Cobalt catalyzed asymmetric hydrogenation of alkenes

Abstract

In one aspect, there is provided a compound of Formula I where R1 and R1' are each independently C1-6 alkyl, C4-6 cycloalkyl, or C6 aromatic, or together form a C4-10 cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2 groups, each R2 group independently being halogen, C1-4 alkyl or C1-4 heteroalkyl, and / or two adjacent R2 groups together forming an aromatic or heteroaromatic group, and Formula II represents a chiral diol.

Description

COBALT CATALYZED ASYMMETRIC HYDROGENATION OF ALKENES FIELD

[0001] The present disclosure relates generally to the cobalt catalyzed asymmetric hydrogenation of alkenes. BACKGROUND

[0002] The following paragraphs are not an admission that anything discussed in them is prior art or part of the knowledge of persons skilled in the art.

[0003] The transition metal catalyzed asymmetric hydrogenation of alkenes represents one of the most effective and atom economical methods for accessing single enantiomer compounds. Hydrogenation catalysts based on the second and third row transition metals Ru, Rh, and Ir have found widespread utility in the pharmaceutical, agrochemical, fragrance, and fine chemical industries, as well as in academic settings. INTRODUCTION

[0004] The following introduction is intended to introduce the reader to this specification but not to define any invention. One or more inventions may reside in a combination or sub-combination of the features or method steps described below or in other parts of this document. The inventors do not waive or disclaim their rights to any invention or inventions disclosed in this specification merely by not describing such other invention or inventions in the claims.

[0005] It is an object of the present disclosure to obviate or mitigate at least one disadvantage of previous asymmetric hydrogenation catalysts.

[0006] In one aspect, the present disclosure provides a compound of Formula I (Formula I) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being halogen, C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, and represents a chiral diol.

[0007] A chiral catalyst includes cobalt complexed to a compound according to Formula I.

[0008] A method of making a chiral catalyst includes reacting a compound according to Formula I with a cobalt salt.

[0009] In one aspect, the present disclosure provides a method of making a ligand, the method includes reacting a chiral diol with PCl3to form a chlorophosphine and subsequent reaction of the chlorophosphine with a 2-R1R1’P-bromoarene to form the ligand.

[0010] In one aspect, the present disclosure provides a compound of Formula III(Formula III) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, X are each independently halide or pseudohalide, and represents a chiral diol.

[0011] In one aspect, the present disclosure provides a compound of Formula IV (Formula IV) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, R3and R3' are each independently C1-6alkyl, the C1-6alkyl optionally substituted by an aromatic group or a trialkylsilyl group, and represents a chiral diol.

[0012] In one aspect, the present disclosure provides a compound of Formula V(Formula V) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, Ar is a C6aromatic group optionally modified with one C1-6alkyl substituent or up to three methyl groups, where the Ar group is coordinated to the cobalt cation, represents a chiral diol, and X– is an organic-solvent soluble anion.

[0013] When a chiral catalyst according to the present disclosure is used in a method of alkene hydrogenation, the method may use an enantiopure amount of a chiral catalyst, such as a chiral catalyst of Formula III, IV, or V. The chiral catalyst may be prepared from an enantiopure amount of the compound according to Formula I or II.

[0014] A method of alkene hydrogenation includes reacting an alkene in the presence of hydrogen and a catalytically effective quantity of a chiral catalyst, such as an enantiopure amount of the chiral catalyst, herein disclosed or a compound of Formula III, IV, or V, such as an enantiopure amount of the compound of Formula III, IV, or V.

[0015] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0016] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

[0017] FIG. 1 illustrates the crystallographically determined structure of 1 with thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity.

[0018] FIG. 2 illustrates the crystallographically determined structure of 3 with thermal ellipsoids shown at the 50% probability level; hydrogen atoms have been omitted for clarity. Selected interatomic distances (Å) and angles (deg): Co-P1 2.2171(17), Co-P22.1250(15), Co-C452.009(6), Co-C472.017(6), C45-Co-C47 90.3(3), C45-Co-P2176.6(2), C47-Co-P291.20(19), C45-Co-P191.8(2), C47-Co-P1 177.44(19), P2-Co-P186.66(6).

[0019] FIG. 3 illustrates the crystallographically determined structure of 4 with thermal ellipsoids shown at the 50% probability level; hydrogen atoms and the BArF4 anion have been omitted for clarity. Selected interatomic distances (Å) and angles (deg): Co-P12.1570(11), Co-P22.0914(11), Co-C442.119(5), Co-C45 2.124(5), Co-C462.082(5), Co-C472.110(5), Co-C482.137(5), P2-Co-P186.26(4). DETAILED DESCRIPTION

[0020] Generally, the present disclosure provides compounds and methods for the cobalt catalyzed asymmetric hydrogenation of alkenes.

[0021] Catalysts employing first row 3d-transition metals (i.e., Mn, Fe, Co, Ni) represent an attractive, yet underdeveloped, area of research owing to their relatively high abundance and low cost when compared to their second and third row congeners. The last decade has seen an increased focus on the discovery of catalysts employing these Earth-abundant metals and has led to the development of several Co- and Ni- based catalysts that exhibit high hydrogenation activity and enantioselectivity. These advances notwithstanding this area of research remains in its infancy. The continued investigation of new strategies for facilitating 3d-metal catalyzed asymmetric hydrogenation is key to the development of efficient synthetic protocols that can supplant platinum group metal based technology.

[0022] As demonstrated in Example 1, the application of the readily prepared enantiopure ligand 1 and corresponding Co complexes in the asymmetric varying in oxidation state between Co(I) and Co(II) were shown to be active catalysts for the hydrogenation of (Z)-N-acetyl-phenylalanine, with the cationic Co(I) complex 4 supporting highly enantioselective hydrogenation. The authors of the present acids displaying good functional group tolerance under relatively mild conditions (2.5-5.0 mol% Co, 10 atm H2, 50 °C). The 1.0 mmol scale hydrogenation of (Z)- dehydro-N-acetyl-(a4-acetoxy-3-methoxy) phenylalanine (substrate 5r) also demonstrates the utility of 4 on larger scales, furnishing the precursor to D-DOPA 6r in good isolated yield (75%) and high enantioselectivity (99:1 e.r). Moreover, this reaction could be performed under 40 atm H2to ensure complete conversion with no degradation in enantioselectivity. Deuterium labeling experiments suggest the plausibility of a Co(I / III) mechanism wherein H2undergoes homolytic cleavage by the Co(I) cation followed by alkene insertion into the Co–H bond and subsequent reductive elimination to furnish the hydrogenated product.

[0023] "Additive" refers to a substance added to something in relatively small quantities to alter or improve it, or to counteract undesirable properties.

[0024] "Alkene" refers to a hydrocarbon unsaturated compound with at least one carbon-to-carbon double bond.

[0025] "Alkyl" refers to a group formed by removing one hydrogen from an alkane chain and is described by the formula CnH2n+1. The alkyl group may be a straight or branched chain.

[0026] "Ar group" or “aryl group” refers to any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl or naphthyl.

[0027] "Aromatic" refers to a chemical compound that consists of conjugated planar ring systems accompanied by delocalized pi-electron clouds in place of individual alternating double and single bonds. These are also called arenes. Aromatic compounds usually refer to organic compounds with a chemistry typified by benzene.

[0028] "C1-6" refers to a group or compound having one to six carbon atoms.

[0029] "C4-10" refers to a group or compound having four to ten carbon atoms.

[0030] "C6" refers to a group or compound having six carbon atoms.

[0031] "Catalyst" refers to a substance that increases the rate of a chemical reaction without itself being stoichiometrically consumed by the chemical reaction.

[0032] "Catalytically effective quantity" refers to the amount of substance used in a chemical reaction as a catalyst, primer, or sparker. It is generally much smaller than the stoichiometric amounts of either reactants or products. For example, in the method of alkene hydrogenation, the catalytically effective quantity may be at least 0.5 mol%, such as between 1 and 10 mol%.

[0033] "Chiral diol" refers to a chemical compound or group containing two hydroxyl groups, which is also asymmetric in such a way that the structure and its mirror image are not superimposable.

[0034] “Chiral catalyst” refers to a catalyst (defined above) that is asymmetric in such a way that the structure and its mirror image are not superimposable.

[0035] "Chlorophosphine" refers to a compound having a -PCl group.

[0036] "Cobalt cation" refers to a positively charged cobalt species.

[0037] "Cobalt salt" refers to a cobalt species in an ionic assembly with a negatively charged counterion, such that the compound has no net electric charge.

[0038] "Compound" refers to a chemical substance composed of many identical molecules containing atoms from more than one chemical element held together by chemical bonds.

[0039] "Cycloalkyl" refers to a univalent group derived from cycloalkane by removal of a hydrogen atom from a ring carbon atom and has the general formula of - CnH2n-1. A cycloalkyl is a cyclic version of an alkyl. Cycloalkyl is not aromatic. The cycloalkyl may be monocyclic, bicyclic, or multicyclic.

[0040]

[0041] "Diol" refers to a chemical compound or group containing two hydroxyl groups.

[0042] "Double bond" refers to a chemical bond in which two pairs of electrons are shared between two atoms.

[0043] "Enantiomer" refers to one of two stereoisomers that are non-superimposable onto their own mirror image (for a compound with one chiral carbon). The number of stereoisomers a molecule has can be determined by the number of chiral carbons it has.

[0044] “Enantiopurity” refers to the purity of one specific enantiomer in a mixture of enantiomers. For example, a compound may be referred to as having an enantiopurity of 60%, 70%, 80%, 90%, 95%, or 99%. An amount of a compound may be considered “enantiopure” if the mixture of enantiomers contains a majority of one specific enantiomeric form, such as at least 60% of one specific enantiomer. In some examples, an enantiopure amount of the compound may have an enantiopurity of at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some examples, an enantiopure amount of the compound may have an enantiopurity from 97 to 99%. For convenience, the present disclosure may, for example, refer to an “enantiopure compound” when referring to an enantiopure amount of a mixture of enantiomers of the compound.

[0045] "Heteroalkyl" refers to a straight or branched chain including at least one carbon atom and at least one heteroatom (e.g. O, N, P, Si, or S). The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. If the heteroatom is nitrogen or sulfur, the heteroatom may optionally be oxidized, or the nitrogen heteroatom may optionally be quaternized. Heteroalkyl is an uncyclized chain. The heteroalkyl may include one heteroatom, two or three heteroatoms, or more. If the heteroalkyl contains more than one heteroatom, the heteroatoms may be the same or different.

[0046] "Heteroaromatic" refers to a compound or group with a ring structure which is both heterocyclic and aromatic. In other words, the heteroaromatic has the characteristics of an aromatic compound whilst having at least one non-carbon atom (e.g. O, N, S) in the ring.

[0047] "Heterocycloalkyl" refers to a cyclic version of a heteroalkyl. A heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule, or another position within the ring.

[0048] "Increased pressure" refers to a pressure greater than atmospheric pressure.

[0049] "Increased temperature" refers to a temperature greater than room temperature.

[0050] "Ligand" refers to an ion or molecule with a functional group that can bind to a central metal atom to form a coordination complex.

[0051] "Organic-solvent soluble anion" refers to an anion that is soluble in organic solvent.

[0052] "Pseudohalide" refers to a compound or ion that is not a halide, but which resembles a halide in its charge and reactivity. Examples of pseudohalides include but are not limited to triflate (OTf).

[0053] "Reacting" refers to a chemical reaction, a process in which one or more substances, the reactants, are converted to one or more different substances, the products.

[0054] "Substituted" refers to an atom, group, or molecule which has a substituent. The substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant molecule. The term substituent may be used interchangeably with functional group, side chain, or pendant group.

[0055] "Trialkylsilyl group" refers to a functional group consisting of three alkyl groups bonded to a silicon atom, which in turn is bonded to the rest of a molecule. Examples of trialkylsilyl groups include but are not limited to trimethylsilyl.

[0056] "Unsubstituted" refers to an atom, group, or molecule which does not have a substituent. In the case of an unsubstituted aromatic, for example, the aromatic group is defined as above, except that it has no substituent groups.

[0057] In one aspect, there is provided a compound of Formula I(Formula I) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being halogen, C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, and represents a chiral diol.

