WO2023086016A2

WO2023086016A2 - Methods of alkene functionalisation

Info

Publication number: WO2023086016A2
Application number: PCT/SG2022/050789
Authority: WO
Inventors: Ming Joo KOH; Chen-fei LIU; Hongyu Wang
Original assignee: National University Of Singapore
Priority date: 2021-11-15
Filing date: 2022-10-31
Publication date: 2023-05-19
Also published as: WO2023086016A3

Abstract

The present disclosure concerns a method of functionalising an alkene to a trisubstituted stereocenter or tetrasubstituted stereocenter, comprising reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the trisubstituted stereocenter or tetrasubstituted stereocenter.

Description

METHODS OF ALKENE FUNCTIONALISATION

Technical Field

The present invention relates, in general terms, to methods of alkene functionalisation.

Background

The design of new catalytic methods to promote site-selective alkene carbofunctionalization is a central objective in modern chemical research. By providing a convenient avenue to generate complexity in molecules, the field continues to have far-reaching impact on various aspects of Chemistry, ranging from olefin feedstock transformations to applications in compound library development for drug discovery programs. Owing to the weak electron ic/steric bias of unactivated aliphatic alkenes, conceiving a general catalytic manifold that promotes regioselective addition of carbogenic moieties, without the use of contrived directing groups, is a longstanding goal in Chemistry. Previous strategies utilize either substrate control or auxiliary control to achieve high regioselectivity. However, these are subjected to severe starting material limitations and engender greater costs. In some instances, dual catalytic systems are required, and undesired side reactions with certain substrate classes are inevitable.

It would be desirable to overcome or ameliorate at least one of the above-described problems.

Summary

A general catalytic method is disclosed that takes advantage of a catalyst control blueprint to address at least some of the aforementioned challenges. Using catalytic amounts of earth-abundant N-heterocyclic carbene (NHC)-Ni(0)-based complexes, it is shown that highly regioselective hydroarylation, hydroalkenylation, diarylation, aryl- alkenylation, aryl-alkynylation and aryl-alkylation of both unactivated and activated alkenes can be achieved without the need for any directing groups. The resulting products are readily diversifiable to a wide range of key building blocks in chemical synthesis. Utility of this work is highlighted through preparation of various biologically

active compounds. The catalyst control method described herein is expected to set new paradigms for designing general site-selective olefin functionalizations that no longer rely on waste-generating directing groups, which otherwise require pre-installation and subsequent removal.

The present invention provides a method of functionalising an alkene to a tri- or tetrasubstituted stereocenter, comprising: reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the tri- or tetrasubstituted stereocenter; wherein the alkene and first coupling partner undergo a carbonickelation step in the presence of the NHC-Ni(O) catalyst followed by a carbon-nickel bond transformation with the second coupling partner; and wherein the first coupling partner is coupled to a carbon on the alkene which is more sterically hindered.

The method allows for a variety of three-component alkene hydrocarbofunctionalization and dicarbofunctionalization reactions with high efficiency and regioselectivity, resulting in enantioenriched tri- and tetrasubstituted stereocenters. C-C bond formation with the first coupling partner occurs in a Markovnikov-selective fashion.

In some embodiments, the NHC-Ni(O) catalyst is generated in situ from a Ni(0) complex and an imidazolium or imidazolinium salt.

The imidazolium or imidazolinium salt preferably comprises a strongly o-donating and sterically shielded NHC.

In some embodiments, the imidazolium or imidazolinium salt is a compound of Formula (I):

wherein Ar is independently selected from aryl or heteroaryl;

Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; 2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl;

R3 is independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;

L is independently a direct bond or optionally substituted alkylene; represents a single bond or a double bond; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; p is an integer selected from 0 to 2; and

X- is a counterion. salt is a compound of Formula (I'"):

wherein Ar is independently selected from aryl or heteroaryl;

Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; 2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; and

X- is a counterion.

In some embodiments, the Ar is independently selected from 6 membered aryl or 6 membered heteroaryl.

In some embodiments, the imidazolium salt is a compound of Formula (I'"a):

wherein Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; R2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; and

X- is a counterion.

In some embodiments, Ri is optionally substituted alkyl.

In some embodiments, Ri is selected from methyl, ethyl, propyl, iso-propyl, phenylmethyl, phenylethyl, 2-phenylpropyl, 3-phenylpropyl, 1,1-diphenylmethyl, or a combination thereof.

In some embodiments, n is 3.

In some embodiments, R2 is optionally substituted alkyl.

In some embodiments, R2 is selected from selected from methyl, ethyl, propyl, isopropyl, phenylmethyl, phenylethyl, 2-phenylpropyl, 3-phenylpropyl, 1,1- diphenylmethyl, or a combination thereof.

In some embodiments, m is 3.

In some embodiments, R3 is independently optionally substituted aryl, or optionally substituted heteroaryl.

In some embodiments, p is 2.

In some embodiments, the compound of Formula (I) is:

In some embodiments, the Ni(0) complex is selected from bis(cyclooctadiene)nickel(0), tetra kis(triphenylphosphite)nickel(0), tetrakis(triphenylphosphine)nickel(0), bis(triphenylphosphine)dicarbonyl nickel, bis(l,5-cyclooctadiene)(d uroquinone) nickel(O),

, or a combination thereof.

In some embodiments, the NHC-Ni(O) catalyst comprises a mono-substituted NHC. In some embodiments, the first coupling partner is an electrophilic coupling partner and the second coupling partner is a nucleophilic coupling partner.

In some embodiments, the reaction step comprises a step of forming a first intermediate of Formula (Ila) or (lib):

wherein G is the first coupling partner; and

Y is a counterion of the first coupling partner. In some embodiments, the reaction step comprises reacting the intermediate of Formula (Ila) with the first coupling partner or the intermediate of Formula (lib) with the alkene in order to form a second intermediate.

This carbonickelation step across the n-bond may be regio- and/or enantioselective.

In some embodiments, the first coupling partner is derived from organotriflate, organohalide, organosulfonate, organotosylate, organomesylate, or a combination thereof.

In some embodiments, the first coupling partner is derived from optionally substituted aryl triflate, optionally substituted alkenyl triflate, optionally substituted alkyl triflate, optionally substituted alknyl triflate, optionally substituted aryl halide, optionally substituted alkenyl halide, optionally substituted alkyl halide, optionally substituted alknyl halide, optionally substituted aryl sulfonate, optionally substituted alkenyl sulfonate, optionally substituted alkyl sulfonate, optionally substituted alknyl sulfonate, optionally substituted aryl tosylate, optionally substituted alkenyl tosylate, optionally substituted alkyl tosylate, optionally substituted alknyl tosylate, optionally substituted aryl mesylate, optionally substituted alkenyl mesylate, optionally substituted alkyl mesylate, optionally substituted alknyl mesylate, or a combination thereof.

In some embodiments, the first coupling partner is derived from

In some embodiments, the first coupling partner is added at about 1 to about 6 molar equivalence relative to the alkene.

In some embodiments, the reaction step further comprises a step of reacting the second intermediate with the second coupling partner in order to form a third intermediate.

In some embodiments, the second coupling partner is derived from a hydride donor or organometallic reagent.

