FIELD OF THE INVENTION

[0001 ] This invention relates generally to dirhodium compound and their use as catalysts in stereoselective synthesis. In particular, the dirhodium catalysts include ligands that are substituted cyclic imide protected amino acids. The use of the dirhodium catalysts in reactions that proceed via a rhodium carbene or nitrene intermediate is also described.

BACKGROUND OF THE INVENTION

[0002] Dirhodium catalysts have played a prominent role in the metal catalyzed reactions of diazo-compounds with carbene intermediates resulting the formation of one or more carbon-carbon bonds. These reactions are useful in both intermolecular and

intramolecular reactions and have been utilized in the synthesis of commercially useful compounds.

[0003] Some efforts have been made to prepare various dirhodium tetracarboxylate catalysts that have high asymmetric induction. The Hashimoto and Ikegami group prepared a series of N-phthaloyl protected amino acids as ligands for dirhodium complexes. Of these dirhodium complexes, N-phthaloyl protected /ert-leucine (Rh ₂ (S-PTTL) ₄ ) and N- tetrachlorophthaloyl protected tert-leucine (Rh ₂ (S-TCPTTL) ₄ ) derived dirhodium catalysts have shown the highest asymmetric induction. (Kitagaki et al, 1999; Yamawaki et al., 2002; Tsutsui et al, 2003; Tsutsui et al, 2005; El Deftar et al, 2012).

[0004] Other groups have continued to develop analogues in an attempt to improve enantioselectivity, reaction diversity and yield. For example, Muller's group developed the catalyst Rh ₂ (S-NTTL) ₄ derived from N-l,8-naphthanoyl-(S)-/er/-leucine (Miiller and Ghanem, 2004, Ghanem et al, 2010). Other similar catalysts include dirhodium catalysts Rh ₂ (S- PTAD) ₄ and Rh ₂ (S-TCPTAD) ₄ derived from N-phthaloyl protected adamantyl glycine and N- tetrachlorophthaloyl protected adamantyl glycine produced by the Davies group (Reddy et al, 2006; Denton et al, 2007; Denton et al, 2008).

[0005] Despite the number of catalysts belonging to this family, none can be considered a universal catalyst affording high asymmetric induction with different classes of substrates and under different reaction conditions. Furthermore, some of the tetracarboxylate dirhodium catalysts have long synthetic routes which reduce their attractiveness for industrial use. There is still a need for synthetically accessible and highly stereoselective chrial dirhodiura catalysts that can be used in diverse reactions.

SUMMARY OF THE INVENTION

[0006] The present invention is at least in part based on the discovery that substitution of the cyclic imide group of the ligand of the dirhodium catalyst with a substituent that is a branched alkyl having at least one tertiary carbon, an aryl group or a polycyclic saturated or unsaturated hydrocarbon group provides high asymmetric induction while being a synthetically accessible catalyst.

[0007] In a first aspect, the present invention provides a dirhodium compound of formula (I):

wherein

A is a 5 to 8 membered cyclic imide ring;

B is a monocyclic or polycyclic group; R _\ is selected from a branched alkyl group having at least one tertiary carbon atom or a polycyclic saturated or unsaturated hydrocarbon group;

Each R ₂ is independently selected from hydrogen, halogen, -Cu^alkyl, -OR ₄ , -SR ₄ , -N0 ₂ , -CN, aryl, -Ci.ioalkylaryl, cycloalkyl, -Ci.ioalkylcycloalkyl, cycloalkenyl, -C _\ .

loalkylcycloalkenyl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl, -Ci-ioalkylheteroatyl, -N(R ₅ ) ₂ , -N(R5)C(=0)R ₆ , -N(R ₅ )S(0)„R ₆ , -C(=0)R ₆ and -S(0) _n R ₆ ;

R is selected from a branched alkyl group having at least one tertiary carbon atom, a polycyclic saturated or unsaturated hydrocarbon group and an aryl group;

R ₄ is selected from hydrogen, -Ci-ioalkyl, cycloalkyl, -Ci.ioalkylcycloalkyl, cycloalkenyl, -Ci_ _l oalkylcycloalkenyl, aryl, -Ci-ioalkylaryl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl, -Ci-ioalkylheteroaryl and -C(=0)Ci.ioalkyl; Each R ₅ is independently selected from hydrogen, -Cuioalkyl, cycloalkyl, -Cj. _l oalkylcycloalkyl, cycloalkenyl, -Cuioalkylcycloalkenyl, aryl, -Ci-ioalkylaryl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl and -Ci-ioalkylheteroaryl;

R ₆ is selected from hydrogen, -Q.ioalkyl, cycloalkyl, -Ci.ioalkylcycloalkyl, cycloalkenyl, -Ci. _l oalkylcycloalkenyl, aryl, -Q.ioalkylaryl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl, -Ci-ioalkylheteroaryl, -OR ₄ , -SR ₄ and N(R ₅ ) ₂ ; m is an integer from 3 to 7; and n is an integer selected from 1 or 2; or a salt or stereoisomer thereof; wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and polycyclic saturated or unsaturated hydrocarbon group may be optionally substituted with one or more optional substituents.

[0008] In another aspect of the invention there is provided a use of the dirhodium catalyst of the inventi on in a a -C-H or -N-H acti vation reacti on.

DETAILED DESCRIPTION OF THE INVENTION

1. Definitions

[0009] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0010] The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0011 ] Throughout this specification, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

[0012] As used herein, the term "alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, Ci.ealkyl which includes alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.

Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, /?-propyl, /-propyl, /?-butyl, /-butyl, /-butyl, /?-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, w-pentyl, «-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2- dimethyl butyl, 3,3-dimethylbutyl, «-hexyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl, decyl and the branched alkyl groups having at least one tertiary carbon atom described below.

[0013] The term " branched alkyl having at least one tertiary carbon atom" is a subset of alkyl groups in which at least one carbon atom in the alkyl group has no hydrogen substituents. Examples of suitable branched alkyl groups having at least one carbon atom include, but are not limited to, /-butyl (1 , 1-dimethylethyl), 1 ,1-dimethylpropyl,

2,2-dimethylpropyl, 1 -ethyl- 1 -methylpropyl, 1 , 1-diethylpropyl, 1 , 1 -dimethylbutyl, 2,2- dimethyl butyl, 3,3-dimethylbutyl, 1 -ethyl- 1-methylbutyl, 2-ethyl-2-methylbutyl, 3-ethyl-3- methylbutyl, 1, 1-diethylbutyl, 2,2-diethylbutyl, 3,3-diethylbutyl, 1 -methyl- 1-propylbutyl, 2- methyl-2-propylbutyl, 3-methyl-3-propylbutyl, 1 -ethyl- 1 -propylbutyl, 2-ethyl-2-propylbutyl, 3-ethyl-3-propylbutyl, 1 ,1 -dipropylbutyl, 2,2-dipropylbutyl, 3,3-dipropylbutyl, 1 , 1- dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1 -ethyl-l - methylpentyl, 2-ethyl-2-methylpentyl, 3-ethyl-3-methylpentyl, 4-ethyl-4-methylpentyl, 1 , 1- diethylpentyl, 2,2-diethylpentyl, 3,3-diethylpentyl, 4,4-diethylpentyl, 1 -ethyl- 1-propylpentyl, 2-ethyl-2-propylpentyl, 3-ethyl-3-propylpentyl, 4-ethyl-4-propylpentyl, 1 ,1 ,2,2- tetramethylpropyl, 1 , 1 ,2,2-tetramethylbutyl, 1 , 1 ,3,3-tetramethylbutyl, 2,2,3,3-tetramethylbutyl 1,1 ,2,2-tetramethylpentyl, 1,1,3,3-tetramethylpentyl, 1,1 ,4,4-tetramethylpentyl, 2,2,3,3- tetramethylpentyl, 2,2,4,4-tetramethylpentyl and 3,3,4,4-tetramethylpentyl, especially /-butyl, 1,1-dimethylpropyl and 2,2-dimethylpropyl.

