WO2025096445A1 - Synthesis of intermediates for the preparation of macrocyclic compounds - Google Patents

Abstract

Provided are methods for synthesizing intermediates useful in the preparation of compounds having activity against orexin-2 receptor.

Description

SYNTHESIS OF SUBSTITUTED MACROCYCLIC COMPOUNDS

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application No. 63/546,358, filed October 30, 2023, the entire contents of which are incorporated herein by reference.

BACKGROUND

[0002] Orexin is a neuropeptide synthesized and released by a subpopulation of neurons within the lateral hypothalamus and its surrounding regions. It consists of two subtypes: orexin A and orexin B. Orexin A and orexin B bind to orexin receptors. Orexin receptors are G protein-coupled receptors expressed preferentially in the brain. There are two subtypes (type 1 and type 2) of orexin receptors (Cell, Vol. 92, 573-585, 1998). Activation of orexin receptors is known to be important for a variety of central nervous system functions, such as maintenance of wakefulness, energy homeostasis, reward processing and motivation (Saper et al., TRENDS in Neuroscience 2001; Yamanaka et al., Neuron 2003; Sakurai, Nature Reviews Neuroscience 2014).

[0003] Compounds having activity against orexin-2 receptor have been previously described (see e.g., WO 2021/108628, WO 2022/140316, and WO 2022/232025) and are believed to be useful for treating, preventing, or ameliorating the risk of neurological and psychiatric diseases associated with alterations in sleep/wake function (e.g., narcolepsy and idiopathic hypersomnia). To facilitate further studies and the development of new compounds, alternative methods for preparing such compounds are needed.

SUMMARY

[0004] Provided herein are methods of preparing compounds having the Formula I:

and salts thereof, wherein:

R¹ is -C(O)R^A or -SO₂R^B; R^A and R^B are each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, -(Ci-C4)alkyl(Ci-C4)alkoxy, (C2-C4)alkenyl, halo(C2-C4)alkenyl, hydroxy(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, hydroxy(C2-C4)alkynyl, (Ci- C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkyleneNR’R”, (C3-C6)cycloalkyl, (Ci-C4)alkylene(C3- C6)cycloalkyl, 4- to 7-membered heterocyclyl, (Ci-C4)alkylene[4- to 7-membered heterocyclyl], 5- to 7-membered heteroaryl, (Ci-C4)alkylene[5- to 7-membered heteroaryl], phenyl, (Ci-C4)alkylenephenyl, -C(O)NR’R” and -NR’R”, wherein each of said (C3- C6)cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 7-membered heteroaryl, and phenyl, alone, or connected to said (Ci-C4)alkylene, is optionally substituted with 1 or 2 groups selected from halo, (Ci-C4)alkyl, and (Ci-C4)alkoxy; and

R’ and R” are each independently selected from hydrogen and (Ci-C4)alkyl. [0005] Also provided are catalytic methods for the reduction of pyridine rings on intermediates associated with the preparation of compounds having the Formula I. Such methods include asymmetric iridium catalyzed hydrogenations according to the following general procedure:

[0006] Also provided are nucleophilic addition procedures to form intermediates involved in the preparation of compounds having the Formula I. Such methods include e.g., the base induced nucleophilic reaction between a primary alcohol and bromide according to the following general procedure:

[0007] Further provided are stereoselective enzymatic reduction cyclic ketals to form intermediates involved in the preparation of compounds having the Formula I. Such methods include e.g., the enzymatic reduction of a ketal according to the following general procedure:

DETAILED DESCRIPTION

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0009] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0010] The use of any and all examples, or exemplary language e.g., “such as”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0011] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0012] The term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means a saturated straight-chain or branched monovalent hydrocarbon radical.

[0013] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0014] The term “haloalkyl” includes mono, di, tri, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0015] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHF2 or -OCF3.

[0016] As used herein, the term “alkylene” refers to divalent aliphatic hydrocarbyl groups, for example, having from 1 to 4 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), and the like. [0017] As used herein, the term “alkenyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-12”) in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CH=CH2; C2alkenyl), allyl (-CH2-CH=CH2; Caalkenyl), propenyl (-CH=CHCH3; Caalkenyl), isopropenyl (-C(CH3)=CH2; Csalkenyl), butenyl (-CH=CHCH2CH3; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso-butenyl (-CH=C(CH3)2; C4alkenyl), 2-butenyl (- CH₂CH=CHCH₃; C₄alkyl), pentenyl (-CH=CHCH₂CH₂CH₃; Csalkenyl), and the like. In some embodiments, the alkenyl group is a C2-6 alkenyl group; in other embodiments, it is C2- 4alkenyl.

[0018] As used herein, the term “alkynyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-12”) in the group, and wherein the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (-C=CH; C2alkynyl), propargyl (-CH2-C=CH; Csalkynyl), propynyl (-C=CCH3; Csalkynyl), butynyl (- C=CCH2CH3; C4alkynyl), pentynyl (-C^CCthCtECth; Csalkynyl), and the like.