[0058] As used herein, “A” or "A group" may be an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups. The A group may be any suitable substituted or unsubstituted aromatic or heteroaromatic group. For example, the A group may be substituted or unsubstituted phenyl, naphthyl, anthracene, furan, pyrrole, thiophene, imidazole, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline, or isoquinoline, preferably wherein A is substituted or unsubstituted phenyl. In the case of a C6- aromatic, A may be optionally modified with up to four R2groups. In the case of other aromatic or heteroaromatic groups, A may be optionally modified with as many R2as the A group allows. In some embodiments, A may be substituted or unsubstituted phenyl. For example, A may be a C6-aromatic and the compound may be of formula II(Formula II).

[0059] As used herein, R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl. In any given structure, R1and R1' may be the same or different. R1and R1' may be used interchangeably. For example, R1and R1' may be (each independently) phenyl, ethyl, propyl, iso-propyl or cyclohexyl, preferably wherein R1and R1' are both phenyl.

[0060] As used herein, each R2group may be independently halogen, C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group. As A may be optionally modified with R2groups, the R2groups may also be hydrogen. The compounds herein disclosed may comprise none, one, two, three, four, or more R2groups. The compound may comprise one, two, three, or four R2groups and each R2group may be independently methyl, fluoro, or methoxy. R2may be absent.

[0061] As used herein, the following structure represents a chiral diol: . Any suitable chiral diol may be represented by this structure, such as 1,2-diols, 1,3- diols, 1,4-diols, 1,5-diols, or 1,6-diols. For example, may representor an enantiomer thereof, wherein each R4group is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and / or two adjacent R4groups together forming a double bond, a cycloalkyl, a heterocycloalkyl, an aromatic, or a heteroaromatic group. Some exemplary chiral diols according to the present disclosure do not include two adjacent R4groups that together form an aromatic or heteroaromatic group. Should an R4be aryl, may representor an enantiomer thereof, wherein each R4group is as definedpreviously. In some embodiments, may represent or anenantiomer thereof, wherein each R4group is as defined previously. Should two adjacent R4groups together form an aromatic, may represent or anenantiomer thereof, wherein each R4group is as defined previously. In someexamples, least one R4group is a C1-6alkyl group or two adjacent R4groups form a cycloalkyl or a heterocycloalkyl. In some examples where two adjacent R4groups together form an aromatic group, the aromatic group does not include two adjacent R4groups that together form an aromatic or heteroaromatic group. In some examples, may representor an enantiomer thereof, wherein each R4group is as definedpreviously. For example, may represent ,or an enantiomer thereof. In some examples, each R4group is independently H, Me, OMe, Ph, 3,5-Me2-C6H3, or naphthyl.

[0062] The compound may be, or an enantiomer thereof. The compound may be , or an enantiomer thereof.

[0063] In one aspect, there is provided a method of making a chiral ligand, the method includes reacting a chiral diol with PCl3to form a chlorophosphine and subsequent reaction of the chlorophosphine with a 2-R1R1'P-bromoarene to form the ligand. The chiral ligand may be a compound herein disclosed, such as a compound of Fomula I or II.

[0064] In one aspect, there is provided a chiral catalyst comprising cobalt complexed to a compound according to an embodiment herein, such as a compound of Formula I or II. In one aspect, there is provided a method of making a chiral catalyst comprising reacting a compound according to an embodiment herein, such as a compound of Formula I or II, with a cobalt salt. The chiral catalyst, the compound of Formula I, or the compound of Formula II may be enantiopure.

[0065] In one aspect, there is provided a compound of Formula III(Formula III) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, X are each independently halide or pseudohalide, and represents a chiral diol.

[0066] In Formula III, R1and R1', A, and R2are defined as above. In Formula III, X are each independently halide or pseudohalide. For example, X may be Cl, Br, I, OAc, or OTf.

[0067] In one aspect, there is provided a compound of Formula IV (Formula IV) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, eachR2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, R3and R3' are each independently C1-6alkyl, the C1-6alkyl optionally substituted by an aromatic group or a trialkylsilyl group, and represents a chiral diol.

[0068] In Formula IV, R1and R1', A, and R2are defined as above. As used herein, R3and R3' are each independently C1-6alkyl, the C1-6alkyl optionally substituted by an aromatic group or a trialkylsilyl group. For example, R3and R3' may be each independently benzyl, neopentyl, neophyl, or -CH2SiMe3.

[0069] In one aspect, there is provided a compound of Formula V (Formula V) where R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl, A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group, Ar is a C6aromatic group optionally modified with one C1-6alkyl substituent or up to three methyl groups, where the Ar group is coordinated to the cobalt cation, represents a chiral diol, and X– is an organic-solvent soluble anion.

[0070] In Formula V, R1and R1', A, and R2are defined as above. In Formula V, X– may be an organic-solvent soluble anion. For example, X– may be BarF4, BPh4, orOTf. In Formula V, Ar is a C6aromatic group optionally modified with one C1-6alkyl substituent or up to three methyl groups.

[0071] In one aspect, there is provided a method of alkene hydrogenation including reacting an alkene in the presence of hydrogen and a catalytically effective quantity of the chiral catalyst or compound herein disclosed, such as a compound of Formula I or II complexed to cobalt, or a compound of Formula III, IV, or V. The method may include using a catalytically effective quantity the enantiopure chiral catalyst, the compound herein disclosed complexed to cobalt, or the compound of Formula III, IV or V.

[0072] In methods of alkene hydrogenation according to the present disclosure, the reacting may be performed at an increased pressure, such as between 10 atm H2and 40 atm H2; at an increased temperature, such as about 50 °C; in an organic solvent, such as iPrOH (isopropanol), TFE (tetrafluoroethylene), or THF (tetrahydrofuran); in the presence of an additive, such as 1 equivalent of Zn(0); or any combination thereof. EXAMPLES

[0073] Amino Acids Scheme 1

[0074] In an effort to access asymmetric hydrogenation, the authors of the present disclosure synthesized and characterized a family of Co complexes supported by the enantiopure phosphino-phosphonite ligand (S)-2-(diphenylphosphino)P(Phen) (Phen =acids is described herein. While all the complexes that were investigated displayed catalytic activity and some degree of enantioselectivity, a cationic arene complex was found to provide both high conversion and enantioselectivity for a broad scope of

[0075] Ligand synthesis. The enantiopure diol (S S)-diol) is commercially available and can be readily condensed with PCl3to afford the enantiopure chlorophosphine (S)-ClP(Phen) in good yield (Scheme 2a). Furthermore, the synthesis of 2-R2P-bromobenzene derivatives provides a useful handle for tuning the steric and electronic properties of the ligand by varying the R substituents on phosphorus.

[0076] The synthesis of the C1 symmetric enantiopure variant 1 was achieved in 63% yield via the lithiation of (2-diphenylphosphino)bromobenzene and subsequent reaction with the enantiopure chlorophosphine (S)-ClP(Phen) (Scheme 2). Compound 1 crystallizes in the chiral space group P212121 and single crystal X-ray crystallographic analysis confirmed the connectivity in this molecule (FIG. 1). Scheme 2. (a) Synthesis of (S)-Cl(Phen). (b) Synthesis of 1.

[0077] Synthesis of Co Complexes. The ability of the first-row transition metals to support oxidation states that differ by only one electron has proven to be an added variable to be considered when designing and optimizing new catalysts. Neutral Co(II) complexes, neutral or cationic Co(I) complexes, and neutral Co(0) complexes have all displayed excellent catalytic activity and enantioselectivity for the asymmetric hydrogenation of substituted alkenes including 1,1-disubstituted alkenes,

[0078] To begin investigating the coordination chemistry of 1 with Co, the Co(II) chloride complex 2 was prepared. Complex 2 was obtained as a paramagnetic purple solid in 81% yield by treatment of a THF suspension of CoCl2with 1 (Scheme 3). Solution magnetic moment measurements for 2 (Evans method, methylene chloride- d2, 300K) resulted in a calculated µeffvalue of 3.89 µB(S = 3 / 2 ground state). Despite repeated attempts single crystals of 2 suitable for X-ray diffraction could not be obtained. As a result, the authors of the present disclosure tentatively assign the structure of 2 as a high spin tetrahedral complex on the basis of the observed magnetic susceptibility. Scheme 3. Synthetic route for the preparation of complexes 2, 3, and 4.

[0079] Subsequent treatment of 2 with two equiv. of LiCH2SiMe3in THF afforded the dialkyl complex 3 as a paramagnetic red solid in 79% yield (Scheme 3). Solution magnetic moment measurements for 3 (Evans method, benzene-d6, 300K) resulted in a calculated µeffvalue of 1.72 µB(S = ½ ground state), which is consistent with a low spin, square planar complex. The solid-state structure of 3 confirmed this assignment and displays the expected square planar geometry at Co (FIG. 2). Despite the large steric profile of the phosphonite donor, the Co-P2 distance of 2.1250(15) Å in 3 wasfound to be shorter than the Co-P1 distance of 2.2171(17) Å involving the PPh2Interestingly, there was relatively little difference in the interatomic distances for either of the Co-C bonds (Co-C452.009(6) Å vs. Co-C472.017(6) Å).

[0080] Although cationic bis(phosphine) Rh complexes are employed industrially as catalysts for asymmetric hydrogenation, the Co analogs were unknown until recently due to the lack of synthetic methods to access them. Cationic Co(I) arene complexes can be accessed through oxidatively induced reductive elimination of in-situ generated bis(phosphine) Co(III) dialkyl complexes. In this regard, exposure of (py)2Co(CH2SiMe3)2to a bis(phosphine) ligand in the presence of benzene, followed by the addition of ferrocenium salts of the type [Fc][X] (Fc = Cp2Fe+; X = BarF4–, BF4–, PF6–, or BPh4–), was found to be a general method to access 18 electron complexes of the form [(P2)Co( 6 – C6H6)][X]. This protocol was successfully extended to 3, such that treatment with the one electron oxidant [Fc][BarF4] in a 1:1 mixture of diethyl ether and benzene afforded the corresponding cationic complex 4 as a diamagnetic orange complex in 80% yield (Scheme 5). The X-ray crystal structure of 4 (FIG. 3) 6-coordination of the benzene ligand to the Co center and revealed a slight contraction of both Co-P bonds in comparison to 3 (Co-P1 2.1570(11) Å, Co-P2 2.0914(11) Å).

[0081] Catalyst Optimization. The Co complexes 2, 3, and 4 were screened as pre- catalysts for the asymmetric hydrogenation of dehydro-N-acetyl-phenylalanine (Table 1). All three pre-catalysts afforded good conversion to product. In the case of 2, one equiv. of Zn(0) was employed as an additive as this has been shown to promote increased catalytic activity and enantioselectivity. Quantitative conversion and an e.r. of 94:6 e.r. were obtained for (R)-N-acetyl-phenylalanine with a loading of 5% 2 after 18 h at 50 °C under 40 atm H2in the presence of one equiv. of Zn(0) (Table 1, entry 1; absolute configuration determined relative to an authentic sample of (R)-N-acetyl- phenylalanine). In an effort to reduce H2pressure, it was found that 72% conversion to product with an e.r. 95:5 of can be obtained in 2,2,2-trifluoroethanol (TFE) solvent at 5 atm H2with identical loadings of 2 / Zn(0) (Table 1, entry 5). Pre-catalyst 4 also afforded both quantitative conversion and an e.r of 99:1 for (R)-N-acetyl-phenylalanine with a loading of 5 mol% Co after 18 h at 50 °C iniPrOH solution under 40 atmH2(Table 1, entry 7). Control experiments employing 5 mol% 1 in the absence of Co under 10 atm H2, 50 °C, in TFE for 18 h led to no conversion to product. Table 1. Pre-catalyst screen.