[0014 J As used herein, the temi "cycloalkyl" refers to a saturated cyclic

hydrocarbon. The cycloalkyl ring may include a specified number of carbon atoms. For example, a 3 to 8 membered cycloalkyl group includes 3, 4, 5, 6, 7 or 8 carbon atoms.

Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0015] The term "polycyclic saturated or unsaturated hydrocarbon group" as used herein refers to two or more saturated or unsaturated cyclic hydrocarbons that are fused together forming a multicyclic system. The polycyclic hydrocarbon group may be a condensed or bridged or spirocyclic polycyclic hydrocarbon group. The polycyclic hydrocarbon group may have two or more, such as two, three or four rings, fused together. Polycyclic hydrocarbon groups may share one bond in a ring (condensed) or may share more than one bond in a ring forming a bicyclo or tricyclo bridged ring system. The polycyclic hydrocarbon group may include rings sharing one atom thereby forming a spirocyclic ring system. Examples of polycyclic alkyl groups include, but are not limited to,

bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane, bicyclo[3.3.0]octene, bicyclo[3.3.0]octadiene, bicyclo[4.3.0]nonene, bicyclo[4.3.0]nonadiene, bicyclo[4.4.0]decene, bicyclo[4.4.0]decadiene, bicyclo[2.2.1]heptane, bicyclo[2.2.1 ]heptene,

bicyclo[2.2.1]heptadiene, bicyclo[2.2.2]octane, bicyclo[2.2.2]octene, bicyclo[2.2.2]octadiene, bicyclo[3.1.1 Jheptane, bicyclo[3.1.1 Jheptene, bicyclo[3.3. ljnonane, bicyclo[3.3.1 Jnonene, bicyclo[3.3.1]nonadiene, bicyclo[3.2.2]nonane, bicyclo[3.2.2]nonene,

bicyclo[3.2.2]nonadiene, tricyclo[3.3.1.1]decane (adamantane), spiro[2.2]pentane,

spiro[2.3]hexane, spiro[3.3]heptane, spiro[3.4]octane, spiro[2.4]heptane, spiro[4.4]nonane, spiro[2.5]octane, spiro[3.5]nonane, spiro[4.5]decane and spiro[5.5]undecane. [0016] As used herein, the term "cycloalkenyl" refers to an unsaturated cyclic hydrocarbon. The cycloalkenyl ring may include a specified number of carbon atoms. For example, a 5 to 8 membered cycloalkenyl group includes 5, 6, 7 or 8 carbon atoms. The cycloalkenyl group has one or more double bonds and when more than one double bond is present, the double bonds may be unconjugated or conjugated, however the cycloalkenyl group is not aromatic. Examples of suitable cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl and cyclooctatrienyl rings.

[0017] As used herein, the term "aryl" refers to any stable, monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic. This term includes "mono or polycyclic aryl groups". Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indenyl, fluorenyl, anthracenyl, phenanthrenyl, biphenyl and binaphthyl.

[0018] As used herein, the term "halogen" or "halo" refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). [0019] The term "heterocyclic" or "heterocyclyl" as used herein, refers to a cyclic hydrocarbon in which one to four carbon atoms have been replaced by heteroatoms independently selected from the group consisting of N, N(R), S, S(O), S(0) ₂ and O. A heterocyclic ring may be saturated or unsaturated but not aromatic. Examples of suitable heterocyclyl groups include azetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, dioxazolyl, oxathiozolyl, oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomoφholinyl, dithianyl, trithianyl and oxazinyl.

[0020] The term "heteroaryl" as used herein, represents a stable monocyclic, bicyclic or tricyclic aromatic ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, lH,3H-l-oxoisoindolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,

tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1 ,2,4,5-tetrazinyl and tetrazolyl.

[0021 J The term "cyclic imide" as used herein refers to a group of the formula:

in which X represents the number of carbon atoms required to complete a 5 to 8 membered ring.

[0022] Each alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and polycyclic saturated or unsaturated hydrocarbon group, whether an individual entity or as part of a larger entity may be optionally substituted with one or more optional substituents selected from the group consisting of Ci-ealkyl, C _-6 cycloalkyl, polycyclic saturated or unsaturated hydrocarbon group, oxo (=0), -OH, -SH, Ci-ealkylO-, C _3-6 cycloalkylO-, C _1-6 alkylS-,

C _-6 cycloalkylS-, -C0 ₂ H, -C0 ₂ C _1-6 alkyl, -NH ₂ , -NH(Ci _-6 alkyl), -N(C _1-6 alkyl) ₂ , -NH(phenyl), -N(phenyl) ₂ , -CN, -N0 ₂ , -halogen, -CF ₃ , -OCF ₃ , -SCF ₃ , -CHF ₂ , -OCHF ₂ , -SCHF ₂ , -phenyl, -Ci^alkylphenyl, -heterocyclyl, -heteroaryl, -Oheteroaryl, -Oheterocyclyl, -Ophenyl,

-C(0)phenyl and -C(0)Ci- alkyl. Examples of suitable substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy, hydroxym ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fiuoro, chloro, bromo, iodo, cyano, nitro, -C0 ₂ H, -C0 ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ , trifluoromethyl, trifluoromethoxy, trifiuoromethylthio, difluororaethyl, difluoromethoxy, difiuoromethylthio, morpholino, adamantyl, amino, methylamino, dimethylamino, ethylamino, diethylamino, phenyl, phenoxy, phenyl carbonyl, benzyl and acetyl. [0023] The compounds of the invention may be in the form of a salts. Suitable salts include, but are not limited to, salts inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicylic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. Basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

[0024] It will also be recognised that the dirhodium compounds and compounds produced in the synthetic methods described may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee or de, such as about 95% or 97% ee or de or greater than 99% ee or de, as well as mixtures, including racemic mixtures, thereof.

Dirhodium Compounds

[0025] In a first aspect, the present invention provides a dirhodium compound of formula (I):

wherein A is a 5 to 8 membered cyclic imide ring;

B is a monocyclic or polycyclic

Ri is selected from a branched alkyl group having at least one tertiary carbon atom or a polycyclic saturated or unsaturated hydrocarbon group; Each R ₂ is independently selected from hydrogen, halogen, -Ci.ioalkyl, -OR ₄ , -SR ₄ , -N0 ₂ , -CN, aryl, -Ci-ioalkylaryl, cycloalkyl, -Ci-ioalkylcycloalkyl, cycloalkenyl, -Ci_

loalkylcycloalkenyl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl, -Ci-ioalkylheteroaryl, -N(R ₅ ) ₂ , -N(R ₅ )C(=0)R ₆ , -N(R ₅ )S(0) _n R6, -C(=0)R ₆ and -S(0) _n R ₆ ;

R3 is selected from a branched alkyl group having at least one tertiary carbon atom, a polycyclic saturated or unsaturated hydrocarbon group and an aryl group;

R ₄ is selected from hydrogen, -Ci-ioalkyl, cycloalkyl, -Ci-ioalkylcycloalkyl, cycloalkenyl, -Ci_ _l oalkylcycloalkenyl, aryl, -Q.ioalkylaryl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl, -Ci-ioalkylheteroaryl and -C(=0)Ci _-1( )alkyl;

Each R5 is independently selected from hydrogen, -Ci-ioalkyl, cycloalkyl, -Ci_

loalkylcycloalkyl, cycloalkenyl, -Cj-ioalkylcycloalkenyl, aryl, -Cj.ioalkylaryl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl and -Ci_ioalkylheteroaryl;

R is selected from hydrogen, -Ci.ioalkyl, cycloalkyl, -Ci-ioalkylcycloalkyl, cycloalkenyl, -Ci_ _l oalkylcycloalkenyl, aryl, -Ci_ioalkylaryl, heterocyclyl, -Ci-ioalkylheterocyclyl, heteroaryl, -Ci-ioalkylheteroaryl, -OR ₄ , -SR ₄ and N(R ₅ ) ₂ ; m is an integer from 3 to 7; and n is an integer selected from 1 or 2; or a salt or stereoisomer thereof; wherein each alkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl and polycyclic saturated or unsaturated hydrocarbon group may be optionally substituted with one or more optional substituents. [0026] In some embodiments, ring A is a 5-membered cyclic imide. In other embodiments, ring A is a 6-membered cyclic imide.

