Alkylation process

Abstract

A method includes reacting a carbonyl compound with an olefin compound in the presence of an iridium catalyst wherein the carbonyl compound comprises a nitrogen-based group at the alpha or beta position of the carbonyl group, and wherein the process comprises a step of alpha-alkylation of the carbonyl compound by forming a carbon-carbon bond between the carbon atom alpha of the carbonyl group and the carbon atom of the double bond of the olefin compound. The method allows the preparation of amino acid derivatives and other compounds. The method is flexible to produce compounds having a series of substituents, with a good level of steps and atom economy as well as selectivity.

Description

[0001] The present invention relates to the field of organic chemical synthesis, and more particularly to metal-catalyzed alkylation of carbonyl compounds. The present invention allows the preparation of amino acid derivatives and other compounds.

[0002] Amino acids are of great synthetic importance, underpinning substantial aspects of biochemistry, and serve as important building blocks for small molecule targets or chiral materials. One way of obtaining amino acids is via hydrogenation of dehydroaminoesters, and perhaps the best known commercial application of this technology is the production of L-DOPA, as disclosed in W. S. Knowles, J. Chem. Ed. 1986, 63 , 222-225. However, hydrogenation over a range of compounds is challenging. In particular, tetra-substituted olefins are difficult to obtain and to hydrogenate.

[0003] The present invention addresses the need to provide a method that has flexibility to produce compounds with a range of substituents, with good levels of step and atom economy and selectivity.

[0004] According to a first aspect, the present invention provides a method comprising reacting a carbonyl compound with an olefin compound in the presence of an iridium catalyst, wherein the carbonyl compound comprises a nitrogen-based group in the alpha or beta position of the carbonyl group, and wherein the method comprises the step of alpha-alkylating the carbonyl compound by forming a carbon-carbon bond between the carbon atom alpha of the carbonyl group and a carbon atom of the double bond of the olefin compound.

[0005] We have found that the above-mentioned nitrogen-based group (alpha or beta of the carbonyl group) in combination with an iridium catalyst can effectively facilitate the reaction. The nitrogen atom of the nitrogen-based group is in combination with the carbon atom in the alpha position or the carbon atom in the beta position. The nitrogen-based group can act as an effective linker group.

[0006] Due to the presence of the nitrogen-based group and the carbonyl group, the product is an amino acid derivative.

[0007] The term "amino acid derivative" generally denotes a compound having (i) an amino moiety or a moiety that can be considered to be derived from (e.g. structurally related to) an amino moiety (including a primary, secondary or tertiary amine); and (ii) an acid moiety (i.e. a carboxylic acid moiety) or a moiety that can be considered to be derived from (e.g. structurally related to) an acid moiety (including a moiety containing a carbonyl group, such as a ketone or an amide).

[0008] Naturally occurring a-amino acids and amino acid derivatives contain a nitrogen-bearing group and a carbonyl group attached to the same carbon atom. This architecture is achieved in the present invention when the nitrogen-bearing group is located a to the carbonyl group. It is also possible, according to the present invention, for the architecture in which the nitrogen-bearing group is b to the carbonyl group, in which case two carbon atoms rather than one separate the nitrogen-bearing group from the carbonyl group.

[0009] a-alkylation between the carbonyl group and the nitrogen-bearing group results in a side chain corresponding to the side chain position in naturally occurring amino acids. Typically, in the present invention, a-alkylation occurs in this way. This is in contrast to alkylation on the other side of the carbonyl group, which can be referred to as the a'-position.

[0010] The nitrogen-bearing group can optionally be a directing group. The nitrogen-bearing group can control the selectivity of the reaction. For aliphatic ketone systems, the nitrogen-bearing group ensures a-alkylation and prevents possible alkylation on the other side of the carbonyl group, which can be referred to as the a'-position. The nitrogen-bearing group can exert control over the diastereoselectivity of the reaction.

[0011] Optionally, the iridium catalyst can be a chiral iridium catalyst, which can be non-racemic or enantiomerically enriched or substantially enantiomerically pure, allowing for asymmetric catalysis.

[0012] The method of the present invention is broadly applicable to a range of carbonyl compounds and a range of olefin compounds. Optional substituents herein include substituents that are compatible with the alkylation reaction conditions and do not produce adverse interactions with these conditions.

[0013] The method of the present invention is not only surprisingly effective and versatile, but far from predictable, this method will work in practice. The method is a convergent method in which a new C-C bond and (typically) two stereocenters are established in a single operation. This is a catalytic method that allows for the direct a-alkylation of carbonyl compounds. This area has proven extremely challenging for systems lacking additional strongly acidic groups. Surprisingly, the combination of features of the method of the present invention results in effective alkylation. Without wishing to be bound by theory, it is possible that the nitrogen-bearing group triggers a metal-catalyzed "soft" enolization, which occurs en route to the enolate even in less acidic systems. The iridium catalyst can activate a relatively non-acidic pronucleophile and a non-polarized proelectrophile. This: (a) enables access to b-substituted a-amino acids; (b) provides a unique directing group-based approach to the direct stereocontrolled a-alkylation of carbonyl compounds; and (c) provides a more extensive framework for the unproductive installation of consecutive tertiary stereocenters. This enables enantiomeric and diastereomeric selective reactions when chiral catalysts are used.

[0014] One suitable class of carbonyl compounds includes those in which the carbonyl group is part of an amide (e.g., a primary amide, a secondary amide, or a tertiary amide). For example, we find that the present invention works particularly well with tertiary amides, and we present a number of examples of these herein. The amide can optionally be substituted. In the case where the amide is a tertiary amide, the two groups on the nitrogen atom can be separate groups, or can together form a ring, e.g., a pyrrolidine ring, a piperidine ring, or a morpholine ring.

[0015] Another suitable class of carbonyl compounds includes ketones in which an aliphatic or aromatic (which can include a heteroaromatic) group is attached to the carbonyl group on the other side of the ketone relative to the side that carries the nitrogen-bearing group. The aliphatic group can include a saturated or unsaturated, straight chain or branched chain, substituted or unsubstituted alkyl chain, optionally having 1 to 20 carbon atoms, optionally 1 to 10 carbon atoms, optionally 1 to 5 carbon atoms. The aromatic group can include a substituted or unsubstituted aromatic or heteroaromatic group, optionally having up to 20 carbon atoms, optionally up to 10 carbon atoms.

[0016] The carbon atom to which the nitrogen-bearing group is attached (i.e., the alpha carbon or the beta carbon) can be unsubstituted (i.e., can carry two hydrogen atoms), or can carry one other substituent and a hydrogen atom.

[0017] One suitable type of nitrogen-bearing group includes an amine, e.g., a secondary amine, e.g., an aromatic secondary amine. These can have the structure -NHAr, where Ar can be an aromatic group (e.g., a phenyl group), which can optionally be substituted.

[0018] Olefinic compounds contain a carbon-carbon double bond, which can optionally be mono-, di-, tri-, or tetra-substituted, or unsubstituted, i.e., each carbon atom of the double bond can carry up to two moieties. The present invention is most suitable for olefinic compounds containing a carbon-carbon double bond that is mono-, di-, or tri-substituted, or unsubstituted, particularly olefinic compounds containing a carbon-carbon double bond that is mono- or di-substituted, or unsubstituted. One suitable class of olefinic compounds includes mono-substituted olefinic compounds, i.e., where one carbon atom of the double bond carries a moiety and a hydrogen atom, and the other carbon atom of the double bond carries two hydrogen atoms: in this case, we typically observe regioselectivity in favor of branched-chain products over straight-chain products, i.e., the substituted carbon atom of the double bond forms the carbon-carbon bond. Further substitution arrangements are possible: for example, another suitable class of olefinic compounds includes olefinic compounds in which one carbon atom of the double bond is di-substituted, and in which the other carbon atom of the double bond carries two hydrogen atoms (i.e., 1,1-disubstituted olefins); and another suitable class of olefinic compounds includes olefinic compounds in which one carbon atom of the double bond is mono-substituted and in which the other carbon atom of the double bond is also mono-substituted (i.e., 1,2-disubstituted olefins).

[0019] It will be appreciated that the chemical structure of the moiety carried by the olefinic compound is not particularly limited, provided that the moiety is compatible with the alkylating reaction conditions. Indeed, one advantage of the present application is that it allows a wide range of side chains, including side chains of complex structure, to be introduced into amino acid derivatives.

[0020] One possible process according to the present application is a process comprising reacting a compound of formula I with a compound of formula II in the presence of an iridium catalyst and a chiral (e.g. non-racemic, e.g. enantiomerically enriched) phosphine ligand to form a compound of formula III:

[0021]

[0022] wherein:

[0023] n is 0 or 1 ; and

[0024] R 1 to R 10 each independently is any suitable group.

[0025] By "suitable group" is meant any group that is compatible with the reaction of the compound of formula I with the compound of formula II to form the compound of formula III. This is an alkylation reaction in which a bond is formed between the a-carbon atom of the compound of formula I and one of the carbon atoms of the double bond of the compound of formula II, and synthetic organic chemists know or can readily determine which groups are suitable in each of the R 1 to R 10 positions.

[0026] Typically, the R 1 to R 10 in the starting materials (i.e. in I and II) remain unchanged in the product (i.e. in III). However, in some cases, one or more of the R 1 to R 10 may change in the product.

[0027] Optionally, R 1 may be NR 11 R 12 wherein R 11 and R 12 are independently selected from: saturated or unsaturated, straight chain or branched, unsubstituted or substituted alkyl or heteroalkyl; unsubstituted or substituted aryl or heteroaryl; or H; or R 11 and R 12 may together form a ring. Optionally, in this position, primary amides can be excluded from the definition of the present application, i.e. the proviso (R 11 and R 12 cannot both be H) can apply.

[0028] Optionally, R 1 may be selected from saturated or unsaturated, straight-chain or branched, unsubstituted or substituted alkyl or heteroalkyl; unsubstituted or substituted aryl or heteroaryl.

[0029] Each "alkyl" or "heteroalkyl" group can optionally have 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 or 2 carbon atoms, or 1 carbon atom (i.e., in some cases can be a methyl group).

[0030] Each "aryl" or "heteroaryl" group can comprise a monocyclic or fused ring with or without heteroatoms, and optionally can have up to 20 carbon atoms, or up to 10 carbon atoms or up to 6 carbon atoms, e.g., in some cases can be a phenyl group. Possible "aryl" types include metallocenes.

[0031] where R 1 is NR 11 R 12 , and where R 11 and R 12 together form a ring, optionally, NR 11 R 12 The (including the nitrogen atom) can be a 3-, 4-, 5-, 6-, 7- or 8-membered ring, or can comprise such a ring optionally fused or bonded to one or more other rings.

[0032] The term "substituted" means that any suitable substituent can be present. Thus, for example, an alkyl or heteroalkyl group can be substituted by virtue of bearing an aryl or heteroaryl group, or vice versa. The term "substituted" also means that a linking group (e.g., an ester, ether and amide) can be present, and multiple moieties can be present in the substituents. Non-limiting examples of possible substituents and linking groups include alkyl, heteroalkyl, aryl, heteroaryl, halide, ether, ester and amide.

[0033] R 1 may be, for example, N(CH3)2, NHCH3, N(CH2CH3)2, NHPh, pyrrolidine, piperidine, morpholine, CH3, t-butyl or phenyl.

[0034] Optionally, R 2 may be: unsubstituted or substituted aryl or heteroaryl; saturated or unsaturated, straight-chain or branched, unsubstituted or substituted alkyl or heteroalkyl; or H.

[0035] In R 2In R2, "aryl" or "heteroaryl" can comprise a monocyclic or fused ring with or without heteroatoms, and optionally can have up to 20 carbon atoms, or up to 10 carbon atoms or up to 6 carbon atoms, e.g., in some cases, can be phenyl. R2may be or can comprise a metallocene moiety. "Alkyl" or "heteroalkyl" can optionally have 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 or 2 carbon atoms, or 1 carbon atom (i.e., in some cases can be methyl). The term "substituted" indicates that any suitable substituent can be present. Thus, for example, an alkyl or heteroalkyl group can be substituted by virtue of bearing an aryl or heteroaryl group, or vice versa. The term "substituted" also indicates that linking groups (e.g., ester, ether, and amide) can be present, and multiple moieties can be present in the substituents. Non-limiting examples of possible substituents and linking groups include alkyl, heteroalkyl, aryl, heteroaryl, halide, ether, ester, and amide.

[0036] R 2 may, for example, be an aromatic or heteroaromatic moiety (e.g., phenyl), which can optionally bear additional substituents.

[0037] R 3 may be: unsubstituted or substituted aryl or heteroaryl; or saturated or unsaturated, straight chain or branched, unsubstituted or substituted alkyl or heteroalkyl.

[0038] In R 3 , "aryl" or "heteroaryl" can comprise a monocyclic or fused ring with or without heteroatoms, and optionally can have up to 20 carbon atoms, or up to 10 carbon atoms or up to 6 carbon atoms, e.g., in some cases, can be phenyl. R 3 may be or can comprise a metallocene moiety. "Alkyl" or "heteroalkyl" can optionally have 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 or 2 carbon atoms, or 1 carbon atom (i.e., in some cases can be methyl). The term "substituted" indicates that any suitable substituent can be present. Thus, for example, an alkyl or heteroalkyl group can be substituted by virtue of bearing an aryl or heteroaryl group, or vice versa. The term "substituted" also indicates that linking groups (e.g., ester, ether, and amide) can be present, and multiple moieties can be present in the substituents. Non-limiting examples of possible substituents and linking groups include alkyl, heteroalkyl, aryl, heteroaryl, halide, ether, ester, and amide.

[0039] R 4 may be independently selected from the groups designated herein for R 3 , or can be H. R 3 and R4 may form a ring together. An important subset of the present invention is where R 4 is H.

[0040] R 3 may, for example, be phenyl or substituted phenyl. R 4 may, for example, be H.

[0041] When R 3 is substituted phenyl, possible non-limiting examples of the substituents include hydroxyl, methoxy, methyl, fluoro, chloro, trifluoromethyl, or two or more of these. One of the substituents may, for example, be located at the para position.

[0042] R 5 , R 9 , and R 10 may each be independently selected from the groups designated herein for R 2 . R 5 may, for example, be H or methyl. R 9 and R 10 may, for example, be H.

[0043] Optionally, R 6 , R 7 , and R 8 may each be independently selected from: saturated or unsaturated, straight chain or branched, unsubstituted or substituted alkyl or heteroalkyl; unsubstituted or substituted aryl or heteroaryl; or H. Each "alkyl" or "heteroalkyl" group may, optionally, have 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or 1 or 2 carbon atoms, or 1 carbon atom (i.e., in some cases can be methyl). Each "aryl" or "heteroaryl" group may, optionally, comprise a monocyclic or fused ring with or without heteroatoms, and may, optionally, have up to 20 carbon atoms, or up to 10 carbon atoms or up to 6 carbon atoms, e.g., in some cases can be phenyl. Possible "aryl" types include metallocenes.

[0044] R 6 , R 7 , and R8may each be H.

[0045] The above definitions of possible moieties, groups, and substituents represent only some possibilities. Alternatively or additionally, other moieties, groups, or substituents can be used, so long as these are compatible with the compound of formula I reacting with the compound of formula II to form the compound of formula III.

[0046] For example, R 2Other possibilities include boron-containing groups, including boronic acids or esters, or boronate esters. These can optionally include or be attached to alkyl or heteroalkyl groups as described above, can optionally include or be attached to aryl or heteroaryl groups, can be saturated or contain unsaturation, and / or can be unsubstituted or substituted, as defined above, including the possibility that linking groups can optionally be present and multiple moieties can optionally be present in substituents. One example of a boron-containing group is pinacolborane ("BPin").

[0047] Thus, optionally, R 2 may be: unsubstituted or substituted aryl or heteroaryl; saturated or unsaturated, straight-chain or branched, unsubstituted or substituted alkyl or heteroalkyl; H; or a boron-containing group. R 5 may be, for example, H or methyl. R 9 and R 10 may each be, for example, H. 2 Each of R 5 may be, for example, H or methyl. R 9 and R 10 may each be, for example, H.

[0048] It is possible that the olefin compound is substituted on only one of the two carbon atoms of the double bond, i.e., R 9 and R 10 are both H. In this case, the structural formula can be as follows:

[0049]

[0050] The above representation of Formula III assumes that the alpha-carbon atom of the carbonyl compound forms a bond with the multiply substituted carbon atom of the double bond, resulting in a branched compound having a methyl and R 2 and R 5 groups carried by the carbon atom in product III. Alternatively, in some cases, the reaction can occur by forming a bond with the CH2group of the double bond, resulting in a less branched (or linear, if one of R 2 and R 5 is H). We find that, generally, the reaction exhibits selectivity in favor of the more branched product as described above, rather than the less branched or linear isomer.

[0051] It is possible that n is 0, in which case the structural formula is as follows. In this case, the nitrogen-based group is on the alpha carbon.

[0052]

[0053] It is possible that both n are 0, and the olefin compound is substituted on only one of the two carbon atoms of the double bond, i.e., R 9 and R10 are H. In this case, the structure can be as follows:

[0054]

[0055] It is possible that the nitrogen-based group is a secondary amine, i.e. R 4 may be H.

[0056] It is possible that the olefin compound has only one substituent, i.e. not only R 9 and R 10 but also R 5 may be H.

[0057] It is possible that the carbonyl compound is not substituted at the alpha position in addition to the nitrogen-based group, i.e. R 6 may be H.

[0058] These possibilities can be combined, so for example the method can be performed according to the following structure:

[0059]

[0060] One of the advantages of the present invention is that it provides access to molecules that are otherwise difficult to synthesize. The present invention allows the preparation of many types of amino acid derivatives, since the coupling step tolerates a wide range of chemical structures and functional groups in the starting materials (I and II). If desired, either or both of the starting materials (I and II) can have complex structures. In particular, it should be noted that the alkylation coupling step adds an amino acid side chain, so the present invention allows this to be customized simply by choosing a suitable olefin compound II.

[0061] The alkylation process at the alpha carbon atom of the carbonyl compound forms a chiral center on that carbon atom.

[0062] The method can be regioselective, favoring the formation of a bond to the carbon atom of the double bond of the olefin compound carrying R 2 . In the case where R 5 , R 9 and R 10 are H, this results in a branched structure, referred to herein as “B”. The alternative product is a linear product, referred to herein as “L”. The ratio of B to L formed in the reaction (“B:L”) can optionally be >10:1 or >20:1 or >30:1.

[0063] In the case where R 5 , R 9 and R 10 are H, the branched product contains a chiral center at the carbon atom carrying R 2 , but the linear product does not have a chiral center at that position.

[0064] Thus, when the reaction product is a branched product, two adjacent chiral centers are formed.

[0065] The iridium catalyst can optionally be a chiral iridium catalyst. This can lead to some degree of regioselectivity, enantioselectivity and / or diastereoselectivity. We have observed that the branching selectivity is combined with enantioselectivity and diastereoselectivity.

[0066] Optionally, the reaction can be diastereoselective, resulting in a diastereomeric ratio of 2:1 or more, or 3:1 or more, or 4:1 or more, or 5:1 or more, or 6:1 or more, or 7:1 or more, or 8:1 or more, or 9:1 or more, or 10:1 or more, or 15:1 or more, or 20:1 or more.

[0067] Optionally, the reaction can be enantioselective, resulting in an enantiomeric ratio of 70:30 or more, or 75:25 or more, or 80:20 or more, or 85:15 or more, or 90:10 or more, or 95:5 or more, or 96:4 or more, or 97:3 or more, or 98:2 or more.

[0068] Without wishing to be bound by theory, it is hypothesized that the nitrogen-based directing group (of the carbonyl compound) and the chiral iridium catalyst facilitate enolization via an initial NH metallation, and the resulting stereochemically defined enolate binds to the olefin in a selective orientation. Without wishing to be bound by theory, it is possible that the process proceeds via a sequence of olefin carbon metallation and C-H reductive elimination.

[0069] Compound I is particularly well configured to form an enolate with the chiral Ir catalyst formed. Without wishing to be bound by theory, it is believed that the adjacent directing groups link to the chiral Ir-based system. The coordination of the carbonyl unit in Compound I is such that it facilitates enolization prior to bond formation events. The cyclic nature of the enolate chelate automatically controls the geometry of the enolate, which in turn can control selectivity, the presence of the redox active Ir center provides many possibilities for the C-C bond formation step with the reaction partner compound II.

[0070] R 1 to R 10 The large number of possible structures for the R

[0071] If an asymmetric reaction is desired, then the iridium catalyst is suitably an iridium species with a chiral ligand, which is non-racemic or enantiomerically enriched. This can be prepared in situ from an iridium compound and a chiral ligand. The iridium compound can comprise a cyclooctadiene (cod) ligand or other ligand, such as 2 cod ligands, coordinated to the iridium centre. The iridium species can be an iridium (I) species. A range of counterions can be used for the cationic iridium (I): these include, for example, tetra[3,5-bis(trifluoromethyl)phenyl]borate (BARF), tetrafluoroborate (BF 4 ), triflate (OTf), chloride (CI) or methoxide (OMe), and the like. Examples of suitable iridium compounds are: Ir(cod)2BARF; Ir(cod)2BF4; Ir(cod)2OTf; [Ir(cod)CI]2; and [Ir(cod)OMe]2.

[0072] The iridium catalyst can be an iridium source, which can be combined with a chiral or achiral ligand in situ or non-in situ to form a suitable iridium species.

[0073] Suitable ligands include phosphine (e.g. diphosphine) ligands. Phosphine-modified iridium systems (e.g. diphosphine-modified cationic iridium (I) systems) are Lewis acidic, and this is beneficial in facilitating the reaction. Other Lewis acidic systems can be used.

[0074] The iridium species can be combined with a chiral ligand which is a phosphine ligand. The phosphine ligand can be a diphosphine ligand. The chiral ligand can replace other ligands on the iridium centre. Some examples of suitable chiral phosphine ligands are: R )-BINAP; ( R )-Xyl-BINAP; ( tol )-BINAP; ( R )-DM-BINAP; ( R )-H8-BINAP; ( R )-SEGPHOS; ( R )-DM-SEGPHOS; ( R )-DTBM-SEGPHOS; ( R )-MeOBIPHEP; and ( R )-SDP. Other chiral phosphine ligands can be used. The chiral phosphine ligand can be monodentate or bidentate.

[0075]

[0076] The reagents and catalytic systems are compatible with a range of solvents. Some solvents that have been used include: toluene; 1,4-dioxane; THF; PhCI; PhCF3; t t-BuOH; or 1,2-DCP.

[0077] Some possible reaction conditions will now be described.

[0078] The process can be conducted under inert gas conditions, for example under nitrogen or argon. Suitable apparatus for this purpose include Schlenk tubes or other apparatus that allow the vessel to be evacuated or filled with inert gas. Optionally, the gaseous environment in the reaction vessel can be at least 99 volume %, or at least 99.5 volume %, or at least 99.9 volume % inert gas.

[0079] The process can be conducted under anhydrous conditions using an anhydrous solvent. Optionally, the water present in the solvent can be less than 1 volume %, or less than 0.5 volume %, or less than 0.1 volume %, or less than 0.01 volume %.

[0080] The amount of solvent used can vary. The molar concentration of the carbonyl compound (compound I) can be 0.01-10 M, or 0.05-5 M, or 0.1-2 M, or 0.1 M-1 M or about 0.5 M.

[0081] The relative molar amounts of the carbonyl compound (I) and the olefin compound (II) used as reagents can vary. Optionally, 1-10 equivalents, or 1-6 equivalents, or 1.5-6 equivalents, or 1.5-3 equivalents, or 1.5-2.5 equivalents, or about 2 equivalents of the olefin compound (II) are used relative to the carbonyl compound (I).

[0082] The reaction can be conducted at an appropriate temperature for an appropriate time to effect an appropriate conversion. Optionally, the reaction temperature can be room temperature (e.g., about 20 to 25 degrees Celsius), or higher, for example room temperature (e.g., about 20 to 24 degrees Celsius) to 300 degrees Celsius, or in the range of 30-300, or 40-300, or 50-300, or 60-300, or 70-300, or 80-250, or 80-200, or 100-200, or 100-150, or 105-140, or 110-130, or about 130 degrees Celsius. Optionally, the reaction time can be 3 hours to 4 days, or 12 hours to 4 days, or 1 to 4 days, or 2 to 4 days, or about 3 days.