In some embodiments, the second coupling partner is derived from metal alkoxide, alcohol, hydrosilane, optionally substituted aryl Mg halide, optionally substituted alkenyl Mg halide, optionally substituted alkyl Mg halide, optionally substituted alknyl Mg

halide, optionally substituted aryl Zn halide, optionally substituted alkenyl Zn halide, optionally substituted alkyl Zn halide, optionally substituted alknyl Zn halide, or a combination thereof.

In some embodiments, the second coupling partner is derived from sodium isopropoxide, KOEt, NaOCH(Me)Ph, PhMgBr, or a combination thereof.

In some embodiments, the second coupling partner is added at about 1 to about 6 molar equivalence relative to the alkene.

In some embodiments, the second coupling partner is characterised by a concentration of at least 3 times relative to a concentration of the alkene.

In some embodiments, the second coupling partner is characterised by a concentration of at least 5 times relative to a concentration of the alkene.

In some embodiments, the reaction further comprises a -H elimination step or a carbon transfer step.

In some embodiments, the reaction further comprises a reductive elimination step.

In some embodiments, the alkene is selected from an unactivated alkene or an activated alkene.

In some embodiments, the alkene is selected from an acyclic terminal alkene or a cyclic internal alkene.

In some embodiments, the alkene is monosubsituted or 1,1-disubstituted with aryl, alkyl, alkenyl, amino, oxo, silyl, or a combination thereof.

In some embodiments, the alkene is characterised by an absence of a directing group.

In some embodiments, the reaction is performed in a non-polar solvent.

In some embodiments, the non-polar solvent is selected from toluene.

In some embodiments, the reaction is performed at about 30 °C to about 60 °C.

In some embodiments, the reaction is performed for about 6 h to about 24 h.

In some embodiments, the reaction is performed under an inert atmosphere.

In some embodiments, the inert atmosphere is selected from argon, nitrogen, or a combination thereof.

In some embodiments, the reaction is performable in an absence of a glovebox.

In some embodiments, the reaction is stable to an oxygen concentration of less than about 100 ppm.

In some embodiments, the reaction is stable to a water concentration of less than about 100 ppm.

In some embodiments, the reaction is characterised by an efficiency of at least 60%.

In some embodiments, the reaction is characterised by a regioselectivity of at least 90%.

In some embodiments, the method is characterised by an enantioselectivity of at least 70%.

Brief description of the drawings

Embodiments of the present invention will now be described, by way of non-limiting example, with reference to the drawings in which:

Figure 1 shows the significance of developing enantioselective olefin cross-coupling reactions using nonprecious metal catalysis, a, Tri- and tetrasubstituted stereocenters are commonly embedded within natural products and drugs, b, Established base metal- catalysed carbofunctionalization strategies for introducing stereocenters and their

associated challenges, c, Our report on regio- and enantioselective olefin cross-coupling reactions catalysed by a bulky chiral NHC-nickel(O) complex. R, G, functional group; Ar, aryl group; L, ligand; M, metal; X, halide or pseudohalide; Tf, triflyl.

Figure 2 shows reaction design and mechanistic studies, a, Proposed mechanistic rationale for regio- and enantioselective olefin cross-coupling using hydrocarbofunctionalization as a model, b, Optimized conditions and X-ray crystal structure of product, c, Increasing alkoxide loading suppresses the undesired branched- selective Heck reaction that leads to 9. Hydroarylation of 10 leads to 12 with no trace of ring cleavage. R, G, functional group; Ar, aryl group; L, ligand; M, metal; X, halide or pseudohalide; cod, 1,5-cyclooctadiene; Tf, triflyl; Bn, benzyl.

Figure 3 shows exploration of olefin scope, a, Reactions to access enantioenriched tetrasubstituted stereocenters, b, Reactions to access enantioenriched trisubstituted stereocenters. Hydroarylation of 10 leads to 12 with no trace of ring cleavage. Unless otherwise stated, all products were obtained in >98:2 regioisomeric ratios. *Ni(cod)2/Ll (20 mol %) was used. +Ni(cod)2/Ll (15 mol %) was used. *NaOC(D)Me2 was used. #NaOC(H)MePh was used. [TNi(cod)2/L2 (10 mol %) was used. §Ni(cod)2/L2 (15 mol %) was used and 94:6 regioisomeric ratio. R, functional group; Ar, aryl group; cod, 1,5- cyclooctadiene; Tf, triflyl; Bn, benzyl; TBS, tert-butyldimethylsilyl.

Figure 4 shows exploration of electrophile and nucleophile scope, a, Reactions with aryl and heteroaryl triflate. b, Reactions with alkenyl triflates. c, Extension to 1,2- dicarbofunctionalization processes using organometallic reagents. Through strategic hydrofunctionalization and difunctionalization, synthesis of both enantiomers of 107 can be achieved. Unless otherwise stated, all products were obtained in >98:2 regioisomeric ratios. *15 mol % Ni(cod)2/Ll was used. tOrganozinc chloride (3D5 equiv.) was used. *95:5 regioisomeric ratio. R, G, functional group; Ar, aryl group; cod, 1,5- cyclooctadiene; Tf, triflyl; Bn, benzyl.

Figure 5 shows a proposed model to account for the observed stereochemical outcome.

Detailed description

Asymmetric transition metal catalysis has had a far-reaching impact on chemical synthesis. However, nonprecious metal-catalysed strategies that provide direct entry to compounds with enantioenriched trisubstituted and fully substituted stereogenic centers are scarce. In some aspects, it is shown that a sterically encumbered chiral N- heterocyclic carbene-Ni(O) catalyst, in conjunction with an organotriflate and a metal

alkoxide as hydride donor, promote 1,2-hydroarylation and hydroalkenylation of diverse alkenes and 1,3-dienes. Replacing the metal alkoxide with an organometallic reagent allows installation of two different carbogenic motifs. Without wanting to be bound by theory, it is believed that these multicomponent reactions proceed through regio- and enantioselective carbonickelation followed by carbon-nickel bond transformation, providing a streamlined pathway towards enantioenriched carbon- or heteroatom- substituted tertiary or quaternary stereogenic centers. Through selective carbofunctionalizations, enantiodivergent access to opposite enantiomers may be achieved using the same catalyst antipode. The method enables practical access to complex bioactive molecules and other medicinally valuable but synthetically challenging building blocks, such as those that contain deuterated methyl groups.

Current catalytic methods for alkene functionalisation usually involve one or more of the following traits: i. Intramolecular two-component dicarbofunctionalizations of alkenes. ii. Three-component dicarbofunctionalizations of activated alkenes.

Hi. Directing groups are incorporated within the substrate to direct efficient and regioselective three-component dicarbofunctionalizations of unactivated alkenes. iv. Two metal catalysts (Co/Ni or Fe/Ni) are required in branched-selective hydrocarbofunctionalization of unactivated alkenes.

In contrast, the present invention does not rely on the use of directing groups and employs a single nonprecious nickel-based complex to promote a variety of three- component alkene hydrocarbofunctionalization and dicarbofunctionalization reactions with high efficiency and regioselectivity. The method works with both unactivated and activated alkenes as well as 1,3-dienes.

In the absence of any directing groups (auxiliaries), it was found that catalytic amounts of NHC-nickel(O) complexes can promote regioselective dicarbofunctionalization of both unactivated and activated alkenes bearing a wide variety of functionalities. A catalyst system derived from an air-stable Ni(0) precursor and a bulky NHC ligand allows the regioselective alkene dicarbofunctionalization to be performed under an inert atmosphere in a standard fume hood without the need for a glovebox.