[0027| In some embodiments, ring B is a phenyl ring fused to ring A. In other embodiments, ring B is a naphthyl group fused to ring A. When ring B is a naphthyl group, it may be fused to ring A at the 1,2, 2,3 or 1 ,9 positions of the naphthyl ring system. In yet other embodiments, ring B is an anthracenyl group which may be fused to ring A in the 1,2, 2,3, 1,1 1 or 1 ,13 positions of the anthracenyl ring system. In further embodiments, ring B is an phenanthrenyl group which may be fused to ring A in the 1,2, 2,3 or 1,1 1 positions of the phenanthrenyl ring system. In yet other embodiments, ring B is a biphenyl group which may be fused to ring A in the 2,2'-positions of the biphenyl ring system.

ring B is a bicyclo-[2,2, 1 ]-hept-3-ene, bicycle-[2,2, 1 ]-heptane or bicyclo-[2,2,2]-oct-3-ene group

In particular embodiments, rings A and B form one of the following groups

where (R ₂ ) _m and R ₃ are substituents on any position of the aromatic ring system (B).

[0028] In some embodiments, one or more R ₂ substituent is hydrogen. In some embodiments, each R ₂ substituent is hydrogen. In other embodiments, one or more R ₂ substituents are not hydrogen. The number of R ₂ substituents (m) present is calculated from the number of available carbon atoms (excluding ring junction carbon atoms) on ring B (x) less the two carbon atoms attached to the ring A cyclic imide and the carbon atom attached to R ₃ (x - 3). For example, where ring B is a phenyl ring, m is 6 - 3 = 3, and when ring B is a naphthyl ring, m is 8 - 3 = 5.

[0029] Each R ₂ may be the same or may be different. In some embodiments, each R ₂ is hydrogen. In other embodiments, one or more R ₂ is a non-hydrogen substituent and the remainder of R ₂ substituents are hydrogen. In yet other embodiments, each R ₂ is a non- hydrogen substituent and each R ₂ may be the same or different.

[0030] In particular embodiments when one or more R ₂ is not hydrogen, the one or more R ₂ may be independently selected from -Cuioalkyl, halogen, -OH, -OC _1-6 alkyl, aryl, -C _l oalkylaryl, cycloalkyl, -Ci-ioalkylcycloalkyl, cycloalkenyl, -Ci-ioalkylcycloalkenyl, heterocyclyl, -Ci.ioalkylheterocyclyl, heteroaryl, -Ci.ioalkylheteroaryl, -N0 ₂ , -CN, -NH ₂ , -NH(C _1-6 alkyl), -N(C _1-6 alkyl) ₂ , -NHC(=0)C _1-6 alkyl, -NHC(=0)NH ₂ , -NHC(=0)NHC _1-6 alkyl, -NHC(=0)N(Ci _-6 alkyl) ₂ , -C(=0)Ci _-6 alkyl, -C(=0)OCi _-6 alkyl, -C(=0)NH ₂ , -C(=0)NHCi. ₆ alkyl, -C(=0)N(C _1-6 alkyl) ₂ , -S(0)Ci _-6 alkyl, -S(0) ₂ C _1-6 alkyl, -S(0) C _1-6 alkyl, -S0 ₂ NH ₂ , -S0 ₂ NH(C _1-6 alkyl) and -S0 ₂ N(C _1-6 alkyl) ₂ , especially -Cuioalkyl, halogen, -OH, -OCi _-6 alkyl, aryl, -N0 ₂ , -CN, -NH ₂ , -C(=0)OC, _-6 alkyl, -C(=0)NH ₂ , -C(=0)NHC, _-6 alkyl and

-C(=0)N(C, _-6 alkyl) ₂ .

[0031 ] In some embodiments R ₃ is a branched alkyl group having at least one tertiary carbon atom. Suitable branched alkyl groups include /-butyl (1, 1 -dimethylethyl), 1 ,1 - dimethylpropyl, 2,2-dimethylpropyl, 1 -ethyl- 1 -methyl propyl, 1 , 1 -diethylpropyl, 1 ,1 - dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethyl- 1 -methyl butyl, 2-ethyl-2- methylbutyl, 3-ethyl-3-methylbutyl, 1 , 1 -diethylbutyl, 2,2-diethylbutyl, 3,3-diethylbutyl, 1 - methyl- l -propylbutyl, 2-methyl-2-propylbutyl, 3-methyl-3-propylbutyl, 1-ethyl-l- propylbutyl, 2-ethyl-2-propylbutyl, 3-ethyl-3-propylbutyl, 1 , 1 -dipropylbutyl, 2,2- dipropylbutyl, 3,3-dipropylbutyl, 1 , 1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl , 1 -ethyl - 1 -methylpentyl, 2 -ethyl -2-methylpentyl, 3 -ethyl -3 -methylpentyl, 4-ethyl-4-methylpentyl, 1,1 -diethylpentyl, 2,2-diethylpentyl, 3,3-diethylpentyl, 4,4- diethylpentyl, 1 -ethyl- 1-propylpentyl, 2-ethyl-2-propylpentyl, 3-ethyl-3-propylpentyl, 4-ethyl- 4-propylpentyl, 1 , 1 ,2,2-tetramethylpropyl, 1 , 1 ,2,2-tetramethylbutyl, 1 , 1 ,3,3-tetramethylbutyl, 2,2,3,3-tetramethylbutyl 1 , 1 ,2,2-tetramethylpentyl, 1 , 1 ,3,3-tetramethylpentyl, 1 , 1 ,4,4- tetramethylpentyl, 2,2,3,3-tetramethylpentyl, 2,2,4,4-tetramethylpentyl and 3,3,4,4- tetramethylpentyl, especially /-butyl, 1,1-dimethylpropyl and 2,2-dimethylpropyl. [0032] In some embodiments, R ₃ is a substituted or unsubstituted polycyclic saturated or unsaturated hydrocarbon group. Suitable condensed polycyclic hydrocarbon groups include optionally substituted:

especially

[0033] Suitable bicyclic and tricyclic polycyclic hydrocarbon groups include optionally substituted:

wherein each ring system may be attached to ring B through one of positions 1 , 2, 3, 4 or 5, especially optionally substituted:

[0034] Suitable spirocyclic polycyclic groups include optionally substituted:

wherein each ring system may be attached to ring B through one of the positions 1, 2, 3, 4 or 5.

[0035] In some embodiments, R ₃ is an atyl substituent. Suitable aryl substituents include optionally substituted:

especially optionally substituted phenyl.