[0083] A suitable amount of iridium catalyst can be used. These include, for example, 0.01-10 mol%, or 0.05-10 mol%, or 0.1-10 mol%, or 0.1-8 mol%, or 1-7 mol%, or 1-6 mol%, or 2-6 mol%, or 3-6 mol%, or 4-6 mol%, or about 5 mol%. A corresponding amount of chiral ligand can be used, for example, 0.1-10 mol%, or 0.1-8 mol%, or 1-7 mol%, or 1-6 mol%, or 2-6 mol%, or 3-6 mol%, or 4-6 mol%, or about 5 mol%.

[0084] The method can comprise charging a vessel (e.g. under inert gas conditions) with the carbonyl compound, the iridium compound and the chiral ligand, subsequently charging the vessel (e.g. under inert gas conditions) with the olefin compound and the (e.g. anhydrous) solvent, and allowing the reaction to proceed, optionally at elevated temperature, for the desired period of time (e.g. under inert gas conditions). Depending on the physical properties of the reagents and the experimental set-up, an alternative order of addition can be used as convenient. The product can then be isolated and purified by conventional techniques (e.g. under air), for example by allowing the reaction mixture to cool to room temperature, removing the solvent under reduced pressure, and using chromatographic or crystallisation techniques.

[0085] According to a further aspect, the present application provides products as described herein, including compounds that are products of the methods of the present application and compounds prepared by derivatisation steps.

[0086] BRIEF DESCRIPTION OF DRAWINGS

[0087] Non-limiting examples according to the present application will now be described in further detail with reference to the following drawings in which:

[0088] Figure 1 Reaction schemes and comparative theoretical alternative methods according to certain embodiments of the present application are shown;

[0089] Figure 2 and Figure 3 Some compounds synthesised by using the methods of the present application are shown; and

[0090] Figure 4 and Figure 5 Some examples of applications and derivatisation facilitated by the present application are shown.

[0091] General experimental details

[0092] All reagents requiring purification were purified using standard laboratory techniques, following the method published by Armarego and Perrin (Pergamon Press, 1966). The catalytic reaction was carried out in Young-type reusable sealed tubes. Styrene and other commercially available olefins (liquid) were rapidly distilled using a Hickman distillation head before use. All other commercially available olefins (solid) were received as is and used without further purification. The procedure was followed as previously reported. 1,2 Synthetic iridium catalyst. Anhydrous THF, toluene, and CH2Cl2 were obtained, respectively, by drying columns supplied by Anhydrous Engineering Ltd or purchased from commercial sources (Acros or Aldrich). Anhydrous 1,4-dioxane, DMF, DMA, DMSO, and CH3CN were purchased in anhydrous grade and stored on activated 4Å molecular sieves before use. Unless otherwise specified, all reactions were carried out using anhydrous solvents. Triethylamine (TEA) was distilled over CaH2 and stored under nitrogen on activated 4Å molecular sieves. Rapid column chromatography (FCC) was performed using silica gel (Aldrich 40–63 µm, 230–400 mesh). Aluminum-backed 60 F... 254 Thin-layer chromatography was performed using silica plates. Visualization was achieved via UV fluorescence or alkaline KMnO4 solution and heating. Proton nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 500 MHz as described. Recording was also performed at 125 MHz as described. 13 C10 NMR spectra. Chemical shifts (δ) are given in parts per million (ppm). Peaks are described as singlets (s), doublets (d), triplets (t), quadruplets (q), sevents (sept), multiplets (m), and broad peaks (br.). Coupling constants ( J Reported as the closest 0.5 Hz. When compounds are separated into mixtures of diastereomers, they are referred to as a (major) and b (minor). In-situ yields were determined using 1,3,5-trimethoxybenzene as an internal standard. High-resolution mass spectra were determined by the University of Liverpool Mass Spectrometry Service and given to four decimal places. Mass spectra were recorded on an Agilent 7200 Accurate Mass QTOF GC / MS (under chemical ionization-CI conditions) and an Agilent 6540 UHD Accurate Mass Q-TOF LC / MS (under electrospray ionization-ESI conditions). Infrared spectra were recorded on a Perkin Elmer Spectrum Two FTIR spectrometer based on the thin film or solid compressed onto a diamond plate. Melting points were determined using a Reichert melting point apparatus without correction. At the stated concentrations and temperatures, an ADP440 was used. +Optical rotation was measured using a polarimeter. Enantiomeric excess was determined using an Agilent 1290 Infinity chiral SFC, as described for each compound.

[0093] Experimental procedures and data

[0094] The following table shows the results for the first series of reactions, where R 1 It is NMe2, R 2 It's Ph, R 3 It's Ph, R 4 To R 10 It is H, and n is zero.

[0095]

[0096] The iridium catalyst was found to be surprisingly effective. The row where the catalyst is a rhodium catalyst is not an example of the present invention, but is provided as a comparative example.

[0097] The above shows that a high yield is reasonable. It should be noted that these improvements are still needed, and even higher yields are expected to be achieved.

[0098] The table above also shows that high enantioselectivity and diastereoselectivity can be achieved.

[0099] Figure 1 The reaction scheme is shown, wherein only some functional groups are shown for clarity. Amino acid derivatives obtainable by the method of the present invention (shown in...) Figure 1 (within the box) Theoretically, this can be achieved through an alternative route (i.e., hydrogenation of unsaturated compounds). Figure 1 The preparation of the right side) is disadvantageous in terms of obtaining starting materials and process efficiency, and has poor compatibility with the preparation of complex structures.

[0100] Figure 2 and Figure 3 Examples of the chemical structures of the products of the method of the present invention are shown, along with data on yield, enantiomeric ratio, diastereomeric ratio, and branched:linear (B:L) ratio. Experimental details of the synthesis and characterization of these products are provided below, but in summary, the conditions are as follows:

[0101]

[0102] Make the following changes: Use a R-3,5-( t -Bu)2-8H-BINAP serves as a ligand. b The reaction temperature is 90℃. c use R -DTBM-SEGPHOS as a ligand. dThe reaction temperature was 90°C. e The reaction time was 22 hours. f The reaction temperature was 140°C, and the amide starting material was recovered in 35% yield. g In mesitylene at 110°C using an olefin (1000 mol%), R - DM-SEGPHOS (10 mol%) and [Ir(cod)2]BARF (10 mol%). h In mesitylene at 110°C using an olefin (1000 mol%), R - BINAP (10 mol%) and [Ir(cod)2]BARF (10 mol%); the minor diastereomer was formed in 71 :29 e.r.

[0103] Figure 2 and Figure 3 Examples of the R 1 , R 2 , and R 3 groups are shown, as are examples of compounds where n is 0 and examples of compounds where n is 1. In these figures, R 5 through R 10 each is H. However, although not shown in Figure 2 and Figure 3 , many other variations are possible within the scope of the invention. For example, the olefin compound can be ethylene (i.e., R 2 , R 5 , R 9 , and R 10 each can be H), or there can be multiple substituents on the olefin compound (e.g., at R 2 and R 5 ). Examples of these are as follows:

[0104]

[0105]

[0106] BPin = pinacolato boron

[0107] Experimental details are provided below for additional compounds, including where R 1 is morpholinyl, R 2 is meta-chlorophenyl, and R 3 is para-hydroxyphenyl.

[0108] Some examples of applications and derivatizations according to the invention are illustrated in Figure 4 and Figure 5 . Figure 4Part A shows an example of alkylating an olefin using a complex structure derived from indomethacin. Parts B, C, and D show some examples (among many possibilities) of derivatization reactions and how these provide access to other chemical substances. Additional details are provided below, but in summary, the conditions used herein are as follows: a LiAlH4 (200 mol%), THF, 0 o C, 20 min then NaBH4 (400 mol%), MeOH, 0 o C to room temperature (r.t.), 1 h. b LiAlH4 (200 mol%), THF, 0 o C, 20 min. c BH3 THF (500 mol%), THF, 90 o C, 4 h. d PhLi (200 mol%), THF, 0 o C, 15 min. e H2SO4 / AcOH / H2O (1:3:1), 120 o C, 72 h. f CAN (150 mol%), MeCH / H2O, 0 o C, 1 h. g HCl / AcOH, 130 o C, 48 h. h LiAlH4 (220 mol%), THF, 70 o C, 11 h. i Iodobenzene (120 mol%), NaOH, (200 mol%), CuI (5 mol%), DMSO / H2O, 90 o C, 12 h. CAN = Ce(NH4)2(NO3)6.

[0109] Other possible derivatizations include reaction of boron-containing compounds (illustrated in Example 25t) in cross-coupling reactions or oxidation to alcohols.

[0110] Substrate synthesis

[0111] General procedure A for amide 1a-1o synthesis:

[0112] Amides 1a-1o were synthesized according to a modified procedure. 3

[0113]

[0114] An oven-dried round-bottomed flask was charged with aniline (1.00 mmol, 100 mol%), TEA (0.21 mL, 1.50 mmol, 150 mol%) and anhydrous DMF (5.0 mL). Then a-bromoamide (1.20 mmol, 120 mol%) in anhydrous DMF (5.0 mL) was added dropwise at r.t. over 5 min. After the addition was complete, the reaction mixture was stirred at r.t. for 1-2 h and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was transferred to a separatory funnel and brine (~20.0 mL) was added. The aqueous phase was extracted with EtOAc (~3 x 5.0 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC under the conditions indicated.

[0115] N,N - dimethyl-2-(phenylamino)acetamide (1a):

[0116]

[0117] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound (116 mg, 65%) as a colorless solid. 1 H NMR (500 MHz, CDCl3) δ 7.21 – 7.18 (m, 2H, H 5 ), 6.73 –6.71 (m, 1H, H 6 ), 6.63 (d, J = 7.5 Hz, 2H, H 4 ), 4.91 (br s, 1H, H 3 ), 3.85 (s,2H, H 2 ), 3.03 – 3.02 (m, 6H, H 1 ).

[0118] The spectral characteristics are consistent with the data available in the literature. 4

[0119] N - methyl-2-(phenylamino)acetamide (1b):

[0120]

[0121] General procedure A: The reaction mixture was stirred at 70 °C for 19 h using the corresponding a-chloroamide (129 mg, 1.20 mmol, 120 mol%). Purification by column chromatography (hexane / EtOAc, 35:65) afforded the title compound as a light yellow solid (83.7 mg, 51%). 1 H NMR (500 MHz, CDC13) δ 7.23 - 7.20 (m, 2H, H 6 ), 6.83 - 6.80 (m, 1H, H 7 ), 6.75 (br s, 1H, H 2 ), 6.61 (d, J = 8.5 Hz, 2H, H 5 ), 4.26 (br s, 1H, H 4 ), 3.79 (s, 2H, H 3 ), 2.82 (d, J = 5.0 Hz, 3H, H 1 ).

[0122] The spectral characteristics are consistent with the data available in the literature. 5

[0123] N,N - diethyl-2-(phenylamino)acetamide (lc):

[0124]

[0125] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound as a colorless solid (144 mg, 70%). 1 H NMR (500 MHz, CDC13) δ 7.22 - 7.19 (m, 2H, H 6 ), 6.76 - 6.73 (m, 1H, H 7 ), 6.68 - 6.66 (m, 2H, H 5 ), 5.30 (br s, 1H, H 4 ), 3.88 (s, 2H,H 3 ), 3.46 (q, J = 7.0 Hz, 2H, H 2 ), 3.32 (q, J = 7.0 Hz, 2H, H 2’ ), 1.24 (t, J= 7.0 Hz, 3H, H 1 ), 1.17 (t, J = 7.0 Hz, 3H, H 1’ )。

[0126] The spectral characteristics are consistent with the data available in the literature. 6

[0127] 2-(phenylamino)-1-(pyrrolidin-1-yl)ethan-1-one (1d):

[0128]

[0129] General procedure A: Purification by column chromatography (hexane / EtOAc, 65:35) afforded the title compound as a yellow solid (120 mg, 59%). 1 H NMR (500 MHz, CDCl3) δ 7.20 – 7.17 (m, 2H, H 6 ), 6.73– 6.70 (m, 1H, H 7 ), 6.63 (d, J = 7.5 Hz, 2H, H 5 ), 4.63 (br s, 1H, H 4 ), 3.79(s, 2H, H 3 ), 3.54 (t, J = 7.0 Hz, 2H, H 2 ), 3.41 (t, J = 7.0 Hz, 2H, H 2’ ), 2.03– 1.98 (m, 2H, H 1 ), 1.91 – 1.86 (m, 2H, H 1’ )。

[0130] The spectral characteristics are consistent with the data available in the literature. 4

[0131] 2-(phenylamino)-1-(pyrrolidin-1-yl)ethan-1-one (1d):

[0132]

[0133] General procedure A: Purification by column chromatography (hexane / EtOAc, 65:35) afforded the title compound as a yellow solid (120 mg, 59%). 1H NMR (500 MHz, CDCl3) δ 7.21 – 7.17 (m, 2H, H 7 ), 6.73 – 6.70 (m, 1H, H) 8 ), 6.63 (d, J = 7.5 Hz, 2H, H 6 ), 4.97 (br s, 1H, H 5 ),3.86 (s, 2H, H 4 ), 3.62 (t, J = 5.5 Hz, 2H, H 3 ), 3.37 (t, J = 5.5 Hz, 2H, H 3’ ), 1.71 – 1.66 (m, 2H, H) 2 ), 1.63 – 1.56 (m, 4H, H 1 + H 2’ ).

[0134] The spectral characteristics are consistent with the data available in the literature. 4

[0135] 1-Morphyrin-2-(phenylamino)ethyl-1-one (1f):

[0136]

[0137] General Procedure A: Purification was performed by column chromatography (hexane / EtOAc, 50:50) to obtain the title compound as a pale yellow solid (123 mg, 56%). 1 H NMR (500 MHz, CDCl3) δ 7.21 – 7.18 (m, 2H, H 6 ), 6.75–6.72 (m, 1H, H) 7 ), 6.63 (d, J = 8.0 Hz, 2H, H 5 ), 4.82 (br s, 1H, H 4 ), 3.86(s, 2H, H 3 ), 3.71 – 3.67 (m, 6H, H 1 + H 2 ), 3.45 – 3.43 (m, 2H, H 2’ ).

[0138] The spectral characteristics are consistent with the data available in the literature.4

[0139] 2-((4-ethoxyphenyl)amino)- N,N dimethylacetamide (1g):

[0140]

[0141] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound as a yellow solid (118 mg, 61%). 1 H NMR (500 MHz, CDC13) δ 6.72 (d, J = 9.0 Hz, 2H, H 5 ), 6.56 (d, J = 9.0 Hz, 2H, H 4 ), 4.52 (br s, 1H, H 3 ), 3.83 (s, 2H, H 2 ), 3.03 (s, 6H, H 1 ).

[0142] The spectral characteristics are consistent with the data available in the literature. 7

[0143] 2-((4-ethoxyphenyl)amino)- N,N dimethylacetamide (1h):

[0144]

[0145] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound as a yellow solid (118 mg, 61%). 1 H NMR (500 MHz, CDC13) δ 6.79 (d, J = 9.0 Hz, 2H, H 5 ), 6.60 (d, J = 9.0 Hz, 2H, H 4 ), 4.58 (br s, 1H, H 3 ), 3.82 (s, 2H, H 2 ), 3.74 (s, 3H, H 6 ), 3.01 (s, 6H, H 1 ).

[0146] The spectral characteristics are consistent with the data available in the literature. 8

[0147] N,N - dimethyl-2-(p-tolylamino)acetamide (1i):

[0148]

[0149] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound (131 mg, 68%) as a colorless solid. 1 H NMR (500 MHz, CDCl3) δ 7.00 (d, J = 8.0 Hz, 2H, H 5 ),6.57 (d, J = 8.0 Hz, 2H, H 4 ), 4.57 (br s, 1H, H 3 ), 3.84 (s, 2H, H 2 ), 3.02 (s,6H, H 1 ), 2.24 (s, 3H, H 6 ).

[0150] The spectral characteristics are consistent with the data available in the literature. 9

[0151] 2-((4-Fluorophenyl)amino)- N,N dimethylacetamide (1j):

[0152]

[0153] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound (131 mg, 68%) as a colorless solid. 1 H NMR (500 MHz, CDCl3) δ 6.91 – 6.87 (m, 2H, H 5 ), 6.57 –6.54 (m, 2H, H 4 ), 4.72 (br s, 1H, H 3 ), 3.81 (s, 2H, H 2 ), 3.02 (s, 6H, H 1 ).

[0154] The spectral characteristics are consistent with the data available in the literature. 9

[0155] 2-((4-Chlorophenyl)amino)- N,NDimethylacetamide (1k):

[0156]

[0157] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound (160 mg, 75%) as a colorless solid. 1 H NMR (500 MHz, CDC13) δ 7.12 (d, J = 8.5 Hz, 2H, H 5 ), 6.54 (d, J = 8.5 Hz, 2H, H 4 ), 4.90 (br s, 1H, H 3 ), 3.81 (s, 2H, H 2 ), 3.02 (s, 6H, H 1 ).

[0158] The spectral characteristics are consistent with the data available in the literature. 9

[0159] N,N Dimethyl-2-((4-(trifluoromethyl)phenyl)amino)acetamide (11):

[0160]

[0161] General procedure A: Purification by column chromatography (hexane / EtOAc, 50:50) afforded the title compound (143 mg, 58%) as a colorless solid. 1 H NMR (500 MHz, CDC13) δ 7.42 (d, J = 8.5 Hz, 2H, H 5 ), 6.62 (d, J = 8.5 Hz, 2H, H 4 ), 5.29 (br s, 1H, H 3 ), 3.87 (s, 2H, H 2 ), 3.05 (s, 6H, H 1 ).

[0162] The spectral characteristics are consistent with the data available in the literature. 9

[0163] 2-((4-Fluoro-3-methoxyphenyl)amino)- N,N dimethylacetamide (1m):

[0164]

[0165] General Procedure A: Purification was performed by column chromatography (hexane / EtOAc, 50:50) to obtain the title compound as a colorless solid (129 mg, 57%). Melting point = 105–107 °C (hexane / EtOAc); IR (thin film) ν max / cm -1 : 3384 (br), 2933 (s), 1652 (s), 1520 (s), 1225 (s); 1 H NMR (500 MHz, CDCl3) δ 6.90 – 6.86(m, 1H, H 9 ), 6.28 – 6.26 (m, 1H, H 10 ), 6.06 – 6.03 (m, 1H, H 5 ), 4.77 (br s,1H, H 3 ), 3.84 (s, 3H, H 7 ), 3.80 (s, 2H, H 2 ), 3.01 (s, 6H, H 1 ); 13 C NMR (126MHz, CDCl3) δ 168.8 (C=O), 148.0 (d, J = 11.5 Hz, C 6 ), 145.7 (d, J = 234.5 Hz, C 8 ), 144.4 (C 4 ), 116.1 (d, J = 19.0 Hz, C 9 ), 103.2 (d, J = 6.5 Hz, C 10 ), 99.6(C 5 ), 56.1 (C 7 ), 45.6 (C 2 ), 35.7 (C 1 ), 35.6 (C 1’ ); 19 F NMR (471 MHz, CDCl3) δ -149.8; HRMS (ESl): for C 11 H 15 FN2O2Na [M+Na] + Calculation required m / z249.1010, found m / z 249.1012.

[0166] 2-((4-Hydroxyphenyl)amino)-1-morpholinoethan-1-one (In):

[0167]

[0168] General Procedure A: Purification was performed by column chromatography (hexanes / EtOAc, 50:50) to afford the title compound as a yellow solid (135 mg, 57%). Melting point = 178-180 °C (hexanes / EtOAc); IR (thin film) v max / cm -1 : 3352 (br), 2860 (s), 1636 (s), 1517 (s), 1440 (s), 1114 (s); 1 H NMR (500 MHz, DMSO- d 6 ) δ 8.43 (s, 1H, H 9 ), 6.56 - 6.50 (m, 4H, H 6 + H 7 ), 4.93 (t, J = 5.5 Hz, 1H, H 4 ), 3.80 (d, J = 5.0 Hz, 2H, H 3 ), 3.60 - 3.55 (m, 4H, H 1 ), 3.49 - 3.45 (m, 4H, H 2 ; 13 C NMR (126 MHz, DMSO- d 6 ) δ 168.4 (C=O), 148.6 (C 8 ), 141.1 (C 5 ), 115.6(C 7 ), 113.8 (C 6 ), 66.1 (C 1 ), 66.0 (C 1’ ), 45.6 (C 3 ), 44.5 (C 2 ), 41.7 (C 2’ ); HRMS (ESI): calcd for C 12 H 17 N2O3 [M+H]+ Computational needs m / z 237.1234, found m / z 237.1231.

[0169] 2-((4-hydroxyphenyl)amino)- N -benzeneacetamide (10):

[0170]

[0171] General Procedure A: Purification was performed by column chromatography (hexanes / EtOAc, 35:65) to afford the title compound as a colorless solid (148 mg, 61%). Melting point = 174-176 °C (hexanes / EtOAc); IR (thin film) v max / cm -1 : 3312 (br), 1660 (s), 1598 (s), 1513 (s), 1243 (s); 1 H NMR (500 MHz, CD3OD- d 4 ) δ 7.55 (d, J = 7.5 Hz, 2H, H 3 ), 7.33 - 7.30 (m, 2H, H 2 ), 7.13 - 7.10 (m, 1H, H 1 ), 6.68 (d, J = 9.0 Hz, 2H, H 8 ), 6.59 (d, J = 9.0 Hz, 2H, H 7 ), 3.83 (s, 2H, H 5 ); 13 C NMR (126 MHz, CD3OD- d 4 ) δ 171.2 (C=O), 149.7 (C 9 ), 141.1 (C 6 ), 137.8 (C 4 ), 128.4(C 2 ), 124.1 (C 1 ), 120.0 (C 3 ), 115.6 (C 8 ), 114.4 (C 7 ), 49.4 (C 5 );HRMS (ESl): calcd for C 14H 14 N₂O₂Na [M+Na] + Calculation required m / z 265.0947, obtained m / z 265.0954.

[0172] N,N -Dimethyl-3-(phenylamino)propionamide (1p):

[0173] Amide 1p was prepared using the reported procedure. 10

[0174]

[0175] Aniline (93.1 mg, 1.00 mmol, 100 mol%) was added to a round-bottom flask that had been dried in an oven at room temperature. N,N - Dimethylacrylamide (129 mg, 1.30 mmol, 130 mol%) and imidazolium chloride (31.2 mg, 0.30 mmol, 30 mol%). After addition, the reaction mixture was stirred at 120 °C for 4 hours, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and then transferred to a separatory funnel, and water (approximately 10.0 mL) was added. The aqueous phase was extracted with EtOAc (approximately 3 × 5.0 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (hexane / EtOAc, 50:50) to give the title compound (96.1 mg, 50%) as a colorless solid. 1 H NMR (500 MHz, CDCl3) δ 7.18 – 7.15 (m, 2H, H 7 ), 6.71 – 6.68 (m, 1H, H 8 ), 6.63 (d, J = 7.5 Hz, 2H, H 6 ), 4.34 (br s, 1H, H 4 ), 3.49 (t, J = 6.0 Hz, 2H, H 3 ), 2.96 –2.95 (m, 6H, H 1 ), 2.59 (t, J = 6.0 Hz, 2H, H 2 ).

