WO2025064852A1

WO2025064852A1 - Catalytic dirhodium tetrakis(binaphthylphosphate) complexes and synthetic methods related thereto

Info

Publication number: WO2025064852A1
Application number: PCT/US2024/047738
Authority: WO
Inventors: Huw M. L. Davies; Ziyi CHEN
Original assignee: Emory University
Current assignee: Emory University
Priority date: 2023-09-20
Filing date: 2024-09-20
Publication date: 2025-03-27
Anticipated expiration: 2026-03-20

Abstract

Disclosed herein are dirhodium tetrakis(binaphthylphosphate) complexes for uses in catalyzing synthetic processes. In certain embodiments, this disclosure relates to compositions comprising dirhodium tetrakis(binaphthylphosphate) complexes disclosed herein. In certain embodiments, this disclosure relates to methods of making compounds disclosed herein by contacting compounds with catalytic dirhodium tetrakis(binaphthylphosphate) complexes disclosed herein.

Description

CATALYTIC DIRHODIUM TETRAKIS(BINAPHTHYLPHOSPHATE) COMPLEXES AND SYNTHETIC METHODS RELATED THERETO CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/584,026 filed September 20, 2023. The entirety of this application is hereby incorporated by reference for all purposes. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under GM099142 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Homoleptic chiral dirhodium tetracarboxylates are reported as catalysts for carbene and nitrene transfer reactions. Depending on the nature of the chiral ligands, they can self-assemble during formation of the dirhodium complexes to generate catalysts. Hodgson et al. report dirhodium(II)-catalyzed enantioselective intramolecular 1,3-dipolar cycloadditions of carbonyl ylides with alkene and alkyne dipolarophiles. Synlett, 2003, 1, 59–62. Hrdina et al. report catalytic properties of tetrakis(binaphthyl or octahydrobinaphthyl phosphate) dirhodium(II,II) complexes. Organometallics, 2013, 32, 473-479. Garlets et al. report extended C₄−symmetric dirhodium tetracarboxylate catalysts. ACS Catal, 2022, 12, 10841-10848. Konda et al. report chiral (R)-3,3′-disubstituted BINOL-Phosphates. Russian J Gen Chem, 2022, 92(5):898–907. Yang et al. report chiral dirhodium tetraphosphate-catalyzed enantioselective Si-H bond insertion of alpha-aryldiazoacetates. J Org Chem, 2021, 86(14):9692-9698. See also US Patent No.6,962,891; 8,975,428; and 10,766,833. References cited herein are not an admission of prior art. SUMMARY Disclosed herein are dirhodium tetrakis(binaphthylphosphate) complexes for uses in catalyzing synthetic processes. In certain embodiments, this disclosure relates to compositions comprising dirhodium tetrakis(binaphthylphosphate) complexes disclosed herein. In certain embodiments, this disclosure relates to methods of making compounds disclosed herein by contacting compounds with catalytic dirhodium tetrakis(binaphthylphosphate) complexes disclosed herein. In certain embodiments, this disclosure relates to compositions comprising a dirhodium tetrakis (binaphthylphosphate) complex of the following formula:

aryl, substituted aryl, heteroaryl, or fused aryl. In certain embodiments, the substituted aryl is 3,5-dialkylphenyl. In certain embodiments, the substituted aryl is 2,4,6-trialkylphenyl. In certain embodiments, the substituted aryl is 4-alkylphenyl.

In certain embodiments, this disclosure relates to compositions comprising a dirhodium tetrakis (binaphthylphosphate) complex of the following formula: .