[0036] In some embodiments, Ri is a branched alkyl group having at least one tertiary carbon atom. Suitable branched alkyl groups include /-butyl (1, 1 -dimethylethyl), 1 ,1 - dimethylpropyl, 2,2-dimethylpropyl, 1 -ethyl- 1 -methyl propyl, 1 , 1 -diethylpropyl, 1 ,1 - dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethyl- 1 -methylbutyl, 2-ethyl-2- methylbutyl, 3-ethyl-3-methylbutyl, 1, 1 -diethylbutyl, 2,2-diethylbutyl, 3,3-diethylbutyl, 1 - methyl- 1-propylbutyl, 2-methyl-2-propylbutyl, 3-methyl-3-propylbutyl, 1 -ethyl- 1 - propylbutyl, 2-ethyl-2-propylbutyl, 3-ethyl-3-propylbutyl, 1,1 -dipropylbutyl, 2,2- dipropylbutyl, 3,3-dipropylbutyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1 -ethyl- 1-methylpentyl, 2-ethyl-2-methylpentyl, 3-ethyl-3-methylpentyl, 4-ethyl-4-methylpentyl, 1 , 1 -diethylpentyl, 2,2-diethylpentyl, 3,3-diethylpentyl, 4,4- diethylpentyl, 1 -ethyl- 1 -prop ylpentyl, 2-ethyl-2-propylpentyl, 3-ethyl-3-propylpentyl, 4-ethyl- 4-propylpentyl, 1 ,1,2,2-tetramethylpropyl, 1,1,2,2-tetramethylbutyl, 1,1,3,3-tetramethylbutyl, 2,2,3,3-tetramethylbutyl 1 , 1 ,2,2-tetramethylpentyl, 1 , 1 ,3,3-tetramethylpentyl, 1 , 1 ,4,4- tetramethylpentyl, 2,2,3,3-tetramethylpentyl, 2,2,4,4-tetramethylpentyl and 3,3,4,4- tetramethylpentyl, especially /-butyl.

[0037J In some embodiments, Ri is an optionally substituted polycyclic saturated or unsaturated hydrocarbon group. Suitable condensed polycyclic hydrocarbon groups include optionally substituted:

- 16 -

- 17 - [0038] Suitable bicyclic and tricyclic polycyclic hydrocarbon groups include optionally substituted:

[0039] Suitable spirocyclic polycyclic groups include optionally substituted:

wherein each ring system may be attached to ring B through one of the positions 1 , 2, 3, 4 or [0040] In particular embodiments, the dirhodium compound is selected from one of the following compounds:

or where the rhodium compound is substantially optically pure:

[0041] The dirhodium compounds of the invention may be prepared using methods known in the art (Tsutsui et al., 2005).

[0042] Generally, the rhodium ligand may be prepared by reaction of a suitably substituted cyclic anhydride with a suitably substituted a-amino acid as known in the art, for example, as shown in Scheme 1 :

Scheme 1

[0043] The dirhodium compound is then prepared by ligand exchange as known art, for example, as shown in Scheme 2:

(6 equiv.)

Scheme 2

3. Use of the dirhodium compounds of the invention

10044] The dirhodium compounds of the invention may be used in dirhodium (II) catalyzed reactions, particularly those catalyzed reactions that proceed via a dirhodium- carbene or dirhodium-nitrene intermediate. The dirhodium compounds act as catalysts with high activity and efficiency and therefore may be used in very small quantities.

[0045] The dirhodium compounds are particularly useful for activation of C-H bonds to form new carbon-carbon bonds (Davies and Morton, 201 1). The reactions may be intermolecular reactions joining two separate molecules together or intramolecular reactions forming a cyclic group such as a cycloalkyl or heterocyclyl group from a linear molecule or linear part of a molecule.

[0046] An example of a suitable intermolecular catalysed reaction is:

[0048] In particular embodiments, the dirhodium compounds catalyze a reaction that is stereoselective producing one enantiomer or diasteriomer in excess of the other possible enantiomer or diasteriomers. In some embodiments, the dirhodium compound is able to catalyze a reaction to product a product having at least 70% ee or de, especially 75% to 100%o ee or de, more especially 80 to 100%. ee or de, 85 to 100%. ee or de or 90 to 100%o ee or de, most especially the dirhodium compound is able to catalyze a reaction that produces a product compound having 95 to 100% ee or de, for example, 96 to 100% ee or de, 97 to 100% ee or de, 98 to 100% ee or de or 99 to 100% ee or de.

[0049] In some embodiments, the amount of dirhodium compound used in the reaction is from 0.005 to 0.05 equivalents of the carbene or nitrene forming reactant, especially 0.008 to 0.03, more especially about 0.01 to 0.02 equivalents.

[0050] In some embodiments, the dirhodium compounds are useful in forming carbon-carbon bonds with rhodium carbenes that have carbene substituents that are i) electron-withdrawing and electron donating, ii) electron-withdrawing and hydrogen or iii) electron-withdrawing and electron-withdrawing. The carbenes of ii) and iii) are very reactive and are particularly useful in intramolecular reactions. The carbenes of i) are stabilized and are also known as donor/acceptor carbenes. Donor/acceptor carbenes are useful for a large number of reactions, both intramolecular and intermolecular and are highly selective. [0051 J Suitable electron-donating groups include phenyl, alkenes (-CH=CR ₂ ), alkyl groups, acyl groups (-OC(O)R), amides (-NHC(O)R), alkoxy groups, hydroxy, amino and dialkyl amino groups. In particular embodiments, the electron-donating group is a phenyl.

[0052] Suitable electron-withdrawing groups include -C0 ₂ H, -C0 ₂ alkyl, -C(0)H, -C(0)alkyl, -CF ₃ , -CN, -P(0)(OH) ₂ , -P(0)(Oalkyl) ₂ , -S0 ₃ H and -N0 ₂ . In particular embodiments, the electron-withdrawing group is -C0 ₂ alkyl or -P(0)(Oalkyl) ₂ .

[0053] The dirhodium-carbene intennediates are readily fomied from diazo- compounds (Tsutsui et ah, 2003; Davies and Morton, 201 1 ) or from phenyl iodonium ylides (Ghanem et ah, 2005; Ghanem et ah, 2010).

[0054] In some embodiments, the dirhodium compounds are useful in

cyclopropanation reactions, especially enantioselective or diastereoselective cyclopropanation reactions. In some embodiments, the cyclopropanation reaction occurs between a

donor/acceptor bearing diazo compound and an alkene. In particular embodiments, the donor-acceptor bearing diazo compound is a substituted diazo phosponate, such as a phenyl substituted diazo phosponate. In some embodiments, the phosphonate is a Ci _-3 alkyl phosponate, especially a Ci _-2 alkyl phosphonate, most especially a dimethyl phosphonate.

[0055] In some embodiments, the dirhodium compound may catalyse a -C-H amination reaction (Collet et ah, 2010; Yamawaki et ah, 2002). The amination reactions may also be intermolecular or intramolecular and may also be enantioselective or

diastereoselective. Examples of typical amination reactions are shown in Schemes 3 and 4.

Ns

Phl(OAc) ₂

MgO

Scheme 3

Scheme 4 EXAMPLES

EXAMPLE 1

Synthesis of N-(4-tert-ButylphthaloylH^>fe -Leucine (S- ^tert PTTL) [0056] To a mixture of 4-/er/-butylphthalic anhydride (0.514g, 2.52 mmol) and ter/-leucine (0.3g, 2.29 mmol) in anhydrous toluene, triethylamine (0.1 equiv) was added and the mixture was heated to reflux for 12 hours under nitrogen atmosphere. The reaction mixture was then diluted with ethyl acetate, washed with 0. I M HQ solution, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was then purified on silica gel column chromatography using ethyl acetate-ft-hexane as an eluent to provide a colourless oil (0.7 g, 96%); [a] _D ²⁵ = -0.35 ( 1 , CHCI ₃ ); R/= (1 : 1 ethyl acetate: ??-hexane); ¹ H IM MR (400 MHz, CDCI ₃ ): δ; 7.88-7.71 (m, 3H, Ar-H), 4.69 (s, 1 H, NCH), 1 .34 (s, 9H, C(CHj) ₃ ), 1.15 (s, 9H, C(CHj) ₃ ); ¹ C NMR (100 MHz, CDCI ₃ ): δ 173.3 (COOH ). 168.4, 168.0 (2 x CON), 158.9, 131 .8, 131 .3, 128.9, 123.4, 120.8 (6 x Ar-C), 59.8 (NCH), 35.7, 35.6 (2 x C(CH ₃ ) ₃ ), 31 .1 , 27.9 (2 x C(CH ₃ ) ₃ ); IR (film) v 2963, 2873, 171 1 , 1372, 1 101 , 908, 729 cm ^"1 .