[0019] The term oxo means the group =0.

[0020] The term “heteroaryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position.

[0021] The term “heterocyclyl” means, unless otherwise specified, a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position.

[0022] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0023] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0024] The term “bridged” refers to two rings that share three ring atoms with one another.

[0025] The terms “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position. [0026] It is to be understood that if an aryl, heteroaryl, cycloalkyl, or heterocyclyl moiety may be bonded or otherwise attached to a designated moiety through differing ring atoms (z.e., shown or described without denotation of a specific point of attachment), then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term “pyridinyl” means 2-, 3- or 4-pyridinyl, the term “thiophenyl” means 2- or 3-thiophenyl, and so forth.

[0027] The term “optionally substituted,” as used herein to describe a chemical moiety defined herein, means that the moiety may, but is not required to be, substituted with one or more suitable functional groups or other substituents as provided herein.

[0028] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0029] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. A “geometric isomer” refers to isomers that differ in the orientation of substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers to substituents oriented on the same side of the ring, whereas “trans” refers to substituents oriented on opposite sides of the ring.

[0030] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.

“Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0031] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicated geometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture.

[0032] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0033] In one embodiment, provided is a method of preparing a compound having the Formula I:

or a salt thereof, wherein R¹ is as described above, said method comprising: reacting a compound having the structure:

with a compound of the Formula LG-C(O)R^A or LG-SO2R^B, wherein LG is a leaving group (e.g., a halogen, anhydride, or ester) and R^A and R^B are as defined above, to form the compound of Formula I. In some embodiments, LG is a halogen. In some embodiments, LG is chloride. In some embodiments, the reaction is performed in the presence of a base. In some embodiments, the reaction is performed in the presence of an organic base. In some embodiments, the reaction is performed in the presence of an organic amine base. In some embodiments, the reaction is performed in the presence of a non-nucleophilic organic amine base (e.g., N,N-Diisopropylethylamine, l,8-diazabicycloundec-7-ene, 1,5- diazabicyclo(4.3.0)non-5-ene, 2,6-di-tert-butylpyridine).

[0034] In some embodiments, R^A and R^B on the compounds of Formula I prepared by the described methods are each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkyleneNR’R”, (C3-C6)cycloalkyl, (Ci-C4)alkylene(C3-C6)cycloalkyl, 4- to 7-membered heterocyclyl, and 5- to 7-membered heteroaryl, C(O)NR’R”, wherein each of said (C3-C6)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7-membered heteroaryl, and said (C3-C6)cycloalkyl on said (Ci-C4)alkylene(C3-C6)cycloalkyl, is optionally substituted with 1 or 2 groups selected from halo, (Ci-C4)alkyl, and (Ci-C4)alkoxy, and wherein R’ and R” are as described above for Formula I. In some embodiments, R^A and R^B on the compounds of Formula I prepared by the described methods are each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkyleneNR’R”, (C3-C6)cycloalkyl, (Ci-C4)alkylene(C3-C6)cycloalkyl, 4- to 7-membered heterocyclyl, and 5- to 7-membered heteroaryl, C(O)NR’R”, wherein each of said (C3-C6)cycloalkyl, 4- to 7- membered heterocyclyl, 5- to 7-membered heteroaryl, and said (C3-C6)cycloalkyl on said (Ci-C4)alkylene(C3-C6)cycloalkyl, is optionally substituted with 1 or 2 groups selected from (Ci-C4)alkyl and (Ci-C4)alkoxy, and wherein R’ and R” are as described above for Formula I. In some embodiments, R^A and R^B on the compounds of Formula I prepared by the described methods are each independently selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydoxy(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkyleneNR’R”, cyclopropyl, cyclopentyl, cyclobutyl, (Ci-C4)alkylene(cyclopropyl), (Ci- C4)alkylene(cyclobutyl), tetrahydrofuranyl, oxetanyl, 1,4-dioxanyl, tetrahydropyranyl, azetidinyl, morpholinyl, pyrrolidinyl, and oxazolyl, C(O)NR’R”, wherein each of said cyclopropyl, cyclopentyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, 1,4-dioxanyl, tetrahydropyranyl, azetidinyl, morpholinyl, oxazolyl, pyrrolidinyl, cyclopropyl on (Ci- C4)alkylene(cyclopropyl), and cyclobutyl on (Ci-C4)alkylene(cyclobutyl), is optionally substituted with 1 or 2 groups selected from (Ci-C4)alkyl and (Ci-C4)alkoxy and wherein R’ and R” are as described above for Formula I. In some embodiments, R’ and R” are each (Ci- C₄)alkyl.