Alkene 1,2-dicarbofunctionalizations are highly sought-after transformations as they enable a rapid increase of molecular complexity in one synthetic step. The method provides a general and sustainable method (nonprecious nickel catalysis) to transform cheap and readily available alkene feedstock chemicals to sp³-hybridized carbon frameworks through hydrocarbofunctionalization and dicarbofunctionalization reactions. No pre-installation and post-reaction removal of directing auxiliaries are needed, in contrast to current state-of-the-art protocols. This provides attractive advantages in terms of cost savings, step economy and waste reduction. The resulting products can be used as building blocks in the synthesis of high-value chemicals such as natural products, pharmaceuticals and new drug candidates.

Additionally, a single nonprecious nickel-based complex is used as the catalyst to promote hydrocarbofunctionalization reactions. This is more practical than current methods which employs two metal catalysts.

Without wanting to be bound by theory, it is believed that steric repulsions between the alkene substituents and the carbon-nickel bond that contains a sterically encumbered ligand on the nickel is elevated in the energetically less favored transition state. Hence, one regioisomer of the product is kinetically favored to form based on steric arguments, and there are no restrictions on the type of alkene substrate that can be used. The mechanism is believed to involve branched-selective olefin carbonickelation followed by hydrogenation or a second carbofunctionalization. The sequence of bond formation is opposite to that of prior art and long-lived radical species are not involved.

In contrast, prior art in dicarbofunctionalization of unactivated alkenes rely on: (1) Substrate control in which intramolecularity drives carbometallation to form a cyclic intermediate; (2) Auxiliary control with a strategically-positioned directing group that coordinates and stabilizes the metal center in the putative organometallic species. These strategies place significant constraints on the type of alkene substrates that can be used. The mechanism in previous hydrocarbofunctionalization methods (with unactivated alkenes) involves nickel-hydride addition or metal-hydride atom transfer (producing radicals) followed by carbofunctionalization. The mechanism in previous dicarbofunctionalization methods (with unactivated alkenes) involves terminal-selective carbonickelation followed by a second carbofunctionalization. Because of the sequence of bond formation, certain alkene substrates (e.g. aliphatic 1,3-dienes,

vinylcyclopropanes) that are prone to side reactions (e.g. allyl isomerization, radical ring-opening) cannot be used.

"Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so- butyl, n-hexyl, and the like.

"Alkoxy" refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

"Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

"Oxo/hydroxy" refers to groups =0, HO-.

"Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.

"Heteroaryl" refers to a monovalent aromatic heterocyclic group which fulfils the Huckel criteria for aromaticity (ie. contains 4n + 2 n electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen). Such heteroaryl groups can have a single ring (eg. pyridyl, pyrrolyl or N- oxides thereof or furyl) or multiple condensed rings (eg. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).

Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine,

phenothiazine, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine and the like.

"Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1,2,3,4-tetrahydronapthalenyl and the like.

"Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R2 or R' is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.

Examples of heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1, 2, 3, 4-tetra hydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetra hydrofuranyl, triazole, and the like.

In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino,

phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like, and may also include a bond to a solid support material, (for example, substituted onto a polymer resin). For instance, an "optionally substituted amino" group may include amino acid and peptide residues.

"Isomer" includes especially optical isomers (for example essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof) as well as conformation isomers (i.e. isomers that differ only in their angles of at least one chemical bond), position isomers (particularly tautomers), and geometric isomers (e.g. cis-trans isomers), E- and Z- isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched. in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

It will also be recognised that compounds of the invention 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, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, eg., chromatography, or use of a resolving agent.

The present invention provides a method of alkene functionalisation, comprising : reacting an alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst.

In some embodiments, the method of functionalising an alkene to a tri- or tetrasubstituted stereocenter comprises: reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the tri- or tetrasubstituted stereocenter.

In cross-coupling reactions, the component reagents are called cross-coupling partners or coupling partners. These reagents can be further classified according to their nucleophilic vs electrophilic character. For example, electrophilic coupling partner can be an aryl halide, or aryl triflates. For example, nucleophilic coupling partners can be boronic esters or boronic acids.

In some embodiments, the the NHC-Ni(O) catalyst is generated in situ. In some embodiments, the NHC-Ni(O) catalyst is generated in situ from a Ni(0) complex and an imidazolium salt. Imidazolium is an aromatic heterocycle, classified as a diazole, and has non-adjacent nitrogen atoms.

In some embodiments, the method of functionalising an alkene to a tri- or tetrasubstituted stereocenter comprises: reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the tri- or tetrasubstituted stereocenter;

wherein the NHC-Ni(O) catalyst is generated in situ.

In some embodiments, the imidazolium or imidazolinium salt is a compound of Formula

(I):

wherein Ar is independently selected from aryl or heteroaryl;

Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl;

R2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl;

L is independently a direct bond or optionally substituted alkylene;

represents a single bond or a double bond; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; p is an integer selected from 0 to 2; and

X- is a counterion.

In some embodiments, L is optionally substituted alkylene. In some embodiments, L is optionally substituted methylene. In this regard, Ar is spaced apart from NHC by 1 carbon. The optional substituent may be oxo, alkyl, alkoxy, or oxyalkyl. For example, the optional substituent may be methyl, ethyl, propyl, t-butyl, methoxy, or oxymethyl.

In some embodiments, L is a direct bond. In some embodiments, the imidazolium or imidazolinium salt is a compound of Formula (I¹):

wherein Ar is independently selected from aryl or heteroaryl;

R3 is independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; represents a single bond or a double bond; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; p is an integer selected from 0 to 2; and

X- is a counterion.

wherein Ar is independently selected from aryl or heteroaryl;

Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; 2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; represents a single bond or a double bond; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; p is an integer selected from 0 to 2; and

X- is a counterion.

In some embodiments, the imidazolium salt is a compound of Formula (I'"):

wherein Ar is independently selected from aryl or heteroaryl;

R2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; and

X- is a counterion.

In some embodiments, X- is selected from halide, carbonate, hydroxide, nitrate, nitrite, sulfate, sulphite, phosphate, hexafluorophosphate, or tetrafluoroborate. In some embodiments, X- is selected from halide, hexafluorophosphate, or tetrafluoroborate.

In some embodiments, the Ar is independently selected from 6 membered aryl or 6 membered heteroaryl. In some embodiments, the Ar is independently aryl. In some embodiments, the Ar is independently phenyl. In some embodiments, the Ar is independently phenyl, naphthalenyl or 2,3-dihydroindenyl.

^A da) wherein Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; 2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; s is independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;

L is independently a direct bond or optionally substituted alkylene; represents a single bond or a double bond; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5;

p is an integer selected from 0 to 2; and

X- is selected from halide, carbonate, hydroxide, nitrate, nitrite, sulfate, sulphite, or phosphate.

wherein Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; R2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl;

wherein Ri is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; R2 is independently halo, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl; represents a single bond or a double bond;

n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; p is an integer selected from 0 to 2; and

In some embodiments, the imidazolium salt is a compound of Formula (I'"a):

In some embodiments, Ri is independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In some embodiments, Ri is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In some embodiments, Ri is optionally substituted alkyl.

