the carbon atom to which they are attached, can form a substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings), substituted or unsubstituted cycloalkenyl (monocyclic or polycyclic, such as fused cycloalkenyl rings), substituted or unsubstituted cycloalkynyl (monocyclic or polycyclic, such as fused cycloalkynyl rings), substituted or unsubstituted aryl, substituted or unsubstituted polyaryl, substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxacyclohexyl, substituted or unsubstituted thiacyclohexyl, substituted or unsubstituted oxacyclopentyl, substituted or unsubstituted thiacyclopentyl, etc.), substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteropolyaryl; when present, the substituents are independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted polyaryl, substituted or unsubstituted polyheteroaryl, substituted or unsubstituted aralkyl, carbonyl, halide, hydroxyl, phenoxy, aryloxy, alkylthio, phenylthio, arylthio, cyano, isocyano, alkoxy, nitro, carboxyl, amino, amido, oxo, silyl, siloxy, sulfinyl, sulfonyl, sulfonic acid, phosphonium, phosphinyl, phosphoryl, phosphonyl, or thiol, or combinations thereof, such as substituted or unsubstituted alkyl, substituted or unsubstituted aryl, carbonyl, oxo, amino, or alkoxy.

17. The method of claim 16, wherein: (a) R 19 is hydrogen, R 20 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), or R 20 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl (including monocyclic, such as substituted or unsubstituted cyclopentyl and cyclohexyl, and polycyclic, such as substituted or unsubstituted fused cycloalkyl rings) or a substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted oxanyl, substituted or unsubstituted thianyl, substituted or unsubstituted oxolanyl, substituted or unsubstituted thiolanyl, etc.); or (b) R 15 - R 18 independently hydrogen, halide, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C10 straight or branched chain alkyl, substituted or unsubstituted C1-C8 straight or branched chain alkyl, substituted or unsubstituted C1-C6 straight or branched chain alkyl, etc.), substituted or unsubstituted aryl (e.g., substituted or unsubstituted phenyl or benzyl), alkoxy (e.g., methoxy, ethoxy, etc.), carbonyl, or silyloxy; or (c) a combination thereof.

18. The method of claim 16, wherein, R 15 , R 16 , and R 18 are hydrogen, and R 17 is hydrogen, halide, a substituted or unsubstituted alkyl group (e.g., a substituted or unsubstituted C1-C10 straight or branched chain alkyl group, a substituted or unsubstituted C1-C8 straight or branched chain alkyl group, a substituted or unsubstituted C1-C6 straight or branched chain alkyl group, etc.), a substituted or unsubstituted aryl group (e.g., a substituted or unsubstituted phenyl or benzyl group), an alkoxy group (e.g., methoxy, ethoxy, etc.), a carbonyl group, or a silyloxy group.

19. The method of claim 14, wherein, R' is Tces, Ts, Ns, halobenzenesulfonyl, or halobenzenesulfonate (e.g., p-chlorobenzenesulfonyl or p-chlorobenzenesulfonate); and R" is unsubstituted phenyl or phenyl substituted with alkyl or halide (e.g., chlorobenzene or alkylbenzene).

20. The method of claim 13, wherein, the nitrogen source reactant in the reaction mixture is PhINTces. the nitrogen source reactant in the reaction mixture is PhINTces.

21. The method of claim 13, wherein the substrate has the following structure: and the product has the structure:

22. The method of claim 13, wherein, the molar ratio of the substrate to the nitrogen source reactant is in the range of 10: 1 to 1 : 1 or 10: 1 to 5: 1, such as 8:

1.

23. The method of claim 13, wherein, the host catalyst has a loading in the range of about 5 mole % to about 30 mole % or about 10 mole % to about 20 mole %, such as about 15 mole %.

24. The method of claim 13, wherein: (a) the solvent is CH3CN, THF, HFIP, or C6H6, preferably wherein the solvent is CH3CN; or (b) the reaction mixture further comprises a drying agent or molecular sieves, such as molecular sieves, molecular sieves or molecular sieves; or (c) the reaction is carried out under an inert gas environment, optionally wherein the inert gas is argon; or (d) a combination thereof.

25. The method of claim 13, wherein, the reaction mixture is maintained in the range of about 30 minutes to about 24 hours, about 1 hour to about 20 hours, or about 2 hours to about 18 hours, such as about 16 hours.

26. The method of claim 13, wherein, the product has a yield of at least 30%, at least 40%, at least 50%, in the range of about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

27. The method of claim 13, wherein, the product has an enantiomeric ratio of at least 2: 1, such as in the range of 2: 1 to 99: 1, 4: 1 to 99: 1, 9: 1 to 99: 1, or 19: 1 to 99: 1, as determined by chiral HPLC.

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