EXAMPLE 2

Synthesis of N-a-phenyl-2,3-naphthanoylHS)-fc -leucine (S-l-Ph-BPTTL)

[0057] A mixture of l -phenyl-2,3-naphthalene dicarboxylic anhydride (0.47 g, 1 .7 mmol) and L-/er/-leucine (0.2 g, l .6 mmol) in anhydrous DMF was heated at reflux under nitrogen attnosphere overnight. The reaction mixture was then diluted in water and extracted with ethyl acetate twice. The organic layer was washed with water three times, dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The residue was then purified on silica gel column chromatography using ethyl acetate: /?-hexane (1 : 1 ) as an eluent to afford the title compound as a yellow oil (0.825 g, 89%); [a] _D ²⁵ = -0.89 (c 1 , CHCI ₃ ); R/= 0.38 (1 :3 ethyl acetate: «-hexane); 1H NMR (400 MHz, CDC1 ₃ ): δ 9.47 (br s, 1 H, COOH), 8.79 (d, 1H, J =

8.1 Hz, Ar-H), 8.03 (d, 1 H, J= 8.3 Hz, Ar-H), 7.81 (d, 1H, J = 8.1 Hz, Ar-H), 7.74 (d, 1 H, J =

8.2 Hz, Ar-H), 7.58-7.52 (m, 2Η, Ar-H), 4.68 (s, 1Η, NCH), 1.12 (s, 9Η, C(CH ₃ ) ); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 172.8 (COOH), 168.0, 167.5 (2 x CON), 135.6, 134.2, 129.8, 128.5, 127.8, 127.6, 126.9, 125.9, 123.9, 1 17.5 (10 x Ar-C), 58.7 (NCH), 34.6 (C(CH ₃ ) ₃ ), 26.9 (C(CH ₃ ) ₃ ); IR (film) v 323 1 , 2922, 1751 , 1698, 1374, 1 104, 1014, 796, 766, 725, 662 cm ^"1 ; MS (ESI) m/z: 309.9 (C ₁₈ Hi ₆ N0 ₄ ; calc. 310.1 ), 266.0 (Ci ₈ H ₁₆ N0 ₄ - C0 ₂ ; calc. 266.1 ), 209.2 (Ci ₈ Hi ₆ N0 ₄ - C0 ₂ - C ₄ H ₉ ; calc. 209.1 ).

EXAMPLE 3

General Procedure for Ligand Exchange [0058] A mixture of the carboxylate ligand (6 equiv.) and dirhodium acetate

(Rh ₂ (OAc) ₄ , 1 equiv.) in dry chlorobenzene was refluxed for 24 hours under nitrogen atmosphere using a soxhelt extractor fitted with a thimble containing a dry mixture of Na ₂ C0 ₃ and sand (1 : 1 ) for the removal of acetic acid. After this time, the solvent was evaporated in vacuo and the residue was dissolved in CH ₂ C1 ₂ , washed with saturated NaHC0 ₃ , dried over anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuo. The green residue was then purified on silica gel column chromatography using ethyl acetate: /?-hexane as an eluent. Products were dried overni ght under vacuum at 50°C. The amounts of carboxylate ligand and Rh ₂ (OAc) ₄ are presented in that order.

EXAMPLE 4

Preparation of Dirhodium (II) Tetrakis| -(4-fc -butylphthaloyl)-ffl-fe Leucine]

(Rh7.(S- ^ferf PTTL

[0059] Using the method set out in Example 3, ligand (0.645 g, 2.032 mmol), and Rh ₂ (OAc) ₄ (0.150 g, 0.339 mmol); produced a green solid (0.35 g, 71%); R/= 0.50 (1 :2 ethyl acetate: «-hexane); Ή NMR (400 MHz, CDC1 ₃ ): δ 7.85 (br s, 4H, Ar-H), 7.67-7.62 (m, 12Η, Ar-H), 4.88 (s, 4Η, 4 x NCH), 1.35 (s, 36Η, 4 x C(CH ₅ ) ₃ ), 1.1 1 (s, 36Η, 4 x C(CH ₅ ) ₃ ); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 187.1 (COO), 172.1 , 168.2 (CON), 158.0, 132.1 , 130.5, 129.4, 122.9, 120.5 (Ar-Q, 61.26 (NCH), 35.6, 35.5 (2 x C(CH ₃ ) ₃ ), 31 .1 , 27.9 (2 x C(Oi ₃ ) ₃ ); IR (film) v 2959, 2873 1713, 1612, 1366, 1 103, 752, 693 cm ^"1 ; HRMS (MALDI-TOF) m/z: 1476.8 (C ₇₂ H ₈₈ N ₄ 0 ₁₆ Rh ₂ + 6H , calc. 1476.4), 1 158.1 (C ₇₂ H ₈₈ N ₄ Oi ₆ Rh ₂ + 4H ¹ - C ₁₈ H ₂₂ N0 ₄ , calc. 1 158.3), 839.5 (C ₇₂ H ₈₈ N ₄ Oi ₆ Rh ₂ + 2H ⁺ - C ₃₆ H ₄₄ N ₂ 0 ₈ , calc. 840.1 ).

EXAMPLE 5

Preparation of Dirhodium (II) Tetrakis| -(l-phenylnaphthanoyl)-(S -ferf Leucine]

[0060] Using the example set out in Example 3, ligand (0.621 g, 1 .6 mmol), Rh ₂ (OAc) ₄ (0.12 g, 0.27 mmol), produced a green solid (0.31 g, 67%), R _f = 0.77 (1 : 1 ethyl acetate: «-hexane); 1H NMR (400 MHz, DMSO-c¾: δ 8.07 (s, 4H, Ar-H), 7.60 (d, 8H„ J = 8.2 Hz, Av-H), 7.51-7.30 (m, 32H, Av-H , 7.12 (d, 4H, J= 6.9 Hz, Av-H), 4.92 (s, 4H, 4 x CHN), 1 .19- 1 .16 (m, 36H, 4 x C(C¾) ₃ ); IR (film) v 2962, 1709, 1617, 1397, 1365, 1340, 1260, 1 109, 1030, 801 , 761 , 696 cm ^"1 ; MS (ESI) m/z: 1758.1 (C ₉₆ H ₈ ()N ₄ Oi ₆ Rh ₂ + 711 \ calc. 1758.4), 1369.1 (C ₉₆ H ₈ oN ₄ 0, ₆ Rh ₂ + 5H - C ₂₄ H ₂₀ NO ₄ , calc. 1369.2), 980.1 (C ₉₆ H ₈ oN ₄ Oi ₆ Rh ₂ + 2Ι Γ - C ₄ 8H ₄ oN ₂ 0 ₈ , calc. 980.1 ), 608.9 (C ₉₆ H ₈₀ N ₄ O ₁₆ Rh ₂ - C7 ₂ H ₆₀ N ₃ O ₁₂ - 1H ⁺ , calc. 608.9), 341 .7 (C ₂ H ₂₀ NO ₂ , calc. 342.1 ).