In some embodiments, the optional substituent is independently selected from halo, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or a combination thereof. In some embodiments, the optional substituent is independently selected from alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or a combination thereof. In some embodiments, the optional substituent is independently selected from alkyl, aryl, or a combination thereof. The aryl may be phenyl.

In some embodiments, n is selected from 0 to 4, 0 to 3, 1 to 3, or 2 to 3. In some embodiments, n is 3.

In some embodiments, R2 is independently optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In some embodiments, R2 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl. In some embodiments, R2 is optionally substituted alkyl.

In some embodiments, m is selected from 0 to 4, 0 to 3, 1 to 3, or 2 to 3. In some embodiments, m is 3.

In some embodiments, the moieties at Ri and R2 are the same.

In some embodiments, R3 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R3 is independently optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, R3 is optionally substituted phenyl.

The optional substituent may be independently selected from halo, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, or a combination thereof. In some embodiments, the optional substituent is independently selected from alkyl, cycloalkyl,

heterocyclyl, aryl, heteroaryl, or a combination thereof. In some embodiments, the optional substituent is independently selected from alkyl, aryl, or a combination thereof.

In some embodiments, p is 0, 1 or 2. In other embodiments, p is 1 or 2. In other embodiments, p is 2.

In some embodiments, when p is 2, both R3 are 1,2 substituted relative to each other.

In some embodiments, when p is 2, both R3 are fused to form optionally substituted aryl or optionally substituted heteroaryl. In some embodiments, when p is 2, both R3 are fused to form optionally substituted aryl.

In some embodiments, the compound of Formula (I), (I¹), (I"), (I'"), (la), (I'a), (I"a) or (I'"a) is:

(Ni(^4-tBustb)3), or a combination thereof.

In some embodiments, the NHC-Ni(O) catalyst comprises a mono-substituted NHC. In other embodiments, the NHC-Ni(O) catalyst comprises a di-substituted NHC.

In some embodiments, the alkene and first coupling partner undergo a carbonickelation step in the presence of the NHC-Ni(O) catalyst.

Accoridngly in some embodiments, the method of functionalising an alkene to a tri- or tetrasubstituted stereocenter comprises: reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the tri- or tetrasubstituted stereocenter; wherein the alkene and first coupling partner undergo a carbonickelation step in the presence of the NHC-Ni(O) catalyst.

i Alkene (Ha)

wherein G is the first coupling partner; and

Y is a counterion of the first coupling partner.

In some embodiments, the reaction step comprises reacting the intermediate of Formula (Ila) with the first coupling partner or the intermediate of Formula (lib) with the alkene in order to form a second intermediate.

In some embodiments, the first coupling partner is an electrophilic coupling partner or a nucleophilic coupling partner. In some embodiments, the first coupling partner is an electrophile or a nucleophile. In some embodiments, the first coupling partner is an electrophilic coupling partner. In some embodiments, the first coupling partner is an electrophile.

In some embodiments, the first coupling partner is coupled to the carbon on the alkene which is more sterically hindered. Sterically hindered alkenes are compounds in which at least one of the alkene carbon is at least partially shielded by neighbouring groups so that larger molecules cannot easily approach and react with the alkene carbon. In this regard, C-C bond formation occurs in a Markovnikov-selective fashion. In other embodiments, the first coupling partner is coupled to the carbon on the alkene which is conjugated to a more bulky substitutent. In other embodiments, the first coupling partner is coupled to the carbon on the alkene which is conjugated to an electron withdrawing group or electron donating group. In other embodiments, the first coupling partner is coupled to an internal carbon on a terminal alkene.

wherein the alkene and first coupling partner undergo a carbonickelation step in the presence of the NHC-Ni(O) catalyst; and wherein the first coupling partner is coupled to a carbon on the alkene which is more sterically hindered.

In some embodiments, the first coupling partner is derived from a substituted aryl, substituted alkenyl or has a triflate moiety. In other embodiments, the first coupling partner is derived from an alkenyl triflate. In other embodiments, the first coupling

In some embodiments, the first coupling partner is added at about 1 to about 6 molar equivalence relative to the alkene. In other embodiments, the ratio is about 1 to about 5 molar equivalence, about 1 to about 4 molar equivalence, about 1 to about 3 molar equivalence, or about 2 to about 3 molar equivalence.

In some embodiments, the method of functionalising an alkene to a tri- or tetrasubstituted stereocenter comprises:

reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the tri- or tetrasubstituted stereocenter; wherein the alkene and first coupling partner undergo a carbonickelation step in the presence of the NHC-Ni(O) catalyst followed by a carbon-nickel bond transformation with the second coupling partner; and wherein the first coupling partner is coupled to a carbon on the alkene which is more sterically hindered.

In some embodiments, the second coupling partner is an electrophilic coupling partner or a nucleophilic coupling partner. In some embodiments, the second coupling partner is an electrophile or a nucleophile. In some embodiments, the second coupling partner is a nucleophilic coupling partner. In other embodiments, the second coupling partner is a nucleophile.

In some embodiments, the second coupling partner is coupled to the carbon on the alkene which is less sterically hindered. In other embodiments, the second coupling partner is coupled to the carbon on the alkene which is conjugated to a less bulky substitutent. In other embodiments, the second coupling partner is coupled to a terminal carbon on a terminal alkene.

In some embodiments, the second coupling partner is derived from metal alkoxide, alcohol, hydrosilane, optionally substituted aryl Mg halide, optionally substituted alkenyl Mg halide, optionally substituted alkyl Mg halide, optionally substituted alknyl Mg halide, optionally substituted aryl Zn halide, optionally substituted alkenyl Zn halide, optionally substituted alkyl Zn halide, optionally substituted alknyl Zn halide, or a combination thereof.

In some embodiments, the second coupling partner is derived from substituted aryl, substituted alkenyl, substituted alkynyl, alkyl magnesium halide (such as R-MgBr) or alkyl zinc halide (such as R-ZnCI). In other embodiments, and for hydride addition, the

second coupling partner can be NaOi-Pr or other metal alkoxides such as KOEt and NaOCH(Me)Ph. In some embodiments, the second coupling partner is ^PhM9^Br .

In some embodiments, the second coupling partner is added at about 1 to about 6 molar equivalence relative to the alkene. In other embodiments, the ratio is about 1 to about 5 molar equivalence, about 1 to about 4 molar equivalence, about 1 to about 3 molar equivalence, or about 2 to about 3 molar equivalence.

In some embodiments, the second coupling partner is characterised by a concentration of at least 3 times relative to a concentration of the alkene. In some embodiments, the second coupling partner is characterised by a concentration of at least 4 or 5 times relative to a concentration of the alkene.

In some embodiments, the reaction further comprises a p-H elimination step or a carbon transfer step.

In some embodiments, the alkene is selected from an unactivated alkene or an activated alkene. In some embodiments, the alkene is an unactivated alkene.

Activation of an alkene means that the double bond has a higher or lower electron density than that of a normal isolated double bond. The alkene displays a greater nucleophilic or electrophilic nature than it normally should due to increased or decreased electron density That is, the electron density in the double bond is greater or lower (double bond is more polarized) than the one observed in ethene. Corollary, unactivated alkene refers to an alkyl-substituted alkene without electron-withdrawing groups (EWG) and/or electron donating groups (EDG) directly attached to the double bond.