[0082] Upon further optimization with 4 it was found that the H2pressure could be lowered from 40 to 10 atm with no loss in conversion or enantioselectivity (Table 1, entry 8). Furthermore, THF and iPrOH were found to be interchangeable as solvents, while TFE, acetonitrile, and dichloromethane did not afford high conversion (Table 1, entries 9-12). Lastly, the loading of 4 could be decreased to 2.5 mol% (Table 1, entry 13) with no degradation in conversion or enantioselectivity. However, reactions performed using 1 mol% 4 suffered from lower conversion (67%), albeit with similarly high enantioselectivity (Table 1, entry 14). Increasing the pressure to 40 atm in the presence of 1 or 0.5 mol% 4 increased conversion to 85% and 60% respectively, with no loss in enantioselectivity (Table 1, entries 15 and 16). The conditions employed in entries 5 and 13 were chosen as optimal for investigating the scope of the reaction owing to the balance of conversion and enantioselectivity with moderately reduced catalyst loading.

[0083] Substrate Scope. Having screened catalysis conditions, a library of dehydro- 4 and 5). The optimized conditions could be extended to substrates bearing halogen (5c – 5i) and polyaromatic substitution (5b). In some cases an increase in reaction time and / or catalyst loading was necessary to afford full conversion to product. In all cases the enantioselectivity remained high, with the exception of 5e and 5q.Scheme 4. catalyzed by 2. Reaction conditions: substrate (0.2 mmol), 2 (specified mol %), 5 atm H2, TFE (1 mL), 50 °C, 18 h. Conversion to product was determined on the basis of1H NMR (nuclear magnetic resonance) spectroscopy.Scheme 5. catalyzed by 4. Reaction conditions: substrate (0.2 mmol), 4 (specified mol %), 10 atm H2(unless otherwise noted), THF (1 mL), 50 °C, 18 h. Conversion to product was determined on the basis of1H NMR (nuclear magnetic resonance) spectroscopy (isolated yield in parentheses). [a] Reaction performed under 20 atm H2. [b] Reaction performed for 48 h.

[0084] Substrates featuring ortho-substitution were found to be a challenging class of substrates for both 2 and 4. Substrate 5e, which possesses o-fluoro substitution, proceeded to completion but a decrease in enantioselectivity was observed, providing enantiomer ratios of 79:21 and 88:12 for pre-catalyst 2 and 4, respectively. Surprisingly, substrate 5h (the Cl analogue of 5e) was also completely hydrogenated under these conditions, yet afforded a higher e.r of 98:2 (Scheme 5). In the case of the o-tolyl derivative 5l, only 33% conversion was obtained with pre-catalyst 2 after 48 h (Scheme 4), while an increase in both the H2pressure (20 atm) and reaction time (48 h) were found to be helpful for the reaction to proceed to completion at 5 mol% loading of 4 (Scheme 5). While 5l displayed high enantioselectivity under these conditions, the asymmetric hydrogenation of substrate 5q (o-methoxy) was found to have an enantiomer ratio of 72:28 and 76:24 for pre-catalyst 2 and 4, respectively, and a 10 mol% loading of 4 was necessary for the reaction to proceed to completion.

[0085] Heteroaryl substitution was found to be compatible with both 2 / Zn(0) and 4, as shown by substrates 5s and 5t which contain 2- and 3-substituted thiophene moieties, respectively. The asymmetric hydrogenation of substrate 5r with Rh to produce the precursor to L-DOPA (L-3,4-dihydroxyphenylalanine) was a key reaction that Knowles performed in the work for which he was awarded the 2001 Nobel Prize in Chemistry. Through high-throughput experimentation Chirik and co-workers were able to demonstrate that a Co(0) complex supported by the chiral bis(phosphine) 1,2- bis(t-butylmethylphosphino)benzene ((R,R)-BenzP*) could also achieve this hydrogenation with high conversion (>99%) and enantioselectivity (99% ee) to give the precursor to D-DOPA (D-3,4-dihydroxyphenylalanine). Applying either 2 / Zn(0) or 4 for the asymmetric hydrogenation of this same substrate proceeded with complete conversion and a similarly high enantioselectivity (99:1 selectivity for 6r, precursor to D-DOPA).

[0086] The utility of 4 on a larger scale (1.0 mmol) was also evaluated (Scheme 6). Substrate 5r was chosen for this experiment due to its historical importance and relevant status as a highly functionalized amino acid precursor. Pre-catalyst 4 was found to cleanly hydrogenate 5r on a 1.0 mmol scale to afford the precursor to D- DOPA in 75% isolated yield. The H2pressure was increased to 40 atm to ensure complete conversion with no accompanied degradation of the enantioselectivity. Thisis notable as increasing the H2pressure has led to a decrease in enantioselectivity for many bis(phosphine) supported Rh catalysts. Scheme 6

[0087] Deuterium Labeling Studies. Chirik and co-workers have recently shown that in the case of alkene hydrogenation mediated by bis(phosphine) Co(0) species a Co(II) dihydride mechanism is in effect. Catalytic hydrogenation of (Z)-dehydro-N- acetyl-phenylalanine under 4 atm D2in the presence of natural abundance MeOH as solvent led exclusively to 1,2-d2-incorporation in the product. Moreover, of the two position resulting from cis-D2addition. This resulted in a single isotopomer and is consistent with a dihydride mechanism similar to what has previously been invoked in Rh catalyzed asymmetric hydrogenation of the same substrate.

[0088] The similarity of 4 to the cationic Rh(I) catalysts that have been historically employed as alkene hydrogenation catalysts led us to postulate that a similar dihydride mechanism to both the Rh(I) and Co(0) systems described previously may be possible. Oxidative addition of H2by 4 would provide a cationic Co(III) dihydride intermediate that could then undergo alkene insertion and subsequent C-H reductive elimination to provide the hydrogenated product (Scheme 8). When the hydrogenation of substrate 5a (Z)-dehydro-N-acetyl-phenylalanine was performed under 10 atmD2the authors of the present disclosure observed exclusive 1,2-2H incorporation in the product 6a-d2 (Scheme 7). Furthermore, deuterium incorporation in the cis-D2addition. As a result, a single isotopomer was observed, supporting the possibility of a Co(III) dihydride mechanism resulting from oxidative addition of H2to the cationic Co(I) complex 4. To date, efforts to observe such a dihydride complex resulting from H2addition to 4 have not been successful.Scheme 7 Scheme 8. Proposed mechanism for asymmetric alkene hydrogenation mediated by 4.

[0089] Experimental

[0090] General Considerations

[0091] All experiments were conducted under nitrogen in a glovebox or using standard Schlenk techniques. Tetrahydrofuran and diethyl ether were distilled from Na / benzophenone ketyl. Benzene, toluene, and pentane were first sparged with nitrogen and subsequently dried by passage through a double-column (one activatedalumina column and one column packed with activated Q-5). All purified solvents were stored over 4 Å molecular sieves. Benzene-d6was degassed via three freeze- pump-thaw cycles and stored over 4 Å molecular sieves. The chlorophosphine (S)- ClP(Phen) was prepared by previously reported methods. (Z)-dehydro-N-acetyl- phenylalanine, D / L-N-acetyl-phenylalanine, and L-N-acetyl-phenylalanine were literature procedure. All other reagents were purchased from commercial suppliers and used without further purification. Unless otherwise stated,1H, 13C, 11B, and 31P characterization data were collected at 300K, with chemical shifts reported in parts per million downfield of SiMe4 (for1H and 13c), BF3·OEt2 (for 11B), or 85% H3PO4 in D2O (for 31P).1H and 13C NMR chemical shift assignments are based on data obtained from13C{1H},13C-DEPTQ,1H-1H COSY,1H-13C HSQC, and1H-13C HMBC NMR experiments. X-ray data collection, solution, and refinement were carried out by Dr. Katherine N. Robertson at Saint Mary’s University, Halifax, Nova Scotia on a fee-for- structure basis.

[0092] Synthetic Procedures and Characterization Data

[0093] Synthesis of 1. In a glovebox, (2-bromophenyl)diphenylphosphine (0.48 g, 1.41 mmol) was weighed into a 4-dram vial equipped with a stir bar. Diethyl ether (12 mL) was added and the resulting solution was cooled to -35 °C. Simultaneously, the chlorophosphine (S)-ClP(Phen) (0.589 g, 1.41 mmol) was weighed into a separate 4- dram vial equipped with a stir bar, dissolved in diethyl ether (5 mL), and cooled to - 35 °C. nBuLi (0.564 mL, 1.41 mmol) was then added dropwise to the vial containing (2-bromophenyl)diphenylphosphine and the mixture was allowed to warm to room temperature. The resulting suspension was allowed to stir at room temperature for 30 minutes before it was once more cooled to -35 °C. The cooled suspension was then added dropwise to the vial containing the chlorophosphine. The mixture was then allowed to warm to room temperature and stir for 18 h after which it was filtered, triturated with pentane (3 x 3 mL), and washed with pentane (3 x 5 mL) to afford 1 as a white solid (0.582 g, 0.902 mmol, 64% yield).1H NMR (500 MHz, benzene-d67.50 – 7.49 (m, 2 H, Harom), 7.45 – 7.39 (overlapping resonances, 3 H), 7.22 (s,1 H, Harom), 7.19 (s, 1 H, Harom), 7.16 (s, 1 H, Harom), 7.13 – 7.05 (overlapping resonances, 7 H), 6.90 – 6.88 (m, 1 H, Harom), 6.84 – 6.81 (m, 1 H, Harom), 2.19 (s, 3 H, CH3), 2.10(s, 3 H, CH3), 1.91 (s, 3 H, CH3), 1.75 (s, 3 H, CH3), 1.30 – 1.28 (overlapping resonances, 18 H, CMe3).13C{1H} NMR (125.7 MHz, benzene-d6148.8 (s, Carom), 146.4 (d, JC-P = 7.2 Hz, Carom), 145.1 – 144.2 (m), 138.4 (d, JC-P = 2.6 Hz, Carom), 138.3 (s, Carom), 137.7 (s, Carom), 137.6 – 137.5 (m), 135.2 (s, Carom), 134.7 (d, JC-P = 16.7 Hz, CHarom), 134.7 – 134.5 (m, CHarom), 133.2 (d, JC-P = 5.7 Hz, Carom), 132.9 (d, JC-P = 5.6 Hz, Carom), 132.7 (s, Carom), 132.4 (d, JC-P = 2.3 Hz, Carom), 132.1 (s, Carom), 131.6 (s, Carom), 130.4 (apparent q, Carom), 129.0 – 128.9 (overlapping resonances), 128.7 (s, CHarom), 128.5 (s, CHarom), 128.3 (s, Carom), 35.3 (s, CMe3), 34.9 (s, CMe3), 31.7 (s, CMe3), 31.4 (d, JC-P = 5.0 Hz, CMe3), 20.6 (s, CH3), 20.4 (s, CH3), 16.9 (s, CH3), 16.5 (s, CH3).31P{1H} NMR (202.5 MHz, benzene-d6160.6 (d,3JP-P= 239.9 Hz, PPhen), -11.4 (d, 3JP-P = 239.9 Hz, PPh2).

[0094] Synthesis of 2. In a glovebox, CoCl2(0.157 g, 1.21 mmol) was weighed into a 4-dram vial equipped with a stir bar. THF (10 mL) was added and the resulting suspension was stirred vigorously for 10 minutes until most of the CoCl2had dissolved. Compound 1 (0.782 g, 1.21 mmol) was then added as a THF solution (ca. 5 mL) and a color change from blue to dark purple was observed. The resulting solution was stirred until all of the CoCl2was dissolved at which time the solvent was removed in vacuo. The remaining crude solid was washed with diethyl ether (3 x 10 mL) to afford 2 as a light purple solid (0.700 g, 0.895 mmol, 74% yield).1H NMR (300 MHz, CD2Cl212.32, 10.84, 10.12, 9.52, 9.46, 9.34, 9.32, 8.55, 7.40, 7.06, 6.55, 5.36, 5.34, 5.32, 3.59, 3.44, 2.68, 2.56, 2.43, 0.87, 0.53, 0.23, 0.21. µeff= 3.89 µ42H46Cl2CoO2P2: C, 65.12; H, 5.99. Found: C, 61.44; H, 5.86. HRMS (ESI): calculated m / z (M)+ [C42H46ClCoO2P2]+: 738.1988; found: 739.1994.