EXAMPLE 6

Crystal Structure of Rh?!S - ^tert PTTL)

[0061 ] Single crystal X-ray quality crystals of Rh^S-^PTTL^ were grown by dissolving the prepared complex (~40 mg) in THF (~1 mL). The resulting solution was subjected to sonication and Pasteur pipette filtration. Green needle crystals were obtained by the slow evaporation of the solvent and used directly for measurement. Single crystal X-ray diffraction data were collected on MX2 beamline at the Australian Synchrotron, Melbourne, Australia. [0062] Single crystal X-ray diffraction data for crystals of both acetone and THF adducts of Rh ₂ (.S-' ^er PTTL) were collected. Both adducts revealed full α,α,α,α conformation in solid state, featuring the /e/-/-butyl substituent similarly disposed towards the "corner" of the nearly square-shaped cavity. The four N-4-/er/-butyl-phthaloyl groups incorporation maintains the chiral nature of the crown cavity surrounding the axial Rh coordination site through the clockwise twist of these groups. The X-ray also revealed that, the reduced TV- protecting group symmetry reinforces the chiral twist to the crown cavity.

EXAMPLE 7

General procedure for the preparation of cyclopropylphosphonate with

[0063] To a stirred solution of alkene (5 equiv.) and Rh ₂ (S- ^te "PTTL) ₄ (0.01 equiv.) in 2,2-dimethylbutane (2,2-DMB, 5 mL) under nitrogen atmosphere, a solution of a- diazobenzylphosphonate (1 equiv.) in 2,2-DMB (10 mL) was added drop-wise via syringe pump over a period of 1 hour. After the addition, the reaction was stirred at room temperature until the TLC indicated a complete consumption of the diazo starting material. The diastereomeric ratio (dr) of the product was determined by ^l H NMR of the crude mixture. The product was purified by means of preparative TLC (ethyl acetate/ft-hexane) and the enantiomeric excess (ee%) of the product was detem ined by chiral HPLC analysis.

(IS,2R)- Dimethyl 1,2-diphenylcyclopropylphosphonate

10064] Colourless oil; [a] _D ²⁵ = -0.25 (c 0.53, CHC1 ₃ ); R/= 0.15 (1 : 1 ethyl acetate: /?-hexane); ^l H NMR (400 MHz, CDC1 ₃ ): δ 7.00 (m, 3H, Ar-H), 6.99 (m, 5Η, Ar-H), 6.68 (m, 2Η, Ar-H), 3.67 (d, 3Η, .½> = 10.5 Hz, OCHj), 3.62 (d, 3Η, J _IiP = 10.5 Hz, OCH ₅ ), 2.95 (ddd, 1Η, ./HP = 16.5, J = 8.8, 6.7 Hz, CH), 1.99 (ddd, 1Η, J _m = 17.3, J = 8.8, 5.1 Hz, CH ₂ ), 1 .66 (ddd, 1Η, ./HP = 12.2, J = 6.7, 5.1 Hz, CH ₂ ); Enantiomer separation by HPLC (Chiralcel® OJ column, 25 x 0.46 cm, 2% 2-propanol in »-hexane (v/v%); 1 mL/min, 220 nm, τι = 18 min, τ ₂ = 21 min). The spectroscopic data are consistent with previously reported data.

(LV,2/?)-Dimethyl l -pheny-2-(/ -chlorophenyl)-cyclopropylphosphonate

10065] Colourless oil; [a] _D ²⁵ = -0.54 (c 0.87, CHC1 ₃ ); R = 0.1 1 (1 : 1 ethyl acetate: »-hexane); 1H NMR (400 MHz, CDC1 ₃ ): δ 7.14-7.1 1 (m, 3H, Ar-H), 7.04 (m, 2Η, Ar-H), 7.01 (d, 2Η, J = 8.5 Hz, Ar-H), 6.64 (d, 2Η, J = 8.4 Hz, Ar-H), 3.70 (d, 3Η, J _HP = 10.6 Hz, OCHj), 3.66 (d, 3Η, J _HP = 10.6 Hz, OCHj), 2.96 (ddd, 1 Η, J _HP = 16.5, J = 8.8, 6.7 Hz, CH), 2.06 (ddd, 1 Η, J _HP = 17.4, J = 9.0, 5.3 Hz, CH ), 1.66 (ddd, 1Η, J _flP = 12.4, J = 6.5, 5.3 Hz, CH ₂ ); Enantiomer separation by HPLC (Chiralcel© OJ column, 25 x 0.46 cm, 8% 2-propanol in A7-hexane (v/v%); 1 mL/min, 220 nm, τ _\ = 10 min, τ ₂ = 12 min). The spectroscopic data are consistent with previously reported data. (LV,2R)- Dimethyl l-pheny-2-(p-methoxyphenyl)-cyclopropylphosphonate

10066] Colourless oil; [a] _D ²⁵ = -0.57 (c 1 , CHC1 ₃ ); R/= 0.1 1 ( 1 : 1 ethyl acetate: n- hexane); Ή NMR (400 MHz, CDC1 ₃ ): δ 7. 12-7. 10 (m, 3H, Ar-H), 7.05 (m, 2Η, Ar-H), 6.62 (dd, 4Η, J = 23.0, 8.9 Hz, Ar-H), 3.71 (d, 3Η, J _HP = 10.6 Hz, OCH ₅ ), 3.68 (s, 3Η, OCHj), 3.66 (d, 3Η, ./HP = 10.6 Hz, OCHj), 2.96 (ddd, 1 Η, J _]1P = 16.1 , J= 9.1 , 6.6 Hz, CH), 2.03 (ddd, 1Η, JHP = 17.5, J = 9.1 , 5.2 Hz, CH ₂ ), 1.64 (ddd, 1 Η, J _HP = 12.4, J = 6.5, 5.3 Hz, CH ₂ );

Enantiomer separation by HPLC (Chiralcel© OJ column, 25 x 0.46 cm, 3% 2-propanol in n- hexane (v/v%); 1 mL/min, 220 nm, τι = 37 min, τ ₂ = 42 min). The spectroscopic data are consistent with previously reported data. (LV,2R)-Dimethyl l-pheny-2-(/j-methylphenyl)-cyclopropylphosphonate

[0067] White solid; [a] _D ²⁵ = -0.57 (c 0.93, CHC1 ₃ ); R/ = 0.17 (1 : 1 ethyl acetate: n- hexane); ^] H NMR (400 MHz, CDC1 ₃ ): δ 7.13-7.10 (m, 3H, Ar-H), 7.07-7.04 (m, 2Η, Ar-H), 6.85 (d, 2Η, J = 7.8 Hz, Ar-H), 6.61 (d, 2Η, J = 8.2 Hz, Ar-H), 3.72 (d, 3Η, J _HP = 10.6 Hz, OCH ₃ ), 3.66 (d, 3H, J _HP = 10.6 Hz, OCH _? ), 2.97 (ddd, 1 Η, J _11P = 16.1 , J = 9.1 , 6.6 Hz, CH), 2.19 (s, 3Η, CHj), 2.03 (ddd, 1Η, J _FIP = 17.5, J= 9.0, 5.1 Hz, CH _? ), 1.67 (ddd, 1Η, J _HP = 12.5, J = 6.6, 5.1 Hz, CH2) ; Enantiomer separation by HPLC (Chiralcel® OJ column, 25 x 0.46 cm, 3% 2-propanol in /7-hexane (v/v%); 1 mL/min, 220 nm, Τ[ = 12 min, τ ₂ = 15 min).