In some embodiments, the alkene is selected from an acyclic terminal alkene or a cyclic internal alkene. In this regard, acyclic internal alkene are less preferred. When the double bond is located at the end of a molecule, it is referred to as a terminal alkene. By contrast, alkenes that do not have their double bond located at the end of the molecule are called internal alkenes.

In some embodiments, the alkene is monosubsituted or 1,1-disubstituted. In other embodiments, the substituent is selected from aryl, alkyl, alkenyl, amino, oxo, silyl, or a combination thereof.

Intermolecular 1,2-dicarbofunctionalization reactions are underdeveloped owing to the challenge of controlling chemo- and regioselectivity for two coupling partners, especially if they have similar reactivity. Directing groups have been used to overcome this issue to control the selectivity. For example, directing groups can be acetates, amines, nitriles, imines, amides, pyridines, pyrimidines, or heterocycle directing groups, such as saccharin, phthalimide, pyridone, pyrazole, quinoline, triazole, tetrazole, and benzoxazole. In some embodiments, the alkene is characterised by an absence of a directing group.

In some embodiments, the reaction is performed in a non-polar solvent. In some embodiments, the non-polar solvent is selected from toluene. Other solvents that can be used includes benzene, cyclohexane, hexane and pentane.

In some embodiments, the reaction is performed at about 30 °C to about 60 °C. In other embodiments, the reaction is performed at about 40 °C to about 60 °C, or about 40 °C to about 50 °C.

In some embodiments, the reaction is performed for about 6 h to about 24 h. In other embodiments, the duration is about 8 h to about 24 h, about 10 h to about 24 h, or about 12 h to about 24 h.

In some embodiments, the reaction is performed under an inert atmosphere. In some embodiments, the inert atmosphere is selected from argon, nitrogen, or a combination thereof.

In some embodiments, the reaction is performable in the presence of trace amount of oxygen. In some embodiments, the reaction is performable in the presence of trace amount of water. In some embodiments, the reaction is performable in an absence of a glovebox.

In some embodiments, the reaction is stable to an oxygen concentration of less than about 100 ppm. Accordingly, the reaction can be performed using conventional Schlenk techniques instead of a glovebox.

In some embodiments, the reaction is stable to a water concentration of less than about 100 ppm. Accordingly, the reaction can be performed using conventional Schlenk techniques instead of a glovebox.

In some embodiments, the reaction is characterised by an efficiency of at least 60%. In other embodiments, the efficiency is at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.

In some embodiments, the reaction is characterised by a regioselectivity of at least 90%. In other embodiments, the regioselectivity is at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%.

In some embodiments, the method is characterised by an enantioselectivity of at least 70%. In other embodiments, the enantioselectivity is at least 75%, 80%, 85%, 90%, 92%, 94%, 96% or 98%.

Examples

Enantioenriched tri- and tetrasubstituted stereogenic centers, particularly those linked to aromatic or olefinic moieties widely feature among natural products and synthetic drug candidates (Figure la). The spatial arrangement of atoms around such centers often dictates the overall shape of a molecule and influences its biological function or toxicity. Since opposite enantiomers may possess vastly different activities, the ability to exert exquisite control over the absolute configuration to access enantiomerically pure compounds through asymmetric catalysis is of utmost importance in pharmaceutical and agrochemical research. In addition, catalytic enantioselective synthesis helps to avoid the necessity for cumbersome resolutions of racemic mixtures.

Transition meta I -catalysed enantioselective multicomponent coupling of carbogenic functionalities with prochiral carbon-carbon n-frameworks represents an attractive

avenue of generating molecular complexity and stereogenicity. In particular, the process of Markovnikov-selective 1,2-hydrocarbofunctionalization in which adjacent C-C and C- H bonds can be installed with precision, offers the opportunity to control the stereochemical outcome when a chiral organometallic catalytic species is involved to promote enantiofacial discrimination of the substrate. To this end, seminal advances in Pd-catalysed reductive Heck-type reactions that forge C(sp²)-C(sp³) bonds were reported. In recent years, the surge in demand for nonprecious metal catalysis as a more sustainable alternative led to a number of related developments in enantioselective olefin coupling transformations (Figure lb). A significant proportion of these olefin hydrocarbofunctionalizations proceed through sequential hydrometallation/carbofunctionalization regimes, via a chiral metal-hydride intermediate I derived from a hydride donor such as an alcohol or hydrosilane. Enantioselectivity is typically dictated during the regioselective hydrometallation event from I to II (electronic stabilization by the a-substituent R), before reaction with a carbon electrophile or organometallic nucleophile to give the final product. On the other hand, transformations that incorporate two carbogenic moieties via III and IV have been documented, although the scope is restricted to styrene homo-diarylation using aryl halides to deliver enantioenriched triarylethanes.

Despite these efforts, established base meta I -catalysed regimes are often plagued by critical problems which preclude their widespread adoption across chemical research (Figure lb, grey inset). For instance, the scope of most reported methods centered on constructing enantioenriched tertiary stereocenters. Analogous reactions that lead to crowded tetrasubstituted carbon centers remain underdeveloped. This is not surprising since access to these products is often thwarted by the increased steric congestion within the putative tertiary alkylmetal intermediate obtained after metal-hydride addition to 1,1-disubstituted alkenes, which inadvertently raises the energy barriers for hydrometallation and the subsequent C-C bond formation. Added to this complication is the inability of a chiral catalytic entity to appreciably differentiate the enantiotopic faces of a 1,1-disubstituted olefin (vs. a monosubstituted variant) for high selectivity. Although the enantioselective generation of all-carbon quaternary stereocenters is a primal objective in organic synthesis, methodologies that achieve this by direct carbofunctionalization of readily available olefin feedstocks, without relying on intramolecularity or activating/directing auxiliaries using nonprecious metal catalysis are unexpectedly scarce.

Furthermore, most of these hydroarylation and hydroalkenylation protocols employed either styrenes, N-acyl enamines or aryl-l,3-dienes as substrates that give rise to a limited range of enantioenriched products. In addition, poor regio- and enantioselectivities were observed with alkyl-substituted 1,3-dienes, which are prone to allylic rearrangement and thereby difficult to undergo selective carbo-additions The corresponding transformations with the less reactive enol ethers, N-vinylheteroarenes or vinylsilanes affording heteroatom-substituted stereocenters that are prevalent in pharmaceuticals are also exceedingly rare. For dicarbofunctionalization, efficient addition of two distinct carbon units is challenging owing to undesired side reactions arising from competitive coupling between the reagents, as well as adventitious p-H elimination of the alkylmetal intermediate analogous to IV.

In light of the aforementioned challenges, a unified enantioselective olefin crosscoupling manifold that enables access to various categories of enantioenriched tri- and tetrasubstituted stereocenters would be especially desirable and complementary to existing methods, including those involving radical relay processes which are limited to stabilized alkyl radical additions. Herein, the inventors report a versatile nickel-catalysed strategy that is broadly applicable to hydrocarbofunctionalization and dicarbofunctionalization (Figure lc). Through mechanistic studies, these three- component reactions are found to operate via a chiral carbonickel complex undergoing carbonickelation with inverse site selectivity to give a p-branched alkylnickel species (vs. a-branched II and IV from Figure lb).