[0095] Synthesis of 3. Method A: In a glovebox, complex 2 (0.101 g, 0.130 mmol) was weighed into a 4-dram vial equipped with a stir bar and subsequently dissolved in 4 mL of THF. The solution was then cooled to -35 °C and LiCH2TMS (0.050 g, 0.520 mmol) was added dropwise as a THF solution (ca. 2 mL) whereupon an immediate color change from purple to dark red was observed. The resulting solution was allowed to warm to room temperature and the volatile components were then removed in vacuo. The crude residue was triturated with pentane (3 x 3 mL), extracted with 12 mL of a 1:1 mixture of pentane:benzene, and filtered through Celite to afford a cleardark red filtrate. The solvent was removed in vacuo and the resulting red solid was washed with cold (-35 °C) pentane (2 x 0.5 mL) to afford 3 as a free-flowing red powder (0.072 g, 0.082 mmol, 63% yield). Single crystals suitable for X-ray crystallographic analysis were obtained from a concentrated diethyl ether solution at - 35 °C.

[0096] Method B: CoCl2(0.034 g, 0.264 mmol) was weighed into a 4-dram vial equipped with a stir bar. THF (4 mL) was added, and the resulting suspension was stirred vigorously for 10 minutes until most of the CoCl2had dissolved. Compound 1 (0.170 g, 0.264 mmol) was then added as a THF solution (ca. 3 mL) and a color change from blue to dark purple observed. The resulting reaction mixture was stirred until all of the CoCl2was dissolved, at which point the solution was cooled to -35 °C. LiCH2TMS (0.050 g, 0.528 mmol) was added dropwise as a THF solution (ca. 2 mL) whereupon an immediate color change from purple to dark red was observed. The resulting solution was allowed to warm to room temperature and the volatile components were then removed in vacuo. The crude residue was triturated with pentane (3 x 3 mL), extracted with 12 mL of a 1:1 mixture of pentane:benzene, and filtered through Celite to afford a clear dark red filtrate. The solvent was removed in vacuo and the resulting red solid was washed with cold (-35 °C) pentane (2 x 0.5 mL) to afford 3 as a free-flowing red powder (0.173 g, 0.198 mmol, 75% yield).1H NMR (300 MHz, benzene-d6): 33.97, 19.96, 18.26, 17.53, 17.50, 15.37, 9.63, 5.91, 4.25, 4.05, 3.95, 2.77, 2.39, 2.22, 2.10, 2.08, 1.84, 1.70, 1.62, 1.49, 1.40, 1.30, -0.87, -1.08, -1.54, -2.00, -2.73. µeff= 1.72 µ 1 / 2). Anal Calcd for C50H68CoO2P2Si2: C, 68.39; H, 7.81. Found: C, 65,16; H 7.42.

[0097] Synthesis of 4. Complex 3 (0.213 g, 0.242 mmol) was weighed into a 4-dram vial equipped with a stir bar and was dissolved in 6 mL of a 1:1 mixture of diethyl ether:benzene. Ferrocenium tetrakis(3,5-bis(trifluoromethyl)phenyl) borate ([Fc][BArF]) was then added dropwise as an ether solution (ca. 2 mL) and the resulting mixture was stirred for 30 minutes. A color change from dark red to dark orange was observed. The volatile components of the reaction mixture were then removed in vacuo, and the crude mixture was triturated with pentane (3 x 3 mL). The resulting oily solid residue was washed with pentane until all of the ferrocene was removed (as evidenced by the washes becoming colorless) and was subsequentlyextracted with diethyl ether (ca. 12 mL) and filtered through Celite to afford a clear orange filtrate solution. The solvent was removed in vacuo to afford 4 as a crystalline orange powder (0.318 g, 0.194 mmol, 80% yield).1H NMR (500 MHz, THF-d87.78 – 7.50 (overlapping resonances, 30 H), 7.35 (broad s, 1 H, Harom), 6.93 (broad m, 1 H, Harom6-C6H6), 2.45 (s, 3 H, CH3), 2.39 (s, 3 H, CH3), 2.03 (s, 3 H, CH3), 1.88 (s, 3 H, CH3), 1.42 (s, 9 H, C(CH3)3), 1.18 (s, 9 H, C(CH3)3).13C{1H} NMR (125.7 MHz, THF-d8162.5 (q, 1JB-C = 50.1 Hz, B[3,5-(CF3)2C6H3]4), 147.6 (d, JC-P = 14.4 Hz, Carom), 146.1 (s, Carom), 146.0 (s, Carom), 145.5 (d, JC-P = 37.7 Hz), 145.0 (d, JC-P = 35.6, Carom), 139.7 (apparent t, Carom), 138.6 (s, CPhen), 137.2 (s, CPhen), 136.5 (d, JC-P = 26.4 Hz, CHarom), 135.3 (br s, B[3,5-(CF3)2C6H3]4), 134.8 (d, JC-P = 34.0 Hz, Carom), 133.4 (d, JC-P = 11.3 Hz, CHarom), 132.9 (br s, Carom), 132.8 (d, JC-P = 11.2 Hz, CHarom), 132.3 (br s, B[3,5-(CF3)2C6H3]4), 131.7 (d, JC-P = 19.7 Hz, Carom), 131.2 (s, Carom), 130.2 – 129.3 (overlapping resonances, B[3,5-(CF3)2C6H3]4), 125.1 (q, 1JC-F = 272.5 Hz, B[3,5-(CF3)2C6H3]4), 117.9 (s, CHarom6-C6H6), 35.9 (s, C(CH3)3), 35.3 (s, C(CH3)3), 32.3 (s, C(CH3)3), 31.6 (s, C(CH3)3), 20.2 (s, CH3), 20.1 (s, CH3), 16.3 (s, CH3), 16.2 (s, CH3).31P{1H} NMR (202.5 MHz, THF- d8192.9 (d, 3JP-P = 97.4 Hz, PPhen), 77.8 (d, 3JP-P = 97.4 Hz, PPh2). 19F{1H} NMR (376.5 MHz, THF-d8-63.4 (s, B[3,5-(CF3)2C6H3]4). 11B NMR (160.5 MHz, THF- d8-6.5 (s, B[3,5-(CF3)2C6H3]4). Anal Calcd for C80H64BCoF24O2P2: C, 58.41; H, 3.92. Found: C, 56.49; H, 4.04. HRMS (ESI): calculated m / z (M)+ [C48H52CoO2P2]+: 781.2769; found: 781.2759. Calculated m / z (M)-[C32H12BF24]-: 863.0654; found: 863.0643.

[0098] amino acids with pre-catalyst 2. The substrate (0.2 mmol), Co pre-catalyst (0.01 mmol), and Zn(0) (0.2 mmol) were weighed into a 1-dram vial and 1 mL of 2,2,2- trifluoroethanol was added. The vial was equipped with a stirbar and closed with a screw cap featuring a PTFE septum. A needle was then inserted through the septum to allow for the introduction of H2gas. The vial was subsequently transferred to a Parr reactor which was sealed and pressurized to 5 atm H2pressure. The Parr reactor was heated to 50 °C in an oil bath for the duration of the reaction time. Afterward, the Parr reactor was removed from the oil bath and depressurized. The volatile components of the crude reaction mixture were removed in vacuo and the residue was then treatedwith 0.1 M NaOH solution (2 equiv. NaOH relative to substrate). The aqueous solution was washed with ethyl acetate (3 x 10 mL), then acidified with 0.1 M HCl solution (3 equiv. HCl), and subsequently extracted with 3 x 10 mL ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo to afford the hydrogenated product in the specified yield. Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column using the specified conditions.

[0099] amino acids with pre-catalyst 4. The substrate (0.2 mmol) was weighed into a 1- dram vial and 1 mL of a freshly prepared 0.005 M, 0.01 M, or 0.02 M THF stock solution of 4 was added via microsyringe (for 2.5 mol%, 5 mol%, and 10 mol% runs respectively). The vial was equipped with a stirbar and closed with a screw cap featuring a PTFE septum. A needle was then inserted through the septum to allow for the introduction of H2gas. The vial was subsequently transferred to a Parr reactor which was sealed and pressurized to either 10 or 20 atm H2pressure. The Parr reactor was heated to 50 °C in an oil bath for the duration of the reaction time. Afterward, the Parr reactor was removed from the oil bath and depressurized. The volatile components of the crude reaction mixture were removed in vacuo and the residue was then treated with 0.1 M NaOH solution (2 equiv. NaOH relative to substrate). The aqueous solution was washed with ethyl acetate (3 x 10 mL), then acidified with 0.1 M HCl solution (3 equiv. HCl), and subsequently extracted with 3 x 10 mL ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo to afford the hydrogenated product in the specified yield. Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD- H column using the specified conditions.

[0100] Procedure for the Asymmetric Hydrogenation of (Z)-dehydro-N-acetyl- (a4-acetoxy-3-methoxy) phenylalanine (5r). Substrate 5r (0.293 g, 1.0 mmol) was weighed into a 4-dram vial and 5 mL of a freshly prepared 0.005M THF stock solution of 4 was added via microsyringe. The vial was equipped with a stirbar and closed with a screw cap featuring a PTFE septum. A needle was then inserted through the septum to allow for the introduction of H2gas. The vial was subsequently transferred to a Parr reactor which was sealed and pressurized to 40 atm H2pressure.The Parr reactor was heated to 50 °C in an oil bath for the duration of the reaction time. Afterward, the Parr reactor was removed from the oil bath and depressurized. The volatile components of the crude reaction were removed in vacuo and then treated with 0.1 M NaOH solution (2 equiv. NaOH to substrate). The aqueous solution was washed with ethyl acetate (3 x 20 mL), then acidified with 0.1 M HCl solution (3 equiv. HCl), and was subsequently extracted with 3 x 20 mL ethyl acetate. The combined ethyl acetate extracts were dried over MgSO4, filtered, and the solvent was removed in vacuo to afford (R)-N-acetyl-(a4-acetoxy-3-methoxy) phenylalanine as a white solid (6r, 0.221 g, 75% yield). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor= 28.890 min, tmin= 31.222 min. Enantiomeric ratio = 99:1.

[0101] Selected NMR Spectra and HPLC Chromatograms for Reported Compounds

[0102] (R)-N-acetyl-phenylalanine (6a). White solid (0.037 g, 89% yield).1H NMR (500 MHz, MeOD-d4): 7.28 – 7.25 (m, 2 H), 7.23 – 7.18 (overlapping resonances, 3 H, Harom), 4.65 (dd,3JH-H= 9.1 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.19 (dd,2JH-H= 13.8 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.94 (dd, 2J H-H = 13.8 Hz,3JP-P= 9.1 Hz, 1 H, CH2), 1.89 (s, 3 H, COCH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.7 (s, COOH), 173.1 (s, HNCOCH3), 138.5 (s, Carom), 130.2 (s, CHarom), 129.4 (s, CHarom), 127.8 (s, CHarom), 55.1 (s, CH), 38.4 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 15.425 min, tmin = 19.266 min. Enantiomer ratio = 99:1.

[0103] (R)-N-acetyl-phenylalanine-d2 (6a-d2). White solid (0.040 g, 94% yield).1H NMR (500 MHz, MeOD-d4): 7.30 – 7.26 (m, 2 H), 7.23 –7.18 (overlapping resonances, 3 H, Harom), 2.91 (s, 1 H, CHD), 1.89 (s, 3 H, COCH3). 2H NMR (76.8 MHz, MeOH): 4.58 (s, 1 D, CD), 3.13 (s, 1 D, CHD).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.7 (s, COOH), 173.1 (s, HNCOCH3), 138.4 (s, Carom), 130.2 (s, CHarom), 129.4 (s, CHarom), 127.8 (s, CHarom), 54.8 (t, 1JC-D = 21.5 Hz, CD), 38.0 (t, 1JC-D = 20 Hz, CHD), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 15.425 min, tmin = 19.266 min. Enantiomer ratio = >99:1.

[0104] (R)-2-acetamido-3-(napthalen-2-yl)propanoic acid (6b). White solid (0.046 g, 90% yield).1H NMR (500 MHz, MeOD-d4): 7.81 – 7.77 (overlapping resonances, 3 H, Harom), 7.69 (s, 1 H, Harom), 7.46 – 7.40 (overlapping resonances, 2 H, Harom), 7.39 – 7.47 (overlapping resonances, 2 H, Harom), 4.76 (dd, 3J H-H = 9.1 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.37 (dd, 2J H-H = 13.9 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 3.11 (dd, 2J H-H = 13.9 Hz, 3J H-H = 9.1 Hz, 1 H, CH2), 1.88 (s, 3 H. CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.5 (s, COOH), 173.1 (s, HNCOCH3), 136.1 (s, Carom), 134.9 (s, Carom), 133.9 (s, Carom), 129.9 (s, CHarom), 128.9 (s, CHarom), 128.8 (s, CHarom), 128.6 (s, CHarom), 128.4 (s, CHarom), 127.0 (s, CHarom), 126.6 (s, CHarom), 55.2 (s, CH), 38.7 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 24.959 min, tmin = 32.618 min. Enantiomer ratio = 90:10.