relates to compositions comprising a dirhodium tetrakis (binaphthylphosphate) complex of the following formula:

substituted aryl, heteroaryl, or fused aryl. In certain embodiments, the substituted aryl is -(2,4,6-Me₃-C₆H₂), -(3,5-Ph₂-C₆H₃), or -(3,5-tBu2-C6H3). In certain embodiments, the substituted aryl is 3,5-dialkylphenyl, 2,4,6-trialkylphenyl, 4- alkylphenyl. In certain embodiments, this disclosure relates to methods of making a synthetic compound by forming a carbon to carbon bond comprising contacting a) a diazo compound comprising a diazo carbon atom and two diazo nitrogen atoms, b) a compound with a carbon to hydrogen bond, and c) a dirhodium tetrakis (binaphthylphosphate) complex as disclosed herein, wherein contacting is under conditions such that a synthetic compound is formed comprising a carbon to carbon bond, and wherein the carbon to carbon bond includes the diazo carbon atom and the carbon of the carbon hydrogen bond. In certain embodiments, this disclosure relates to methods of making a synthetic compound by forming a carbon to nitrogen bond comprising contacting a) a diazo compound comprising a diazo carbon atom and two diazo nitrogen atoms, b) a compound with a nitrogen to hydrogen bond, and c) a dirhodium tetrakis (binaphthylphosphate) complex as disclosed herein, wherein contacting is under conditions such that a synthetic compound is formed comprising a carbon to nitrogen bond, and wherein the carbon to nitrogen bond includes the diazo carbon atom and the nitrogen of the nitrogen hydrogen bond. DETAILED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art. An “embodiment” refers to an example of this disclosure, and it is not intended that the claims are necessarily limited to such example. The claims are solely limited to the express terms of the claims as presented or as amended or as presented in divisional or continuation applications or modified during patent prosecution. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. Further, the dates of publication provided could be different from the actual publication dates that may need to be independently confirmed. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. For any element disclosed herein expressly, by chemical formula, by inference, or by a letter(s) designation, the element is contemplated to include that element in its natural abundance or versions accessible in enriched forms in excess of natural abundance using standard synthetic techniques. For example, “H” or “hydrogen” refers to the hydrogen element or versions accessible as enriched in excess of natural abundance for common isotopes thereof, e.g., deuterium, ²H, or tritium ³H. Similarly, enriched halogen isotopes are contemplated, e.g., ¹⁸F, ¹⁹F, or ⁷⁶Br. As used herein, the term “derivative” refers to a structurally similar compound that retains sufficient functional attributes of the identified analogue. The derivative may be structurally similar because it is lacking one or more atoms, substituted, a salt, in different hydration/oxidation states, or because one or more atoms within the molecule are switched, such as, but not limited to, replacing an oxygen atom with a sulfur atom or replacing an amino group with a hydroxy group. Derivatives may be prepared by any variety of synthetic methods or appropriate adaptations presented in synthetic or organic chemistry textbooks, such as those provide in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, hereby incorporated by reference. The term "substituted" refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are "substituents." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SOR_a, -S(=O)₂R_a, -OS(=O)₂R_a and -S(=O)₂OR_a. R_a and R_b in this context may be the same or different and independently hydrogen, halogen hydroxy, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl. When used in reference to compound(s) disclosed herein, "salts" refer to derivatives of the disclosed compound(s) where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. As used herein, "alkyl" means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2- butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3- dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3- methyl-1-butynyl, and the like. Non-aromatic mono or polycyclic alkyls are referred to herein as "carbocycles" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, and the like. "Heterocarbocycles" or heterocarbocyclyl" groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. "Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. As used herein, "heteroaryl" or “heteroaromatic” refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term "heteroaryl" includes N-alkylated derivatives such as a 1-methylimidazol- 5-yl substituent. As used herein, "heterocycle" or "heterocyclyl" refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like. "Alkylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., -S-CH₃). "Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n- butoxy, s-butoxy, t-butoxy, n- pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i- propoxy, n-butoxy, s-butoxy, t-butoxy. "Alkylamino" refers an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., -NH-CH₃). "Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bridge (i.e., -(C=O)alkyl). "Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., -S(=O)₂alkyl) such as mesyl and the like, and "Arylsulfonyl" refers to an aryl attached through a sulfonyl bridge (i.e., -S(=O)2aryl). "Alkylsulfamoyl" refers to an alkyl as defined above attached through a sulfamoyl bridge (i.e., -S(=O)2NHalkyl), and an "Arylsulfamoyl" refers to an alkyl attached through a sulfamoyl bridge (i.e., -S(=O)₂NHaryl). "Alkylsulfinyl" refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfinyl bridge (i.e. -S(=O)alkyl). The terms "halogen" and "halo" refer to fluorine, chlorine, bromine, and iodine. Certain of the compounds described herein may contain one or more asymmetric centers and may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry at each asymmetric atom, as (R)- or (S)-. The present chemical entities, compositions and methods are meant to include all such possible isomers, including racemic mixtures, tautomer forms, hydrated forms, optically substantially pure forms and intermediate mixtures. In certain embodiments, the compounds may be present in a composition with enantiomeric excess or diastereomeric excess of greater than 60%. In certain embodiments, the compounds may be present in enantiomeric excess or diastereomeric excess of greater than 70%. In certain embodiments, the compounds may be present in enantiomeric excess or diastereomeric excess of greater than 80%. In certain embodiments, the compounds may be present in enantiomeric excess or diastereomeric excess of greater than 90%. In certain embodiments, the compounds may be present in enantiomeric excess or diastereomeric excess of greater than 95%. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.