[0176] The spectral characteristics are consistent with the data available in the literature. 10

[0177] 1 -phenyl-2-(phenylamino)ethan-1 -one (1q):

[0178] Ketone 1q was prepared by the reported procedure. 11

[0179]

[0180] A dry round bottom flask oven dried at room temperature was charged with aniline (93.1 mg, 1.00 mmol, 100 mol%), NaHC03(84.0 mg, 1.00 mmol / 100 mol%) and EtOH (5.0 mL). Then 2-bromo-1-phenylethan-1-one (198 mg, 1.00 mol%) in EtOH (2.0 mL) was added dropwise to the stirred solution at room temperature over 3 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours and the progress of the reaction was monitored by TLC. Upon completion, the crude product was obtained as a yellow precipitate which was recrystallized from EtOH to afford the title compound as a light yellow solid (158 mg, 75%). 1 H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 7.0 Hz, 2H, H 3 ), 7.65 – 7.62(m, 1H, H 1 ), 7.54 – 7.51 (m, 2H, H 2 ), 7.26 – 7.22 (m, 2H, H 8 ), 6.78 – 6.72 (m,3H, H 7 + H 9 ), 5.03 (br s, 1H, H 4 ), 4.63 (s, 2H, H 5 ).

[0181] The spectral characteristics are consistent with the data available in the literature. 11

[0182] General procedure B for the synthesis of ketones 1r-1s:

[0183] Ketones 1r-1s were synthesized according to the modified procedure. 12

[0184]

[0185] An oven-dried round-bottom flask was charged with aniline (93.1 mg, 1.00 mmol, 100 mol%), K2CO3(207 mg, 1.50 mmol, 150 mol%) and acetone (5.0 mL) and stirred at 60 °C. After 1 h, the bromoketone (1.00 mmol, 100 mol%) was added dropwise to the stirring solution over 3 min at rt. After the addition was complete, the reaction mixture was stirred at 60 °C for 20 h and the progress of the reaction was monitored by TLC. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by FCC under the conditions indicated.

[0186] 1-(phenylamino)propan-2-one (1r):

[0187]

[0188] General procedure B: Purification by column chromatography (hexanes / EtOAc, 85:15) afforded the title compound as a brown solid (89.4 mg, 60%). 1 H NMR (500 MHz, CDCl3) 7.22 – 7.19 (m, 2H, H 5 ), 6.76 –6.73 (m, 1H, H 6 ), 6.60 (d, J = 7.5 Hz, 2H, H 4 ), 4.57 (br s, 1H, H 3 ), 4.00 (d, J = 4.5 Hz, 2H, H 2 ), 2.25 (s, 3H, H 1 ).

[0189] The spectral characteristics are consistent with the data available in the literature. 12

[0190] 3,3-dimethyl-l-(phenylamino)butan-2-one (1s):

[0191]

[0192] General procedure B: Purification by column chromatography (hexanes / EtOAc, 90:10) afforded the title compound as a colorless solid (155 mg, 81%). 1 H NMR (500 MHz, CDCl3) 7.22 – 7.19 (m, 2H, H 5 ), 6.75 –6.72 (m, 1H, H6 ), 6.64 (d, J = 7.5 Hz, 2H, H 4 ), 4.76 (br s, 1H, H 3 ), 4.12 (s,2H, H 2 ), 1.24 (s, 9H, H 1 )。

[0193] The spectral characteristics are consistent with the data available in the literature. 13

[0194] Olefins:

[0195] Styrene, simply substituted styrenes, vinylferrocene and a-olefins were purchased and used as received.

[0196] Olefins were prepared by reported procedures: tosyl-3-vinyl-1 H -indol-3-yl)acetate 2b and tert-butyl(hex-5-en-1-yloxy)dimethylsilane 2c. H 14-16

[0197] 1-tosyl-3-vinyl-1 H -indole (2a):

[0198]

[0199] 1 H NMR (500 MHz, CDCl3) 7.99 (d, J = 8.0 Hz, 1H, H 5 ), 7.78 – 7.73 (m,3H, H 2 + H 12 ), 7.61 (s, 1H, H 10 ), 7.35 – 7.32 (m, 1H, ArH), 7.29 – 7.25 (m, 1H,ArH), 7.22 (d, J = 8.0 Hz, 2H, H 13 ), 6.77 (dd, J = 18.0, 11.5 Hz, 1H, H 8 ),5.80 (d, J = 18.0 Hz, 1H, H 9 ​), 5.35 (d, J = 11.5 Hz, 1H, H 9’ ), 2.33 (s, 3H,H 15 ).

[0200] The spectral characteristics are consistent with the data available in the literature. 14

[0201] 4-Vinylbenzyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H -Indole-3-yl)acetate (2b):

[0202]

[0203] 1 H NMR (500 MHz, CDCl3) 7.64 (d, J = 8.5 Hz, 2H, H 8 ), 7.45 (d, J = 8.5Hz, 2H, H 9 ), 7.37 (d, J = 8.0 Hz, 2H, ArH), 7.27 – 7.25 (m, 2H, ArH), 6.92 –6.88 (m, 2H, ArH), 6.74 – 6.66 (m, 2H, ArH + H 23 ), 5.76 (d, J = 17.5 Hz, 1H,H 24 ), 5.27 (d, J = 11.0 Hz, 1H, H 24 ), 5.12 (s, 2H, H 18 ), 3.76 (s, 3H, H 1 ), 3.71(s, 2H, H 16 ), 2.36 (s, 3H, H 12 ).

[0204] The spectral characteristics are consistent with the data available in the literature. 15

[0205] tert-Butyl(hex-5-en-1-yloxy)dimethylsilane (2c):

[0206]

[0207] 1H NMR (500 MHz, CDCl3) 5.85 – 5.77 (m, 1H, H 8 ), 5.02 – 4.98 (m, 1H,H 9 ), 4.95 – 4.93 (m, 1H, H 9 ), 3.61 (t, J = 6.5 Hz, 2H, H 4 ), 2.09 – 2.04 (m,2H, H 7 ), 1.56 – 1.40 (m, 4H, H 5 + H 6 ), 0.89 (s, 9H, H 1 ), 0.05 (s, 6H, H 3 ).

[0208] The spectral characteristics are consistent with the data available in the literature. 16

[0209] Coupling reaction

[0210] General procedure for asymmetric alkylation C:

[0211] The substrate (0.10 mmol, 100 mol%) and [Ir(cod)2]BARF (6.36 mg, 5.00 μmol, 5 mol%) were loaded into Schlenk tubes. R SEGPHOS (3.05 mg, 5.00 μmol, 5 mol%) and styrene derivatives (200 mol%) if non-volatile. The Schlenk tube was emptied and refilled with N2 (three cycles), followed by the addition of an olefin partner (200-1000 mol%) if volatile, and then anhydrous 1,4-dioxane (0.2 mL, 0.5 M). The tube was sealed and heated at 130 °C for 72 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the crude reaction mixture was purified by FCC. The racemic product (using...) was also obtained using the above procedure. rac -BINAP replaces ( R (-SEGPHOS), and purified by FCC.

[0212] ( 2S, 3S )- N,N -Dimethyl-3-phenyl-2-(phenylamino)butyramide (3a):

[0213]

[0214] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (23.1 mg, 82%, >30:1 B:L, dr=18:1) as a pale yellow solid. a:b (er=97.5:2.5). Crude material 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 10:1. Melting point = 103-105℃ (hexane / EtOAc). =-7.8 (c=1.0, CHCl3); IR (thin film) ν max / cm -1 : 3335 (br), 3027 (s), 2931 (s), 1638 (s), 1602 (s), 1495 (s), 699 (s); The main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.35 – 7.25 (m, 5H, H 12 + H 13 + H 14 ), 7.20 – 7.16 (m, 2H, H 7 ), 6.75 – 6.72 (m, 1H, H 8 ), 6.66(d, J = 7.5 Hz, 2H, H 6 ), 5.32 – 4.13 (m, 2H, H 3 + H 4 ), 3.39 – 3.34 (m, 1H,H 9 ), 2.92 (s, 3H, H 1 ), 2.66 (s, 3H, H 1’ ), 1.40 (d, J = 7.0 Hz, 3H, H 10 Characteristic signal of minor diastereomer b: 2.76 (s, 3H, H) 1 ), 2.64 (s, 3H, H 1’ ), 1.49 (d, J = 7.0Hz, 3H, H 10 ); Only the main diastereomer a 13C NMR (126 MHz, CDCl3) data: δ 171.5 (C 2 ), 146.9 (C 5 ), 142.5 (C 11 ), 129.3 (C 7 ), 128.4 (C 13 ), 127.9 (C 12 ), 126.9 (C 14 ), 117.9 (C 8 ), 113.9 (C 6 ), 58.1 (C 3 ), 42.3 (C 9 ), 36.8 (C 1 ), 35.6 (C 1’ ), 15.7 (C 10 ); HRMS (ESI): for C 18 H 22 N2ONa [M+Na] + calcd m / z 305.1624, found 305.1627; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: m / z -PrOH 90:10, 2.0 mL / min, 145 bar, 40 °C. Retention time: 6.7 min (major), 7.2 min (minor), e.r. = 97.5:2.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC. i

[0215] 2S, 3S - methyl-3-phenyl-2-(phenylamino)butanamide (3b): N

[0216] General procedure C: reaction with substrate 1b (16.4 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound as a light yellow oil (14.5 mg, 54%, >30:1 B:L, d.r. = 18:1

[0217] , e.r. = 96:4). The crude material was used as such for the next step. Yield: 14.5 mg, 54%, >30:1 B:L, d.r. = 18:1 a:b , e.r. = 96:4). The crude material was used as such for the next step. Yield: 14.5 mg, 54%, >30:1 B:L, d.r. = 18:1 1 ​​H NMR analysis showed a B:L ratio >30:1 and dr = 7:1.

[0218] =+50.3 (c=1.0, CHCl3); IR (thin film) ν max / cm -1 : 3308 (br), 2928 (s), 1650 (s), 1603 (s), 1504 (s), 1316 (s), 700 (s); The main diastereomer a 1 H NMR (500MHz, CDCl3) data : δ 7.39 – 7.26 (m, 5H, H 13 + H 14 + H 15 ), 7.20 – 7.17 (m, 2H,H 8 ), 6.82 – 6.79 (m, 1H, H 9 ), 6.57 (d, J = 8.0 Hz, 2H, H 7 ), 6.53 (br s, 1H,H 2 ), 4.14 – 3.72 (m, 2H, H 4 + H 5 ), 3.57 – 3.51 (m, 1H, H 10 ), 2.76 (d, J = 4.5Hz, 3H, H 1 ), 1.46 (d, J = 7.0 Hz, 3H, H 11 Characteristic signal of minor diastereomer b: 2.80 (d, J = 4.5 Hz, 2H, H 1 ), 1.43 (d, J = 7.0 Hz, 2H, H 11 ); Only the main diastereomer a 13 CNMR (126 MHz, CDCl3) data: δ 173.2 (C 2 ), 146.8 (C 6 ), 141.2 (C 12 ), 129.4 (C 8 ),128.9 (C 14 ), 127.6 (C 13 ), 127.3 (C15 ), 119.1 (C 9 ), 113.7 (C 7 ), 64.6 (C 4 ), 42.1(C 10 ), 26.0 (C 1 ), 18.4 (C 11 ); HRMS (ESl): for C 17 H 20 N₂ONa [M+Na] + Calculation required m / z 291.1468, obtained m / z 291.1482; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 12.3 min (major), 13.6 min (minor), er=96:4. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0219] ( 2S, 3S )- N,N -Diethyl-3-phenyl-2-(phenylamino)butyramide (3c):

[0220]

[0221] General procedure C: The reaction was carried out with substrate 1c (20.6 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound as a colorless solid (26.1 mg, 84%, >30:1 B:L, dr>20:1). a:b (er=98:2). Crude matter 1 HNMR analysis showed a B:L ratio >30:1 and a dr ratio of 5:1. Melting point = 60-62℃ (hexane / EtOAc). =-42.2 (c=1.0, CHCl3); IR (thin film) ν max / cm -1 : 3334 (br), 2973 (s), 2933 (s), 1631 (s), 1601 (s), 1496 (s), 750 (s), 699 (s); only the main diastereomer a 1H NMR (500 MHz, CDC13) data: δ 7.33 - 7.23 (m, 5H, H 13 + H 14 + H 15 ), 7.17 - 7.14 (m, 2H, H 8 ), 6.72 - 6.69 (m, 1H, H 9 ), 6.63 (d, J = 7.5 Hz, 2H, H 7 ), 4.60 - 4.32 (m, 2H, H 4 + H 5 ), 3.68 - 3.61 (m, 1H, H 2 ), 3.36 - 3.30 (m, 1H, H 10 ), 3.12 - 3.03 (m, 2H, H 2’ ), 2.94 - 2.86 (m, 1H, H 2 ), 1.41 (d, J = 7.0 Hz, 3H, H 11 ), 1.12 (t, J = 7.0 Hz, 3H, H 1 ), 1.02 (t, J = 7.0 Hz, 3H, H 1’ ); only major diastereomer a 13 C NMR (126 MHz, CDC13) data: δ 170.7 (C 3 ), 147.1 (C 6 ), 142.6 (C 12 ), 129.2 (C 8 ), 128.3 (C 14 ), 128.1 (C 13 ), 126.9 (C 15 ), 117.8 (C 9 ), 114.0 (C 7 ), 58.5 (C 4 ), 42.6 (C 10 ), 41.4 (C 2 ), 40.3 (C 2’ ), 16.1 (C 11 ), 14.3 (C 1 ), 12.8 (C 1’); HRMS (ESl): for C 20 H 26 N₂ONa [M+Na] + Calculation required m / z 333.1937, obtained m / z 333.1948; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 98:2, 2.0 mL / min, 140 bar, 40 °C. Retention times: 18.7 min (minor), 23.9 min (major), er=98:2.

[0222] ( 2S, 3S )-3-phenyl-2-(phenylamino)-1-(pyrrolidone-1-yl)but-1-one (3d):

[0223]

[0224] General procedure C: The reaction was carried out with substrate 1d (20.4 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound as a colorless solid (21.3 mg, 69%, >30:1 B:L, dr>20:1). a:b (er=98:2). Crude matter 1 HNMR analysis showed a B:L ratio >30:1 and a dr ratio of 9:1. Melting point = 115-117℃ (hexane / EtOAc). =-34.3 (c=1.0CHCl3); IR (thin film) ν max / cm -1 : 3335 (br), 3006 (s), 2989 (s), 1631 (s), 1602 (s), 1261 (s), 766 (s); only the main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.32 –7.21 (m, 5H, H 13 + H 14 + H 15 ), 7.17 – 7.14 (m, 2H, H 8 ), 6.73 – 6.70 (m, 1H, H 9 ),6.65 (d, J = 8.0 Hz, 2H, H7 ), 4.78 (br s, 1H, H 5 ), 4.36 (d, J = 6.0 Hz, 1H,H 4 ), 3.49 – 3.44 (m, 1H, H 2 ), 3.41 – 3.34 (m, 2H, H 2 + H 10 ), 3.25 – 3.20 (m, 1H, H) 2’ ), 2.59 – 2.55 (m, 1H, H 2’ ), 1.77 – 1.56 (m, 4H, H 1 ), 1.39 (d, J = 7.0Hz, 3H, H 11 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 169.7 (C10 NMR (126 MHz, CDCl3) 3 ),146.6 (C 6 ), 142.7 (C 12 ), 129.3 (C 8 ), 128.4 (C 14 ), 127.9 (C 13 ), 126.9 (C 15 ),118.0 (C 9 ), 113.9 (C 7 ), 60.4 (C 4 ), 46.3 (C 2 ), 45.8 (C 2’ ), 42.0 (C 10 ), 25.6 (C 1 ),23.9 (C 1’ ), 15.4 (C 11 ); HRMS (ESl): for C 20 H 24 N₂ONa [M+Na] + Calculation required m / z 331.1781, obtained m / z 331.1788; Chiral SFC:YMC chiral ART Cellulose-SB column (25 cm), CO2: i- PrOH 95:5, 2.0 mL / min, 140 bar, 40 °C. Retention time: 25.3 min (minor), 28.2 min (major), e.r. = 98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0225] ( 2S, 3S )-3-phenyl-2-(phenylamino)-1-(piperidin-1-yl)butan-1-one (3e):

[0226]

[0227] General procedure C: Reaction with substrate 1e (21.8 mg, 0.10 mmol, 100 mol%) and styrene (23.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound as a light yellow oil (25.1 mg, 78%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 94.5:5.5). H NMR analysis gave >30:1 B:L and d.r. = 4:1. 1 H NMR analysis gave >30:1 B:L and d.r. = 4:1. = 3.2 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3336 (br), 2935 (s), 2855 (s), 1627 (s), 1601 (s), 1495 (s), 1249 (s), 793(s); only major diastereomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.35 – 7.17 (m, 5H, H 14 + H 15 + H 16 ), 7.19 – 7.15 (m, 2H, H 9 ), 6.74 – 6.71 (m, 1H, H 10 ), 6.65 (d, J = 7.5 Hz, 2H, H 8 ), 4.74 – 4.39 (m, 2H, H 5 + H 6 ), 3.70 – 3.66 (m, 1H, H 3 ), 3.45 –3.29 (m, 3H, H 3+ H 11 ), 3.12 – 3.07 (m, 1H, H 3 ), 1.65 – 1.46 (m, 5H, H 1 ), 1.41(d, J = 7.0 Hz, 3H, H 12 ), 1.38 – 1.32 (m, 1H, H 1 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 170.0 (C10 NMR (126 MHz, CDCl3) 4 ), 147.2 (C 7 ), 142.4 (C 13 ), 129.2 (C 9 ), 128.4(C 15 ), 128.0 (C 14 ), 126.8 (C 16 ), 117.9 (C 10 ), 113.9 (C 8 ), 58.1 (C 5 ), 46.5 (C 3 ),43.1 (C 3’ ), 42.4 (C 11 ), 26.2 (C 2 ), 25.5 (C 2’ ), 24.4 (C 1 ), 16.7 (C 12 ); HRMS (ESl): for C 21 H 26 N₂ONa [M+Na] + Calculation required m / z 345.1937, obtained m / z 345.1951; Chiral SFC: DAICELCHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 6.5 min (minor), 8.2 min (major), er = 94.5:5.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0228] ( 2S, 3S )-1-morpholino-3-phenyl-2-(phenylamino)but-1-one (3f):

[0229]

[0230] General procedure C: The reaction was performed with substrate 1f (22.0 mg, 0.10 mmol, 100 mol%) and styrene (23.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound as a yellowish oil (22.0 mg, 68%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 98:2). The crude material was analyzed by1H NMR to give >30:1 B:L and d.r. = 5:1. 1 = 7.0 Hz, 3H, H = 7.0 Hz, 3H, H max = 7.0 Hz, 3H, H -1 : 3344 (br), 2922 (s), 2854 (s), 1635 (s), 1601 (s), 1495 (s), 1423 (s), 1113 (s); only major diastereomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.35 – 7.24 (m, 5H, H 13 + H 14 + H 15 ), 7.18 – 7.15 (m, 2H, H 8 ), 6.74 – 6.71 (m, 1H, H 9 ), 6.64 (d, J = 7.5 Hz, 2H, H 7 ), 4.56 – 4.47 (m, 2H, H 4 + H 5 ), 3.63 – 3.50 (m, 4H, H 1 ), 3.43 –3.26 (m, 3H, H 2 + H 10 ), 3.22 – 3.18 (m, 1H, H 2’ ), 3.00 – 2.95 (m, 1H, H 2’ ), 1.39 (d, J = 7.0 Hz, 3H, H 11 ); only major diastereomer a 13 C NMR (126 MHz, CDCl3) data: δ 170.2 (C3 ), 146.7 (C 6 ), 142.2 (C 12 ), 129.4 (C 8 ), 128.6 (C 14 ), 128.0 (C 13 ), 127.1(C 15 ), 118.3 (C 9 ), 113.9 (C 7 ), 66.7 (C 1 ), 66.1 (C 1’ ), 57.9 (C 4 ), 46.0 (C 2 ), 42.3(C 2’ ), 42.0 (C 10 ), 15.7 (C 11 ); HRMS (ESl): for C 20 H 24 N₂O₂Na [M+Na] + Calculation required m / z 347.1730, obtained m / z 347.1742; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 8.7 min (minor), 10.9 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0231] ( 2S, 3S )-2-((4-hydroxyphenyl)amino)- N 3-Diphenylbutyramide (3o):

[0232]

[0233] General procedure C: The reaction was carried out with substrate 1O (24.2 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound (23.9 mg, 69%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=91:9). Coarse materials 1H NMR analysis gave >30:1 B:L and d.r. = 4:1. = 27.4 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3320 (br), 2928 (s), 1669 (s), 1599 (s), 1512 (s), 1444 (s), 1238 (s), 756(s), 702 (s); only major diastereomer a 1 H NMR (500 MHz, CD3OD- d 4 ) data: δ 7.47 (d, J = 8.0 Hz, 2H, H 3 ), 7.32 - 7.18 (m, 7H, H 2 + H 14 + H 15 + H 16 ), 7.11 - 7.08 (m, 1H, H 1 ), 6.58 (d, J = 8.5 Hz, 2H, H 9 ), 6.49 (d, J = 8.5 Hz, 2H, H 8 ), 3.97 (d, J = 8.0 Hz, 1H, H 6 ), 3.27 - 3.21 (m, 1H, H 11 ), 1.39 (d, J = 7.0 Hz, 3H, H 12 ); only major diastereomer a 13 C NMR (126 MHz, CD3OD- d 4 ) data: δ 173.5 (C 5 ), 149.7 (C 10 ), 142.8 (C 7 ), 140.5 (C 13 ), 137.7 (C 4 ), 128.4 (C 2 ), 128.3 (C 15 ), 127.4 (C 14 ), 126.6(C 16 ), 124.2 (C 1), 120.3 (C 3 ), 115.5 (C 9 ), 115.2 (C 8 ), 66.0 (C 6 ), 43.1 (C 11 ),18.0 (C 12 ); HRMS (ESl): for C 22 H 22 N₂O₂Na [M+Na] + Calculation required m / z 369.1573, obtained m / z 369.1583; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2: i -PrOH (with 0.5% TEA) 70:30, 2.0 mL / min, 190 bar, 40 °C. Retention times: 4.9 min (major), 5.8 min (minor), er=91:9. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0234] ( 2S, 3S )-1,3-Diphenyl-2-(phenylamino)but-1-one (3q):

[0235]

[0236] General procedure C: At 90 °C, use substrate 1q (21.1 mg, 0.10 mmol, 100 mol%), styrene (23.0 µL, 0.20 mmol, 200 mol%), and ( R )-3,5-( t The reaction was carried out with -Bu)2-H8-BINAP (5.40 mg, 5.00 μmol, 5 mol%). The residue was purified by FCC (hexane / EtOAc 95:5) to give the title compound (26.8 mg, 85%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=71:29). Crude matter 1 H NMR analysis showed a ratio of >30:1 B:L and dr=8:1.