[0105] (R)-2-acetamido-3-(4-fluorophenyl)propanoic acid (6c). White solid (0.046 g, 90% yield).1H NMR (500 MHz, MeOD-d4): 7.23 (m, 2 H, Harom), 6.96 (m, 2 H, Harom), 4.63 (dd,3JH-H= 8.9 Hz,3JH-H= 5.20 Hz, 1 H, CH), 3.18 (dd,2JH-H= 14.0 Hz,3JH-H= 5.2 Hz, 1 H, CH2), 2.93 (dd,2JH-H= 14.0 Hz,3JH-H= 8.9 Hz, 1 H, CH2), 1.90 (s, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.6 (s,COOH), 173.1 (s, HNCOCH3), 163.2 (d,1JC-F= 242.3 Hz, C-F), 134.4 (d,4JC-F= 2.8 Hz, Carom), 131.9 (d,3JC-F= 7.9 Hz, CHarom), 116.0 (d,2JC-F= 21.5 Hz, CHarom), 55.1 (s, CH), 37.6 (s, CH2), 22.3 (s, CH3). 19F{1H} NMR (470.5 MHz, MeOD-d4): -116.6 (s). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 17.676 min, tmin = 23.330 min. Enantiomer ratio = 99:1.

[0106] (R)-2-acetamido-3-(3-fluorophenyl)propanoic acid (6d). White solid (0.039 g, 87% yield).1H NMR (500 MHz, MeOD-d4): 7.31 – 7.26 (m, 1 H), 7.05 – 7.04 (m, 1 H), 6.99 – 6.92 (overlapping resonances, 2 H), 4.66 (dd,3JH-H= 9.1 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.21 (dd,2JH-H= 14.0 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.95 (dd,2JH-H= 14.0 Hz,3JH-H= 9.1 Hz, 1 H, CH2), 1.91 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.4 (s, COOH), 173.1 (s, HNCOCH3) 164.1 (d, 1JC-F = 244.9 Hz, CF), 141.4 (d,3JC-F= 7.1 Hz, Carom), 131.1 (d,3JC-F= 8.3 Hz, CHarom), 126.1 (d,4JC-F= 2.7 Hz, CHarom), 116.92J (Cd-,F= 21.5 Hz, CHarom), 114.52J (Cd-,F= 21.3 Hz, CHarom), 54.8 (s, CH), 38.1 (s, CH2), 22.3 (s, CH3). 19F{1H} NMR (470.5 MHz, MeOD-d4): -119.8. Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 15.877 min, tmin = 18.832 min. Enantiomer ratio = 98:2.

[0107] (R)-2-acetamido-3-(2-fluorophenyl)propanoic acid (6e). White solid (0.040 g, 88% yield).1H NMR (500 MHz, MeOD-d4): 7.27 – 7.22 (overlapping resonances, 2 H), 7.10 – 7.02 (overlapping resonances, 2H), 4.70 (dd,3JH-H= 9.0 Hz,3JH-H= 5.4 Hz, 1 H, CH), 3.29 (dd,2JH-H= 14.2 Hz,3JH-H= 5.4 Hz, 1 H, CH2), 2.96 (dd,2JH-H= 14.1 Hz,3JH-H= 9.0 Hz, 1 H, CH2), 1.89 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.4 (s, COOH), 173.1 (s, HNCOCH3) 162.8 (d, 1JC-F = 244.4 Hz, CF), 132.7 (d,3JC-F= 4.3 Hz, CHarom), 129.7 (d,3JC-F= 8.0Hz, CHarom), 125.42J (Cd-,F= 15.7 Hz, Carom), 125.2 (d,4JC-F= 3.2 Hz, CHarom), 116.12J (Cd-,F= 22.0 Hz, CHarom), 53.9 (s, CH), 32.0 (s, CH2), 22.3 (s, CH3). 19F{1H} NMR (470.5 MHz, MeOD-d4): -115.8. Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 20.460 min, tmin = 21.942 min. Enantiomer ratio = 88:12.

[0108] (R)-2-acetamido-3-(4-chlorophenyl)propanoic acid (6f). White solid (0.046 g, 95% yield).1H NMR (500 MHz, MeOD-d4): 7.28 – 7.26 (m, 2 H, Harom), 7.22 – 7.20 (m, 2 H, Harom), 4.65 (dd,3JH-H= 9.0 Hz,3JH-H= 5.2 Hz, 1 H, CH), 3.18 (dd,2JH-H= 13.9 Hz,3JH-H= 5.3 Hz, 1 H, CH2), 2.93 (dd, 2J = 13.9 Hz, 3JH-H= 9.0 Hz, 1 H, CH2), 1.90 (s, 3 H. CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.4 (s, COOH), 173.1 (s, HNCOCH3), 137.4 (s, CCl), 133.7 (s, Carom), 131.9 (s, CHarom), 129.5 (s, CHarom), 54.9 (s, CH), 37.8 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 18.170 min, tmin = 23.409 min. Enantiomer ratio = 98:2.

[0109] (R)-2-acetamido-3-(3-chlorophenyl)propanoic acid (6g). White solid (0.048 g, quantitative yield).1H NMR (500 MHz, MeOD-d4): 7.28 – 7.21 (overlapping resonances, 3 H), 7.17 – 7.15 (overlapping resonances, 2 H), 4.65 (dd,3JH-H= 9.1 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.19 (dd,2JH-H= 14.0 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.94 (dd,2JH-H= 14.0 Hz,3JH-H= 9.1 Hz, 1 H, CH2), 1.91 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.4 (s, COOH), 173.1 (s, HNCOCH3), 140.9 (s, CCl), 135.1 (s, Carom), 130.9 (s, CHarom), 130.3 (s, CHarom), 128.7 (s, CHarom), 127.9 (s, CHarom), 54.8 (s, CH), 38.0 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-Hcolumn with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 15.492 min, tmin = 17.942 min. Enantiomer ratio = >99:1.

[0110] (R)-2-acetamido-3-(2-chlorophenyl)propanoic acid (6h). White solid (0.041 g, 86% yield).1H NMR (500 MHz, MeOD-d4): 7.37 – 7.35 (m, 1 H, Harom), 7.29 – 7.28 (m, 1 H, Harom), 7.23 – 7.20 (overlapping resonances, 2 H), 4.78 (dd,3JH-H= 9.6 Hz,3JH-H= 5.2 Hz, 1 H, CH), 3.41 (dd,2JH-H= 13.9 Hz,3JH-H= 5.2 Hz, 1 H, CH2), 3.01 (dd,2JH-H= 13.9 Hz,3JH-H= 9.6 Hz, 1 H, CH2), 1.88 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.5 (s, COOH), 173.1 (s, HNCOCH3), 136.3 (s, CCl), 135.4 (s, Carom), 132.6 (s, CHarom), 130.6 (s, CHarom), 129.5 (s, CHarom), 127.9 (s, CHarom), 53.0 (s, CH), 36.3 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 21.919 min, tmin = 23.690 min. Enantiomer ratio = 98:2.

[0111] (R)-2-acetamido-3-(3-bromophenyl)propanoic acid (6i). White solid (0.052 g, quantitative yield).1H NMR (500 MHz, MeOD-d4): 7.41 (broad m, 1 H, Harom), 7.37 – 7.36 (m, 1 H, Harom), 7.22 – 7.18 (overlapping resonances, 2 H), 4.65 (dd,3JH-H= 9.1 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.19 (dd,2JH-H= 14.0 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.93 (dd,2JH-H= 14.0 Hz,3JH-H= 9.1 Hz, 1 H, CH2), 1.91 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.3 (s, COOH), 173.1 (s, HNCOCH3), 141.2 (s, CBr), 133.3 (s, CHarom), 131.2 (s, CHarom), 130.9 (s, CHarom), 129.1 (s, CHarom), 123.2 (s, Carom), 54.9 (s, CH), 37.9 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 16.618 min, tmin = 19.023 min. Enantiomer ratio = >99:1.

[0112] (R)-2-acetamido-3-(p-tolyl)propanoic acid (6j). White solid (0.028 g, 64% yield).1H NMR (500 MHz, MeOD-d4): 7.11 – 7.07 (overlapping resonances, 4 H, Harom), 4.61 (dd,3JH-H= 9.1 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.15 (dd,2JH-H= 14.1 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.89 (dd,2JH-H= 14.1 Hz,3JH-H= 9.1 Hz, 1 H, CH2), 2.89 (s, 3 H, CH3), 1.89 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.9 (s, COOH), 173.1 (s, HNCOCH3), 137.4 (s, Carom), 135.4 (s, Carom), 130.1 (s, CHarom), 130.0 (s, CHarom), 55.2 (s, CH), 38.0 (s, CH2), 22.3 (s, CH3), 21.1 (s, p-CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 94.0: 5.0: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 14.386 min, tmin = 20.978 min. Enantiomer ratio = 99:1.

[0113] (R)-2-acetamido-3-(m-tolyl)propanoic acid (6k). White solid (0.036 g, 95% yield).1H NMR (500 MHz, MeOD-d4): 7.14 (m, 1 H, Harom), 7.04 – 6.99 (overlapping resonances, 2 H), 4.64 (dd,3JH-H= 8.8 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.15 (dd,2JH-H= 13.9 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.90 (dd,2JH-H= 13.9 Hz,3JH-H= 8.8 Hz, 1 H, CH2), 2.30 (s, 3 H, CH3), 1.89 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.8 (s, COOH), 173.1 (s, HNCOCH3), 139.1 (s, Carom), 138.4 (s, Carom), 130.9 (s, CHarom), 129.3 (s, CHarom), 128.4 (s, CHarom), 127.3 (s, CHarom), 55.2 (s, CH), 38.4 (s, CH2), 22.3 (s, CH3), 21.4 (s, p-CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 13.040 min, tmin = 16.534 min. Enantiomer ratio = 98:2.

[0114] (R)-2-acetamido-3-(o-tolyl)propanoic acid (6l). White solid (0.030 g, 80% yield).1H NMR (500 MHz, MeOD-d4): 7.14 – 7.07 (overlapping resonances, 4 H), 4.66 (dd,3JH-H= 9.5 Hz,3JH-H= 5.4 Hz, 1 H, CH), 3.25 (dd,2JH-H= 14.3 Hz,3JH-H= 5.4 Hz, 1 H, CH2), 2.90 (dd,2JH-H= 14.3 Hz,3JH-H= 9.5 Hz, 1 H, CH2), 2.36 (s, 3 H, CH3), 1.89 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.5 (s, COOH), 173.1 (s, HNCOCH3), 137.7 (s, Carom), 136.6 (s, Carom), 131.3 (s, CHarom), 130.8 (s, CHarom), 127.9 (s, CHarom), 126.8 (s, CHarom), 53.9 (s, CH), 36.1 (s, CH2), 22.3 (s, CH3), 19.4 (s, p-CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 18.562 min, tmin = 22.077 min. Enantiomer ratio = >99:1.

[0115] (R)-2-acetamido-3-(4- trifluoromethyl)phenyl)propanoic acid (6m). White solid (0.045 g, 82% yield).1H NMR (500 MHz, MeOD-d4): 7.58 (apparent d, 2 H, Harom), 7.42 (apparent d, 2 H, Harom), 4.71 (dd,3JH-H= 9.1 Hz,3JH-H= 5.2 Hz, 1 H, CH), 3.29 (dd,2JH-H= 14.4 Hz,3JH-H= 5.2 Hz, 1 H, CH2), 3.04 (dd,2JH-H= 14.4 Hz,3JH-H= 9.1 Hz, 1 H, CH2), 1.91 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.3 (s, COOH), 173.1 (s, HNCOCH3), 143.3 (s, Carom), 130.9 (s, CHarom), 130.0 (apparen2JtCd-,F= 32.3 Hz, CCF3), 126.2 (q,3JC-F= 3.6 Hz, CHarom), 125.8 (apparent d, 1JC-F = 271.1 Hz, CF3), 54.7 (s, CH), 38.2 (s, CH2), 22.3 (s, CH3). 19F{1H} NMR (470.5 MHz, MeOD-d4): - 64.0. Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD- H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 15.381 min, tmin = 19.920 min. Enantiomer ratio = 99:1.