Dirhodium Tetrakis (binaphthylphosphate) Complexes and Synthetic Transformations In certain embodiments, this disclosure relates to compositions comprising a dirhodium tetrakis (binaphthylphosphate) complex of the following formula:

aryl, substituted aryl, heteroaryl, or fused aryl. In certain embodiments, the substituted aryl is 3,5-dialkylphenyl. In certain embodiments, the substituted aryl is 2,4,6-trialkylphenyl. In certain embodiments, the substituted aryl is 4-alkylphenyl. In certain embodiments, this disclosure relates to compositions comprising a dirhodium tetrakis (binaphthylphosphate) complex of the following formula: .

r, substituted aryl, heteroaryl, or fused aryl. In certain embodiments, the substituted aryl is -(2,4,6-Me3-C6H2), -(3,5-Ph2-C6H3), or - (3,5-tBu2-C6H3). In certain embodiments, the substituted aryl is 3,5-dialkylphenyl, 2,4,6-trialkylphenyl, 4- alkylphenyl. In certain embodiments, this disclosure relates to methods of making a synthetic compound by forming a carbon to carbon bond comprising contacting a) a diazo compound comprising a diazo carbon atom and two diazo nitrogen atoms, b) a compound with a carbon to hydrogen bond, and c) a dirhodium tetrakis (binaphthylphosphate) complex as disclosed herein, wherein contacting is under conditions such that a synthetic compound is formed comprising a carbon to carbon bond, and wherein the carbon to carbon bond includes the diazo carbon atom and the carbon of the carbon hydrogen bond. In certain embodiments, this disclosure relates to methods of making a synthetic compound by forming a carbon to nitrogen bond comprising contacting a) a diazo compound comprising a diazo carbon atom and two diazo nitrogen atoms, b) a compound with a nitrogen to hydrogen bond, and c) a dirhodium tetrakis (binaphthylphosphate) complex as disclosed herein, wherein contacting is under conditions such that a synthetic compound is formed comprising a carbon to nitrogen bond, and wherein the carbon to nitrogen bond includes the diazo carbon atom and the nitrogen of the nitrogen hydrogen bond. Dirhodium Tetrakis(binaphthylphosphate) Catalysts for Enantioselective Functionalization of Unactivated C−H Bonds C2-symmetric binaphthylphosphate (BNP) ligands were designed to generate Rh2(BNP)4 complexes of D₄ symmetry with both rhodium sites having distinctive characteristics. Experiments were performed to determine their the enantioselectivity in C−H functionalization reactions. The binaphthylphosphate dirhodium catalyst, Rh2(S-megaBNP)4 (S-1), has conformational mobility and is very effective for asymmetric C−H functionalization with donor/acceptor carbenes. The Rh₂(S-BNP)₄, S-2, of up to 50 % ee in cycloaddition

reactions. In the

capable of relatively high levels of asymmetric induction but only when methoxy substituents were present in the aryl ring. The main challenge associated with the binaphthylphosphate ligands is how to modify their structure to enhance the asymmetric induction. Large functionality at C3 of the naphthyl group may interfere with the adjacent ligands. The tetraphenyl derivative S-6a was prepared because the phenyl groups are amenable for modification into larger groups by means of metal-catalyzed cross- coupling reactions.