[0237] =+28.6 (c=1.0 CHCl3); IR (thin film) ν max / cm -13379 (br), 3027 (s), 1682(s), 1601 (s), 1506 (s), 748 (s), 693 (s); only major diastereomer a of 1 H NMR (500MHz, CD2Cl2) data: δ 7.93 (d, J = 7.5 Hz, 2H, H 3 ), 7.61 - 7.58 (m, 1H, H 1 ), 7.49- 7.46 (m, 2H, H 2 ), 7.26 - 7.18 (m, 3H, H 16 + H 17 ), 7.12 - 7.08 (m, 4H, H 10 + H 15 ), 6.68 - 6.65 (m, 3H, H 9 + H 11 ), 5.19 (d, J = 5.0 Hz, 1H, H 6 ), 4.37 (br s, 1H, H 7 ), 3.45 - 3.40 (m, 1H, H 12 ), 1.44 (d, J = 7.0 Hz, 3H, H 13 ); only major diastereomer a of 13 C NMR (126 MHz, CD2Cl2) data: δ 200.4 (C 5 ), 147.8 (C 8 ), 141.4 (C 14 ), 136.3 (C 4 ), 133.5 (C 1 ), 129.3 (C 10 ), 128.9 (C 3 ), 128.4 (C 16 ), 128.3 (C 2 ), 128.2 (C 15 ), 127.0 (C 17 ), 118.2 (C 11 ), 114.0 (C 9 ), 63.5 (C 6 ), 42.9 (C 12 ), 18.2 (C13 ); HRMS (ESl): for C 22 H 21 NONa [M+Na] + Calculation required m / z 338.1515, obtained m / z 338.1524; Chiral SFC: DAICL CHIRALCEL IE column (25 cm), CO2: i -PrOH 95:5, 1.0 mL / min, 140 bar, 40 °C. Retention times: 42.8 min (minor), 53.1 min (major), er=71:29. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0238] ( 3S, 4S )-4-phenyl-3-(phenylamino)pentan-2-one (3r):

[0239]

[0240] General Procedure C: Using substrate 1r (14.9 mg, 0.10 mmol, 100 mol%), styrene (23.0 µL, 0.20 mmol, 200 mol%), and ( R The reaction was carried out with DTBM-SEGPHOS (5.90 mg, 5.00 μmol, 5 mol%) and run at 90 °C for 22 h. The residue was purified by FCC (hexane / EtOAc 85:15) to give the title compound (17.7 mg, 70%, >30:1 B:L, dr=9:1) as a pale yellow oil. a:b (er=90:10). Coarse materials 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 2:1. =-1.5 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3378 (br), 2934(s), 1709 (s), 1603 (s), 1506 (s), 751 (s), 701 (s); The main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.39 – 7.27 (m, 5H, H 12 + H 13 + H 14 ), 7.17 – 7.14 (m,2H, H7 ), 6.75 – 6.72 (m, 1H, H 8 ), 6.54 (d, J = 7.5 Hz, 2H, H 6 ), 4.19 – 3.89(m, 2H, H 3 + H 4 ), 3.30 – 3.24 (m, 1H, H 9 ), 2.06 (s, 3H, H 1 ), 1.37 (d, J = 7.0Hz, 3H, H 10 Characteristic signal of minor diastereomer b: 6.47 (d, J = 7.5 Hz, 2H, H 6 ), 1.99(s, 3H, H 1 ), 1.42 (d, J = 7.0 Hz, 3H, H 10 ); Only the main diastereomer a 13 C10 NMR (126MHz, CDCl3) data: δ 211.3 (C10) 2 ), 146.9 (C 5 ), 141.5 (C 11 ), 129.4 (C 7 ), 128.9 (C 13 ),127.6 (C 12 ), 127.4 (C 14 ), 118.3 (C 8 ), 113.2 (C 6 ), 69.2 (C 3 ), 41.5 (C 9 ), 26.7(C 1 ), 18.2 (C 10 ); HRMS (ESl): for C 17 H 19 NONa [M+Na] + Calculation required m / z 276.1359, obtained m / z 276.1361; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2: i-PrOH 95:5, 1.0 mL / min, 140 bar, 40 °C. Retention times: 12.9 min (major), 14.2 min (minor), er=90:10. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0241] ( 4S, 5S )-2,2-Dimethyl-5-phenyl-4-(phenylamino)hexane-3-one (3s):

[0242]

[0243] General procedure C: with substrate 1s (19.1 mg, 0.10 mmol, 100 mol%), styrene (23.0 µL, 0.20 mmol, 200 mol%) and ( R The reaction was carried out with DTBM-SEGPHOS (5.90 mg, 5.00 μmol, 5 mol%). The residue was purified by FCC (hexane / EtOAc 90:10) to give the title compound (21.3 mg, 72%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=74.5:25.5). Crude material 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 2:1. =+51.5 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3338 (br), 2974 (s), 1698 (s), 1601 (s), 1513 (s), 1314 (s), 1060 (s), 699 (s); only the main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.34 – 7.21 (m, 5H, H 13 + H 14 + H 15 ), 7.17 – 7.14 (m, 2H,H 8 ), 6.73 – 6.70 (m, 1H, H 9 ), 6.59 (d, J = 8.0 Hz, 2H, H 7 ), 4.59 (d, J = 8.0Hz, 1H, H 4 ), 4.08 (br s, 1H, H5 ), 3.31 – 3.25 (m, 1H, H 10 ), 1.39 (d, J = 7.0Hz, 3H, H 11 ), 0.87 (s, 9H, H 1 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 215.5 (C10) 3 ), 147.3 (C 6 ), 143.3 (C 12 ), 129.3 (C 8 ), 128.5 (C 14 ), 128.2 (C 13 ),126.8 (C 15 ), 118.0 (C 9 ), 113.6 (C 7 ), 62.3 (C 4 ), 43.4 (C 2 ), 42.7 (C 10 ), 25.9(C 1 ), 16.3 (C 11 ); HRMS (ESl): for C 20 H 26 NO [M+H] + Calculation required m / z 296.2009, obtained m / z 296.2016; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2: i -PrOH 95:5, 1.0 mL / min, 140 bar, 40 °C. Retention times: 9.8 min (major), 10.8 min (minor), er = 74.5:25.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0244] ( 2S, 3S )-2-((4-hydroxyphenyl)amino)- N,N -Dimethyl-3-phenylbutyramide (3g):

[0245]

[0246] General procedure C: The reaction was performed with substrate 1g (19.4 mg, 0.10 mmol, 100 mol%) and styrene (23.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexanes / EtOAc 65:35) to give the title compound as a yellowish oil (25.9 mg, 87%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 98:2). The crude material was used without further purification. 1 H NMR analysis gave >30:1 B:L and d.r. = 6:1. = -11.8 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3331 (br), 3027 (s), 2968 (s), 1623 (s), 1514 (s), 1240 (s), 700 (s); only major diastereomer a's 1 H NMR (500 MHz, CDCl3) data: δ 7.34 - 7.23 (m, 5H, H 12 + H 13 + H 14 ), 6.64 (d, J = 8.0 Hz, 2H, H 7 ), 6.50 (d, J = 8.0 Hz, 2H, H 6 ), 4.60 - 3.61 (m, 2H, H 3 + H 4 ), 3.30 - 3.24 (m, 1H, H 9 ), 2.89 (s, 3H, H 1 ), 2.72 (s, 3H, H 1’ ), 1.38 (d, J = 7.0 Hz, 3H, H 10 ); only major diastereomer a's 13 C NMR (126 MHz, CDCl3) data: δ 172.7 (C 2 ), 149.4 (C 8 ), 142.6 (C 5 ), 140.2 (C 11 ), 128.4 (C 13 ), 127.8 (C 12 ), 126.8 (C 14), 116.4 (C 7 ), 116.2 (C 6 ), 60.3 (C 3 ), 42.5 (C 9 ), 37.0 (C 1 ), 35.8(C 1’ ), 16.3 (C 10 ); HRMS (ESl): for C 18 H 22 N₂O₂Na [M+Na] + Calculation required m / z 321.1573, obtained m / z 321.1583; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 85:15, 2.0 mL / min, 160 bar, 40 °C. Retention times: 10.2 min (major), 11.2 min (minor), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0247] ( 2S, 3S )-2-((4-methoxyphenyl)amino)- N,N -Dimethyl-3-phenylbutyramide (3h):

[0248]

[0249] General Procedure C: The reaction was carried out for 1 h with substrate (20.8 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound (17.2 mg, 55%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=90.5:9.5). The crude material... 1 H NMR analysis showed a B:L ratio >30:1 and dr = 9:1. =-5.8 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3334 (br), 2931 (s), 1637 (s), 1510 (s), 1236 (s), 701 (s); only the main diastereomer a 11H NMR (500 MHz, CDCl3) data: δ 7.35 – 7.24 (m, 5H, H 13 + H 14 + H 15 ), 6.77(d, J = 9.0 Hz, 2H, H 7 ), 6.62 (d, J = 9.0 Hz, 2H, H 6 ), 4.61 – 3.89 (m, 2H, H 3 + H 4 ), 3.75 (s, 3H, H 9 ), 3.34 – 3.28 (m, 1H, H 10 ), 2.91 (s, 3H, H 1 ), 2.68 (s, 3H, H 1’ ), 1.39 (d, J = 7.0 Hz, 3H, H 11 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.9 (C10 NMR (126 MHz, CDCl3) 2 ), 152.6 (C 8 ), 142.7 (C 5 ), 141.1 (C 12 ), 128.4 (C 14 ), 127.8(C 13 ), 126.8 (C 15 ), 115.9 (C 7 ), 114.8 (C 6 ), 59.8 (C 3 ), 55.7 (C 9 ), 42.4 (C 10 ),36.8 (C 1 ), 35.6 (C 1’ ), 16.0 (C 11 ); HRMS (ESl): for C 19 H 24 N₂O₂Na [M+Na] + Calculation required m / z 335.1730, obtained m / z 335.1739; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2:i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 6.9 min (minor), 8.3 min (major), er = 90.5:9.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0250] ( 2S, 3S )- N,N -Dimethyl-3-phenyl-2-(p-tolylamino)butyramide (3i):

[0251]

[0252] General procedure C: The reaction was carried out with substrate 1i (19.2 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound (26.4 mg, 89%, >30:1 B:L, dr>20:1) as a pale yellow solid. a:b (er=97:3). Coarse materials 1 HNMR analysis showed a B:L ratio >30:1 and a dr ratio of 8:1. Melting point = 103-105℃ (hexane / EtOAc). =-10.9 (c=1.0CHCl3); IR (thin film) ν max / cm -1 : 3333 (br), 2923 (s), 1639 (s), 1520 (s), 1396 (s), 1055 (s), 701 (s); only the main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.35 –7.24 (m, 5H, H 13 + H 14 + H 15 ), 6.99 (d, J = 8.5 Hz, 2H, H 7 ), 6.59 (d, J = 8.5Hz, 2H, H 6 ), 4.71 – 4.31 (m, 2H, H 3 + H 4 ), 3.38 – 3.32 (m, 1H, H 10 ), 2.91 (s,3H, H 1), 2.66 (s, 3H, H 1’ ), 2.25 (s, 3H, H 9 ), 1.40 (d, J = 7.0 Hz, 3H, H 11 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.6 (C10 NMR (126 MHz, CDCl3) 2 ), 144.6 (C 5 ), 142.6(C 12 ), 129.7 (C 7 ), 128.4 (C 14 ), 127.8 (C 13 ), 127.2 (C 15 ), 126.8 (C 8 ), 114.2 (C 6 ),58.6 (C 3 ), 42.2 (C 10 ), 36.8 (C 1 ), 35.5 (C 1’ ), 20.3 (C 9 ), 15.8 (C 11 ); HRMS (ESl): for C 19 H 24 N₂ONa [M+Na] + Calculation required m / z 319.1781, obtained m / z 319.1795; Chiral SFC: DAICELCHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 5.8 min (minor), 7.1 min (major), er=97:3. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0253] ( 2S, 3S )-2-((4-fluorophenyl)amino)- N,N -Dimethyl-3-phenylbutyramide (3j):

[0254]

[0255] General procedure C: The reaction was performed with substrate 1j (19.6 mg, 0.10 mmol, 100 mol%) and styrene (23.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound as a yellowish oil (25.8 mg, 86%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 97.5:2.5). The crude material was used without further purification. 1 H NMR analysis gave >30:1 B:L and d.r. = 8:1.

[0256] = 2.6 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3331 (br), 2932 (s), 1637 (s), 1509 (s), 1395 (s), 1216 (s), 823 (s), 701 (s); only major diastereomer a's 1 H NMR (500 MHz, CDCl3) data: δ 7.33 - 7.22 (m, 5H, H 12 + H 13 + H 14 ), 6.86 - 6.83 (m, 2H, H 7 ), 6.56 - 6.53 (m, 2H, H 6 ), 4.46 (d, J = 6.5 Hz, 1H, H 3 ), 4.35 (br s, 1H, H 4 ), 3.31 - 3.25 (m, 1H, H 9 ), 2.90 (s, 3H, H 1 ), 2.69 (s, 3H, H 1’ ), 1.37 (d, J = 7.0 Hz, 3H, H 10 ); only major diastereomer a's 13 C NMR (126 MHz, CDCl3) data: δ 171.6 (C 2 ), 156.1 (d, J = 236.9 Hz, C 8 ), 143.4 (d, J = 1.3 Hz, C 5), 142.4 (C 11 ),128.4 (C 13 ), 127.8 (C 12 ), 126.9 (C 14 ), 115.6 (d, J = 21.4 Hz, C 7 ), 115.1 (d, J = 7.6 Hz, C 6 ), 59.3 (C 3 ), 42.4 (C 9 ), 36.8 (C 1 ), 35.6 (C 1’ ), 16.1 (C 10 ); 19 F NMR (471 MHz, CDCl3) δ -126.9; HRMS (ESl): for C 18 H 21 FN2ONa [M+Na] + Calculation required m / z 323.1530, obtained m / z 323.1548; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 95:5, 2.0 mL / min, 140 bar, 40 °C. Retention times: 8.7 min (minor), 10.4 min (major), er = 97.5:2.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0257] ( 2S, 3S )-2-((4-chlorophenyl)amino)- N,N -Dimethyl-3-phenylbutyramide (3k):

[0258]

[0259] General procedure C: The reaction was carried out with substrate 1k (21.2 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound (27.8 mg, 88%, >30:1 B:L, dr>20:1) as a pale yellow solid. a:b (er=97:3). Coarse materials 1HNMR analysis gave >30:1 B:L and d.r. = 8:1. Melting point = 98-100 °C (hexane / EtOAc); =-32.0 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3327 (br), 2929 (s), 1635 (s), 1492 (s), 1394 (s), 816 (s), 699 (s); only major diastereomer a's 1 H NMR (500 MHz, CDCl3) data: δ 7.32 - 7.22 (m, 5H, H 12 + H 13 + H 14 ), 7.08 (d, J = 9.0 Hz, 2H, H 7 ), 6.53 (d, J = 9.0 Hz, 2H, H 6 ), 4.69 - 4.26 (m, 2H, H 3 + H 4 ), 3.32 - 3.27 (m, 1H, H 9 ), 2.90 (s, 3H, H 1 ), 2.67 (s, 3H, H 1’ ), 1.36 (d, J = 7.0 Hz, 3H, H 10 ); only major diastereomer a's 13 C NMR (126 MHz, CDCl3) data: δ 171.2 (C 2 ), 145.5 (C 5 ), 142.2 (C 11 ), 129.1 (C 7 ), 128.4 (C 13 ), 127.8 (C 12 ), 127.0 (C 14 ), 122.4 (C 8 ), 114.9 (C 6 ), 58.3 (C 3 ), 42.3 (C 9 ), 36.8 (C 1 ), 35.6 (C 1’ ), 15.9 (C 10); HRMS (ESI): m / z calcd for C 18 H 21 ClN2ONa [M+Na] + Computational requirements m / z 339.1235, found m / z 339.1248; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 95:5, 2.0 mL / min, 140 bar, 40 °C. Retention time: 6.3 min (minor), 7.5 min (major), e.r. = 97:3. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0260] ( 2S, 3S )- N,N - dimethyl-3-phenyl-2-((4-(trifluoromethyl)phenyl)amino)butanamide (3l):

[0261]

[0262] General procedure C: reaction with substrate 1l (24.6 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound as a light yellow solid (26.3 mg, 75%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 98:2). H NMR analysis gave >30:1 B:L and d.r. = 10:1. Melting point = 88-90 °C (hexane / EtOAc); 1 HNMR analysis gave >30:1 B:L and d.r. = 10:1. Melting point = 88-90 °C (hexane / EtOAc); =-8.0 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3324 (br), 2935 (s), 1639 (s), 1616 (s), 1324 (s), 1106 (s), 1065 (s), 701 (s); H NMR (500 MHz, CDCl3) data for major diastereomer a only: 1 H NMR (500 MHz, CDCl3) data: δ 7.39 (d, J = 8.5 Hz, 2H, H 7 ), δ 7.36 – 7.25 (m, 5H, H 13 + H 14 + H15 ), 6.63 (d, J = 8.5 Hz, 2H, H 6 ), 4.92 (br s, 1H, H 4 ), 4.62 (d, J = 6.0 Hz, 1H, H 3 ), 3.38 –3.33 (m, 1H, H 10 ), 2.94 (s, 3H, H 1 ), 2.69 (s, 3H, H 1’ ), 1.40 (d, J = 7.0 Hz, 3H, H 11 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 170.8 (C10 NMR (126 MHz, CDCl3) 2 ), 149.4(C 5 ), 141.9 (C 12 ), 128.5 (C 14 ), 128.0 (C 13 ), 127.8 (C 15 ), 126.6 (q, J = 3.8 Hz,C 7 ), 124.8 (q, J = 270.9 Hz, C 9 ), 119.1 (q, J = 32.8 Hz, C 8 ), 112.6 (C 6 ), 57.4(C 3 ), 42.3 (C 10 ), 36.9 (C 1 ), 35.6 (C 1’ ), 15.7 (C 11 ); 19 F NMR (471 MHz, CDCl3) δ -61.1; HRMS (ESl): for C 19 H 21 F3N2ONa [M+Na] + Calculation required m / z 373.1498, obtained m / z 373.1509; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i-PrOH 95:5, 2.0 mL / min, 140 bar, 40 °C. Retention times: 6.9 min (minor), 8.8 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0263] ( 2S, 3S )-2-((4-fluoro-3-methoxyphenyl)amino)- N,N -Dimethyl-3-phenylbutyramide (3m):

[0264]

[0265] General procedure C: The reaction was carried out with substrate 1m (22.6 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound (27.4 mg, 83%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=96.5:3.5). Crude material 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 8:1. =+10.1 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3328 (br), 2934 (s), 1636 (s), 1519 (s), 1221 (s), 1121 (s), 701 (s); only the main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.32 – 7.21 (m, 5H, H 15 + H 16 +H 17 ), 6.85 – 6.81 (m, 1H, H 7 ), 6.22 – 6.20 (m, 1H, H 6 ), 6.08 – 6.05 (m, 1H,H 10 ), 4.45 – 4.21 (m, 2H, H 3 + H 4 ), 3.79 (s, 3H, H 11 ), 3.30 – 3.25 (m, 1H, H 12 ),2.90 (s, 3H, H1 ), 2.72 (s, 3H, H 1’ ), 1.37 (d, J = 7.0 Hz, 3H, H 13 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.6 (C10 NMR (126 MHz, CDCl3) 2 ), 147.9 (d, J = 11.3 Hz, C 9 ),145.8 (d, J = 235.6 Hz, C 8 ), 144.0 (d, J = 2.5 Hz, C 5 ), 142.3 (C 14 ), 128.4(C 16 ), 127.8 (C 15 ), 126.9 (C 17 ), 116.0 (d, J = 18.9 Hz, C 7 ), 114.5 (d, J = 6.3Hz, C 6 ), 110.9 (C 10 ), 59.2 (C 3 ), 56.0 (C 11 ), 42.5 (C 12 ), 36.8 (C 1 ), 35.5 (C 1’ ),16.2 (C 13 ); 19 F NMR (471 MHz, CDCl3) δ -148.7; HRMS (ESl): for C 19 H 23 FN2O2Na [M+Na] + Calculation required m / z 353.1636, obtained m / z 353.1664; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i-PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 6.6 min (minor), 8.3 min (major), er = 96.5:3.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0266] ( 2S, 3S )-2-((4-hydroxyphenyl)amino)-1-morpholino-3-phenylbut-1-one (3n):

[0267]

[0268] General procedure C: The reaction was carried out with substrate 1n (23.6 mg, 0.10 mmol, 100 mol%) and styrene (23.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 50:50) to give the title compound (27.6 mg, 81%, >30:1 B:L, dr=15:1) as a pale yellow oil. a:b (er=96.5:3.5). Crude material 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 4:1. =-12.0 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3337 (br), 2969 (s), 1619 (s), 1515 (s), 1452 (s), 1224 (s), 1114 (s), 701 (s); The main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.36 – 7.26 (m, 5H, H 14 +H 15 + H 16 ), 6.67 (d, J = 8.5 Hz, 2H, H 8 ), 6.55 (d, J = 8.5 Hz, 2H, H 7 ), 5.10(br s, 1H, H 10 ), 4.42 (d, J = 6.5 Hz, 1H, H 4 ), 4.13 (br s, 1H, H 5 ), 3.67 –3.52 (m, 4H, H1 ), 3.41 – 3.24 (m, 4H, H 2 + H 11 ), 3.13 – 3.08 (m, 1H, H 2 ), 1.40(d, J = 7.0 Hz, 3H, H 12 Characteristic signal of minor diastereomer b: 1.52 (d, J = 7.0 Hz, 2H,H 12 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 170.9 (C10 NMR (126 MHz, CDCl3) 3 ), 148.8(C 9 ), 142.4 (C 6 ), 140.7 (C 13 ), 128.6 (C 15 ), 127.9 (C 14 ), 127.1 (C 16 ), 116.4 (C 8 ),116.2 (C 7 ), 66.8 (C 1 ), 66.2 (C 1’ ), 66.1 (C 4 ), 46.0 (C 2 ), 42.4 (C 11 ), 42.6 (C 2’ ),16.2 (C 12 ); HRMS (ESl): for C 20 H 24 N₂O₃Na [M+Na] + Calculation required m / z 363.1679, obtained m / z 363.1684; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 32.3 min (minor), 35.2 min (major), er = 96.5:3.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0269] N,N- Dimethyl-2-(phenylamino)-3-(p-tolyl)butanamide (4a):

[0270]

[0271] General procedure C: Reaction with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-methyl-4-vinylbenzene (26.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (19.8 mg, 67%, >30:1 B:L, d.r. = 8:1 a:b , e.r. = 96.5:3.5) as a light yellow solid. H NMR analysis gave >30:1 B:L and d.r. = 8:1. Melting point = 121-123 °C (hexane / EtOAc); 1 = 121-123 °C (hexane / EtOAc); = +15.1 (c = 0.14, CHCl3); IR (thin film) v max / cm -1 : 3379 (br), 3009 (s), 2931 (s), 2855 (s), 1611 (s); major diastereoisomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.17 - 7.09 (m, 6H, H 7 + H 12 + H 13 ), 6.72 - 6.69 (m, 1H, H 8 ), 6.63 (d, J = 8.0 Hz, 2H, H 6 ), 4.69 - 4.31 (m, 2H, H 3 + H 4 ), 3.32 - 3.27 (m, 1H, H 9 ), 2.90 (s, 3H, H 1 ), 2.67 (s, 3H, H 1’ ), 2.32 (s, 3H, H 15 ), 1.35 (d, J = 7.0 Hz, 3H, H 10 ). Characteristic signals of minor diastereoisomer b: 6.55 (d, J = 8.0 Hz, 2H, H 6 ), 2.75 (s, 3H, H1 ), 2.62 (s,3H, H 1’ ), 1.44 (d, J = 7.0 Hz, 3H, H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.7 (C10 NMR (126 MHz, CDCl3) 2 ), 147.1 (C 5 ), 139.5 (C 11 ), 136.6 (C 14 ), 129.4 (C 7 ), 129.3(C 13 ), 127.9 (C 12 ), 118.1 (C 8 ), 114.1 (C 6 ), 58.5 (C 3 ), 42.0 (C 9 ), 37.1 (C 1 ),35.8 (C 1’ ), 21.2 (C 15 ), 16.2 (C 9 ); HRMS (ESl): for C 19 H 25 N2O [M+H] + Calculation required m / z 296.1961, obtained m / z 297.1962; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 95:5, 2.5 mL / min, 140 bar, 40 °C. Retention times: 11.1 min (major), 11.6 min (minor), er = 96.5:3.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0272] ( 2S, 3S )-3-(4-bromophenyl)- N,N -Dimethyl-2-(phenylamino)butyramide (5a):

[0273]

[0274] General procedure C: Reaction at 140 °C with substrate la (17.8 mg, 0.10 mmol, 100 mol%) and 1-bromo-4-vinylbenzene (26.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound as a yellowish solid (18.0 mg, 50%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 98:2). The crude material was purified by FCC (hexane / EtOAc 70:30) to give the title compound as a yellowish solid (18.0 mg, 50%, >30:1 B:L, d.r. >20:1 1 H NMR analysis gave >30:1 B:L and d.r. = 8:1. Melting point = 102-104 °C (hexane / EtOAc);