[0116] (R)-2-acetamido-3-(3- trifluoromethyl)phenyl)propanoic acid (6n). White solid (0.050 g, 95% yield).1H NMR (500 MHz, MeOD-d4): 7.54 – 7.46 (overlapping resonances, 4 H), 4.69 (dd,3JH-H= 9.1 Hz,3JH-H= 5.2 Hz, 1 H, CH), 3.29 (dd,2JH-H= 14.0 Hz,3JH-H= 5.2 Hz, 1 H, CH2), 3.03 (dd,2JH-H= 14.0 Hz,3JH-H= 9.1 Hz, 1 H, CH2), 1.90 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.3 (s, COOH), 173.1 (s, HNCOCH3), 139.9 (s, Carom), 134.0 (s, CHarom), 131.62J (Cq-,F= 32.1 Hz, CCF3), 130.2 (s, CHarom), 127.0 (q,3JC-F= 3.5 Hz, CHarom), 126.8 (apparent s, CF3), 124.6 (q,3JC-F= 3.7 Hz, CHarom), 54.8 (s, CH), 38.1 (s, CH2), 22.2 (s, CH3). 19F{1H} NMR (470.5 MHz, MeOD-d4): -64.1. Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 12.298 min, tmin = 13.715 min. Enantiomer ratio = 99:1.

[0117] (R)-2-acetamido-3-(4- methoxyphenyl)propanoic acid (6o). White solid (0.040g, 84% yield).1H NMR (500 MHz, MeOD-d4): 7.14 – 7.12 (m, 2 H, Harom), 6.85 – 6.82 (m, 2 H, Harom), 4.60 (dd,3JH-H= 8.7 Hz,3JH-H= 5.2 Hz, 1 H, CH), 3.77 (s, 3 H, OCH3), 3.12 (dd,2JH-H= 14.1 Hz,3JH-H= 5.2 Hz, 1 H, CH2), 2.84 (dd,2JH-H= 14.1 Hz,3JH-H= 8.7 Hz, 1 H, CH2), 1.90 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.8 (s, COOH), 173.1 (s, HNCOCH3), 160.1 (s, Carom), 131.2 (s, CHarom), 130.4 (s, Carom), 114.5 (s, CHarom), 55.6 (s, OCH3), 55.3 (s, CH), 37.7 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 24.111 min, tmin = 33.369 min. Enantiomer ratio = 98:2.

[0118] (R)-2-acetamido-3-(3- methoxyphenyl)propanoic acid (6p). White solid (0.043 g, 92% yield).1H NMR (500 MHz, MeOD-d4): 7.19 – 7.16 (m, 1 H, Harom), 6.81 – 6.76 (overlapping resonances, 3 H), 4.65 (dd,3JH-H= 9.0 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.17 (dd,2JH-H= 13.9 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.91 (dd,2JH-H= 13.9 Hz,3JH-H= 9.0 Hz, 1 H, CH2), 1.90 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD- d4): 174.7 (s, COOH), 173.1 (s, HNCOCH3), 161.2 (s, Carom), 139.9 (s, Carom), 130.4 (s, CHarom), 122.5 (s, CHarom), 115.8 (s, CHarom), 113.3 (s, CHarom), 55.6 (s, OCH3), 55.0 (s, CH), 38.4 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 21.757 min, tmin = 29.156 min. Enantiomer ratio = >99:1.

[0119] (R)-2-acetamido-3-(3-methoxyphenyl)propanoic acid (6q). White solid (0.034 g, 73% yield).1H NMR (500 MHz, MeOD-d4): 7.22 – 7.18 )m, 1 H, Harom), 7.12 – 7.11 (m, 1 H, Harom), 6.93 – 6.91 (m, 1 H, Harom), 6.86 – 6.82 (m, 1 H, Harom), 4.70 (dd,3JH-H= 9.2 Hz,3JH-H= 5.4 Hz, 1 H, CH), 3.84 (s, 3 H, OCH3), 3.25 (dd,2JH-H= 13.5 Hz,3JH-H= 5.4 Hz, 1 H, CH2), 2.87 (dd,2JH-H= 13.5 Hz,3JH-H= 9.2 Hz, 1 H, CH2), 1.86 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD- d4): 175.2 (s, COOH), 173.0 (s, HNCOCH3), 159.2 (s, Carom), 131.9 (s, CHarom), 129.4 (s, CHarom), 126.5 (s, Carom), 121.3 (s, CHarom), 111.5 (s, CHarom), 55.8 (s, OCH3), 53.8 (s, CH), 33.6 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 22.540 min, tmin = 24.967 min. Enantiomer ratio = 76:24.

[0120] (R)-2-acetamido-3-(4-acetoxy-3- methoxyphenyl)propanoic acid (6r). White solid (0.050 g, 84% yield).1H NMR (500 MHz, MeOD-d4): 6.94 – 6.92 (overlapping resonances, 2 H, Harom), 6.82 – 6.79 (m, 1 H, Harom), 4.68 (dd,3JH-H= 8.8 Hz,3JH-H= 5.1 Hz, 1 H, CH), 3.80 (s, 3 H, OCH3), 3.20 (dd,2JH-H= 14.1 Hz,3JH-H= 5.1 Hz, 1 H, CH2), 2.97 (dd,2JH-H= 14.1 Hz,3JH-H= 8.8 Hz, 1 H, CH2), 2.24 (s, 3 H, OC(O)CH3), 1.89 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.6 (s, COOH), 173.2 (s, HNCOCH3), 170.9 (s, OC(O)CH3), 152.4 (s, Carom), 140.0 (s, Carom), 137.6 (s, Carom), 123.5 (s, CHarom), 122.4 (s, CHarom), 114.5 (s, CHarom), 56.3 (s, OCH3), 54.9 (s, CH), 38.1 (s, CH2), 22.3 (s, CH3), 20.4 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD- H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 28.890 min, tmin = 31.222 min. Enantiomer ratio = 99:1.

[0121] (R)-2-acetamido-3-(thiophen-2-yl)propanoic acid (6s). White solid (0.033 g, 77% yield).1H NMR (500 MHz, MeOD-d4): 7.23 – 7.22 (m, 1 H, Harom), 6.93 – 6.91 (m, 1 H, Harom), 6.89 – 6.88 (m, 1 H, Harom), 4.64 (dd,3JH-H= 8.4 Hz,3JH-H= 4.8 Hz, 1 H, CH), 3.40 (dd,2JH-H= 15.2 Hz,3JH-H= 4.8 Hz, 1 H, CH2), 3.22 (dd,2JH-H= 15.2 Hz,3JH-H= 8.4 Hz, 1 H, CH2), 1.96 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.0 (s, COOH), 173.2 (s, HNCOCH3), 140.1 (s, Carom), 127.8 (s, CHarom), 127.4 (s, CHarom), 125.4 (s, CHarom), 55.2 (s, CH), 32.5 (s, CH2), 22.4 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 22.794 min, tmin = 25.330 min. Enantiomer ratio = >99:1.

[0122] (R)-2-acetamido-3-(thiophen-3-yl)propanoic acid (6t). White solid (0.038 g, 88% yield).1H NMR (500 MHz, MeOD-d4): 7.32 – 7.31 (m, 1 H, Harom), 7.12 – 7.11 (m, 1 H, Harom), 6.99 – 6.97 (m, 1 H, Harom), 4.64 (dd, 3JH- H = 8.8 Hz,3JH-H= 4.9 Hz, 1 H, CH), 3.20 (dd,2JH-H= 14.5 Hz,3JH-H= 4.9 Hz, 1 H, CH2), 3.02 (dd,2JH-H= 14.5 Hz,3JH-H= 8.8 Hz, 1 H, CH2), 1.93 (s, 3 H, CH3).13C{1H} NMR (125.7 MHz, MeOD-d4): 174.7 (s, COOH), 173.2 (s, HNCOCH3), 138.6 (s, Carom), 129.3 (s, CHarom), 126.5 (s, CHarom), 123.3 (s, CHarom), 54.6 (s, CH), 32.9 (s, CH2), 22.3 (s, CH3). Enantioselectivity was determined by chiral HPLC analysis on a Chiralpak AD-H column with a 91.5: 7.5: 1.0 Hexane: iPrOH: Formic acid mobile phase at a 1.0 mL / min flow rate. tmajor = 21.667 min, tmin = 29.106 min. Enantiomer ratio = 99:1.

[0123] Further Synthetic Procedures and Characterization Data

[0124] Unless otherwise noted, all experiments were conducted under nitrogen in a glovebox or using standard Schlenk techniques. Dry, deoxygenated solvents were used throughout. (R)-(Ph-BinolPhos) was prepared according to a modified literature procedure: Schull, T. S; Knight, D. A. Tetrahedron: Asymmetry 1999, 10, 207–211. See also: Reetz, M. T.; Gosberg, A. Tetrahedron: Asymmetry 1999, 10, 2129–2137.

[0125] (rac)-(Ph-PhenPhos)CoBr2. A slurry of CoBr2 (0.051 g, 0.232 mmol) in THF (ca. 10 mL) was treated with a solution of (rac)-(Ph-PhenPhos) (0.150 g, 0.232 mmol) in THF (ca. 5 mL). A color change from blue to dark purple observed. The resulting reaction mixture was magnetically stirred at room temperature until all the CoBr2 was dissolved (ca. 2 h). The volatile components of the reaction mixture were then removed in vacuo. The remaining solid was washed with diethylether (3 × 10 mL), and the residue was dried in vacuo to afford the product as a dark purple / red solid (0.161 g, 0.186 mmol, 81% yield).1H NMR (300 MHz, CD2Cl210.73, 9.49, 9.27, 8.59, 7.35, 7.31, 7.28, 7.25, 7.22, 7.13, 7.06, 7.02, 6.83, 6.69, 6.42, 6.36, 6.14, 6.02, 5.92, 5.73, 4.88, 4.65, 4.34, 2.65, 2.45, 2.40, 2.29, 2.26, 2.17, 2.02, 1.87, 1.80, 1.53, 1.43, 1.29, 1.26, 1.05, 1.00, 0.90, 0.88, 0.85, 0.39, 0.21, 0.08, -0.15, - 0.54, -1.01. Evans method (CD2Cl2, 300K): µeff= 3.85 µB(S = 3 / 2).

[0126] (rac)-(Ph-PhenPhos)CoI2. A slurry of CoI2 (0.073 g, 0.232 mmol) in THF (ca. 10 mL) was treated with a solution of (rac)-(Ph-PhenPhos) (0.150 g, 0.232 mmol) in THF (ca. 5 mL). A color change from blue to dark purple observed. The resulting reaction mixture was magnetically stirred until all the CoI2 was dissolved (ca. 2 h). The volatile components of the reaction mixture were then removed in vacuo. The remaining solid was washed with diethyl ether (3 × 10 mL), and the residue was dried in vacuo to afford the product as a dark purple / red solid (0.142 g, 0.148 mmol, 64% yield).1H NMR (300 MHz, CD2Cl26.45, 6.26, 5.71, 4.29, 2.58, 2.46, 2.27, 2.03, 1.63, 1.28, 1.23, 1.00, 0.88, 0.58, 0.49, 0.25, -0.10. Evans method (CD2Cl2, 300K): µeff= 4.05 µB(S = 3 / 2).