Catalyst S-6a was evaluated in a standard C−H functionalization reaction as a reference reaction and then modifications of its structure were performed to understand the benefits of additional derivatives. A series of more bulky derivatives were shown to enhanced enantioselectivity. The synthetic route to a series of the 4,4′,6,6′-tetraarylbinaph-thylphosphate catalysts is summarized in Scheme 1. Scheme 1. Synthesis of Tetraarylbinaphthylphosphate Catalysts S-6a,c,d

ons, but the 4,4′ position can also be brominated under more forcing conditions to generate the tetrabromo derivative S-8. Tetra-fold Suzuki coupling on S-8 generated a series of tetraaryl derivatives S- 9a,c,d, which on de-etherification to form S-10a,c,d, followed by generation of the phosphonic acid S-11a,c,d and ligand exchange with dirhodium tetraacetate, generated the desired binaphthylphosphate catalysts S-6a,c,d. The binaphthylphosphate catalysts S-2, S-6a, S-6c, and S-6d were tested for their effectiveness at asymmetric induction in a standard C−H functionalization of cyclohexane (Table 1) using the bromoaryldiazoacetate 12a as the carbene source to form the functionalized product 13a.

Table 1 shows initial catalyst screening of C−H functionalization of cyclohexane

, 1 mL of CH₂Cl₂ in a 4 mL vial, diazo (0.1 mmol) in 1 mL of CH₂Cl₂ was added over 1 h via syringe pump at 23 °C. The ee values were determined by chiral HPLC analysis. b) NMR yields were determined with trichloroethylene as internal standard (6.47 ppm). The parent catalyst S-2 generated 13a in only 27% ee, while the tetraphenyl catalyst S-6a7e gave 13a in 44% ee. A significant enhancement was obtained with the 3,5-disubstituted aryl catalysts S-6c and S-6d, which generated 13a in 79% and 85% ee, respectively. Additional catalysts were designed to focus on bulky 4,4′-diaryl substituents, while maintaining the same groups at the 6,6′ positions. The direct synthesis of 4,4′-disubstituted binaphthols with no substituents at the 6,6′ positions was challenging because the 6,6′ positions are favored for electrophilic aromatic substitution. The synthesis of additional binaphthylphosphate catalysts included bulky aryl substituents at C4, C4′ and smaller chlorine substituents at C6, C6′, as illustrated in Scheme 2.

Scheme 2 shows the synthesis of the Rh2-[6,6′-dichloro-4,4′-diarylbinaphthylphosphate] Catalysts S-18 and Rh2(S-megaBNP)4 (S-1)

the 6,6′- dibromo derivative S-14. Treatment of S-14 with copper(I) chloride generated the 6,6′-dichloro derivative S-15,14 which then could be dibrominated at the 4,4′ positions to form S-16. Double Suzuki coupling of S-16 occurred at the bromide and subsequent reactions that were used in Scheme 1, generated the desired ligands S-17a and S-17b with 4,4′-aryl substituents. The ligand exchange with dirhodium tetraacetates generated the desired catalysts S- 18 and Rh2(S-megaBNP)4 (S-1). The catalysts were evaluated in the standard C−H functionalization with cyclohexane, and the results are summarized in Table 2. Table 2 shows data on C−H Functionalization of Cyclohexane Using S-18 and S-1 as Catalysts

the enantioselectivity during the formation of 13a remained moderate (54% ee). In contrast, the 3,5- di-tert-butylphenyl catalyst S-1 was exceptional, generating 13a in 99% ee. In these studies, a vast excess of cyclohexane was used. Good yield and enantioselectivity were achieved with 10 equiv of cyclohexane, generating 13a in an 85% isolated yield and 99% ee. Less than 10 equiv of cyclohexane led to a slightly decreased yield and enantioselectivity. With 1 equiv of cyclohexane, 13a was formed in 70% NMR yield and 97% ee (Table 2, entry 4). The difference in enantioselectivity observed with catalysts S-18 and S-1 is substantial. The X-ray structure of the optimum catalyst, Rh2(S-megaBNP)4 (S- 1), indicates that it adopts a D4-symmetric arrangement. Experiments were performed to examine the influence of p-substituted aryldiazoacetates and a few heteroaryldiazoacetates on the enantioselectivity of the C−H functionalization reaction (Table 3).