Chiral NHC-nickel complexes as effective catalysts

The lack of generality in past catalytic protocols could be attributed to the over-reliance on chiral bidentate N- or P-based ligands. To circumvent this issue, the inventors opted to devise a reaction system that takes advantage of an earth-abundant organonickel(O) catalyst bearing a sizeable enantioenriched monodentate N-heterocyclic carbene (NHC) ligand (Figure 2a).

Based on findings in non-enantioselective Ni(I)-catalysed processes, it is postulated that a chiral aryl(alkenyl)nickel species V (from initial reaction of the NHC-Ni(O) with a sp²- hybridized carbon electrophile) would preferentially undergo regio- and enantioselective carbonickelation across the n-bond to give VI (instead of VII), in order to minimize

unfavorable steric interactions between the ligand and the olefinic substitutents. We reasoned that the strongly o-donating and sterically shielded NHC could sufficiently stabilize V and provide the appropriate chiral environment to induce efficient and stereoselective n-complexation/migratory insertion. This is followed by alkoxide ligand substitution and hydride transfer (from p-H elimination of Ni-alkoxide VIII) to give IX, before the ensuing reductive elimination furnishes the desired hydrocarbofunctionalization adduct. Mechanistically, the overall carbonickelation/hydride transfer sequence differs from previous methods (Figure lb) in two fundamental aspects: a stereo-determining C-C bond formation precedes C-H bond formation; the regiochemical outcome from V to VI is largely governed by steric effects (vs. electronic effects from I to II). Since the stereochemical outcome is already set in the carbonickelation step, functionalizing the C-Ni bond in VI with a carbon-based reagent (instead of hydride) will give rise to dicarbofunctionalization adducts (see Figure 4c for more details), which is not attainable by catalytic systems that commence with hydrometallation (Figure lb).

This approach would offer straightforward access to enantioenriched building blocks, many of which were inaccessible by previous methodologies, for the concise assembly of various biologically active compounds (Figure la). Furthermore, enantioselective hydro- or deuterofunctionalization of an olefin or its gem-dideutero-substituted derivative could deliver molecules containing differentially D-labeled methyl units. These are prized for their role in medicine and agrochemicals (for example, 1-3, 5) arising from the beneficial effect of C-D bonds, but remain a challenge to synthesize.

To test the hypothesis proposed in Figure 2a, we examined conditions to promote the three-component union of styrene 6 with a carbon electrophile and a hydride source. After an extensive survey, we identified Ni(cod)2 (10 mol %) in combination with a diastereo- and enantioenriched C2-symmetric imidazolium salt LI (10 mol %) and NaOtBu (20 mol %) as the preferred catalytic system to mediate enantioselective crosscoupling of 6, aryl triflate 7 and sodium isopropoxide, furnishing the desired adduct 8 in 95% yield, >98:2 regioisomeric ratio (r.r.) and 98:2 enantiomeric ratio (e.r.) under mild conditions within 16 h (Figure 2b). The absolute configuration of 8 was unambiguously ascertained by X-ray crystallography analysis. Other Ni(II) precatalysts containing different counterions, solvents and/or temperatures may be used. In line with our proposal, the electron-donating NHC derived from deprotonation of LI was

uniquely crucial for the transformation as other non-NHC ligands failed to promote cross-coupling. Furthermore, increasing the size or modifying the electronics of the NHC ligand resulted in different yields and selectivities. Switching triflate 7 to other halide/sulfonate substrates also had an effect on reaction efficiency. Under our conditions, simple metal alkoxides are more effective hydride donors compared to alcohols or hydrosilanes, and sodium isopropoxide was found to be optimal. A proposed model to account for the observed stereochemical outcome is shown in Figure 5.

Control experiments revealed that the presence of excess sodium isopropoxide is advantageous for suppressing the undesired branched-selective Heck reaction that gave rise to alkene 9 (Figure 2c). A decrement in sodium isopropoxide loading (<5 equivalents) led to a corresponding drop in reaction efficiency and increase in formation of 9 without affecting site and enantioselectivity. This may be rationalized by the fate of the alkylnickel intermediate VI generated after regio- and enantioselective carbonickelation (see Figure 2a), which is susceptible to competitive p-H elimination when R2 = H (i.e. monosubstituted olefins) to afford 9. Sufficient amounts of the exogenous alkoxide is therefore needed to enable efficient conversion of VI to the hydroarylation product 8 via VIII and IX. These results further support that C-C bond formation occurs in a Markovnikov-selective fashion prior to hydride transfer, since 8 and 9 were both obtained as single regioisomers. Cross-coupling of racemic transvinylcyclopropane 10 and 11 under standard conditions gave the expected adduct 12 as a diastereomeric mixture in 71% yield and 95:5 r.r. with minimal cyclopropane ringopening, intimating that the transformation is unlikely to proceed through initial hydronickelation via a-branched alkylnickel II (see Figure lb) or long-lived radical species. Analysis of the standard reaction mixture by electron paramagnetic resonance spectroscopy indicated the absence of paramagnetic species generated in the system, suggesting that the present Ni-catalysed olefin cross-coupling likely follows a Ni(0)/Ni(II) mechanism. These results are in contrast with previously reported reactions involving a dimeric Ni(I) complex, which largely proceed through a Ni(I)/Ni(III) pathway.

Scope of enantioselective olefin cross-coupling

We next assessed the generality of our established conditions for enantioselective crosscoupling with a range of functionalized alkenes and 1,3-dienes. In contrast to existing catalytic systems that are incompatible with sterically hindered 1,1-disubstituted

olefins, we observed that such substrates underwent efficient hydroarylation to secure 13 to 29 bearing fully substituted stereocenters with excellent control of regio- and enantioselectivities (Figure 3a). These include products containing a Lewis basic amine (15), an olefin (26, silyl ethers (14, 17), electronically varied arenes (19-22) as well as heterocyclic substituents (18, 23, 24). Access to 25 shows that exocyclic olefins are amenable substrates, although enantioselectivity was slightly lower. The present protocol could be readily extended to the preparation of enantioenriched drug-like scaffolds with deuterated methyl (CH2D, CHD2, CD3)-substituted quaternary carbon centers (27-29) by judicious hydroarylation or deuteroarylation of an alkene or its gem- dideutero-substituted variant with sodium isopropoxide or its deuterated analogue.

Monosubstituted alkenes and 1,3-dienes were also competent substrates for crosscoupling, furnishing a vast array of adducts containing trisubstituted stereocenters in good yields and enantioselectivities (Figure 3b). Styrenes with aryl (30-38) and heteroaryl (39-42) groups of diverse electron density participated in hydroarylation, including one application that involves the synthesis of 43, a NIL protein antagonist. Formation of estrone-derived 38 proves that reducible functional groups such as ketones are tolerated. The stereochemistry of the chiral catalyst, rather than existing stereocentres on the substrate, predominantly determines the configuration of 38. To expand the scope beyond carbon centers, we investigated whether the method can be extended to heteroatom-functionalized olefins. As illustrated by 44 to 50, a variety of synthetically useful products carrying nitrogen-, oxygen- or silicon-functionalized stereocenters (20, 21) were successfully generated, highlighting the robustness of these catalytic conditions. Use of the buttressed NHC derived from imidazolium salt L2 enhanced the level of enantiocontrol for the reactions leading to 46-49.