[0127] (S)-(Cy-PhenPhos). A pre-cooled (-35 °C) solution of (2-bromophenyl)-dicyclohexylphosphine (0.243 g, 0.687 mmol) in diethyl ether (ca.12 mL) was treated with nBuLi (1.6 M in hexanes, 0.430 mL, 0.687 mmol), which was added dropwise. The reaction mixture was allowed to stir at room temperature for 30 minutes, and was subsequently cooled to -35 °C. The cold reaction mixture was thenadded in a dropwise fashion to a pre-cooled (-35 °C) solution of (S)-ClP(Phen) (0.288 g, 0.687 mmol) in diethyl ether (5 mL). The resulting reaction mixture was then allowed to warm to room temperature and stir for 18 h. The reaction mixture was subsequently filtered through Celite. The filtrate solution was collected, and the volatile components were removed in vacuo. The remaining residue was triturated with pentane (3 × 3 mL), washed with pentane (3 × 5 mL), and lastly, dried in vacuo to afford (S)- (Cy-PhenPhos) as a white solid (0.450 g, 0.685 mmol, 99% yield).1H NMR (500 MHz, benzene-d6J = 5.8, 2.6 Hz,1H), 7.28 (s,1H), 7.17 (s,1H), 7.04 (td, J = 7.5, 1.5 Hz,1H), 6.86 (td, J = 7.5, 1.2 Hz,1H), 2.18 (s, 4H), 2.21 – 2.13 (m, 2H), 2.11 (s, 3H), 1.93 (s,1H), 1.90 (s, 3H), 1.82 (s,1H), 1.75 (s, 3H), 1.74 (s,1H), 1.70 – 1.62 (m, 2H), 1.61 (s, 9H), 1.54 (d, J = 13.5 Hz,1H), 1.51 – 1.42 (m,1H), 1.36 – 1.17 (m, 4H), 1.16 (s, 9H), 1.15 (s,1H), 0.99 (tt, J = 12.7, 3.5 Hz,1H), 0.86 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz, benzene-d6148.23, 146.71, 146.64, 143.08, 142.84, 142.74, 142.50, 138.63, 138.57, 138.54, 135.67, 134.88, 133.75, 133.69, 132.94, 132.80, 132.77, 132.21, 132.17, 131.84, 131.38, 131.34, 131.29, 131.26, 131.05, 129.11, 128.82, 36.84, 36.67, 35.58, 35.48, 34.78, 32.39, 32.00, 31.95, 31.28, 31.24, 31.17, 31.14, 31.00, 30.86, 30.51, 30.33, 30.06, 29.99, 28.35, 28.31, 28.28, 28.21, 27.69, 27.58, 27.24, 26.98, 20.92, 20.80, 17.23, 16.84. 31P{1H} NMR (202 MHz, benzene-d6J = 234.9 Hz), -13.90 (d, J = 235.0 Hz).

[0128] (S)-(Cy-PhenPhos)CoCl2. A slurry of CoCl2(0.078 g, 0.597 mmol) in THF (ca. 10 mL) was treated with a solution of (S)-(Cy-PhenPhos) (0.392 g, 0.597 mmol) in THF (ca. 5 mL). A color change from blue to dark purple observed. The resulting reaction mixture was magnetically stirred until all of the CoCl2was dissolved (ca. 2 h). The volatile components of the reaction mixture were then removed in vacuo. The remaining solid was washed with diethyl ether (3 × 10 mL), and the residue was dried in vacuo to afford the product as a purple solid (0.292 g, 0.371mmol, 62% yield).1H NMR (400 MHz, CD2Cl23.63, 3.52, 3.50, 3.38, 2.91, 2.77, 2.71, 2.55, 2.53, 2.42, 2.38, 2.31, 2.28, 1.55, 1.52, 1.36, 1.28, 1.26, 1.24, 1.13, 1.12, 1.10, 0.87, 0.86, 0.84, 0.74, 0.66, -0.26, -0.46, -0.61, -0.90, -1.20, -1.46, -1.87, -3.11. Evans method (benzene-d6, 300K): µeff= 3.25 µB(S = 3 / 2).

[0129] (S)-(Cy-PhenPhos)Co(CH2TMS)2. A pre-cooled (- 35 °C) solution of (S)-(Cy-PhenPhos)CoCl2(0.215 g, 0.273 mmol) in THF (ca. 4 mL) was treated with a solution of LiCH2TMS (0.051 g, 0.546 mmol) in THF (ca. 2 mL), which was added dropwise. An immediate color change from purple to dark red was observed. The resulting reaction mixture was allowed to warm to room temperature over the course of 15 minutes. The volatile components of the reaction mixture were then removed in vacuo. The remaining residue was triturated with pentane (3 × 3 mL) and subsequently extracted into 12 mL of a 1:1 mixture of pentane:benzene. The extracts were collected and filtered through Celite to afford a clear, dark red filtrate solution. The solvent was removed in vacuo and the resulting red residue was washed with cold (-35 °C) pentane (2 × 0.5 mL) and dried under vacuum to afford the product as a red solid (0.166 g, 0.186 mmol, 68% yield).1H NMR (300 MHz, benzene-d639.00, 27.53, 18.94, 16.83, 12.05, 7.53, 7.25, 7.19, 5.33, 4.29, 2.63, 2.18, 1.89, 1.53, 0.44, 0.40, -0.27, -1.55, -2.50, -4.73, -5.32, -6.61, -9.07, -11.65, -20.98, -26.58. Evans method (benzene-d6, 300K): µeff= 2.77 µB(S = 1 / 2).

[0130] Asolution of (S)-(Cy-PhenPhos)Co(CH2TMS)2 (0.110 g, 0.112 mmol) in ca. 6 mL of a 1:1 mixture of diethyl ether:benzene was treated with a room temperature solution of ferrocenium tetrakis(3,5-bis(trifluoromethyl)phenyl) borate (0.118 g, 0.112 mmol) in diethyl ether (ca.2 mL), which was added dropwise. The resulting reaction mixture was magnetically stirred at room temperature for 30 minutes, over the course of which a color change from dark red to dark orange was observed. The volatile components of the reaction mixture were subsequently removed in vacuo, and the remaining residue was triturated with pentane (3 × 3 mL). The resulting material was washed with pentane until all the ferrocene was removed (as evidenced by the washes becoming colorless; ca.10 mL) and subsequently extracted with diethyl ether (ca.12 mL). The ether extracts were collected and filtered through Celite to afford a clear orange solution. The solvent was removed in vacuo to afford the product as an orange solid (0.146 g, 0.088 mmol, 79% yield).1H NMR (500 MHz, THF-d8J = 15.0 Hz,1H), 6.09 (s,1H), 2.44 (s,1H), 2.35 (s,1H), 2.25 – 2.20 (m,1H), 2.13 (s,1H), 2.00 (s,1H), 1.92 (d, J = 15.2 Hz,1H), 1.81 (s,1H), 1.75 (s, 3H), 1.53 (s,1H), 1.46 (s, 3H), 1.31 (dhept, J = 32.5, 8.5 Hz, 3H), 1.11 (s, 2H), 0.91 (t, J = 7.1 Hz, 2H).13C{1H} NMR (126 MHz, THF-d8132.98, 130.79, 130.46, 130.21, 130.17, 129.96, 129.79, 128.82, 126.66, 124.49, 122.33, 118.23, 96.00, 41.25, 41.06, 38.60, 38.41, 35.96, 35.33, 32.64, 31.69, 31.27, 30.05, 29.73, 29.68, 28.12, 28.09, 28.02, 27.78, 27.46, 27.69, 27.36, 27.08, 26.56, 20.49, 20.33, 16.53, 16.48. 31P{1H} NMR (202 MHz, THF-d8J = 89.6 Hz), 92.04 (d, J = 88.3 Hz). 11B NMR (160 MHz, THF-d819F{1H} NMR (471 MHz, THF-d8

[0131] (rac)-(Et-PhenPhos). A pre-cooled (-35 °C) solution of (2-bromophenyl)-diethylphosphine (0.095 g, 0.386 mmol) in diethyl ether (ca. 5 ml) was treated with nBuLi (1.6 M in hexanes, 0.241 ml, 0.386 mmol), which was added dropwise. An immediate color change from off-white to yellow was observed. The resulting reaction mixture was allowed to stir at room temperature for 30 minutes and was subsequently cooled to -35 °C once again. The cold reaction mixture was then added in a dropwise manner to a pre-cooled (-35 °C) solution of (rac)-ClP(Phen) (0.161 g, 0.386 mmol) in diethyl ether (ca. 5 ml). A gradual color change from yellow to bright orange was observed. The resulting reaction mixture was allowed to magnetically stir overnight at room temperature. The volatile components of the reaction mixture were subsequently removed in vacuo, and the remaining residue was triturated with pentane (3 × 3 mL). The resulting material was extracted with pentane (2 × 4 ml). The pentane extracts were combined and filtered through Celite. The volatile components of the filtrate solution were removed in vacuo to afford the product as an orange oil (0.143 g, 0.26 mmol, 51% yield).1H NMR (400 MHz, benzene-d67.21 (m, 2H), 7.04 (td, J = 7.5, 1.4 Hz,1H), 6.85 (t, J = 7.5 Hz,1H), 2.17 (s, 3H), 2.11 (s, 3H), 1.91 (s, 3H), 1.75 (s, 3H), 1.73 – 1.58 (4H), 1.55 (s, 9H), 1.14 (s, 9H), 1.13 – 0.98 (m, 6H).13C{1H} NMR (101 MHz, benzene-d6146.71, 146.64, 146.52, 145.78, 145.56, 145.42, 145.20, 138.62, 138.59, 138.56, 135.64, 134.85, 133.70, 133.64, 132.98, 132.73, 132.70, 131.97, 131.86, 130.83, 130.79, 130.75, 130.71, 129.85, 129.80, 129.05, 128.92, 128.81, 128.63, 35.49, 35.39, 32.06, 31.89, 31.84, 23.09, 23.05, 22.95, 22.91, 20.92, 20.82, 18.69, 18.55, 18.41, 17.24, 16.83, 10.93, 10.76, 10.52, 10.41. 31P{1H} NMR (162 MHz, benzene-d6159.99 (d, J = 234.2 Hz), -28.42 (d, J = 234.0 Hz).

[0132] (rac)-(Et-PhenPhos)CoCl2. A slurry of CoCl2(0.0569 g, 0.438 mmol) in THF (ca. 5 mL) was treated with a solution of (rac)-(Et- PhenPhos) (0.241 g, 0.438 mmol) in THF (ca. 2 ml). The resulting reaction mixture was magnetically stirred until all of the CoCl2was dissolved (ca. 2 h). The volatile components of the reaction mixture were then removed in vacuo. The remaining solid was washed with pentane (3 × 3 mL), and the residue was dried in vacuo to afford the product as a purple solid (0.228 g, 0.44 mmol, 77% yield).1H NMR (400 MHz, CD2Cl2) 6.10, 6.06, 5.92, 5.78, 4.89, 4.13, 3.06, 2.80, 2.69, 2.60, 2.54, 2.33, 2.30, 2.28, 2.24, 2.21, 2.17, 2.12, 1.88, 1.81, 1.76, 1.68, 1.50, 1.45, 1.44, 1.36, 1.33, 1.31, 1.29, 1.27, 1.20, 1.16, 1.06, 1.00, 0.97, 0.91, 0.89, 0.87, 0.70, 0.36, 0.33, 0.11, 0.08, -0.26, -0.32, -0.44, -0.65, -1.12, -1.32, -3.00. Evans method (CD2Cl2, 300K): µeff= 3.69 µB(S = 3 / 2).