Table 3 shows C−H functionalization of cyclohexane with p-substituted aryldiazoacetates

With the dirhodium tetracarboxylates, it was found that donor/acceptor carbenes with trihaloethyl esters are better than those with a standard methyl ester in the functionalization of unactivated C−H bonds and often result in higher levels of enantioselectivity. The reaction of aryldiazoacetates to form products 13a−c was compared to determine the influence of the ester group on the reactions catalyzed by S-1. All three give effective transformations, but the enantioselectivity with the trichloroethyl ester (99% ee) is higher than the methyl ester (90% ee) and the trifluoroethyl ester (91% ee). High enantioselectivity can be obtained when the p-substituent is electron withdrawing, as seen with 13d−f (92−95% ee), but the trifluoromethanesulfonyl derivative does not do as well, forming 13i in 78% ee. A p-phenyl substituent generates 13g with high enantioselectivity (92% ee), but there is a slight drop in the enantioselectivity with the p-tolyl derivative, forming 13h in 86% ee. Other aromatic systems were also examined to form products 13j−l. The 2-naphthyl and 4-chloropyridyl diazo derivatives perform well, forming 13j in 90% ee and 13k in 94% ee, respectively. The chloropyrimidine derivative generated 13l with 65% ee. The diazo compounds that performed lower were with an electron donating methoxy group (61% ee, product 13m), a bulky tert-butyl group (41% ee, product 13n), and the parent phenyl derivative lacking a para substituent (56% ee, product 13o). Experiments were conducted with differentially substituted aryldiazoacetates. The reference substrate was the p-chloro derivative, which had been shown to generate 13d in 93% ee (Table 4). Table 4. Reactions with differentially substituted haloaryldiazoacetates

vatives, the enantioselectivity was considerably lower (48% ee for 13p and 60% ee for 13q, respectively). Low enantioselectivity was also observed with a variety of meta substituents as shown in the formation of 13r−t (18−49% ee). Interestingly, even though 3,5-dibromo derivative 13u was formed with low levels on enantioselectivity (11% ee), the 3,4-dichloro and 3,4-dibromo derivatives, 13v and 13w, were both formed in 91% ee. These studies further support the hypothesis that an aryl group with a para substituent is a component for achieving high asymmetric induction in the C−H functionalization reactions with S-1. Experiments were performed to evaluate catalyst-controlled site-selective and enantioselective functionalization of unactivated C−H bonds. S-1 was compared against other dirhodium tetracarboxylate catalysts (Scheme 3).

Scheme 3 shows results comparing Rh₂(S-megaBNP)₄ (S-1) with other chiral dirhodium tetracarboxylate catalysts

bulky D₂- symmetric catalyst, Rh₂(R-3,5-di(p-tBuC6H4)TPCP)₄ (R-23) drives the C−H functionalization of donor/acceptor carbenes toward the most accessible secondary C−H bond. In the case of pentane, a clean reaction occurs at C2, favoring 19, with no observed reaction occurring at C3 to form 20. The only regioisomer formed is a trace amount of C−H functionalization at the methyl group. Furthermore, the C−H functionalization to form 19 proceeds with 9:1 dr and in 99% ee. The reaction of pentane with S-1, as catalyst, gave a 14:1 site selectivity for C2 functionalization over C3 functionalization, indicating that it is not as sterically demanding as Rh2(R-3,5-di(p- tBuC₆H₄)TPCP)₄ and thus does not distinguish as well between the two methylene sites. Furthermore, the C2 diastereoselectivity for the formation of 19 is inferior (2:1 d.r) to that of the R-23-catalyzed reaction (9:1 d.r). The second comparison is against the tertiary selective catalyst, Rh₂(S-TCPTAD)₄ (S-24). This catalyst is less sterically demanding than R-23 and preferentially reacts at the most accessible tertiary C−H bond. The head-to-head comparison using 2-methylhexane as a substrate reveals that S-1 competes very well with S-24. Not only does it give enhanced site selectivity for the tertiary site to preferentially form 21 over 22 (11:1 r.r. versus 5:1 r.r.), but also the level of asymmetric induction at the tertiary group to form 21 is enhanced (91% ee for S-1, versus 77% ee for S-24). As Rh2(S-megaBNP)4 (S-1) competes well with S-24 for site-selective tertiary C−H functionalization, a detailed study was conducted on a range of substrates 25a−m, and the results are described in Table 5.