[0275] =-6.7 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3328 (br), 2924 (s), 2852(s), 1637 (s), 1602 (s), 1490 (s), 1398 (s), 750 (s), 693 (s); only major diastereomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.42 (d, J = 8.5 Hz, 2H, H 13 ), 7.16 – 7.11 (m, 4H, H 7 + H 12 ), 6.73 – 6.70 (m, 1H, H 8 ), 6.62 (d, J = 8.5 Hz, 2H, H 6 ),4.69 – 4.10 (m, 2H, H 3 + H 4 ), 3.30 – 3.24 (m, 1H, H 9 ), 2.91 (s, 3H, H 1 ), 2.77(s, 3H, H 1’ ), 1.35 (d, J = 7.0 Hz, 3H, H 10 ); only major diastereomer a 13 C NMR (126MHz, CDCl3) data: δ 171.4 (C 2 ), 146.8 (C 5 ), 141.4 (C11 ), 131.4 (C 13 ), 129.7 (C 12 ),129.3 (C 7 ), 120.7 (C 14 ), 118.4 (C 8 ), 114.1 (C 6 ), 58.2 (C 3 ), 42.0 (C 9 ), 37.1(C 1’ ), 35.7 (C 1 ), 16.3 (C 10 ); HRMS (ESl): for C 18 H 21 BrN2ONa [M+Na] + Calculation required m / z 383.0729, obtained m / z 383.0733; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 9.2 min (minor), 9.8 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0276] ( 2S, 3S )-3-([1,1'-biphenyl]-4-yl)- N,N -Dimethyl-2-(phenylamino)butyramide (6a):

[0277]

[0278] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 4-vinyl-1,1'-biphenyl (36.0 mg, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (34.4 mg, 96%, >30:1 B:L, dr>20:1) as a pale yellow solid. a:b (er=97:3). Coarse materials 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 4:1. Melting point = 103-105℃ (hexane / EtOAc). = -11.6 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3330 (br), 3028 (s), 1638 (s), 1602(s), 1499 (s), 1398 (s), 750 (s), 695 (s); only major diastereomer a 1 H NMR (500MHz, CDCl3) data: δ 7.60 - 7.54 (m, 4H, ArH), 7.46 - 7.43 (m, 2H, H 17 ), 7.36 - 7.32 (m, 3H, ArH), 7.18 - 7.15 (m, 2H, H 7 ), 6.73 - 6.70 (m, 1H, H 8 ), 6.66 (d, J = 7.5 Hz, 2H, H 6 ), 5.30 - 4.37 (m, 2H, H 3 + H 4 ), 3.41 - 3.36 (m, 1H, H 9 ),2.92 (s, 3H, H 1 ), 2.71 (s, 3H, H 1’ ), 1.41 (d, J = 7.0 Hz, 3H, H 10 ); only major diastereomer a 13 C NMR (126 MHz, CDCl3) data: δ 171.5 (C 2 ), 146.8 (C 5 ), 141.6 (C 11 ),140.7 (C 15 ), 139.8 (C 14 ), 129.3 (C 7 ), 128.7 (C 17 ), 128.3 (C 12 ), 127.2 (C 18 ),127.1 (C 16 ), 127.0 (C 13 ), 118.2 (C 8 ), 114.1 (C 6 ), 58.3 (C 3 ), 42.0 (C9 ), 37.0(C 1 ), 35.7 (C 1’ ), 16.0 (C 10 ); HRMS (ESl): for C 24 H 26 N₂ONa [M+Na] + Calculation required m / z 381.1937, obtained m / z 381.1948; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 19.7 min (minor), 21.7 min (major), er=97:3. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0279] ( 2S, 3S )-3-(4-methoxyphenyl)- N,N -Dimethyl-2-(phenylamino)butyramide (7a):

[0280]

[0281] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-methoxy-4-vinylbenzene (27.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (18.7 mg, 60%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=98:2). Crude matter 1 H NMR analysis showed a B:L ratio >30:1 and dr = 9:1. =+2.9 (c=0.26, CHCl3); IR (thin film) ν max / cm -1 : 3711 (s), 3681 (s), 3344 (br), 2966 (s), 2936 (s), 2873 (s), 2835(s), 1636 (s), 1602 (s), 1583 (s), 1510 (s); only the main diastereomer a 1H NMR (500 MHz, CDC13) data: δ 7.17 - 7.14 (m, 4H, H 7 + H 12 ), 6.85 (d, J = 8.5 Hz, 2H, H 13 ),6.72 - 6.69 (m, 1H, H 8 ), 6.64 (d, J = 7.5 Hz, 2H, H 6 ), 4.67 - 4.29 (m, 2H, H 3 + H 4 ), 3.79 (s, 3H, H 15 ), 3.32 - 3.26 (m, 1H, H 9 ), 2.90 (s, 3H, H 1 ), 2.68 (s,3H, H 1’ ), 1.35 (d, J = 7.0 Hz, 3H, H 10 );only major diastereomer a 13 C NMR (126 MHz, CDC13) data: δ 171.5 (C 2 ), 158.5 (C 14 ), 146.9 (C 5 ), 134.4 (C 11 ), 129.3 (C 7 ), 128.8(C 12 ), 118.0 (C 8 ), 113.9 (C 13 ), 113.8 (C 6 ), 58.4 (C 3 ), 55.2 (C 15 ), 41.4 (C 9 ),36.9 (C 1 ), 35.6 (C 1’ ), 16.1 (C 10 );HRMS (ESI): for C 19 H 25 N2O2 [M+H] + calcd m / z 313.1911, found 313.1911. m / z313.1912; Chiral SFC: YMC chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 85:15, 3.0 mL / min, 140 bar, 40 °C. Retention times: 5.6 min (minor), 6.9 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0282] ( 2S, 3S )-3-(4-(tert-butyl)phenyl)- N,N -Dimethyl-2-(phenylamino)butyramide (8a):

[0283]

[0284] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-(tert-butyl)-4-vinylbenzene (37.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (19.6 mg, 58%, >30:1 B:L, dr=8:1) as a pale yellow solid. a:b (er=97:3). Coarse materials 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 8:1. Melting point = 121-123°C (hexane / EtOAc). =-2.5 (c=0.16, CHCl3); IR (thin film) ν max / cm -1 : 3681 (s), 3350 (br), 2960 (s), 2925 (s), 2868 (s), 1638 (s), 1632 (s), 1502 (s); The main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.33 – 7.31 (m, 2H, H 13 ), 7.18 – 7.13 (m, 4H, H 7 + H 12 ), 6.71 –6.68 (m, 1H, H 8 ), 6.62 (d, J = 7.5 Hz, 2H, H 6 ), 4.80 – 4.29 (m, 2H, H 3+ H 4 ), 3.34 – 3.29 (m, 1H, H) 9 ), 2.89 (s, 3H, H 1 ), 2.61 – 2.60 (s, 3H, H 1’ ), 1.35 (d, J = 7.0 Hz, 3H, H 10 ), 1.30 (s, 9H, H 16 Characteristic signal of minor diastereomer b: 6.49 (d, J = 7.5 Hz, 2H, H 6 ), 2.74 (s, 3H, H 1 ), 1.45 (d, J = 7.0 Hz, 3H, H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.7 (C10 NMR (126 MHz, CDCl3) 2 ), 150.0 (C 14 ), 147.0 (C 5 ),139.5 (C 11 ), 129.4 (C 7 ), 127.7 (C 13 ), 125.4 (C 12 ), 118.1 (C 8 ), 114.1 (C 6 ), 58.5(C 3 ), 41.9 (C 9 ), 36.9 (C 1 ), 35.8 (C 1’ ), 34.6 (C 15 ), 31.5 (C 16 ), 15.9 (C 10 ); HRMS (ESl): for C 22 H 31 N2O [M+H] + Calculation required m / z 339.2431, obtained m / z 339.2434; Chiral SFC: DAICELCHIRALCEL OD-H column (25 cm), CO2: i-PrOH 95.5:4.5, 2.5 mL / min, 140 bar, 40 °C. Retention times: 11.5 min (major), 14.1 min (minor), er=97:3. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0285] ( 2S, 3S )-3-(4-fluorophenyl)- N,N -Dimethyl-2-(phenylamino)butyramide (9a):

[0286]

[0287] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-fluoro-4-vinylbenzene (24.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound (18.6 mg, 62%, >30:1 B:L, dr=8:1) as a pale yellow solid. a:b (er=98.5:1.5). Crude material 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 8:1. Melting point = 117-120℃ (hexane / EtOAc). =-5.1 (c=0.19, CHCl3); IR (thin film) ν max / cm -1 : 3709 (s), 3681 (s), 3337 (br), 2968 (s), 2937 (s), 2873 (s), 2845 (s), 1637 (s), 1602 (s), 1508 (s); The main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.22 – 7.13 (m, 4H, H 12 + H 13 ), 7.01 – 6.97 (m,2H, H 7 ), 6.72 – 6.69 (m, 1H, H 8 ), 6.61 (d, J = 8.0 Hz, 2H, H 6 ), 4.73 – 4.29(m, 2H, H 3 + H 4 ), 3.33 – 3.27 (m, 1H, H9 ), 2.90 (s, 3H, H 1 ), 2.76 – 2.75 (m,3H, H 1’ ), 1.36 (d, J = 7.0 Hz, 3H, H 10 Characteristic signal of minor diastereomer b: 6.52 (d, J = 8.0 Hz, 2H, H 6 ), 2.68 (s, 3H, H 1 ), 1.43 (d, J = 7.0 Hz, 3H, H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.7 (C10 NMR (126 MHz, CDCl3) 2 ), 161.9 (d, J = 245.0 Hz,C 14 ), 147.1 (C 5 ), 138.2 (d, J = 3.0 Hz, C 11 ), 129.5 – 129.4 (C 7 + C 12 ), 118.4(C 8 ), 115.3 (d, J = 21.0 Hz, H 13 ), 114.2 (C 6 ), 58.5 (C 3 ), 41.9 (C 9 ), 37.1 (C 1 ),35.8 (C 1’ ), 16.5 (C 10 ); 19 F NMR (471 MHz, CDCl3) δ -115.90; HRMS (ESl): for C 18 H 22 FN2O [M+H] + Calculation required m / z 301.1711, obtained m / z 301.1712; Chiral SFC: DAICELCHIRALCEL OD-H column (25 cm), CO2: i-PrOH 97:3, 2.5 mL / min, 140 bar, 40 °C. Retention times: 15.1 min (minor), 16.2 min (major), er = 98.5:1.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0288] ( 2S, 3S )- N,N -Dimethyl-2-(phenylamino)-3-(o-tolyl)butyramide (10a):

[0289]

[0290] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-methyl-2-vinylbenzene (26.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound (21.9 mg, 74%, >30:1 B:L, dr=13:1) as a pale yellow solid. a:b (er=98:2). Crude matter 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 8:1. Melting point = 135-137℃ (hexane / EtOAc). =+19.4 (c=0.25, CHCl3); IR (thin film) ν max / cm -1 :3681 (s), 3329 (br), 3052 (s), 3017 (s), 2967 (s), 2937 (s), 2873 (s), 2845 (s), 1635 (s), 1602 (s); The main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.21 – 7.10 (m, 6H, H 7 + H 14 + H 15 + H 16 + H 17 ), 6.73 – 6.70 (m, 1H, H 8 ), 6.65 (d, J = 7.5 Hz, 2H, H 6 ), 4.76 – 4.38 (m,2H, H 3 + H 4), 3.66 – 3.61 (m, 1H, H 9 ), 2.86 (s, 3H, H 1 ), 2.56 (s, 3H, H 1’ ),2.44 (s, 3H, H 13 ), 1.34 (d, J = 7.0 Hz, 3H, H 10 Characteristic signal of minor diastereomer b: 2.71 (s, 2H, H) 1 ), 2.62 (s, 2H, H 1’ ), 2.35 (s, 2H, H 13 ), 1.41 (d, J = 7.0 Hz, 2H, H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.8 (C10 NMR (126 MHz, CDCl3) 2 ), 147.0(C 5 ), 140.9 (C 11 ), 136.1 (C 12 ), 130.5 (C 14 ), 129.5 (C 7 ), 126.7 (ArC), 126.6 (ArC), 126.2 (ArC), 118.3 (C 8 ), 114.3 (C 6 ), 56.5 (C 3 ), 37.4 (C 9 ), 36.8 (C 1 ),35.7 (C 1’ ), 19.9 (C 13 ), 15.9 (C 10 ); HRMS (ESl): for C 19 H 25 N2O [M+H] + Calculation required m / z 297.1961, obtained m / z 297.1964; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i-PrOH92:8, 2.0 mL / min, 140 bar, 40 °C. Retention times: 8.6 min (major), 9.7 min (minor), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0291] ( 2S, 3S )-3-(2-chlorophenyl)- N,N -Dimethyl-2-(phenylamino)butyramide (11a):

[0292]

[0293] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-chloro-2-vinylbenzene (25.4 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (11.7 mg, 37%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=98:2). Crude matter 1 H NMR analysis showed a B:L ratio >30:1 and dr = 7:1. =+19.7 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3344 (br), 2933 (s), 1639 (s), 1603 (s), 1504 (s), 752 (s), 693 (s); only the main diastereomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.36 (d, J = 9.5 Hz, 1H,H 13 ), 7.29 – 7.27 (m, 1H, H 16 ), 7.24 – 7.15 (m, 4H, H 7 + H 14 + H 15 ), 6.77 (d, J =8.0 Hz, 2H, H 6 ), 6.75 – 6.72 (m, 1H, H 8 ), 5.24 – 4.50 (m, 2H, H 3 + H 4), 3.99 - 3.94 (m, 1H, H 9 ), 2.80 (s, 3H, H 1 ), 2.55 (s, 3H, H 1’ ), 1.39 (d, J = 7.0 Hz,3H, H 10 ); only major diastereomer a 13 C NMR (126 MHz, CDCl3) data: δ 170.8 (C 2 ), 146.5(C 5 ), 139.6 (C 11 ), 134.2 (C 12 ), 129.4 (ArC), 129.3 (C 7 ), 128.8 (ArC), 128.0(ArC), 126.8 (ArC), 118.2 (C 8 ), 114.2 (C 6 ), 55.2 (C 3 ), 37.5 (C 9 ), 36.6 (C 1 ),35.4 (C 1’ ), 14.7 (C 10 ); HRMS (ESl): for C 18 H 21 ClN2ONa [M+Na] + calcd m / z 339.1235, found 339.1250; Chiral SFC: YMC Chiral ART Cellulose-SB column (25 cm), CO2: m / z -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention time: 7.1 min (major), 7.9 min (minor), e.r. = 98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC. i

[0294] 2S, 3S )-3-(2-Fluorophenyl)- N,N dimethyl-2-(phenylamino)butanamide (12a):

[0295]

[0296] ​​General procedure C: Reaction with substrate la (17.8 mg, 0.10 mmol, 100 mol%) and 2-fluorostyrene (24.0 μL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound as a light yellow solid (23.1 mg, 77%, >30:1 B:L, d.r. = 6:1 a:b , e.r. = 98:2). H NMR analysis gave >30:1 B:L and d.r. = 6:1. Melting point = 78-81 °C (hexane / EtOAc); 1 H NMR analysis gave >30:1 B:L and d.r. = 6:1. Melting point = 78-81 °C (hexane / EtOAc);

[0297] = -2.2 (c = 0.34, CHCl3); IR (thin film) v max / cm -1 : 3681 (s), 3333 (br), 2973(s), 2938 (s), 2874 (s), 2845 (s), 1638 (s), 1602 (s), 1584 (s); major diastereoisomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.27 – 7.00 (m, 6H, H 7 + H 13 + H 14 + H 15 +H 16 ), 6.71 – 6.62 (m, 3H, H 6 + H 8 ), 4.87 – 4.38 (m, 2H, H 3 + H 4 ), 3.70 – 3.64(m, 1H, H 9 ), 2.88 (s, 3H, H 1 ), 2.76 (s, 3H, H 1’ ), 1.37 (d, J = 7.0 Hz, 3H,H 10 ). Characteristic signals of minor diastereoisomer b: 6.37 (d, J = 7.0 Hz, 3H, H 6 ), 3.01 (s, 4H,H 1 ), 2.86 (s, 4H, H 1’ ); only major diastereoisomer a 13C10 NMR (126 MHz, CDCl3) data: δ 171.7 (C10 NMR (126 MHz, CDCl3) 2 ), 161.3 (d, J = 244.0 Hz, C 12 ), 147.1 (C 5 ), 129.5 – 129.2 (m, ArC), 128.5 (d, J = 8.5 Hz, ArC), 124.3 (d, J = 3.5 Hz, C 15 ), 118.2 (C 8 ), 115.3 (d, J = 22.7 Hz, C 13 ), 114.1 (C 6 ), 56.6 (C 3 ), 37.0 (C 1 ), 35.7 (C 1’ ), 35.6 (C 9 ), 15.2(C 10 ); 19 F NMR (471 MHz, CDCl3) δ -117.92 (dt, J = 12.0, 6.5 Hz), -118.48 (dt, J = 12.0, 6.5 Hz); HRMS (ESl): for C 18 H 22 FN2O [M+H] + Calculation required m / z 301.1711, obtained m / z 301.1713; Chiral SFC: YMC chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 7.7 min (minor), 9.6 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0298] ( 2S, 3S )-3-(3-chlorophenyl)- N,N -Dimethyl-2-(phenylamino)butyramide (13a):

[0299]

[0300] General procedure C: Reaction with substrate la (17.8 mg, 0.10 mmol, 100 mol%) and 1-chloro-3-ethenylbenzene (25.0 pL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound as a yellowish oil (13.3 mg, 42%, >30:1 B:L, d.r. = 9:1 a:b , e.r. = 97:3). H NMR analysis gave >30:1 B:L and d.r. = 9:1. 1 H NMR analysis gave >30:1 B:L and d.r. = 9:1. = -8.8 (c = 0.29, CHCI3); IR (thin film) v max / cm -1 : 3668 (s), 3329 (br), 3055 (s), 3025 (s), 2968 (s), 2936 (s), 2877 (s), 1636 (s), 1601 (s), 1572 (s); major diastereoisomer a 1 H NMR (500 MHz, CDCl3) data: d 7.24 - 7.10 (m, 6H, H 7 + H 12 + H 14 + H 15 + H 16 ), 6.73 - 6.70 (m, 1H, H 8 ), 6.62 (d, J = 8.0 Hz, 2H, H 6 ), 4.68 - 4.32 (m, 2H, H 3 + H 4 ), 3.32 - 3.26 (m, 1H, H 9 ), 2.91 (s, 3H, H 1 ), 2.74 (s, 3H, H 1’ ), 1.35 (d, J = 7.0 Hz, 3H, H 10 ). Characteristic signals of minor diastereoisomer b: 6.54 (d, J = 8.0 Hz, 2H, H 6 ), 2.76 (s, 3H, H 1 ), 2.68 (s, 3H, H 1’ ), 1.44 (d, J= 7.0 Hz, 3H, H 10 ); the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data only: δ 171.5 (C10) 2 ), 146.9 (C 5 ), 144.8 (C 11 ), 134.4 (C 13 ), 129.8 (ArC), 129.5 (C 7 ), 128.1 (ArC), 127.2 (ArC), 126.4 (ArC), 118.5 (C 8 ), 114.3 (C 6 ), 58.2(C 3 ), 42.4 (C 9 ), 37.2 (C 1 ), 35.8 (C 1’ ), 16.2 (C 10 ); HRMS (ESl): for C 18 H 22 ClN2O [M+H] + Calculation required m / z 317.1415, obtained m / z 317.1416; Chiral SFC: YMC chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 9.4 min (minor), 11.8 min (major), er=97:3.

[0301] ( 2S, 3S )- N,N -Dimethyl-3-(perfluorophenyl)-2-(phenylamino)butyramide (14a):

[0302]

[0303] General Procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1,2,3,4,5-pentafluoro-6-vinylbenzene (27.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (27.5 mg, 74%, >30:1 B:L, dr=2:1) ​​as a pale yellow oil. a:b, e.r. = 98.5:1.5). The crude material was purified by flash chromatography (SiO2, 0-10% EtOAc in hexanes) to give 2.5 mg (0.006 mmol, 20%) of the desired product as a yellow solid.1H NMR analysis gave >30:1 B:L and d.r. = 2:1. 1 H NMR analysis gave >30:1 B:L and d.r. = 2:1. = 95.3 (c = 0.13, CHCl3); IR (thin film) v max / cm -1 : 3323 (br), 3058 (s), 3031 (s), 2979 (s), 2940 (s), 2887 (s), 1643 (s), 1602 (s), 1521 (s); diastereomers a and b 1 H NMR (500 MHz, CDC13) data: δ 7.18 - 7.15 (m, 0.8H, H 7b ), δ 7.10 - 7.07 (m, 1.2H, H 7a ), 6.75 - 6.72 (m, 0.4H, H 8b ), 6.71 - 6.68 (m, 0.6H, H 8a ), 6.65 (d, J = 8.0 Hz, 0.7H, H 6b ), 6.54 (d, J = 8.0 Hz, 1.2H, H 6a ), 4.83 - 4.79 (m, 1H, H 3 ), 3.72 - 3.63 (m, 1H, H 9 ), 3.18 (s, 1.8H, H 1a ), 2.99 (s, 1.8H, H 1a’ ), 2.96 (s, 1H, H 1b ), 2.80 (s, 1H, H 1b’ ), 1.46 (d, J = 7.0 Hz, 1.2H, H 10b ), 1.34 (d, J = 7.0 Hz, 1.9H, H 10a ); diastereomers a and b 13 C NMR (126 MHz, CDC13) data: δ 172.6 (C 2a ), 171.7 (C 2b ), 147.2 (C 5 ), 146.9 (C 11 ), 129.6 (C7b ), 129.5 (C 7a ), 119.3 (C 8a ), 118.7 (C 8b ), 114.6(C 6a ), 113.7 (C 6b ), 56.4 (C 3 ), 37.7 (C 1a ), 37.3 (C 1b ), 36.0 (C 1a’ ), 35.9 (C 1b’ ),35.1 (C 9a ), 34.9 (C 9b ), 15.8 (C 10b ), 15.7 (C 10a ); diastereomers a and b 19 F NMR (471MHz, CDCl3) data: δ -141.34 (dd, J = 22.5, 7.5 Hz, C 12 -F b ), -142.52 (dd, J =22.5, 7.5 Hz, C 12 -F b ), -156.28 (t, J = 21.0 Hz, C 14 -F b ), -156.61 (t, J = 21.0Hz, C 14 -F a ), -161.85 (td, J = 22.5, 7.5 Hz, C 13 -F b ), -162.45 (td, J = 22.5, 7.5Hz, C 13 -F a ); HRMS (ESl): for C 18 H 18 F5N2O [M+H] + Calculation required m / z 373.1334, obtained m / z 373.1333; Chiral SFC: DAICEL CHIRALPAK IE column (25 cm), CO2: i-PrOH 98:2, 3.5 mL / min, 140 bar, 40 °C. Retention times: 15.0 min (minor), 15.8 min (major), er = 98.5:1.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0304] ( 2S, 3S )- N,N -dimethyl-3-(1-(methyl-(λ) 1 -alkyl oxide)-(p-tolyl)sulfinyl)-1 H -Indole-3-yl)-2-(phenylamino)butyramide (15a):

[0305]