Contrary to previous catalytic systems, hydroarylation with both aryl-l,3-dienes (51- 63) and alkyl-l,3-dienes (64-66) proceeded efficiently on the terminal C=C bond with good regiocontrol and enantioselectivity. This facilitates access to allylic arene moieties such as anti-cancer drug candidate 4 and its trideuterated variant 5, which is of potential interest to the pharmaceutical industry. Reaction of a cyclic internal olefin was feasible to give 66, albeit with slightly diminished enantiopurity. However, cross-coupling of acyclic internal alkenes was inefficient (<10% product) presumably because of increased steric demand.

The reaction scope of the carbon electrophile was also explored. As shown in Figure 4a, we found that electron-rich and electron-poor aryl triflates with ortho-, meta- or parasubstituents underwent site- and enantioselective hydroarylation to give adducts with quaternary (68-71) or tertiary carbon centers (72-82). These include triflates that bear sterically hindered arenes (78, 79, 81), Lewis basic pyridines (71, 82) as well as C(sp²)-Br (69) and C(sp²)-CI (74) bonds that can be further transformed. The latter examples highlight the chemoselectivity of the olefin cross-coupling towards triflates, which allows for orthogonal functionalization. Hydroalkenylation of styrenes using the corresponding alkenyl triflate reagents generated a series of enantioenriched unsaturated building blocks (Figure 4b). Through this reaction manifold, carbocyclic olefins containing six- to eight-membered rings (83-89, 92-94) as well as acyclic olefin motifs (90, 91) can be reliably incorporated with good efficiency and selectivities. Transformations with a 1,3-diene, a vinyl carbazole and a vinyl silane successfully furnished chiral compounds containing a skipped diene (92) that is relevant in natural product synthesis, an allylic carbazole (93) and an allylic silane (94) that may be used for stereocontrolled C-C bond formation, respectively.

Seeking to challenge the limits of the present system, we probed the feasibility of installing two different carbogenic groups by replacing sodium isopropoxide with an organometallic nucleophile, which is expected to afford the requisite alkylnickel intermediate X following transmetalation of VI in Figure 2a. In contrast to a Ni-catalysed homo-diarylation procedure that only affords trisubstituted carbon centers (Figure lb) as well as radical processes that required substrates with activated alkyl units, a wide assortment of sp²- and sp³-hybridized organomagnesium and organozinc compounds served as effective reagents for cross-coupling to afford 95-106 with simultaneous control of regio- and enantioselectivities (Figure 4c). Arylation (95), alkenylation (96)

and alkylation (97) to deliver sterically congested tetrasubstituted centers could be accomplished. The stereochemical identity of 95 was confirmed by X-ray crystallography, which is consistent with the mechanistic proposal outlined in Figure 2. 1,2-Diarylation was similarly enantioselective regardless of the electronic attributes of the arylmetal nucleophile employed (98-102). To minimize side reactions with the susceptible ester, phenylzinc chloride was used instead of a Grignard reagent to secure 101.

Besides styrenes, aromatic- and aliphatic-l,3-dienes as well as heteroatom-substituted C=C bonds could be efficiently converted to the desired diarylation adducts with good enantiomeric purity (103-106), underscoring the excellent regio- and stereochemical fidelity of these processes. By using appropriate combinations of olefin substrates and reagents, hydrocarbofunctionalization or dicarbofunctionalization can be selectively executed to access both enantiomers of the product with the same chiral catalyst under standard conditions. This was exemplified by the enantiodivergent synthesis of mirrorimage stereoisomers 107 and 107', a notable advantage without having to prepare the opposite antipode of the catalyst.

Conclusions

In conclusion, we have developed a nickel-catalysed multicomponent olefin crosscoupling protocol that provides a general platform for the enantioselective carbofunctionalization of a broad spectrum of substituted alkenes and 1,3-dienes. Through the use of a sizeable chiral NHC-Ni(O) catalyst to trigger selective carbonickelation/functionalization cascades, we showed that high-value organic entities containing tertiary or quaternary stereogenic centers could be efficiently accessed in high stereochemical purity. We believe this methodology significantly enriches the toolbox of asymmetric catalysis to facilitate countless applications in stereoselective natural product synthesis and drug discovery.

Alkene functionalisation using NHC-Ni(O) chemistry:

An oven-dried 4 mL or vial (or 5 mL round-bottom flask) equipped with a stir bar was charged with Ni(^{4 tBu}stb)3 (0.1 equiv.), imidazolium salt (0.12-0.15 equiv.) and anhydrous toluene (0.5 mL) under a nitrogen or argon atmosphere using a balloon. After that, alkene (0.1 mmol, 1.0 equiv.), triflate (0.2 mmol, 2.0 equiv.) and organometallic reagent (3.0 equiv.) were added into the mixture. The reaction mixture

was allowed to stir for 10 h at 40 °C. After cooling to ambient temperature, the crude mixture was quenched by adding aqueous NF CI, and the crude mixture was subjected to GC analysis to determine the regioisomeric ratio (r.r.) before it was purified by silica gel chromatography. (Note: The organometallic reagent should ideally be freshly prepared and used.)

The use of an air-stable Ni(0) complex Ni(^4-tBustb)3 (CAS: 2468315-70-8; Strem) and racemic imidazolium salt LI is capable of promoting directing group-free diarylation to give the desired product in good yield and regioselectivity (an example is shown below). The transformation could be conducted in a standard fume hood under an inert atmosphere (Ar or N2) without the need for a glovebox. Thus, this Ni(0) catalyst system could be employed as an alternative to the NHC-Ni(I) dimeric catalyst (a glovebox is typically required) as reported in the aforementioned attachments.

(2 equiv.)

The structure of the in situ-generated NHC-Ni(O) catalyst (derived from simple ligand exchange between Ni(^{4 tBu}stb)3 and LI) in this system is proposed to be Ni-1. To the best of our knowledge, Ni-1 has not been reported in the literature.

General procedure for enantioselective hydroarylation(alkenylation): In a N2- fil led glove box, an oven-dried 4 mL or 8 mL vial equipped with a stir bar was charged with Ni(cod)2 (0.1 equiv.), LI (0.1 equiv.), NaOtBu (0.2 equiv.) and toluene or cyclohexane (2.0 mL or 4.0 mL). The reaction mixture was allowed to stir at r.t. for 1-3 h. Alkene substrate (1.0 equiv.), aryl(alkenyl) triflate (3.0 equiv.) and NaO/Pr (5.0 equiv) were then added to the system. The vial was sealed and the reaction mixture was allowed to stir rigorously at 40 °C for 16-24 h. After cooling to ambient temperature, the resulting mixture was subjected to GC analysis to determine the regioisomeric ratio (r.r.) and then purified by silica gel chromatography. The purified product was subjected to HPLC analysis to determine the enantiomeric ratio (e.r.).