(LY,2/?)-Dimethyl l-pheny-2-(l-naphthyl)-cyclopropylphosphonate 10068] Colourless oil; [a] _D ²⁵ = -0.24 (c 0.5, CHCI ₃ ); R/= 0.14 (1 : 1 ethyl acetate: n- hexane); Ή NMR (400 MHz, CDCI ₃ ): δ 7.72-7.53 (m, 2H, Ar-H), 7.50 (d, 1Η, J = 7.50 Hz, Ar-H), 7.35 (m, 2Η, Ar-H), 7.29 (s, 1 Η, Ar-H), 7.07 (m, 4Η, Ar-H), 6.76 (dd, 1 H, J= 8.5, 1 .8 Hz, Ar-H), 3.75 (d, 3Η, J _HP = 10.6 Hz, OCH ₅ ), 3.70 (d, 3Η, J _IIP = 10.6 Hz, OCH ₃ ), 3.16 (ddd, 1 Η, JHP = 16.1 , .7 = 9.1 , 6.6 Hz, CH), 2.14 (ddd, 1 H, J _HP = 17.5, J = 9.0, 5.3 Hz, CH ₂ ), 1.85 (ddd, 1 H, JHP = 12.5, J = 6.6, 5.1 Hz, CH _? ); Enantiomer separation by HPLC (Chiralpak® AD column, 25 x 0.46 cm, 1 % 2-propanol in /?-hexane (v/v%); 2 mL/min, 220 nm, xi = 36 min, τ ₂ = 42 min).

(LV,2 ?)-Diethyl 1,2-diphenylcyclopropylphosphonate

[0069] Colourless oil; [a] _D ²⁵ = -0.1 1 (c 0.4, CHCI ₃ ); R/= 0.26 (1 : 1 ethyl acetate: n- hexane); ^] H NMR (400 MHz, CDCI ₃ ): S 7.1 1 -7.07 (m, 4H, Ar-H), 7.06-7.01 (m, 4Η, Ar-H), 6.72 (m, 2Η, Ar-H), 4.1 1 -3.95 (m, 4Η, 2 x OCH ₂ CH ₃ ), 2.98 (ddd, l H, J _HP = 16.5, J = 8.8, 6.5 Hz, CH), 1 .99 (ddd, 1 H, J _IIP = 17.5, J = 9.0, 5.1 Hz, CH _? ), 1.68 (ddd, 1H, J _I]P = 12.2, J = 6.7, 5.1 Hz, CH ), 1.26 (td, 3Η, J = 7.0, 0.4 Hz, OCH ₂ CH , 1.22 (td, 3Η, J = 7.0, 0.5 Hz,

OCH ₂ CH ; Enantiomer separation by HPLC (Chiralpak® AD column, 25 x 0.46 cm, 0.6% 2- propanol in «-hexane (v/v%); 0.8 mL/min, 220 nm, τι = 69 min, τ ₂ = 76 min). The

spectroscopic data are consistent with previously reported data.

EXAMPLE 8

COMPARISON WITH OTHER CATALYSTS

|0070] The yield and enantioselectivity of the Rh ₂ (S- ^{tei t} -PTTL) ₄ and Rh ₂ (,S- 1 -Ph- BPTTL) ₄ catalysts in the reaction of styrene with dimethyl ot-diazobenzyl-phosphonate was compared to the same reaction using known catalysts that lack the substituent R ₃ . The results are shown in Table 1 .

Table 1. Asymmetric cyclopropanation of styrene with dimethyl benzyldiazophosphonate.

>20:1 dr

Entry Catalyst Yield (%) ee (%)

1 Rh ₂ (S-PTTL) ₄ 85 92

2 Rh ₂ (S-NTTL) ₄ 87 91

3 Rh ₂ (S-PTAD) ₄ 86 99

4 Rh ₂ (S-l -Ph-BPTTL) ₄ 87 92

5 Rh ₂ (S-' ^e "PTTL) ₄ ^a 92 99 "Stirring at room temperature. Diastereomeric ratios (dr) were determined by Ή NMR of the cnide mixture.

Enantiomeric excess percents (ee%) were determined by chiral HPLC using Chiralcel® OJ column, 2% 2- propanol in w-hexane (v/v%), 1 mL/min., 220 nm, x _t = 18 min, τ ₂ = 21 min.

[0071 ] The catalysts of the present invention had superior yield and/or

enantioselectivity compared to Rh ₂ (S- ^tert -PTTL) _{4 an} d Rh ₂ (-S-NTTL) ₄ and similar yield and comparable enantioselectivity to Rh ₂ (s-PTAD) ₄ .

EXAMPLE 9

[0072] The catalysed reaction between dimethyl ot-diazobenzylphosphonate and a styrene deri vative demonstrated that there can be variation in the structure of the alkene as high yields and enantioselectivity was obtained as shown in Table 2: Table 2. Scope of Rh ₂ (S-' ^ert PTTL) ₄ catalyst investigations with respect to the alkene.

>20:1 dr

Rh ₂ (S- ^tcrt PTTL) ₄

Entry R group

Yield (%) ee (%)

Diastereomeric ratios (dr) were determined by Ή NMR of the crude mixture. Enantiomeric excess percents (ee%) were determined by chiral HPLC.

EXAMPLE 10

The Effect of the Diazophosphonate Ester Size on Yield and Enantioselectivity

[0073 ] The yield and enantioselectivity of the Rh ₂ (S- ^/ert PTTL) ₄ of styrene with a- diazobenzylphosphonates with varying esters was compared. The results are shown in Table 3: Table 3. Effect of the a-diazophosphonate ester group size on the enantioselectivity of Rh ₂ (S- ^ter 'PTTL) ₄ catalyst.

>20:1 dr

Rh ₂ (S- PTTL) ₄

Entry R group

Yield (%) ee (%)

1 Me 92 99

2 Et 74 92

3 -Pr 40 64 ^a

"Reflux for 3 days, Diastereoraeric ratios (dr) were determined by Ή NMR of the crude mixture. Enantiomeric excess percents (ee%) were determined by chiral HPLC.

[0074] Both yield and enantioselectivity decreased with increasing ester group size and the highest levels of enantioselectivity were observed with dimethyl

phenyldiazophosphonate.

EXAMPLE 1 1

Crystal structure of dimethyl l-phenyl-(2-p-methyl phenvD-cvclopropylphosphonate.

[0075] The relative and absolute configuration of dimethyl 1 -pheny-2-(/?- methylphenyl)-cyclopropylphosphonate was readily determined by X-ray crystallo graphic analysis (Single crystal X-ray diffraction data were collected on Nonius Kappa CCD diffractometer equipped with Graphite monochrometer using Mo/K/a radiation (λ = 0.71073)) to be (\S,2R), which is in agreement with the predicted assignment. All other

cyclopropylphosphonates are assigned the same relative and absolute configuration by analogy.

[0076] Single crystal X-ray quality crystals of Dimethyl 1 -pheny-2-(/?- methylphenyl)-cyclopropylphosphonate were grown by dissolving the prepared complex (~0.1 g) in EtOAc - »-hexane (1 :3) mixture (~2 mL). The resulting solution was subjected to sonication and Pasteur pipette filtration. Colourless crystals were obtained by the slow evaporation of the solvent and used directly for measurement.