[0306] General procedure C: with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 1-(methyl-(λ) 1 -alkyl oxide)-(p-tolyl)sulfinyl)-3-vinyl-1 H -Indole (62.4 mg, 0.20 mmol, 200 mol%) was reacted. The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound (40.4 mg, 85%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=98:2). Crude matter 1 H NMR analysis showed a ratio of >30:1 B:L and dr=5:1. =-4.5 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3330 (br), 3053 (s), 1637 (s), 1602 (s), 1497 (s), 1173 (s), 747 (s), 671 (s); only the main diastereomer a 1 H NMR (500 MHz, CDCl3) data: δ 8.02 (d, J = 8.0 Hz, 1H, ArH), 7.70 (d, J =8.0 Hz, 2H, H 20 ), 7.59 (d, J = 8.0 Hz, 1H, ArH), 7.43 (s, 1H, H 18), 7.36 –7.27 (m, 2H, ArH), 7.20 – 7.16 (m, 4H, ArH), 6.76 – 6.74 (m, 1H, H 8 ), 6.66(d, J = 8.0 Hz, 2H, H 6 ), 5.12 – 4.39 (m, 2H, H 3 + H 4 ), 3.61 – 3.56 (m, 1H, H 9 ),2.85 (s, 3H, H 1 ), 2.63 (s, 3H, H 1’ ), 2.34 (s, 3H, H 23 ), 1.45 (d, J = 7.0 Hz, 3H, H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.4 (C10 NMR (126 MHz, CDCl3) 2 ), 146.7(C 5 ), 144.8 (ArC), 135.2 (ArC), 135.1 (ArC), 130.5 (ArC), 129.8 (ArC), 129.3(ArC), 126.6 (C 20 ), 124.8 (ArC), 124.1 (ArC), 123.4 (ArC), 123.2 (ArC), 119.3(ArC), 118.2 (C 8 ), 113.93 (C 6 ), 113.89 (ArC), 56.6 (C 3 ), 37.1 (C 1 ), 35.6 (C 1’ ),33.8 (C 9 ), 21.5 (C 23 ), 16.1 (C 10 ); HRMS (ESl): for C 27 H 29 N3O3SNa [M+Na] + Calculation required m / z 498.1822, obtained m / z498.1826; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2: i -PrOH 70:30, 3.0 mL / min, 180 bar, 40 °C. Retention times: 7.7 min (minor), 8.8 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0307] ( 2S, 3S )- N,N -Dimethyl-3-(naphth-2-yl)-2-(phenylamino)butyramide (16a):

[0308]

[0309] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and 2-vinylnaphthalene (30.8 mg, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (21.9 mg, 66%, >30:1 B:L, dr=7:1) as a pale yellow solid. a:b (er=98:2). Crude matter 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 7:1. Melting point = 148-151℃ (hexane / EtOAc). =-9.6 (c=0.17, CHCl3); IR (thin film) ν max / cm -1 : 3334 (br), 3052 (s), 3017 (s), 2968 (s), 2932 (s), 2874 (s), 1636 (s), 1601 (s), 1504 (s); The main diastereomer a 1 1H NMR (500MHz, CDCl3) data: δ 7.82 – 7.79 (m, 3H, ArH), 7.70 (s, 1H, H 12 ), 7.50 – 7.43 (m,2H, ArH), 7.40 (d, J = 8.5 Hz, 1H, ArH), 7.17 – 7.14 (m, 2H, H 7 ), 6.72 – 6.69 (m, 1H, H) 8 ), 6.66 (d, J= 8.0 Hz, 2H, H 6 ), 4.82 – 4.45 (m, 2H, H 3 + H 4 ), 3.53–3.48 (m, 1H, H) 9 ), 2.89 (s, 3H, H 1 ), 2.62 (s, 3H, H 1’ ), 1.47 (d, J = 7.0 Hz, 3H, H 10 Characteristic signals of minor diastereomer b: 7.13 – 7.10 (m, 2H, H) 7 ), 6.59 (d, J = 8.0Hz, 2H, H 6 ), 2.69 (s, 3H, H 1 ), 2.55 (s, 3H, H 1’ ), 1.56 (d, J = 7.0 Hz, 3H,H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.7 (C10 NMR (126 MHz, CDCl3) 2 ), 147.1(C 5 ), 140.2 (C 11 ), 133.6 (ArC), 132.7 (ArC), 129.5 (C 7 ), 128.2 (ArC), 127.81 (ArC), 127.78 (ArC), 126.6 (ArC), 126.30 (ArC), 126.27 (ArC), 125.8 (ArC), 118.2 (C 8 ), 114.1 (C 6 ), 58.3 (C 3 ), 42.6 (C 9 ), 37.2 (C 1 ), 35.8 (C 1’ ), 16.2 (C 10 ); HRMS (ESl): for C 22 H 25 N2O [M+H] + Calculation required m / z 333.1961, obtained m / z333.1962; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 85:15, 2.0 mL / min, 160 bar, 40 °C. Retention times: 7.9 min (major), 9.5 min (minor), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0310] Compound (17a):

[0311]

[0312] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%) and vinylferrocene (42.4 mg, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (38.2 mg, 98%, >30:1 B:L, dr>20:1) as a yellow oil. a:b (er=98:2). Crude matter 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 5:1. =+126.0 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3335 (br), 3054 (s), 1638 (s), 1602 (s), 1505 (s), 1106 (s), 749 (s); only the main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.18 – 7.15 (m, 2H, H 7 ), 6.71 –6.68 (m, 1H, H 8 ), 6.59 (d, J = 8.0 Hz, 2H, H 6 ), 4.77 (br s, 1H, H 4 ), 4.36 (d, J = 4.0 Hz, 1H, H 3 ), 4.18 – 4.09 (m, 9H, H 12 + H 13 + H 14 + H 15 + H16 + H 17 + H 18 +H 19 + H 20 ), 3.07 – 3.02 (m, 1H, H 9 ), 2.86 (s, 3H, H 1 ), 2.60 (s, 3H, H 1’ ), 1.37(d, J = 6.5 Hz, 3H, H 10 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 171.2 (C10 NMR (126 MHz, CDCl3) 2 ), 146.8 (C 5 ), 129.3 (C 7 ), 117.6 (C 8 ), 113.5 (C 6 ), 69.1 – 66.4 (m,ArC), 58.3 (C 3 ), 37.5 (C 1 ), 36.4 (C 9 ), 35.6 (C 1’ ), 15.2 (C 10 ); HRMS (ESl): for C 22 H 26 FeN2ONa [M+Na] + Calculation required m / z 413.1287, obtained m / z 413.1291; Chiral SFC: YMC chiral ARTCellulose-SC column (25 cm), CO2: i -PrOH 80:20, 3.0 mL / min, 170 bar, 40 °C. Retention times: 7.7 min (minor), 9.3 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0313] (( 2S, 3S )-2-((4-hydroxyphenyl)amino)- N,N -dimethyl-3-(1-(methyl-(λ) 1 -alkyl oxide)-(p-tolyl)sulfinyl)-1 H -Indole-3-yl)butyramide (18a):

[0314]

[0315] General procedure C: The reaction was performed with substrate la (19.4 mg, 0.10 mmol, 100 mol%) and l-(methyl-(λ 1 -oxidoalkyl)-(p-tolyl)sulfinyl)-3-vinyl-l H -indole (62.4 mg, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 35:65) to give the title compound as a light yellow solid (46.2 mg, 94%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 95.5:4.5). The crude material was used as such for the next step. 1 H NMR analysis gave >30:1 B:L and d.r. = 5:1. Melting point = 96-98 °C (hexane / EtOAc); = +2.8 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3348 (br), 3053 (s), 1628 (s), 1515 (s), 1447 (s), 1173 (s), 1125 (s), 747 (s), 671 (s); only major diastereoisomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.98 (d, J = 8.0 Hz, 1H, ArH), 7.68 (d, J = 8.0 Hz, 2H, H 21 ), 7.52 (d, J = 8.0 Hz, 1H, ArH), 7.40 (s, 1H, H 19 ), 7.32 - 7.28 (m, 1H, ArH), 7.25 - 7.22 (m, 1H, ArH), 7.14 (d, J = 8.0 Hz, 2H, H 22 ), 6.60 (d, J = 8.0 Hz, 2H, H 7 ), 6.47 (d, J = 8.0 Hz, 2H, H 6 ), 6.00 (br s, 1H, H 9 ), 4.52 (d, J = 6.0 Hz, 1H, H3 ), 4.15 (br s,1H, H 4 ), 3.51 – 3.46 (m, 1H, H 10 ), 2.81 (s, 3H, H 1 ), 2.63 (s, 3H, H 1’ ), 2.29(s, 3H, H 24 ), 1.41 (d, J = 7.0 Hz, 3H, H 11 ); Only the main diastereomer a 13 C10 NMR (126MHz, CDCl3) data: δ 172.3 (C10) 2 ), 149.1 (C 8 ), 144.9 (C 5 ), 140.5 (ArC), 135.17(ArC), 135.16 (ArC), 130.5 (ArC), 129.8 (C 22 ), 126.6 (C 21 ), 124.8 (ArC), 124.3(ArC), 123.4 (ArC), 123.2 (ArC), 119.4 (ArC), 116.4 (C 7 ), 116.2 (C 6 ), 113.9(C 12 ), 58.8 (C 3 ), 37.1 (C 1 ), 35.8 (C 1’ ), 33.9 (C 10 ), 21.5 (C 24 ), 16.3 (C 11 ); HRMS (ESl): for C 27 H 30 N3O4S [M+H] + Calculation required m / z 492.1952, obtained m / z 492.1966; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i-PrOH 80:20, 2.0 mL / min, 170 bar, 40 °C. Retention times: 13.9 min (major), 16.3 min (minor), er = 95.5:4.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0316] ( 2S, 3S )-3-(3-chlorophenyl)-2-((4-hydroxyphenyl)amino)-1-morpholinobut-1-one (13n):

[0317]

[0318] General procedure C: The reaction was carried out with substrate 1n (23.6 mg, 0.10 mmol, 100 mol%) and 1-chloro-3-vinylbenzene (25.0 µL, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 35:65) to give the title compound (29.9 mg, 80%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=97:3). Coarse materials 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 5:1. =-9.8 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3327 (br), 2968 (s), 1624 (s), 1515 (s), 1432 (s), 1224 (s), 1114 (s), 1033 (s), 827 (s), 783 (s); only the main diastereomer a 1 1H NMR (500 MHz, CDCl3) data: δ 7.24 – 7.21 (m, 3H, H 14 + H 16 + H 17 ), 7.14 – 7.12 (m, 1H, H 18 ), 6.63 (d, J = 8.0Hz, 2H, H 8 ), 6.53 (d, J = 8.0 Hz, 2H, H 7 ), 5.93 (br s, 1H, H 10 ), 4.68 – 3.99(m, 2H, H 4 + H5 ), 3.63 – 3.52 (m, 4H, H 1 + H 2 ), 3.40 – 3.13 (m, 5H, H 1’ + H 2’ +H 11 ), 1.35 (d, J = 7.0 Hz, 3H, H 12 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 170.7 (C10 NMR (126 MHz, CDCl3) 3 ), 149.6 (C 9 ), 144.5 (C 6 ), 139.7 (C 13 ), 134.4 (C 15 ), 129.8(ArC), 127.9 (ArC), 127.2 (ArC), 126.2 (C 18 ), 117.0 (C 8 ), 116.3 (C 7 ), 66.7(C 1 ), 66.2 (C 1’ ), 60.2 (C 4 ), 46.2 (C 2 ), 42.5 (C 2’ ), 42.1 (C 11 ), 16.5 (C 12 ); HRMS (ESl): for C 20 H 24 ClN2O3 [M+H] + Calculation required m / z 375.1470, obtained m / z 375.1479; Chiral SFC: YMC chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 80:20, 2.0 mL / min, 170 bar, 40 °C. Retention times: 7.5 min (minor), 7.9 min (major), er=97:3. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0319] (s)- N,N 3-Trimethyl-3-phenyl-2-(phenylamino)butyramide (19a):

[0320]

[0321] General procedure C: Reaction with substrate la (17.8 mg, 0.10 mmol, 100 mol%) and prop-1-en-2-ylbenzene (52.0 μL, 0.40 mmol, 400 mol%) and run for 96 h at 140 °C. The residue was purified by FCC (hexane / EtOAc 65:35) to give the title compound as a light yellow solid (6.2 mg, 21%, >30:1 B:L, e.r. = 95:5). The crude material was analyzed by1H NMR. 1 H NMR analysis gave >30:1 B:L. Melting point = 121-123 °C (hexane / EtOAc). = 15.8 (c = 1.0, CHCl3); IR (thin film) v max / cm -1 : 3335 (br), 2933 (s), 1636 (s), 1601 (s), 1498 (s), 750 (s), 694 (s); 1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 10.0 Hz, 2H, H 12 ), 7.34 - 7.30 (m, 2H, H 13 ), 7.25 - 7.22 (m, 1H, H 14 ), 7.16 - 7.12 (m, 2H, H 7 ), 6.73 - 6.70 (m, 1H, H 8 ), 6.65 (d, J = 7.5 Hz, 2H, H 6 ), 4.81 (br s, 1H, H 4 ), 4.35 (s, 1H, H 3 ), 2.68 (s, 3H, H 1 ), 2.26 (s, 3H, H 1’ ), 1.59 (s, 3H, H 10 ), 1.52 (s, 3H, H 10’ ); 13 C NMR (126 MHz, CDCl3) δ 172.0 (C 2 ), 147.9 (C 5 ), 146.1 (C 11),129.3 (C 7 ), 128.0 (C 13 ), 126.9 (C 12 ), 126.6 (C 14 ), 118.3 (C 8 ), 114.2 (C 6 ), 61.6(C 3 ), 42.7 (C 9 ), 36.8 (C 1 ), 35.2 (C 1’ ), 26.3 (C 10 ), 22.8 (C 10’ ); HRMS (ESl): for C 19 H 25 N2O [M+H] + Calculation required m / z 297.1961, obtained m / z 297.1959; Chiral SFC: YMC chiral ARTCellulose-SC column (25 cm), CO2: i -PrOH 90:10, 2.0 mL / min, 145 bar, 40 °C. Retention time: 5.4 min (major), 7.8 min (minor), er=95:5.

[0322] ( 2R, 3R )- N,N -Dimethyl-3-phenyl-2-(phenylamino)butyramide (3a'):

[0323]

[0324] General procedure C: The reaction was carried out with substrate 1a (17.8 mg, 0.10 mmol, 100 mol%), styrene (23.0 µL, 0.20 mmol, 200 mol%), and (s)-SEGPHOS (3.05 mg, 5.00 μmol, 5 mol%). The residue was purified by FCC (hexane / EtOAc 70:30) to give the title compound (25.4 mg, 90%, >30:1B:L, dr>20:1) as a pale yellow solid. a:b (er=2.5:97.5). Crude material 1 ¹H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 9:1. Melting point = 101-103℃ (hexane / EtOAc). =+8.8 (c=1.0 CHCl3); Chiral SFC: YMC chiral ARTCellulose-SC column (25 cm), CO2: i -PrOH 80:20, 2.0 mL / min, 170 bar, 40 °C. Retention times: 4.9 min (major), 5.9 min (minor), er = 2.5:97.5. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0325] ( 4S, 5S )-2,2,5-Trimethyl-4-(phenylamino)non-3-one (20s):

[0326]

[0327] General Procedure C: Using substrate 1s (19.1 mg, 0.10 mmol, 100 mol%), hex-1-ene (125 µL, 1.00 mmol, 1000 mol%), Ir(cod)2BARF (12.7 mg, 0.01 mmol, 10 mol%) and ( R The reaction was carried out with DM-SEGPHOS (7.23 mg, 0.01 mol, 10 mol%) and run at 110 °C in mesitylene (0.2 mL). The residue was purified by FCC (hexane / EtOAc 90:10) to give the title compound (20.6 mg, 75%, >30:1 B:L, dr>20:1) as a pale yellow oil. a:b (er=94:6). Coarse materials 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 5:1. =+9.9 (c=1.0 CHC) l3 ); IR (thin film) ν max / cm -1 : 3381 (br), 2960 (s), 2929 (s), 1699 (s), 1601 (s), 1513 (s), 1497 (s), 745 (s), 690 (s); only the main diastereomer a 1 ¹H NMR (500 MHz, CDCl₃) data: δ 7.16 – 7.12 (m, 2H, H₂) 8 ), 6.71 – 6.68 (s, 1H, H 9 ),6.63 (d, J = 7.5 Hz, 2H, H7 ), 4.53 - 3.93 (m, 2H, H 4 + H 5 ), 1.96 - 1.88 (m, 1H, H 10 ), 1.42 - 1.26 (m, 6H, H 12 + H 13 + H 14 ), 1.14 (s, 9H, H 1 ), 0.91 (t, J =7.0 Hz, 3H, H 15 ), 0.86 (d, J = 7.0 Hz, 3H, H 11 );only major diastereomer a 13 C NMR (126 MHz, CDC13) data: δ 216.2 (C 3 ), 148.0 (C 6 ), 129.3 (C 8 ), 118.0 (C 9 ), 114.2 (C 7 ), 60.9 (C 4 ), 43.4 (C 2 ), 35.4 (C 10 ), 34.4 (C 12 ), 29.7 (C 13 ), 26.8 (C 1 ), 22.8 (C 14 ), 14.1 (C 11 ), 13.9 (C 15 ) HRMS (ESI): calcd for C 18 H 30 NO [M+H] + calcd m / z 276.2322, found m / z 276.2334; Chiral SFC: YMC Chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 97:3, 1.0 mL / min, 140 bar, 40 °C. Retention time: 6.1 min (major), 6.5 min (minor), e.r. = 94:6. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0328] ( 4S, 5S)-2,2,5,7-tetramethyl-4-(phenylamino)octan-3-one (21s):

[0329]

[0330] General procedure C: The reaction was performed with substrate 1s (19.1 mg, 0.10 mmol, 100 mol%), 4-methylpent-1-ene (127 µL, 1.00 mmol, 1000 mol%), Ir(cod)2BARF (12.7 mg, 0.01 mmol, 10 mol%) and ( R )-DM-SEGPHOS (7.23 mg, 0.01 mmol, 10 mol%) and run in mese (0.2 mL) at 110 °C. The residue was purified by FCC (hexane / EtOAc 90:10) to give the title compound as a yellowish oil (18.7 mg, 68%, >30:1 B:L, d.r. = 2:1 a:b , e.r. = 90:10. The crude material was analyzed by1H NMR to be >30:1 B:L and d.r. = 2:1. 1 H NMR analysis gave >30:1 B:L and d.r. = 2:1. = +1.5 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3380 (br), 2958 (s), 2971(s), 1699 (s), 1601 (s), 1498 (s), 747 (s), 691 (s); diastereoisomers a and b 1 H NMR (500 MHz, CDCl3) data: δ 7.16 – 7.12 (m, 2H, H 8 ), 6.71 – 6.68 (m, 1H, H 9 ), 6.62(d, J = 7.5 Hz, 2H, H 7 ), 4.42 – 4.30 (m, 1H, H 4 ), 4.18 – 4.07 (m, 1H, H 5 ),2.05 – 1.97 (m, 1H, H 10 ), 1.75 – 1.66 (m, 1H, H 13 ), 1.28 – 1.25 (m, 2H, H 12 ),1.14 – 1.13 (m, 9H, H 1 ), 0.99 (d,J = 6.5 Hz, 1H, H 14b ), 0.94 (d, J = 6.5 Hz, 2H, H 14a ), 0.89 (d, J = 6.5 Hz, 3H, H 11 ), 0.84 (d, J = 6.5 Hz, 2H, H 14a’ ), 0.80 (d, J = 6.5 Hz, 1H, H 14b’ ); diastereoisomers a and b 13 C NMR (126 MHz, CDC13) data: δ 216.2 (C 3b ), 216.1 (C 3a ), 148.1 (C 6a ), 147.9 (C 6b ), 129.3 (C 8 ), 118.0 (C 9a ), 117.8 (C 9b ), 114.1 (C 7a ), 113.8 (C 7b ), 62.3 (C 4b ), 61.4 (C 4a ), 44.3 (C 2a ), 43.3 (C 2b ), 39.8 (C 10 ), 33.6 (C 13b ), 33.0 (C 13a ), 26.73 (C 1a ), 26.66 (C 1b ), 25.24 (C 12a ), 25.17 (C 12b ), 24.3 (C 14b ), 23.5 (C 14a ), 21.9 (C 14a’ ), 21.1 (C 14b’ ), 17.5 (C 11b ), 13.7 (C 11a ); HRMS (ES1): for C 18 H 30 NO [M+H] +Calculated requires m / z 276.2322, found m / z 276.2331 ; Chiral SFC: YMC Chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 97:3, 1.0 mL / min, 140 bar, 40 °C. Retention time: 5.8 min (major), 6.1 min (minor), e.r. = 90:10. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0331] ( 4S, 5S )-2,2,5,6-tetramethyl-4-(phenylamino)heptan-3-one (22s):

[0332]

[0333] General procedure C: reaction with substrate 1s (19.1 mg, 0.10 mmol, 100 mol%), 3-methylbut-1-ene (129 µL, 1.00 mmol, 1000 mol%), Ir(cod)2BARF (12.7 mg, 0.01 mmol, 10 mol%) and ( R )-DM-SEGPHOS (7.23 mg, 0.01 mmol, 10 mol%) and run at 110 °C in mesitylene (0.2 mL). The residue was purified by FCC (hexane / EtOAc 90:10) to give the title compound as a pale yellow oil (11.8 mg, 45%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 71:29). The crude material was analysed by1H NMR to give >30:1 B:L and d.r. = 16:1. 1 H NMR analysis gave >30:1 B:L and d.r. = 16:1. = +20.6 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3374 (br), 2958 (s), 1699(s), 1602 (s), 1498 (s), 749 (s), 566 (s); only major diastereomer a 1 H NMR (500MHz, CDCl3) data: δ 7.16 – 7.12 (m, 2H, H 8 ), 6.71 – 6.68 (m, 1H, H 9 ), 6.62 (d, J = 7.5 Hz, 2H, H 7), 4.66 (d, J = 3.0 Hz, 1H, H 4 ), 4.09 (br s, 1H, H 5 ), 1.75 –1.64 (m, 2H, H 10 + H 12 ), 1.15 (s, 9H, H 1 ), 1.07 (d, J = 6.0 Hz, 3H, H 13 ), 0.95(d, J = 6.0 Hz, 3H, H 13’ ), 0.84 (d, J = 6.5 Hz, 3H, H 11 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 216.4 (C10) 3 ), 147.9 (C 6 ), 129.3 (C 8 ), 118.1(C 9 ), 114.1 (C 7 ), 59.3 (C 4 ), 43.4 (C 2 ), 41.0 (C 10 ), 30.7 (C 12 ), 26.9 (C 1 ), 21.7(C 13 ), 19.5 (C 13’ ), 10.2 (C 11 ); HRMS (ESl): for C 17 H 28 NO [M+H] + The calculation requires m / z 262.2165, so m / z is found to be 262.2181; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2: i -PrOH97:3, 1.0 mL / min, 140 bar, 40 °C. Retention times: 9.5 min (major), 10.3 min (minor), er=71:29. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0334] ( 4S,5S)-9-((tert-butyldimethylsilyl)oxy)-2,2,5-trimethyl-4- (phenylamino)nonan-3-one (23s):

[0335]

[0336] General procedure C: The reaction was performed with substrate 1s (19.1 mg, 0.10 mmol, 100 mol%), tert-butyl(hex-5-en-1-yloxy)dimethylsilane (42.8 mg, 1.00 mmol, 1000 mol%), Ir(cod)2BARF (12.7 mg, 0.01 mmol, 10 mol%) and R -DM-SEGPHOS (7.23 mg, 0.01 mmol / L, 10 mol%) and run in mesitylene (0.2 mL) at 110 °C. The residue was purified by FCC (hexane / EtOAc 97:3) to give the title compound (16.2 mg, 40%, >30:1 B:L, d.r. = 5:1 a:b , e.r. = 96:4) as a light yellow oil. The crude material was analyzed by1H NMR to be >30:1 B:L and d.r. = 5:1. 1 H NMR analysis gave >30:1 B:L and d.r. = 5:1. = +19.7 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3381 (br), 2930 (s), 2857 (s), 1701 (s), 1601 (s), 1498 (s), 1251 (s), 1097 (s), 835 (s), 775 (s), 747 (s); diastereoisomers a and b 1 H NMR (500 MHz, CDCl3) data: δ 7.15 - 7.12 (m, 2H, H 8 ), 6.71 - 6.67 (m, 1H, H 9 ), 6.64 - 6.61 (m, 2H, H 7 ), 4.60 - 4.12 (m, 2H, H 4 + H 5 ), 3.63 - 3.55 (m, 2H, H 15 ), 1.94 - 1.88 (m, 1H, H 10 ), 1.56 - 1.25 (m, 6H, H 12 + H 13 + H 14), 1.14 - 1.12 (m, 9H, H 1 ), 0.90 - 0.86 (m, 12H, H 11 + H 17 ), 0.05 - 0.03 (m, 6H, H 16 ); only major diastereomer a of 13 C NMR (126 MHz, CDC13) data: δ 216.1 (C 3 ), 148.0 (C 6 ), 129.3 (C 8 ), 118.1 (C 9 ), 114.2 (C 7 ), 63.1 (C 15 ), 60.9 (C 4 ), 43.4 (C 2 ), 35.5 (C 10 ), 34.5 (C 14 ), 32.9 (C 12 ), 26.8 (C 17 ), 26.0 (C 1 ), 23.9 (C 13 ), 18.4 (C 18 ), 13.9 (C 11 ), -5.3 (C 16 ); HRMS (ES1): calcd for C 24 H 43 NO2SiNa [M + Na] + found m / z 428.2947; Chiral SFC: YMC Chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 97:3, 0.5 mL / min, 140 bar, 40 °C. Retention time: 13.6 min (major), 14.4 min (minor), e.r. = 96:4. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0337] ( 2R,3R )- N,N - dimethyl-3-phenyl-2-((phenylamino)methyl)butanamide (homologous series):