[0133] (R, R)-(Ph-TaddolPhos). A pre-cooled (-35 °C) solution of (2-bromophenyl)-diphenylphosphine (0.129 g, 0.377 mmol) in diethyl ether (ca. 10 ml) was treated with nBuLi (1.6 M in hexanes, 0.236 ml, 0.377 mmol). An immediate color change from colorless to light orange was observed. The resulting reaction mixture was allowed to stir at room temperature for 30 minutes, and was subsequently cooled back to -35 °C. The cold reaction mixture was added in a dropwise manner to a pre-cooled (-35 °C) solution of (R, R)-ClP(Taddol) (0.200 g, 0.377 mmol) in diethyl ether (ca. 3 ml). The resulting reaction mixture was magnetically stirred for an hour at room temperature and was subsequently filtered through Celite. The filtrate solution wascollected, and the volatile components were removed in vacuo. The remaining residue was triturated with pentane (3 × 3 mL), washed with pentane (3 × 3 ml), and dried under vacuum to afford the product as an off-white solid (0.268 g, 0.35 mmol, 94% yield).1H NMR (400 MHz, benzene-d6J = 6.6, 3.7, 2.4 Hz,1H), 8.15 (dd, J = 7.3, 1.9 Hz, 2H), 7.89 – 7.82 (m, 2H), 7.80 – 7.73 (m, 2H), 7.69 – 7.63 (m, 2H), 7.32 (t, J = 7.5 Hz,1H), 7.24 – 6.86 (m, 30H), 5.99 (dd, J = 8.4, 4.6 Hz,1H), 5.45 (d, J = 8.4 Hz,1H), 1.37 (s, 3H), 0.37 (s, 3H). 13C NMR (101 MHz, benzene-d6147.28, 142.70, 142.53, 142.33, 142.19, 138.64, 137.83, 135.01, 134.96, 134.42, 134.39, 134.23, 134.20, 131.70, 130.32, 130.26, 130.22, 130.16, 130.07, 130.03, 129.98, 129.03, 129.00, 128.97, 128.93, 128.85, 128.82, 128.28, 128.21, 128.16, 127.94, 127.85, 127.74, 112.28, 84.57, 84.32, 84.28, 84.25, 84.16, 83.94, 83.71, 28.21, 25.77. 31P NMR (162 MHz, benzene-d6J = 184.7 Hz), -14.75 (d, J = 185.0 Hz).

[0134] (R, R)-(Ph-TaddolPhos)CoCl2. A slurry of CoCl2(0.0320 g, 0.247 mmol) in THF (ca. 5 ml) was treated with a solution of (R, R)-(Ph- TaddolPhos) (0.187 g, 0.247 mmol) in THF (ca. 2 ml), which was added dropwise. A gradual color change from pale blue to dark blue was observed. The resulting reaction mixture was magnetically stirred until all of the CoCl2was dissolved (ca. 2 h). The volatile components of the reaction mixture were then removed in vacuo. The remaining solid was triturated with pentane (3 × 3 ml), washed with pentane (3 × 3 ml), and dried under vacuum to afford the product as a purple solid (0.212 g, 0.24 mmol, 97% yield).1H NMR (400 MHz, benzene-d61.21, 0.87, 0.33. Evans method (CD2Cl2, 300K): µeff= 3.12 µB(S = 3 / 2).

[0135] (R)-(Ph-BINOLPhos). A solution of (2-bromophenyl)diphenyl phosphine (1.00 g, 2.93 mmol) diethyl ether (ca. 15 mL) was treated with nBuLi (1.6M in hexanes, 3.70 mL, 5.86 mmol) added dropwise. The resulting reaction mixture was allowed to magnetically stir for 15 minutes. The resulting suspension was added dropwise to a cold (-84 °C) solution of PCl3(2.50 mL, 29.3 mmol) in diethyl ether (ca. 15 mL). After warming to room temperature, the reaction mixture was filtered through Celite. The filtrate solution was collected, and the volatile components were removed under reduced pressure. The resulting pale yellow oily solid (2–PCl2phenyl)diphenyl phosphine was used in the next step without further purification. A solution of (2–PCl2phenyl)diphenyl phosphine (0.940 g, 2.59 mmol) in ca. 3 mL of CH2Cl2was treated with (R)-BINOL (0.741 g, 2.59 mmol). Triethylamine (2 mL) was added dropwise to the reaction mixture, which was subsequently allowed to stir at room temperature for 18 h. The volatile components of the reaction mixture were then removed under vacuum, and the remaining residue was redissolved in benzene and filtered through a silica plug. The filtrate solution was collected, and the solvent was removed under reduced pressure. The resulting off white solid was washed with pentane and dried under vacuum to obtain the product as a pale yellow solid (1.49 g, 2.59 mmol, >99% yield).1H NMR (400 MHz, CDCl3J = 8.7 Hz,1H), 7.96 (d, J = 8.2 Hz,1H), 7.83 (d, J = 8.1 Hz,1H), 7.61 (d, J = 4.8 Hz,1H), 7.62 – 7.52 (m, 2H), 7.52 – 7.19 (m, 15H), 7.08 (t, J = 7.5 Hz,131 H), 6.18 (d, J = 8.8 Hz,1H). P NMR (162 MHz, CDCl3J = 211.8 Hz), -19.84 (d, J = 211.9 Hz).

[0136] (R)-(Ph-BINOLPhos)CoCl2. A slurry of CoCl2(0.045 g, 0.347 mmol) in THF (ca. 4 mL) was stirred vigorously for 10 minutes at room temperature until most of the CoCl2had dissolved. Next, a solution of (Ph-BINOLPhos) (0.200 g, 0.347 mmol) in THF (ca. 2 mL) was added dropwise. An immediate color change to dark green was observed. The reaction mixture was left to stir over the course of 18 h at room temperature. The reaction mixture was then filtered through Celite. The filtrate solution was collected and the volatile components were removed under reduced pressure. The remaining residue was washed with 2 × 2 mL of diethyl ether and dried under vacuum to afford the product as a dark green solid (0.240 g, 0.340 mmol, 98% yield).1H NMR (400 MHz, CD2Cl21.50, 1.25, 0.83.

[0137] (R)-(Ph-BINOLPhos)Co(CH2TMS)2. A pre-cooled (-35 °C) solution of (Ph-BINOLPhos)CoCl2(0.250 g, 0.350 mmol) in THF (ca. 4 mL)was treated with Mg(CH2TMS)C1 (1.0 M in Et2O, 0.70 mL, 0.700 mmol) added dropwise. A color change from green to dark orange was observed. The reaction mixture was allowed to warm up to room temperature and stirred over the course of 18 h at room temperature. The volatile components of the reaction mixture were then removed in vacuo. The remaining residue was extracted into 12 mL of benzene. The benzene extracts were combined and filtered through Celite. The dark orange filtrate solution was collected and the solvent was removed in vacuo. The remaining orange solid waswashed with pentane (2 × 1 mL) and dried under vacuum to afford the product as a dark orange solid (0.250 g, 0.249 mmol, 71% yield).1H NMR (400 MHz, benzene-d6– 6.60 (br), 3.45, 1.11, 0.58 - -0.53 (br). Evans method (CD2Cl2, 300K): µeff= 2.27 µB(S = 1 / 2).

[0138] Catalysis Data

[0139] For the purposes of Table 2, the compounds tested therein are numbered as follows.

[0140] For the purposes of Table 2, the following reaction was studied.Table 2. Catalysis Data

[0141] The embodiments described herein are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.

[0142] All publications, patents and patent applications mentioned in this Specification are indicative of the level of skill those skilled in the art to which this invention pertains and are herein incorporated by reference to the same extent as if each individual publication patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0143] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modification as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

CLAIMS What is claimed is:

1. A compound of Formula I: (Formula I) wherein: R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl; A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being halogen, C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group; and represents a chiral diol.

2. The compound according to claim 1, wherein A is substituted or unsubstituted phenyl, naphthyl, anthracene, furan, pyrrole, thiophene, imidazole, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline, or isoquinoline, preferably wherein A is substituted or unsubstituted phenyl.

3. The compound according to claim 1 or 2, wherein A is a C6-aromatic and the compound is of Formula II: (Formula II).

4. The compound according to any one of claims 1 to 3, wherein R1and R1' are each independently phenyl, ethyl, propyl, iso-propyl or cyclohexyl, preferably wherein R1and R1' are both phenyl.

5. The compound according to any one of claims 1 to 4, wherein the compound comprises one, two, three or four R2groups, and each R2group is independently methyl, fluoro, or methoxy.

6. The compound according to any one of claims 1 to 4, wherein R2is hydrogen.

7. The compound according to any one of claims 1 to 6, wherein represents a 1,2-diol, a 1,3-diol, a 1,4-diol, a 1,5-diol, or a 1,6-diol, for exampleor an enantiomer thereof, wherein each R4group is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and / or two adjacent R4groups together forming a double bond, a cycloalkyl, a heterocycloalkyl, an aromatic, or a heteroaromatic group.

8. The compound according to any one of claims 1 to 7, wherein representsor an enantiomer thereof.

9. The compound according to any one of claims 1 to 8, wherein the compound is or an enantiomerthereof.

10. A method of making a chiral ligand, the method comprising reacting a chiral diol with PCl3to form a chlorophosphine and subsequent reaction of the chlorophosphine with a 2-R1R1'P-bromoarene to form the chiral ligand.

11. A chiral catalyst comprising cobalt complexed to a compound according to any one of claims 1 to 9.

12. A method of making a chiral catalyst comprising reacting a compound according to any one of claims 1 to 9 with a cobalt salt.

13. A compound of Formula III: (Formula III) wherein:R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl; A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1- 4 alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group; X are each independently halide or pseudohalide; and represents a chiral diol.

14. The compound of claim 13 wherein each X is independently Cl, Br, I, OAc, or OTf.

15. A compound of Formula IV: (Formula IV) wherein: R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl; A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group;R3and R3' are each independently C1-6alkyl, the C1-6alkyl optionally substituted by an aromatic group or a trialkylsilyl group; and represents a chiral diol.

16. The compound of claim 15 wherein R3and R3' are each independently benzyl, neopentyl, neophyl, or -CH2SiMe3.

17. A compound of Formula V: (Formula V) wherein: R1and R1' are each independently C1-6alkyl, C4-6cycloalkyl, or C6aromatic, or together form a C4-10cycloalkyl; A is an aromatic or heteroaromatic group, the aromatic or heteroaromatic group optionally modified with up to four R2groups, each R2group independently being C1-4alkyl or C1-4heteroalkyl, and / or two adjacent R2groups together forming an aromatic or heteroaromatic group; Ar is a C6aromatic group optionally modified with one C1-6alkyl substituent or up to three methyl groups, where the Ar group is coordinated to the cobalt cation; represents a chiral diol; and X– is an organic-solvent soluble anion.

18. The compound of claim 17 wherein X–is BArF4, BPh4, or OTf.

19. The compound according to claim 17 or 18, wherein A is substituted or unsubstituted phenyl, naphthyl, anthracene, furan, pyrrole, thiophene, imidazole, oxazole, thiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, quinoline, or isoquinoline, preferably wherein A is substituted or unsubstituted phenyl.

20. The compound according to any one of claims 17 to 19 wherein A is a C6- aromatic and the compound is of Formula VI: (Formula VI).

21. The compound according to any one of claims 17 to 20, wherein R1and R1' are each independently phenyl, ethyl, propyl, iso-propyl or cyclohexyl, preferably wherein R1and R1' are both phenyl.

22. The compound according to any one of claims 17 to 21, wherein the compound comprises one, two, three or four R2groups, and each R2group is independently methyl, fluoro, or methoxy.

23. The compound according to any one of claims 17 to 22, wherein R2is hydrogen.

24. The compound according to any one of claims 17 to 23, wherein represents a 1,2-diol, a 1,3-diol, a 1,4-diol, a 1,5-diol, or a 1,6-diol, for exampleor an enantiomer thereof,wherein each R4group is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and / or two adjacent R4groups together forming a double bond, a cycloalkyl, a heterocycloalkyl, an aromatic, or a heteroaromatic group.

25. The compound according to any one of claims 17 to 24, wherein representsor an enantiomer thereof.

26. The compound according to any one of claims 17 to 25, wherein the compound is , or an enantiomerthereof.

27. A method of alkene hydrogenation comprising reacting an alkene in the presence of hydrogen and a catalytically effective quantity of the chiral catalyst of claim 11 or the compound of any one of claims 13 to 26, which catalyst or compound is enantiopure.

28. The method according to claim 27, wherein the catalytically effective quantity is at least 0.5 mol%, such as between 1 and 10 mol%.

29. The method according to claim 27 or 28, wherein the reacting is performed at an increased pressure, such as between 10 atm H2and 40 atm H2.

30. The method according to any one of claims 27 to 29, wherein the reacting is performed at an increased temperature, such as about 50 °C.

31. The method according to any one of claims 27 to 30, wherein the reacting is performed in an organic solvent, such as iPrOH, TFE, or THF.

32. The method according to any one of claims 27 to 31, wherein the alkene is a 33. The method according to any one of claims 27 to 32, wherein the reacting is performed in the presence of an additive, such as 1 equivalent of Zn(0).

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