Table 5. S-1 Catalyzed Selective C−H Functionalization at Tertiary C−H Bonds

The reactions were conducted under two reaction conditions. Condition A uses an excess of trap, and this is very effective for cheap volatile hydrocarbons. Condition B uses 2 equiv of the aryldiazoacetates and was preferred when more elaborate substrates were used. S-1-catalyzed reactions strongly prefer the most accessible tertiary C−H bonds (25a−d) although a readily accessible secondary C−H bond can still be a competitive site (25b). The reaction can be carried out in the presence of other functionality, as illustrated with 25e−i. Bromo, phthalimido, p- substituted phenoxy, and boronates are compatible with these reactions. The enantioselectivity ranged from 80 to 95% ee. The reaction can also be conducted on other cyclic substrates, as illustrated with 25j−l. The reaction with adamantane is particularly impressive, as C−H functionalization product 26l is formed in 96% ee (entry 3). The studies so far have been conducted using aryldiazoacetates, which are the most widely used carbene precursors in extend the chemistry to other acceptor groups such as aryl diazo ketones,3k shown in Scheme 4. Scheme 4. Rh₂(S-megaBNP)₄ (S-1) Catalyzed C−H Functionalization with Diazoketone 27

For an effective reaction with the diazoketone 27, one can use a large excess of cyclohexane but under these conditions the C−H functionalization product 28 was generated with high levels of asymmetric induction (99% ee), yield (46%). It is possible to extend the chemistry to other acceptor groups such as aryl diazo ketones. Experiments were performed to evaluate the kinetic efficiency of S-1 in the reaction of the aryldiazoacetate 12e with cyclohexane. Experiments indicated that the optimum reaction conditions for high TON C−H functionalization with dirhodium tetracarboxylates were conducted at elevated temperature (60 °C) and used cyclohexane as solvent and an aryldiazoacetate with an electron withdrawing group on the aryl ring. Furthermore, the presence of small amount of DCC or DIC enhanced the TONs. A reaction was conducted using the optimized conditions with a catalyst loading of 0.0025 mol % (Scheme 5). Under these conditions, the C−H functionalization product 13e was formed in 68% isolated yield (29,400 TON) and in 91% ee.

Scheme 5. Rh2(S-megaBNP)4 (S-1) Catalyzed C−H Functionalization under Low Catalyst Loading

Claims

CLAIMS 1. A composition comprising a rhodium complex of the following formula:

aryl, substituted aryl, heteroaryl, or fused aryl.

2. The composition of claim 1, wherein the substituted aryl is 3,5-dialkylphenyl.

3. The composition of claim 1, wherein the substituted aryl is 2,4,6-trialkylphenyl.

4. The composition of claim 1, wherein the substituted aryl is 4-alkylphenyl.

5. The composition of claim 1, wherein the rhodium complex is of the following formula: .

6. A composition comprising a rhodium complex of the following formula: substituted aryl, heteroaryl, or fused aryl.

7. The composition of claim 6, wherein the substituted aryl is -(2,4,6-Me₃-C₆H₂), -(3,5-Ph₂- C₆H₃), or -(3,5-tBu₂-C₆H₃). 8. The composition of claim 6, wherein the substituted aryl is 3,5-dialkylphenyl, 2,4,6- trialkylphenyl, 4-alkylphenyl. 9. A method of making a synthetic compound comprising contacting a) a diazo compound comprising a diazo carbon atom and two diazo nitrogen atoms, b) a compound with a carbon to hydrogen bond, and c) a rhodium complex as in any of claims 1-8, wherein contacting is under conditions such that a synthetic compound is formed comprising a carbon to carbon bond.