[0338]

[0339] General procedure C: The reaction was performed with substrate 1p (19.2 mg, 0.10 mmol, 100 mol%) and styrene (35.4 μL, 0.30 mmol, 300 mol%), Ir(cod)Cl 2 BARF (12.7 mg, 0.01 mmol, 10 mol%) and (PPh3)3Rh(COD) (12.7 mg, 0.01 mmol, 10 mol%) were used and run at 140 °C for 96 h. The residue was purified by FCC (hexane / EtOAc 50:50) to give the title compound as a yellowish oil (16.3 mg, 55%, >30:1 B:L, d.r. >20:1 R , e.r. = 71:29). The crude material was purified by HPLC (hexane / EtOAc 80:20) to give the title compound as a yellowish oil (10.0 mg, 33%, >30:1 B:L, d.r. >20:1 a:b , e.r. = 71:29). The crude material was purified by HPLC (hexane / EtOAc 80:20) to give the title compound as a yellowish oil (10.0 mg, 33%, >30:1 B:L, d.r. >20:1 1 H NMR analysis gave >30:1 B:L and d.r. = 2:1. = -16.3 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3348 (br), 2923 (s), 2854 (s), 1628 (s), 1602 (s), 1496 (s), 750 (s), 670 (s); only major diastereoisomer a 1 H NMR (500 MHz, CDCl3) data: δ 7.37 - 7.33 (m, 2H, H 14 ), 7.27 - 7.25 (m, 3H, H 13 + H 15 ), 7.10 - 7.06 (m, 2H, H 8 ), 6.64 - 6.61 (m, 1H H 9 ), 6.33 (d, J = 8.0 Hz, 2H, H 7 ), 3.97 (br s, 1H, H 5 ), 3.34 - 3.30 (m, 1H, H 3 ), 3.26 - 3.22 (m, 1H, H 4 ), 3.13 - 3.07 (m, 1H, H 10 ), 3.00 - 2.96 (m, 4H, H 1 + H 4’ ), 2.86 (s, 3H, H 1’ ), 1.22 (d, J= 7.0 Hz, 3H,H 11 ); Only the main diastereomer a 13 C10 NMR (126 MHz, CDCl3) data: δ 174.5 (C10 NMR (126 MHz, CDCl3) 2 ), 147.7(C 6 ), 144.5 (C 12 ), 129.2 (C 8 ), 128.7 (C 14 ), 127.4 (C 13 ), 126.8 (C 15 ), 117.2 (C 9 ),112.7 (C 7 ), 46.7 (C 3 ), 45.3 (C 4 ), 41.5 (C 10 ), 37.7 (C 1 ), 35.8 (C 1’ ), 20.2 (C 11 ); HRMS (ESl): for C 19 H 25 N2O [M+H] + The calculation requires m / z 297.1961, and the obtained m / z is 297.1968; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 80:20, 2.0 mL / min, 170 bar, 40 °C. Retention times: 3.6 min (minor), 4.9 min (major), er=71:29. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0340] (s)-2-((4-hydroxyphenyl)amino)-3-methyl-1-(pyrrolidone-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)but-1-one (25t):

[0341]

[0342] Substrate 2-((4-hydroxyphenyl)amino)-1-(pyrrolidone-1-yl)ethyl-1-one (22.0 mg, 0.10 mmol, 100 mol%), [Ir(cod)2]BARF (9.54 mg, 7.50 μmol, 7.5 mol%), and (R )-DM-SEGPHOS (5.42 mg, 7.5 μmol, 7.5%). The Schlenk tube was evacuated and backfilled with N2(three cycles) before 4,4,5,5-tetramethyl-2-(prop-1 -en-2-yl)-1,3,2-dioxaborolane (75.0 μL, 0.40 mmol, 400 mol%) was added, followed by t -BuOH (0.1 mL, 1.0 M). The tube was sealed and heated at 110 °C for 96 h. After cooling to rt, the solvent was removed under reduced pressure and the crude reaction mixture was purified by FCC (hexane / EtOAc 50:50) to give the title compound as a pale yellow oil (26.0 mg, 67%, >30:1 B:L, e.r. = 93:7). The crude material was 1 >30:1 B:L by1H NMR analysis. = 32.7 (c = 1.0, CHCl3); IR (thin film) v max / cm -1 : 2917 (s), 2849 (s), 1602 (s), 1508 (s), 1462 (s), 1364 (s), 1228 (s), 730 (s), 7008 (s); 1 H NMR (500 MHz, CDCl3) δ 6.68 (d, J = 8.5 Hz, 2H, H 17 + H 19 ), 6.53 (d, J = 8.0 Hz, 2H, H 16 + H 20 ), 4.47 (br. s, 1H, H 3 ), 3.97 (s, 1H, H 8 ), 3.59 – 3.39 (m, 4H, H 22 +H 25 ), 1.89 – 1.75 (m, 4H, H 23 + H 24 ), 1.28 (s, 12H, H 30-33 ), 1.01 (s, 3H, H 2 ), 0.96 (s, 3H, H 9 ); 13 C NMR (126 MHz, CDCl3) δ 174.6 (C7 ), 148.8 (C 15 ), 141.4(C 18 ), 116.3 (C 17 + C 19 ), 115.4 (C 16 + C 20 ), 83.0 (C 27 ), 82.0 (C 28 ), 75.1 (C 5 ),66.2 (C 8 ), 47.3 (C 22 ), 46.8 (C 25 ), 26.1 (C 30 ), 25.0 (C 23 ), 24.9 (C 24 ), 24.6(C 31 ), 24.0 (C 32 ), 22.9 (C 2 ), 21.3 (C 9 ); HRMS (ESl): for C 21 H 34 BN2O4 [M+H] + Calculation required m / z 389.2606, obtained m / z 389.2615; Chiral SFC: YMC chiral ART Cellulose-SC column (25 cm, CO2: i -PrOH 75:25, 3.0 mL / min, 228 bar, room temperature. Retention time: 2.1 min (minor), 2.5 min (major), er = 93:7.

[0343] The racemic product was also obtained using the above procedure (using...) rac -BINAP replaces ( R (-DM-SEGPHOS), and purified by FCC.

[0344] Applications and Derivatives

[0345] 4-(( 2S,3S )-4-(dimethylamino)-4-oxo-3-(phenylamino)but-2-yl)benzyl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H -Indole-3-yl)acetate (24a):

[0346]

[0347] General procedure C: Reaction with substrate la (17.8 mg, 0.10 mmol, 100 mol%) and 4-vinylbenzyl 2-(l-(4-chlorobenzoyl)-5-methoxy-2-methyl-l H heteroaryl)acetate (94.6 mg, 0.20 mmol, 200 mol%). The residue was purified by FCC (hexane / EtOAc 60:40) to give the title compound as a yellowish oil (41.0 mg, 63%, >30:1 B:L, d.r. = 20:1 a:b , e.r. = 98:2). The crude material was used without further purification. 1 H NMR analysis gave >30:1 B:L and d.r. = 10:1. = -4.0 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3342 (br), 2931 (s), 1736 (s), 1681 (s), 1640 (s), 1602 (s), 1478 (s), 1316 (s), 1262 (s), 1160 (s), 754 (s), 735 (s); only major diastereomer a's 1 H NMR (500 MHz, CDCl3) data: δ 7.68 (d, J = 8.5 Hz, 2H, H 30 ), 7.49 (d, J = 8.5 Hz, 2H, H 31 ), 7.30 - 7.23 (m, 4H, ArH), 7.18 - 7.15 (m, 2H, H 7 ), 6.96 (d, J = 2.5 Hz, 1H, H 20 ), 6.90 (d, J = 9.0 Hz, 1H, ArH), 6.75 - 6.63 (m, 4H, ArH), 5.14 (s, 2H, H 15 ), 4.70 - 4.34 (m, 2H, H 3 + H 4 ), 3.80 (s, 3H, H 22 ), 3.73 (s, 2H, H 17), 3.36 - 3.30 (m, 1H, H 9 ), 2.91 (s, 3H, H 1 ), 2.73 (s, 3H, H 1’ ), 2.40 (s, 3H, H 27 ), 1.39 (d, J = 7.0 Hz,3H, H 10 ); only major diastereomer a 13 C NMR (126 MHz, CDCl3) data: δ 171.5 (C 2 ), 170.6(C 16 ), 168.3 (C 28 ), 156.0 (C 21 ), 146.9 (C 5 ), 142.7 (C 11 ), 139.3 (ArC), 136.0(ArC), 134.3 (ArC), 133.8 (ArC), 131.2 (C 30 ), 130.8 (C 20 ), 130.6 (ArC), 129.3(C 7 ), 129.1 (C 31 ), 128.2 (C 13 ), 128.1 (C 12 ), 118.3 (C 8 ), 114.9 (ArC), 114.1(C 6 ), 112.4 (ArC), 111.7 (ArC), 101.3 (C 20 ), 66.5 (C 15 ), 58.3 (C 3 ), 55.6 (C 22 ),42.2 (C 9 ), 36.9 (C 1 ), 35.6 (C 1’ ), 30.4 (C 17 ), 16.3 (C 10 ), 13.4 (C 27 ); HRMS (ESl): for C 38 H 39 ClN3O5 [M+H] +The calculation requires m / z 652.2573, and the obtained m / z is 652.2592; Chiral SFC: DAICELCHIRALCEL IE column (25 cm), CO2: i -PrOH 70:30, 4.0 mL / min, 180 bar, 40 °C. Retention times: 21.5 min (minor), 23.5 min (major), er=98:2. To facilitate analysis by SFC, the major diastereomer was separated from the minor diastereomer by FCC.

[0348] Synthesis of 3a at a scale of 1.00 mmol:

[0349] Amide 1a (178 mg, 1.00 mmol, 100 mol%), [Ir(cod)2]BARF (63.6 mg, 0.05 mmol, 5 mol%), and ( R )-SEGPHOS (30.5 mg, 0.05 mmol, 5 mol%). The Schlenk tube was emptied and refilled with N2 (three cycles), then styrene (229 µL, 2.00 mmol, 200 mol%) was added, followed by 1,4-dioxane (2.0 mL). The tube was sealed and heated at 130 °C for 72 hours. After cooling to room temperature, the solvent was removed under reduced pressure, and the crude reaction mixture was purified by FCC (hexane / EtOAc 65:35) to give the desired product as a pale yellow solid (265 mg, 94%, >30:1 B:L, dr=10:1, er=98:2). The crude material... 1 H NMR analysis showed a B:L ratio >30:1 and a dr ratio of 10:1.

[0350] ( 2S,3S )-3-phenyl-2-(phenylamino)but-1-ol (50):

[0351]

[0352] LiAlH4(7.60 mg, 0.20 mmol, 200 mol%) was added slowly in portions to a solution of 3f (32.4 mg, 0.10 mmol, 100 mol%) in dry THF (1.0 mL) at 0 °C in a sealed tube. After the addition was complete, the reaction mixture was stirred at 0 °C for 20 min and the progress of the reaction was monitored by TLC. Upon completion, water (1 drop) was added to the reaction mixture, followed by 15% w / w aqueous NaOH (1 drop) and water (2 drops). The resulting suspension was then allowed to warm to room temperature and stirred for 15 min, followed by the addition of anhydrous Na2S04. The mixture was stirred for an additional 15 min before being filtered. The filtrate was collected and the solvent was removed under vacuum to give the aminoaldehyde intermediate, which was used in the next step without purification.

[0353] A solution of the above synthesized aminoaldehyde intermediate in MeOH (1.0 mL) was stirred at 0 °C in a sealed tube. NaBH4(15.1 mg, 0.40 mmol, 400 mol%) was then added to the stirring solution. The solution was then stirred at ambient temperature for 1 h. Upon completion, the reaction mixture was transferred to a separatory funnel and water (~5.0 mL) was added. The aqueous phase was extracted with EtOAc (~3 x 10.0 mL). The combined organic phases were dried over anhydrous MgS04. The filtrate was concentrated in vacuo followed by FCC (hexanes / EtOAc 25:75) to give the desired product as a colorless oil (12.1 mg, 50%, over 2 steps, d.r. >20:1, e.r. = 99:1).

[0354] = +26.4 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3399 (br), 2964 (s), 2928(s), 1600 (s), 1495 (s), 1317 (s), 1261 (s), 747 (s), 691 (s); 1 H NMR (500MHz, CDCl3) δ 7.33 – 7.21 (m, 5H, H 12 + H 13 + H 14 ), 7.16 – 7.13 (m, 2H, H 7 ),6.73 – 6.70 (m, 1H, H 8 ), 6.62 (d, J = 7.5 Hz, 2H, H 6 ), 3.76 – 3.68 (m, 2H,H2 ), 3.61 – 3.26 (m, 2H, H 3 + H 4 ), 3.19 – 3.14 (m, 1H, H 9 ), 1.91 (br s, 1H,H 1 ), 1.35 (d, J = 7.0 Hz, 3H, H 10 ); 13 C NMR (126 MHz, CDCl3) δ 147.9 (C 5 ), 142.7(C 11 ), 129.3 (C 7 ), 128.6 (C 13 ), 127.9 (C 12 ), 126.8 (C 14 ), 118.0 (C 8 ), 113.9 (C 6 ),62.5 (C 2 ), 60.2 (C 3 ), 41.0 (C 9 ), 18.1 (C 10 ); HRMS (ESl): for C 16 H 20 NO [M+H] + The calculation requires m / z 242.1539, and the obtained m / z is 242.1540; Chiral SFC: YMC chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 92:8, 2.0 mL / min, 140 bar, 40 °C. Retention times: 6.4 min (minor), 7.1 min (major), er=99:1.

[0355] ( 2S,3S )-3-Phenylon-2-(Phenylonamino)butanal (51):

[0356]

[0357] LiAIH4(7.60 mg, 0.20 mmol, 200 mol%) was added slowly in portions to a solution of 3f (32.4 mg, 0.10 mmol, 100 mol%) in dry THF (1.0 mL) at 0 °C in a sealed tube. After the addition was complete, the reaction mixture was stirred at 0 °C for 20 min and the progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to 0 °C and water (1 drop) was added, followed by 15% w / w aqueous NaOH solution (1 drop) and water (2 drops). The resulting suspension was then allowed to warm to room temperature and stirred for 15 min, followed by the addition of anhydrous Na2S04. The mixture was stirred for an additional 15 min before it was filtered. The filtrate was concentrated in vacuo followed by FCC (hexane / EtOAc 10:90) to give the desired product as a colorless oil (16.3 mg, 68%, d.r. >20:1, e.r. = 98.5:1.5). = +17.7 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3404 (br), 3027(s), 2970 (s), 2931 (s), 1726 (s), 1599 (s), 1494 (s), 1310 (s), 1266 (s), 748 (s), 698 (s); 1 H NMR (500 MHz, CDCl3) δ 9.53 (d, J = 2.5 Hz, 1H, H 1 ), 7.39– 7.28 (m, 5H, H 11 + H 12 + H 13 ), 7.19 – 7.15 (m, 2H, H 6 ), 6.76 – 6.73 (m, 1H,H 7 ), 6.60 (d, J = 7.5 Hz, 2H, H 5 ), 4.21 – 3.95 (m, 2H, H 2 + H 3 ), 3.43 – 3.38(m, 1H, H 8 ), 1.38 (d, J = 7.0 Hz, 3H, H 9 ); 13 C NMR (126 MHz, CDCl3) δ 202.3(C 1 ), 146.6 (C4 ), 140.8 (C 10 ), 129.4 (C 6 ), 129.0 (C 12 ), 127.8 (C 11 ), 127.4 (C 13 ),118.4 (C 7 ), 113.3 (C 5 ), 67.3 (C 2 ), 39.7 (C 8 ), 17.1 (C 9 ); HRMS (ESl): for C 16 H 18 NO[M+H] + The calculation requires m / z 240.1383, and the result is m / z 240.1389; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i -PrOH 95:5, 1.0 mL / min, 140 bar, 40 °C. Retention time: 15.3 min (major), 16.4 min (minor), er=98.5:1.5.

[0358] N-(( 2S,3S )-1-morpholino-3-phenylbut-2-yl)aniline (52):

[0359]

[0360] BH3 was added to a solution of 3f (32.4 mg, 0.10 mmol, 100 mol%) in anhydrous THF (1.0 mL) at room temperature and under N2. A solution of THF in THF (1.0 M, 0.5 mL, 0.50 mmol, 500 mol%) was prepared. The mixture was then heated to 90 °C for 4 hours, and the progress of the reaction was monitored by TLC. After completion, the mixture was cooled to 0 °C, and water (5.0 mL) was slowly added. The mixture was extracted with EtOAc (approximately 3 × 10.0 mL). The combined organic phases were dried over anhydrous MgSO4. The filtrate was concentrated under vacuum and then subjected to FCC (hexane / EtOAc 35:65) to give the desired product as a colorless oil (21.4 mg, 69%, dr > 20:1, er = 99:1). =-7.9 (c=1.0 CHCl3); IR (thin film) ν max / cm -1: 3366 (br), 2961 (s), 2852 (s), 1601 (s), 1504 (s), 1117 (s), 748 (s), 693 (s); 1 H NMR (500 MHz, CDCl3) δ 7.40 – 7.26 (m, 5H, H 13 + H 14 + H 15 ), 7.22 – 7.19(m, 2H, H 8 ), 6.73 – 6.68 (m, 3H, H 7 + H 9 ), 3.78 – 3.61 (m, 6H, H 1 + H 4 + H 5 ), 3.49 – 3.44 (m, 1H, H) 10 ), 2.56 – 2.17 (m, 6H, H 2 + H 3 ), 1.38 (d, J = 7.0 Hz, 3H, H 11 ; 13 C NMR (126 MHz, CDCl3) δ 148.2 (C 6 ), 142.4 (C 12 ), 129.3 (C 8 ), 128.4(C 14 ), 128.3 (C 13 ), 126.5 (C 15 ), 117.2 (C 9 ), 113.2 (C 7 ), 66.9 (C 1 ), 59.3 (C 3 ),54.5 (C 4 ), 53.6 (C 2 ), 39.9 (C 10 ), 16.2 (C 11 ); HRMS (ESl): for C 20 H 27 N2O [M+H] + The calculation requires m / z 311.2118, and the obtained m / z is 311.2133; Chiral SFC: DAICEL CHIRALCEL OD-H column (25 cm), CO2: i- PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 5.8 min (minor), 7.3 min (major), e.r. = 99:1.

[0361] ( 2S,3S )-1,3-phenyl-2-(phenylamino)butan-1-one (53):

[0362]

[0363] A solution of PhLi in Et20 (1.9 M, 105 µL, 0.20 mmol, 200 mol%) was then added dropwise to a solution of 3f (32.4 mg, 0.10 mmol, 100 mol%) in dry THF (1.0 mL) at 0 °C over 3 min under N2. The mixture was then stirred at 0 °C for 15 min and the progress of the reaction was monitored by TLC. Upon completion, water (5.0 mL) was slowly added to the mixture to quench the excess PhLi. The mixture was extracted with EtOAc (ca. 3 x 10.0 mL). The combined organic phases were dried over anhydrous MgS04. The filtrate was concentrated in vacuo followed by FCC (EtOAc / hexane 10:90) to give the desired product as a colourless oil (28.4 mg, 90%, d.r. >20:1, e.r. = 99:1). = +66.4 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3379 (br), 3027 (s), 1682 (s), 1601 (s), 1506 (s), 748 (s), 693(s); 1 H NMR (500 MHz, CD2Cl2) δ 7.93 (d, J = 7.5 Hz, 2H, H 3 ), 7.61 – 7.58 (m,1H, H 1 ), 7.49 – 7.46 (m, 2H, H 2 ), 7.26 – 7.18 (m, 3H, H 16 + H 17 ), 7.12 – 7.08(m, 4H, H 10 + H 15 ), 6.68 – 6.65 (m, 3H, H 9 + H 11 ), 5.19 (d, J= 5.0 Hz, 1H, H 6 ),4.37 (br s, 1H, H 7 ), 3.45 – 3.40 (m, 1H, H 12 ), 1.44 (d, J = 7.0 Hz, 3H, H 13 ); 13 C NMR (126 MHz, CD2Cl2) δ 200.4 (C 5 ), 147.8 (C 8 ), 141.4 (C 14 ), 136.3 (C 4 ),133.5 (C 1 ), 129.3 (C 10 ), 128.9 (C 3 ), 128.4 (C 16 ), 128.3 (C 2 ), 128.2 (C 15 ), 127.0(C 17 ), 118.2 (C 11 ), 114.0 (C 9 ), 63.5 (C 6 ), 42.9 (C 12 ), 18.2 (C 13 ); HRMS (ESl): for C 22 H 21 NONa [M+Na] + Calculation required m / z 338.1515, obtained m / z 338.1524; Chiral SFC: DAICELCHIRALCEL IE column (25 cm), CO2: i -PrOH 95:5, 1.0 mL / min, 140 bar, 40 °C. Retention times: 41.4 min (minor), 51.6 min (major), er=99:1.

[0364] (s)-N-(2-phenylpropyl)aniline (54):

[0365]

[0366] Then, concentrated sulfuric acid (0.3 mL) was added dropwise over 2 minutes to a solution of 3f (32.4 mg, 0.10 mmol, 100 mol%) in AcOH (0.1 mL) and water (0.1 mL). The mixture was then stirred at 120 °C for 72 hours, and the progress of the reaction was monitored by TLC. After completion, the mixture was cooled and diluted with water (5.0 mL). 2 N aqueous sodium hydroxide was then added until a pH of 9–10 was reached. The mixture was extracted with EtOAc (approximately 3 × 10.0 mL). The combined organic phases were dried over anhydrous MgSO4. The filtrate was concentrated under vacuum and then subjected to FCC (EtOAc / hexane 2:98) to give the desired product (9.5 mg, 45%, er = 97:3) as a colorless oil. =-24.8 (c=1.0 CHCl3); IR (thin film) ν max / cm -1 : 3415 (br), 3026 (s), 2961 (s), 1602 (s), 1506 (s), 1320 (s), 748 (s), 693 (s); 1 H NMR (500 MHz, CD2Cl2) δ 7.35 – 7.23 (m, 5H, H 10 + H 11 + H 12 ), 7.18 – 7.15(m, 2H, H 2 ), 6.72 – 6.69 (m, 1H, H 1 ), 6.60 (d, J = 7.5 Hz, 2H, H 3 ), 4.09 (brs, 1H, H 5 ), 3.37 – 3.23 (m, 2H, H 6 ), 3.11 – 3.04 (m, 1H, H 7 ), 1.35 (d, J = 7.0Hz, 3H, H 8 ); HRMS (ESl): for C 15 H 18 N [M+H] + The calculation requires m / z 212.1434, and the result is m / z 212.1433; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2: i- PrOH 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention time: 3.0 min (major), 3.3 min (minor), e.r. = 97:3.