EXAMPLE 12

Preparation of (IS, 2R -Trifluoromethyl-l,2-diphenyl-cyclopropane

[0077] To a solution of the alkene (5.0 equiv.) and dirhodium catalyst (0.02 equiv.) in dry and degassed α,α,α-trifiuorotoluene (TFT, 3 mL) under nitrogen atmosphere, 1 -phenyl - 2,2,2-triflurodiazoethane ( 1 .0 equiv.) dissolved in the same dry and degassed TFT (2 mL), was added drop-wise over a period of 3 hour using a syringe pump. The reaction was then stirred another hour, after which time, the reaction solvent was removed in vacuo. The diastereoraeric ratio (dr) of the product was determined by ^] H NM R of the crude mixture. The product was purified by means of preparative TLC using «-hexane as eluent. The

enantiomeric excess (ee%) of the product was determined by chiral HPLC analysis. White solid; Rf = 0.29 («-hexane); 1H NMR (400 MHz, CDCI ₃ ): δ 7.13-6.99 (m, 8H, Ar-H), 6.71 - 6.69 (m, 2H, Ar-H), 2.77 (dd, 1 H, J = 9.6, 7.0 Hz, CH), 1 .81 (dd, 1 H, J = 9.6, 5.9 Hz, CH ₂ ), 1.61 (m, 1H, CH?); Enantiomer separation by HPLC (Chiralcel® OJ column, 25 x 0.46 cm, 1% 2-propanol in H-hexane (v/v%); 0.8 mL/min, 220 nm, τι = 6.5 min, τ ₂ = 7.8 min). The spectroscopic data are consistent with previously reported data.

[0078] Single crystal X-ray quality crystals of ( 1 S, 2R)- 1 -Trifluorom ethyl- 1 ,2- diphenyl-cyclopropane were grown by dissolving the prepared compound (-0.05 g) in iso- propyl alcohol (~2 mL). Colourless crystals were obtained by the slow evaporation of the solvent and used directly for measurement. Single-crystal X-ray diffraction data were collected on Agilant SuperNova Dual diffractometer equipped with mirror monochromated radiation (λ = 1.54180 A). The relative and absolute stereochemistry of the product was again unambiguously assigned by X-ray crystallography to be (\S,2R). EXAMPLE 13

Comparative Cyclopropanation Reactions

[0079] The scope of the dirhodium catalysts was further investigated by looking into cyclopropanation reactions involving donor-acceptor carbenoid intermediates containing -CF ₃ as an electron withdrawing group. [0080] The results summarized in Table 4 reveal a similar enhancement in enantioselectivity for cyclopropanation of styrene by 2,2,2-trifluromethyl- l - phenyldiazoethane.. Although Rh ₂ (S-PTAD) ₄ has been reported to generate the product in >98% ee, the enantiomeric induction of Rh ₂ (S-PTAD) ₄ in this reaction did not exceed 88% ee, whereas, with the Rh ₂ (S-PTTL) ₄ - and Rh ₂ (S-NTTL) ₄ -catalyzed reactions the cyclopropane product was generated in 82% and 79% ee, respectively. However, with Rh ₂ (S-' ^e "PTTL) ₄ - catalyzed reaction, the product was generated in 88% ee (Table 10, entries 4 vs. 2 and 3). Furthermore, changing the solvent to 2,2-DMB did not affect the efficiency of the catalyst (Table 4, entries 4 and 5).

Table 4. Asymmetric cyclopropanation of styrene with 2,2,2-trifluromethyl- l- phenyldiazoethane.

>20: 1 dr

Entry Catalyst Solvent Yield (%) ee (%)

1 Rh ₂ (S-PTAD) ₄ TFT 95 88

2 Rh ₂ (S-PTTL) ₄ TFT 96 82

3 Rh ₂ (S-NTTL) ₄ TFT 95 79

4 Rh ₂ (.S- ^ter 'PTTL) ₄ TFT 99 88

5 Rh ₂ (S- ^te "PTTL) ₄ 2,2-DMB 97 88

6 Rh ₂ (S- l ,2-NTTL) ₄ TFT 85 82

Diastereomeric ratios (dr) were determined by H NMR of the cnide mixture. Enantiomeric excess percents (ee%) were detennined by chiral HPLC using Chiralcel® OJ column, 1 % 2-propanol in H-hexane (v/v%), 0.8 mL/min., 220 nm, t _t = 5.5 min., τ ₂ = 6.8 min.

[0081 ] The disclosure of every patent, patent application, and publication cited herein is hereby incorporated herein by reference in its entirety.

[0082] The citation of any reference herein should not be construed as an admission that such reference is available as "Prior Art" to the instant application. [0083] Throughout the specification the aim has been to describe the preferred embodiments of the invention without limiting the invention to any one embodiment or specific collection of features. Those of skill in the art will therefore appreciate that, in light of the instant disclosure, various modifications and changes can be made in the particular embodiments exemplified without departing from the scope of the present inventi on. All such modifications and changes are intended to be included within the scope of the appended claims.

BIBLIOGRAPHY

Collet F., Lescot C, Dauban P., Catalytic C-H amination: the stereoselectivity issue. Chem. Soc. Rev., 201 1, 40: 1926-1936.

Davies H. M. L., Morton D., Guiding principles for site selective and stereoselective intermolecular C-H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev., 201 1 , 40: 1857-1869.

Denton J. R., Sukumaran D., Davies H. M., Enantioselective synthesis of trifluoromethyl- substituted cyclopropanes. Org. Lett, 2007, 9(14):2625-2628.

Denton J. R., Cheng K., Davies H. M., Stereoselective construction of nitrile-substituted cyclopropanes. Chem. Commun., 2008, 14( 10): 1238-1240.

El-Deftar M., Adly G., Gardiner M. G., Ghanem A., Chiral dirhodium catalysts: A new era for asymmetric catalysis. Current Organic Chem., 2012, 16(15): 1808- 1836.

Ghanem A., Lacrampe F., Aboul-Enein H. Y., Schurig V., Diazo compounds and phenyl iodonium ylides in inter- and intramolecular cyclopropanations catalyzed by dihrodium (II). Synthesis and resolution by GC vs HPLC. Monatschefte fur Chemie, 2005, 136: 1205-1219.

Ghanem A., Gardiner M. G., Williamson R. M., Miiller P., First X-ray structure of a N- naphthaloyl-tethered chiral dirhodium (II) complex: structural basis for tether substitution improving asymetric control in olefin cyclopropanation. Chemistry, 2010, 16(1 1):3291-3295.

Kitagaki S., Anada M., Kataoaka O., Matsuno ., Umeda C, Watanabe N., Hashimoto S., Enantiocontrol in tandem carbonyl ylide formation and intermolecular 1 ,2-dipolar cycloaddition of a-diazo ketones mediated by chiral dirhodium (II) carboxylate catalyst. J. Am. Chem. Soc, 1999, 121 : 1417-1418.

Miiller P., Ghanem A., Rhodium (II) catalyzed asymmetric cyclopropanation with dimethyl malonate. Org. Lett., 2004, 6(23):4347-4350. Reddy R.P., Lee G. H., Davies H. M., Dirhodium tetracarboxylate derived from adamantylglycine as a chiral catalyst for carbenoid reactions. Org. Lett., 2006, 8(16):3437- 3440.

Tsutsui H., Yamaguchi Y., Hashimoto S., Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)- /er/-leucinate]: an exectionally effective Rh(II) catalyst fro enantiotopically selective aromatic C-H insertions of diazo ketoesters. Tetrahedron Asymmetry, 2003, 14:817-821 . Tsutsui H., Abe T., Nakamura S., Anada M., Hashimoto S., Practical synthesis of dirhodium (II) tetrakis[N-phthaloyl-(S)-tertleucinate]. Chem Pharai. Bull., 2005, 53: 1366-1368.

Yamawaki M., Tsutsui H., Kitagaki S., Anada M., Hashimoto S., Dirhodium (II) tetrakis[N- tetrachlorophthaloyl-(S)-/er/-leucinate]: a new chiral Rh(II) catalyst for enantioselective amidation of-C-H bonds. Tetrahedron Lett., 2002, 43:9561-9564.