General procedure for enantioselective dicarbofunctionalization: In a l\12-filled glove box, an oven-dried 4 mL vial equipped with a stir bar was charged with Ni(cod)2 (0.1 equiv.), LI (0.1 equiv.), NaOtBu (0.2 equiv.) and toluene (0.5 mL). The reaction mixture was allowed to stir at r.t. for 1 h. Alkene substrate (1.0 equiv.) and aryl triflate (2.0 equiv.) were then added to the system. Aryl/alkenyl/alkyl metal reagent (3.0 equiv.) was slowly added into the system subsequently. The vial was sealed and the reaction mixture was allowed to stir at 40 °C for 8 h. After cooling to ambient temperature, the crude mixture was quenched by aqueous NH4CI, and the mixture was then subjected to GC analysis to determine the regioisomeric ratio (r.r.). The mixture was purified by silica gel chromatography, and the purified product was subjected to HPLC analysis to determine the enantiomeric ratio (e.r.).

of Solvent

Scope of Electrophile (first coupling partner)

65% yield 68% yield 42% yield

94:6 e.r. 94.5:5.5 e.r. 92:8 e.r.

(PhZnCI instead of PhMgBr)

Scope of nucleophile (second coupling partner)

Scope of monosubstituted unactivated alkenes

It will be appreciated that many further modifications and permutations of various aspects of the described embodiments are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of", and variations such as "consists essentially of" will be understood to indicate that the recited element(s) is/are essential i.e. necessary elements of the invention. The phrase allows for the presence of other non-recited elements which do not materially affect the characteristics of the invention but excludes additional unspecified elements which would affect the basic and novel characteristics of the method defined.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

- 46 - Claims

1. A method of functionalising an alkene to a tri- or tetrasubstituted stereocenter, comprising : reacting the alkene with a first coupling partner and a second coupling partner in the presence of a N-heterocyclic carbene-Ni(O) (NHC-Ni(O)) catalyst in order to form the tri- or tetrasubstituted stereocenter; wherein the alkene and first coupling partner undergo a carbonickelation step in the presence of the NHC-Ni(O) catalyst followed by a carbon-nickel bond transformation with the second coupling partner; and wherein the first coupling partner is coupled to a carbon on the alkene which is more sterically hindered.

2. The method according to claim 1, wherein the NHC-Ni(O) catalyst is generated in situ from a Ni(0) complex and an imidazolium or imidazolinium salt.

3. The method according to claim 2, wherein the imidazolium or imidazolinium salt is a compound of Formula (I):

wherein Ar is independently selected from aryl or heteroaryl;

L is independently a direct bond or optionally substituted alkylene; represents a single bond or a double bond; n is an integer selected from 0 to 5; m is an integer selected from 0 to 5; - 47 - p is an integer selected from 0 to 2; and

X- is a counterion.

4. The method according to claim 2 or 3, wherein the imidazolium salt is a

wherein Ar is independently selected from aryl or heteroaryl;

X- is a counterion.

5. The method according to claim 3 or 4, wherein the Ar is independently selected from 6 membered aryl or 6 membered heteroaryl.

6. The method according to any one of claims 3 to 5, wherein the imidazolium salt

X- is a counterion.

7. The method according to any one of claims 3 to 6, wherein Ri and/or R2 are independently optionally substituted alkyl. - 48 -

8. The method according to any one of claims 3 to 7, wherein Ri and/or R2 are independently is selected from methyl, ethyl, propyl, iso-propyl, phenylmethyl, phenylethyl, 2-phenylpropyl, 3-phenylpropyl, 1,1-diphenylmethyl, or a combination thereof.

9. The method according to any one of claims 3 to 8, wherein n is 3 and/or m is 3.

10. The method according to claim 3, wherein R3 is independently optionally substituted aryl, or optionally substituted heteroaryl.

11. The method according to claim 3 or 10, wherein p is 2.

12. The method according to any one of claims 3 to 11, wherein the compound of Formula (I) is:

13. The method according to any one of claims 2 to 12, wherein the Ni(0) complex is selected from bis(cyclooctadiene)nickel(0), tetrakis(triphenylphosphite)nickel(0), tetra kis(triphenylphosphine)nickel(0), bis(triphenyl phosph ine)dicarbonylnickel, bis(l,5-cyclooctadiene)(d uroquinone) nickel(O),

, or a combination thereof.

14. The method according to any one of claims 1 to 13, wherein the NHC-Ni(O) catalyst comprises a mono-substituted NHC.

15. The method according to any one of claims 1 to 14, wherein the first coupling partner is an electrophilic coupling partner and the second coupling partner is a nucleophilic coupling partner.

16. The method according to any one of claims 1 to 15, wherein the reaction step comprises a step of forming a first intermediate of Formula (Ila) or (lib):

wherein G is the first coupling partner; and Y is a counterion of the first coupling partner.

17. The method according to claim 16, wherein the reaction step comprises reacting the intermediate of Formula (Ila) with the first coupling partner or the intermediate of Formula (lib) with the alkene in order to form a second intermediate.

18. The method according to any one of claims 1 to 17, wherein the first coupling partner is derived from organotriflate, organohalide, orga nosulfonate, orga notosylate, organomesylate, or a combination thereof.

19. The method according to any one of claims 1 to 18, wherein the first coupling

20. The method according to any one of claims 1 to 19, wherein the first coupling partner is added at about 1 to about 6 molar equivalence relative to the alkene.

21. The method according to any one of claims 13 to 20, wherein the reaction step further comprises a step of reacting the second intermediate with the second coupling partner in order to form a third intermediate.

22. The method according to any one of claims 1 to 21, wherein the second coupling partner is derived from a hydride donor or organometallic reagent.

23. The method according to any one of claims 1 to 17, wherein the second coupling partner is derived from sodium isopropoxide, KOEt, NaOCH(Me)Ph, PhMgBr, or a combination thereof.

24. The method according to any one of claims 1 to 23, wherein the second coupling partner is added at about 1 to about 6 molar equivalence relative to the alkene.

25. The method according to any one of claims 1 to 24, wherein the second coupling partner is characterised by a concentration of at least 3 times relative to a concentration of the alkene. - 52 -

26. The method according to any one of claims 1 to 25, wherein the reaction further comprises a p-H elimination step or a carbon transfer step.

27. The method according to any one of claims 1 to 26, wherein the reaction further comprises a reductive elimination step.

28. The method according to any one of claims 1 to 27, wherein the alkene is selected from an acyclic terminal alkene or a cyclic internal alkene.

29. The method according to any one of claims 1 to 28, wherein the alkene is monosubsituted or 1,1-disubstituted with aryl, alkyl, alkenyl, amino, oxo, silyl, or a combination thereof.

30. The method according to any one of claims 1 to 29, wherein the alkene is characterised by an absence of a directing group.

31. The method according to any one of claims 1 to 30, wherein the reaction is performed in a non-polar solvent and/or under an inert atmosphere.

32. The method according to any one of claims 1 to 31, wherein the reaction is performed at about 30 °C to about 60 °C and/or for about 6 h to about 24 h.

33. The method according to any one of claims 1 to 32, wherein the reaction is performable in an absence of a glovebox.

34. The method according to any one of claims 1 to 33, wherein the reaction is stable to an oxygen concentration of less than about 100 ppm and/or a water concentration of less than about 100 ppm.

35. The method according to any one of claims 1 to 34, wherein the reaction is characterised by an efficiency of at least 60% and/or a regioselectivity of at least 90%.

36. The method according to any one of claims 1 to 35, wherein the method is characterised by an enantioselectivity of at least 70%.