[0367] The spectral properties were in agreement with the data available in the literature. 17

[0368] 2S,3S -2-amino- N,N - dimethyl-3-phenylbutanamide (55):

[0369]

[0370] To a solution of 1 g (29.8 mg, 0.10 mmol, 100 mol%) in CH3CN (1.0 mL) and water (0.5 mL) was added (bis(trifluoroacyloxy)iodo)benzene (51.6 mg, 0.12 mmol, 120 mol%) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 h and the progress of the reaction was monitored by TLC. Upon completion, the mixture was cooled to 0 °C and saturated Na2S203solution (~0.2 mL) was added slowly to quench the excess PIFA. The mixture was extracted with dichloromethane (~5 x 5.0 mL). The combined organic phases were dried over anhydrous MgS04. The filtrate was concentrated in vacuo followed by FCC (basic AI203, dichloromethane / MeOH 90:10) to give the desired product as a light yellow oil (19.8 mg, 96%, d.r. >20:1, e.r. = 98:2). = +10.1 (c = 1.0 CHC13); 1 H NMR (500 MHz, CD2Cl2) δ 7.34 - 7.20 (m, 5H, H 8 + H 9 + H 10 ), 3.82 (d, J = 8.5 Hz, 1H, H 3 ), 3.05 - 3.00 (m, 4H, H 1 + H 5 ), 2.99 (s, 3H, H 1’ ), 1.58 (br s, 2H, H 4 ), 1.24 (d, J = 7.0 Hz, 3H, H 6 ); HRMS (ESI): calcd for C 12 H 18 ​N2ONa [M+Na] + Calculated m / z 229.1311, found m / z 229.1317; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2:MeOH (with 0.5% TEA) 80:20, 2.0 mL / min, 170 bar, 40 °C. Retention time: 6.5 min (minor), 7.8 min (major), e.r. = 98:2.

[0371] The spectral properties were in agreement with the data available in the literature. 18

[0372] 2S,3S )-2-Amino-3-phenyl-butyric acid hydrochloride 56, 2S,3S )-2-Amino-2-phenylbutan-1-ol 57 and 2S,3S )-3-Phenyl-2-(phenylamino)butan-1-ol 58:

[0373]

[0374] To a solution of 55 (103 mg, 0.50 mmol, 100 mol%) in AcOH (2.5 mL) was then added concentrated hydrochloric acid (2.5 mL) dropwise over 2 min at rt. The mixture was then stirred at 130 °C for 48 h and the progress of the reaction was monitored by TLC. After cooling to rt, the solvent was removed under vacuum and the solid was washed with EtOAc and dried under vacuum to give 56 as a brown solid. This solid was used in the next step without further purification. IR (thin film) ν max / c 1 3386 (br), 2973 (s), 1732 (s), 1646 (s), 1497 (s), 1468 (s), 1228 (s), 703 (s); 1 H NMR (500 MHz, D2O) δ 7.48 – 7.37 (m, 5H, H 6 + H 7 + H 8 ), 4.12 (d, J = 7.5 Hz, 1H, H 2 ), 3.46 – 3.40 (m, 1H, H 3 ), 1.46 (d, J = 7.0 Hz, 3H, H 4 );​13 C NMR (126 MHz, D20) δ 171.8 (C 1 ), 139.3 (C 5 ), 129.3 (C 7 ), 128.2 (C 8 ), 127.8 (C 6 ),59.2 (C 2 ), 34.5 (C 3 ), 17.0 (C 4 )。

[0375] Then a solution of LiAIH4in THF (1.0 M, 1.1 mL, 1.10 mmol, 220 mol%) was added dropwise to the above solid at room temperature under N2over 2 minutes. The mixture was then stirred at 70 °C for 12 hours and the progress of the reaction was monitored by TLC. Upon completion, the mixture was cooled to 0 °C and 5 drops of water were added slowly. This was followed by the addition of 15% w / w aqueous NaOH (5 drops) and water (5 drops). The resulting suspension was then warmed to room temperature and stirred for 15 minutes, followed by the addition of anhydrous Na2S04. The mixture was stirred for an additional 15 minutes before it was filtered. The filtrate was concentrated under vacuum to give the desired product 57 as a colorless oil (66.0 mg, 80%, over 2 steps, d.r. > 20: 1). = -17.7 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3356 (br), 2963 (s), 2929 (s), 1582 (s), 1494 (s), 1453 (s), 1040 (s), 763 (s), 702 (s); 1 H NMR (500 MHz, CDCl3) δ 7.33 - 7.19 (m, 5H, H 8 + H 9 + H 10 ), 3.78 - 3.75 (m, 1H, H 2 ), 3.44 - 3.40 (m, 1H, H 2’ ), 2.96 - 2.92 (m, 1H, H 3 ), 2.71 - 2.64 (m, 1H, H 5 ), 1.99 (br s, 3H, H 1 + H 4 ), 1.26 (d, J= 7.0 Hz, 3H, H 6 ); 13 CNMR (126 MHz, CDCl3) δ 144.2 (C 7 ), 128.7 (C 9 ), 127.8 (C 8 ), 126.6 (C 10 ), 64.4(C 2 ), 58.0 (C 3 ), 43.7 (C 5 ), 18.7 (C 6 ); HRMS (ESl): for C 10 H 16 NO [M+H] + The calculation requires m / z 166.1226, so we get m / z 166.1221.

[0376] Iodobenzene (17.5 µL, 0.16 mmol, 120 mol%), NaOH (10.4 mg, 0.26 mmol, 200 mol%), and CuI (1.2 mg, 6.5 μmol, 5 mol%) were added sequentially to a solution of 57 (21.5 mg, 0.13 mmol, 100 mol%) in DMSO (0.3 mL) and water (0.15 mL) at room temperature under N2. The mixture was then stirred at 90 °C for 12 h, and the progress of the reaction was monitored by TLC. After cooling to room temperature, the mixture was extracted with EtOAc (approximately 3 × 5.0 mL). The combined organic phases were dried over anhydrous MgSO4. The filtrate was concentrated under vacuum and then subjected to FCC (EtOAc / hexane 25:75) to give the desired product 58 (19.4 mg, 62%, dr > 20:1, er = 98:2) as a colorless oil. =+27.4 (c=1.0CHCl3); IR (thin film) ν max / cm -1 : 3399 (br), 2964 (s), 2928 (s), 1600 (s), 1495 (s), 1317 (s), 1261 (s), 747 (s), 691 (s); 1 H NMR (500 MHz, CDCl3) δ 7.33 – 7.21 (m,5H, H 12 + H 13 + H 14 ), 7.16 – 7.13 (m, 2H, H 7), 6.73 - 6.70 (m, 1H, H 8 ), J = 7.5 Hz, 2H, H 6 ), 2 ), 3.61 - 3.26 (m, 2H, H 3 + H 4 ),3.19 - 3.14 (m, 1H, H 9 ), 1.91 (br s, 1H, H 1 ), 1.35 (d, J = 7.0 Hz, 3H, H 10 ); 13 CNMR (126 MHz, CDCl3) δ 147.9 (C 5 ), 142.7 (C 11 ), 129.3 (C 7 ), 128.6 (C 13 ), 127.9(C 12 ), 126.8 (C 14 ), 118.0 (C 8 ), 113.9 (C 6 ), 62.5 (C 2 ), 60.2 (C 3 ), 41.0 (C 9 ),18.1 (C 10 ); HRMS (ESl): calcd for C 16 H 20 NO [M+H] + found m / z 242.1543; Chiral SFC: YMC Chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 92:8, 2.0 mL / min, 140 bar, 40 °C. Retention time: 6.5 min (minor), 7.2 min (major), e.r. = 98:2.

[0377] 4-bromo- N -(( 2S,3S )-1-(dimethylamino)-1-oxo-3-phenylbutan-2-yl)benzamide (59):

[0378]

[0379] At 0 °C, 4-bromobenzoyl chloride (21.8 mg, 0.10 mmol, 100 mol%) was added slowly in portions to a solution of 55 (20.6 mg, 0.10 mol, 100 mol%), Et3N (28.0 μί, 0.20 mmol, 200 mol%) and DCM (1.0 mL). The reaction was stirred at ambient temperature for 12 h. Upon completion, the reaction mixture was diluted with DCM (5.0 mL) and transferred to a separatory funnel. The mixture was washed with 1 N HC1 (10.0 mL). The combined organic phases were dried over anhydrous MgS04. The filtrate was concentrated in vacuo followed by FCC (EtOAc / hexanes 40:60) to give the desired product as a colorless solid (25.2 mg, 65%, d.r. >20:1, e.r. = 98:2). Melting point = 154-156 °C (hexanes / EtOAc); = +52.8 (c = 1.0 CHC13); IR (thin film) v max / cm -1 : 3310 (s), 2926 (s), 1621 (s), 1538 (s), 1484 (s), 1335 (s), 698 (s), 648 (s); 1 H NMR (500 MHz, CDCl3) δ 7.51 (s, 4H, H 7 + H 8 ), 7.34 - 7.23 (m, 5H, H 13 + H 14 + H 15 ), 6.96 (d, J = 8.5 Hz, 1H, H 4 ), 5.35 (t, J = 8.0 Hz, 1H, H 3 ), 3.46 - 3.40 (m, 1H, H 10 ), 2.97 - 2.96 (m, 6H, H 1 ), 1.39 (d, J = 7.0 Hz, 3H, H 11 ); 13 C NMR (126 MHz, CDCl3) δ 170.7 (C 2 ), 165.7 (C 5 ), 141.6(C 12 ), 132.8 (C 6), 131.6 (C 8 ), 128.6 (C 7 ), 128.5 (C 14 ), 127.8 (C 13 ), 127.1 (C 15 ),126.1 (C 9 ), 53.7 (C 3 ), 42.9 (C 10 ), 37.3 (C 1 ), 35.7 (C 1’ ), 16.9 (C 11 ); HRMS (ESl): for C 19 H 21 BrN₂O₂Na [M+Na] + The calculation requires m / z 411.0679, and the obtained m / z is 411.0682; Chiral SFC: DAICELCHIRALCEL IE column (25 cm), CO2: i -PrOH 80:20, 2.0 mL / min, 170 bar, 40 °C. Retention times: 7.2 min (minor), 9.3 min (major), er=98:2.

[0380] The stereochemistry of compound 59 was determined by single-crystal X-ray diffraction of crystals obtained from EtOAc / hexane (CCDC No.: 2245009).

[0381] ( 2S,3S )-2-amino- N 3-Diphenylbutyramide (60):

[0382]

[0383] To a solution of 30 (34.6 mg, 0.10 mmol, 100 mol%) in CH3CN (1.0 mL) and water (0.5 mL) was added (bis(trifluoroacetyloxy)iodo)benzene (51.6 mg, 0.12 mmol, 120 mol%) portionwise slowly at 0 °C. The mixture was then stirred at 0 °C for 1 h and the progress of the reaction was monitored by TLC. Upon completion, saturated Na2S2O3 solution (0.2 mL) was added slowly to the mixture at 0 °C to quench the excess PIFA. The mixture was extracted with dichloromethane (ca. 5 x 5.0 mL). The combined organic phase was dried over anhydrous MgSO4. The filtrate was concentrated in vacuo followed by FCC (basic Al2O3, EtOAc / hexanes 65:35) to give the desired product as a light yellow oil (22.9 mg, 90%, d.r. >20:1, e.r. = 93:7). = 84.1 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3301 (br), 3060 (s), 2928 (s), 1666 (s), 1600 (s), 1523 (s), 1443 (s), 755 (s), 701 (s); 1 H NMR (500 MHz, CDCl3) δ 9.15 (s, 1H, H 5 ), 7.54 (d, J = 8.0 Hz, 2H, H 3 ), 7.35 – 7.22 (m, 7H, H 2 + H 12 + H 13 + H 14 ), 7.11 – 7.08 (m, 1H, H 1 ), 3.61 (d, J = 6.0 Hz, 1H, H 7 ), 3.47 – 3.41 (m, 1H, H 9 ), 1.93 (br s, 2H, H 8 ), 1.42 (d, J = 7.0 Hz, 3H, H 10 ); 13 CNMR (126 MHz, CDCl3) δ 172.0 (C 6 ), 141.5 (C 11 ), 137.6 (C4 ), 128.9 (C 2 ), 128.7(C 13 ), 128.0 (C 12 ), 127.1 (C 14 ), 124.1 (C 1 ), 119.6 (C 3 ), 61.3 (C 7 ), 42.6 (C 9 ),18.4 (C 10 ); HRMS (ESl): for C 16 H 19 N2O [M+H] + The calculation required m / z 255.1492, which was obtained as m / z 255.1494. Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2:MeOH (with 0.5% TEA) 90:10, 2.0 mL / min, 140 bar, 40 °C. Retention times: 23.9 min (minor), 33.9 min (major), er = 93:7.

[0384] ( 2S,3S )-2-amino-3-(1 H -indol-3-yl)- N,N -Dimethylbutyramide (62):

[0385]

[0386] At 0 °C, (bis(trifluoroacetoxy)iodo)benzene (51.6 mg, 0.12 mmol, 120 mol%) was slowly added in portions to a solution of 18a (49.1 mg, 0.10 mmol, 100 mol%) in CH3CN (1.0 mL) and water (0.5 mL). The mixture was then stirred at 0 °C for 1 h, and the progress of the reaction was monitored by TLC. After completion, a saturated Na2S2O3 solution (0.2 mL) was slowly added to the mixture at 0 °C to quench excess PIFA. The mixture was extracted with dichloromethane (approximately 5 × 5.0 mL). The combined organic phases were dried over anhydrous MgSO4. The filtrate was concentrated under vacuum and then subjected to FCC (basic Al2O3, dichloromethane / MeOH 90:10) to give amide intermediate 61 (38.3 mg, 96%, dr > 20:1) as a pale yellow oil.

[0387] The above amide intermediate (39.9 mg, 0.10 mmol, 100 mol%) in DMA (0.50 mL) was slowly added to a solution of NaH (8.00 mg, 0.20 mmol, 200 mol%) in DMA (0.25 mL) at room temperature. The mixture was then stirred at 60 °C for 3 h and the progress of the reaction was monitored by TLC. After cooling to 0 °C, water (~5.0 mL) was added to the reaction mixture, which was then extracted with EtOAc (~5x10.0 mL). The combined organic phase was dried over anhydrous MgS04. The filtrate was concentrated in vacuo followed by FCC (basic AI203, dichloromethane / MeOH 80:10) to give the desired product 62 as a light yellow solid (20.1 mg, 82%, d.r. >20:1, e.r. = 96:4). mp = 92-94 °C (hexane / EtOAc); =+42.7 (c = 1.0 CHCl3); IR (thin film) v max / cm -1 : 3261 (br), 2925 (s), 1631 (s), 1458(s), 1343 (s), 1110 (s), 742 (s); 1 H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H, H 14 ),7.60 (d, J = 8.0 Hz, 1H, H 9 ), 7.36 (d, J = 8.0 Hz, 1H, H 12 ), 7.19 – 7.16 (m,1H, H 11 ), 7.11 – 7.08 (m, 1H, H 10 ), 7.05 (s, 1H, H 15 ), 4.03 (d, J = 8.0 Hz, 1H,H 3 ), 3.40 – 3.35 (m, 1H, H 5 ), 3.01 (s, 3H, H 1 ), 2.96 (s, 3H, H 1’ ), 2.17 (br s,2H, H 4 ), 1.36 (d, J = 7.0 Hz, 3H, H 6 ); 13C NMR (126 MHz, CDCl3) δ 173.9 (C 2 ), 136.5 (C 13 ), 126.9 (C 8 ), 122.1 (C 11 + C 15 ), 119.4 (C 10 ), 119.0 (C 9 ), 117.2 (C 7 ), 111.5 (C 12 ), 55.7 (C 3 ), 37.4 (C 1 + C 5 ), 35.8 (C 1’ ), 17.9 (C 6 ); HRMS (ESI): calcd for C 14 H 20 N3O [M+H] + 246.1601, found 246.1605; Chiral SFC: DAICEL CHIRALCEL IE column (25 cm), CO2:MeOH (with 0.5% TEA) 80:20, 3.0 mL / min, 170 bar, 40 °C. Retention time: 7.7 min (minor), 9.4 min (major), e.r. = 96:4.

[0388] Formal synthesis of 64 and 65:

[0389]

[0390] To a solution of 13n (187 mg, 0.50 mmol, 100 mol%) in AcOH (0.4 mL) was added dropwise concentrated HCl (2.0 mL) at room temperature over 2 min. The mixture was then stirred at 150 °C for 72 h and the progress of the reaction was monitored by TLC. Upon completion, the mixture was cooled to room temperature and diluted with water (5.0 mL). Subsequently, 2 N aqueous NaOH was added until a pH of 9-10 was achieved. The mixture was extracted with EtOAc (~3 x 10.0 mL). The combined organic phases were dried over anhydrous MgSO4. The filtrate was concentrated in vacuo followed by FCC (EtOAc / hexanes 25:75) to give the amine intermediate 63 as a colorless oil (71.8 mg, 55%).

[0391] To a solution of 63 (39.2 mg, 0.15 mmol, 100 mol%) in CH3CN (1.5 mL) and water (0.75 mL) was added (bis(trifluoroacetyloxy)iodo)benzene (77.4 mg, 0.18 mmol, 120 mol%) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 h and the progress of the reaction was monitored by TLC. Upon completion, the mixture was cooled to 0 °C and saturated Na2S203solution (0.2 mL) was added slowly to quench the excess PIFA. Subsequently, 2 N aqueous NaOH was added until a pH of 10-11 was achieved. The mixture was extracted with dichloromethane (ca. 3 x 5.0 mL). The combined organic phases were dried over anhydrous MgS04. The filtrate was concentrated in vacuo to give the free amine intermediate 64 as a light yellow oil. This oil was used in the next step without further purification.

[0392] To a solution of the above free amine intermediate was added Et3N (32.0 μL, 0.23 mmol, 150 mol%) and 4-toluenesulfonyl chloride (34.3 mg, 0.18 mmol, 120 mol%) in DCM (1.5 mL) portionwise at 0 °C. The reaction was stirred at room temperature for 16 h. Upon completion, the reaction mixture was diluted with DCM (5.0 mL), transferred to a separatory funnel and washed with aqueous 1 N HC1 (10.0 mL). The combined organic phases were dried over anhydrous MgS04. The filtrate was concentrated in vacuo followed by FCC (EtOAc / hexanes 25:75) to give the desired product 65 as a light yellow oil (26.9 mg, 56% over 2 steps, e.r. = 93:7). = 8.0 Hz, 2H, H 1 H NMR (500 MHz, CDCl3) δ 7.65 (d, J =8.0 Hz, 2H, H 4 ), 7.29 (d, J = 8.0 Hz, 2H, H 3 ), 7.22 – 7.18 (m, 2H, ArH), 6.99– 6.96 (m, 2H, ArH), 4.30 – 4.28 (m, 1H, H 6 ), 3.21 – 3.16 (m, 1H, H 7 ), 3.01 –2.96 (m, 1H, H 7’ ), 2.88 – 2.82 (m, 1H, H 8 ), 2.43 (s, 3H, H1 ), 1.21 (d, J = 6.9 Hz, 3H, H 9 ); Chiral SFC: YMC Chiral ART Cellulose-SC column (25 cm), CO2: i -PrOH 80:20, 2.0 mL / min, 165 bar, 40 °C. Retention time: 4.9 min (minor), 5.2 min (major), e.r. = 93:7.

[0393] The spectral properties were in agreement with the data available in the literature. 19

[0394] In summary, the present application provides a method that utilizes a directed enolate strategy that is efficient and advantageous compared to alternative routes for the selective construction of consecutive tertiary stereocenters en route to the construction of complex amino acids and other structures.

[0395] References

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[0397] 2. Dervisi, A.; Carcedo, C.; Ooi, L.-L. Chiral Diphosphine Ddppm-Iridium Complexes: Effective Asymmetric Imine Hydrogenations at Ambient Pressures. Adv. Synth. Catal. 2006, 348 , 175-183.

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[0399] 4. Tian, H.; Xu, W.; Liu, Y.; Wang, Q. Unnatural α-Amino Acid Synthesized through α-Alkylation of Glycine Derivatives by Diacyl Peroxides. Org. Lett. 2020, 22 , 5005-5008.

[0400] 5. Cai, C.; Chen, T.-T. Copper Triflate Catalyzed Oxidative α-Allylation of Glycine Derivatives. Synlett 2017, 28, 1368-1372.

[0401] 6. Wang, Z. J.; Peck, N. E.; Renata, H.; Arnold, F. H. Cytochrome P450-Catalyzed Insertion of Carbenoids into N H Bonds. Chem. Sci. 2014, 5 ,598-601.

[0402] 7. Iso, Y.; Shindo, H.; Hamana, H. Efficient Synthesis of Resin-Bond α-TMSdiazoketones and Their use in Solid-Phase Organic Synthesis. Tetrahedron 2000, 56, 5353-5361.

[0403] 8. Xu, Q.; Li, B.; Ma, Y.; Sun, F.; Gao, Y.; Ye, N. K2S2O8-HFIPSynergistically Promoted para -Selective sp 3 C H Bond Diarylation of Glycine Esters. Org. Biomol. Chem. 2020, 18 , 666-670.

[0404] 9. Chen, C.; Zhu, M.; Jiang, L.; Zeng, Z.; Yi, N.; Xiang, J. Copper-Catalyzed Oxidative Cross-Coupling of a-Aminocarbonyl Compounds with Primary Amines toward 2-oxo-Acetamidines. Org. Biomol. Chem. 2017, 15 , 8134-8139.

[0405] 10. Dai, Z.; Tian, Q.; Li, Y.; Shang, S.; Luo, W.; Wang, X.; Li, D.; Zhang, Y.; Li, Z. and Yuan, J. Michael Addition Reaction Catalyzed by Imidazolium Chloride to Protect Amino Groups and Construct Medium Ring Hetereocycles. Molecules 2019, 24 , 4224-4241.

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[0407] 12. Hattori, G.; Sakata, K.; Matsuzawa, H.; Tanabe, Y.; Miyake, Y.; Nishibayashi, Y. Copper-Catalyzed Enantioselective Propargylic Amination of Propargylic Esters with Amines: Copper-Allenylidene Complexes as Key Intermediates. J. Am. Chem. Soc. ​​2010, 132 , 10592-10608.

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[0409] 14. Yan, X.-B.; Li, L.; Wu, W.-Q.; Xu, L.; Li, K.; Liu, Y.-C.; Shi, H. Ni-Catalyzed Hydroalkylation of Olifins with N -Sulfonyl Amines. Nat. Commun. 2021, 12 , 5881.

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Claims

1. A method comprising reacting a carbonyl compound with an olefin compound in the presence of an iridium catalyst, wherein the carbonyl compound comprises a nitrogen-based group at the alpha or beta position of the carbonyl group, and wherein the method comprises the step of alpha-alkylating the carbonyl compound by forming a carbon-carbon bond between the carbon atom alpha to the carbonyl group and a carbon atom of the double bond of the olefin compound.

2. The method according to claim 1, wherein the carbonyl group of the carbonyl compound is part of an amide.

3. The method according to claim 2, wherein the amide is a tertiary amide.

4. The method according to claim 3, wherein the two groups on the nitrogen atom together form a ring.

5. The method according to claim 2, wherein the amide is a secondary amide.

6. The method according to claim 1, wherein the carbonyl group of the carbonyl compound is in the form of a ketone.

7. The method according to any one of the preceding claims, wherein the nitrogen-based group of the carbonyl compound is a secondary amine.

8. The method according to claim 7, wherein the secondary amine has the structure -NHAr, wherein Ar is an aromatic moiety.

9. The method according to any one of the preceding claims, wherein the olefin compound is a monosubstituted olefin.

10. The method according to any one of claims 1 to 8, wherein the olefin compound is disubstituted on one of the carbon atoms of the double bond of the olefin.

11. The method according to any one of the preceding claims, wherein the iridium catalyst is an iridium (I) catalyst.

12. The method according to any one of the preceding claims, wherein the iridium catalyst is a chiral iridium catalyst.

13. The method according to claim 12, wherein the chiral iridium catalyst has a diphosphine ligand.

14. The method according to any one of the preceding claims, comprising charging a vessel with the carbonyl compound, an iridium compound, a chiral ligand, the olefin compound and a solvent, and allowing the reaction to take place at elevated temperature.

15. The method according to any one of the preceding claims, which method is carried out in 1,4-dioxane as solvent.

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