[0035] In one embodiment, provided is a method of preparing a compound having the structure:

said method comprising: reacting a compound having the structure:

with an iridium dimer and an optically active bisphosphine in the presence of a hydrogen atmosphere.

[0036] In some embodiments, the iridium dimer is selected from di-p- chlorotetrakis(cyclooctene)diiridium ([IrCl(coe)2]2), di-p-bromotetrakis(cyclooctene)- diiridium ([IrBr(coe)2]2), di-p -iodotetrakis(cyclooctene)diiridium ([Irl(coe)2]2), di-p- chlorobis(l,5-cyclooctadiene)diiridium, ([IrCl(cod)]2]2), di-p-bromobis(l,5- cyclooctadiene)diiridium, ([IrBr(cod)]2), di-p-iodobis(l,5-cyclooctadiene)diiridium,

([Irl(cod)]2), di-p-chlorobis(bicyclo[2,2,l]hepta-2,5-diene), diiridium([IrCl(nbd)]2), di-p- bromobis(bicyclo[2,2, l]hepta-2,5-diene)diiridium([IrBr(nbd)]2), and di-p-iodobis(bicyclo[2, 2,l]hepta-2,5-diene)diiridium ([Irl(nbd)]2), and the like. In some embodiments, the iridium compound is di-p-chlorotetrakis(cyclooctene)diiridium ([IrCl(coe)2]2).

[0037] In some embodiments, the optically active bisphosphine is of the formula:

, wherein R², R³, R⁴, and R⁵ are each independently a phenyl or cycloalkyl group, each of which is optionally substituted with one or more (Ci-C4)alkyl or (Ci-C- 4)alkoxy groups; and R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halogen, (Ci-C4)acyloxy, and - N[(Ci-C₄)alkyl]2, or R⁷ and R⁸ and/or R⁹ and R¹⁰ are taken together to form an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted oxygen containing heterocyclyl. Examples of optically active bisphosphines which can be used as part of the disclosed methods include, but are not limited to, 2,2’-bis-(diphenylphosphino)-

1,1’ -binaphthyl (BINAP®); 2, 2, -bis-(di-p-tolylphosphino)- 1,1’ -binaphthyl; 2,2’-bis-(di-m- tolylphosphino)- 1,1’ -binaphthyl, 2,2’ -bis(di-3,5-xylylphosphino)- 1,1’ -binaphthyl; 2,2,-bis(di- p-tert-butylphenylphosphino)- 1,1’ -binaphthyl; 2,2,-bis(di-p-methoxyphenylphosphino)- 1,1’- binaphthyl, 2, 2’ -bis(di-p-chlorophenylphosphino)- 1,1’ -binaphthyl; 2,2’ - bis(dicyclopentylphosphino)- 1,1’ -binaphthyl; 2,2’ -bis(dicyclohexylphosphino)- 1,1’- binaphthyl; 2,2’-bis(diphenylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’- bis(di-p-tolylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’-bis(di-m- tolylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’-bis(di-3,5- xylylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’-bis(di-p-tert- butylphenylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’-bis(di-p- methoxyphenylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’-bis(di-p- chlorophenylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’- bis(dicyclopentylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; 2,2’- bis(dicyclohexylphosphino)-5,5’,6,6’,7,7’,8,8’-octahydro-l,l’-binaphthyl; (R)-(+)-5,5’- bis(diphenylphosphino)-4,4’-bi-l,3-benzodioxole ((R)-(+)-SEGPHOS®)); (4, 4’ -bi- 1,3- benzodioxole)-5,5’-diyl)bis(bis(3,5-xylyl)phosphine; (4,4’-bi-l,3-benzodioxole)-5,5’- diyl)bis(bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine; (4,4’-bi-l,3-benzodioxole)-5,5’- diyl)bis(bis(4-methoxyphenyl)phosphine; (4,4’-bi-l,3-benzodioxole)-5,5’- diyl)bis(dicyclohexylphosphine; (4,4’-bi-l,3-benzodioxole)-5,5’-diyl)bis(bis(3,5-di-t- butylphenyl)phosphine; 4,4’-bi(2,2-difluoro-l,3-benzodioxole)-5,5’-diyl) bis(diphenylphosphine); 2,2’-bis(diphenylphosphino)-4,4’,6,6’-tetramethyl- 5,5’-dimethoxy- 1,1’ -biphenyl; 2,2’ -bis(di-p-methoxyphenylphosphino)-4,4’ ,6,6’ -tetramethyl-5,5 ’ -dimethoxy- 1 , 1 ’-biphenyl; 2,2’ -bis(diphenylphosphino)-4,4’ ,6,6’ -tetra(trifluoromethyl)-5,5’ -dimethyl - 1 , l’-biphenyl; 2,2’ -bis(diphenylphosphino)-4,6-di(trifluoromethyl)-4’ ,6’ -dimethyl-5’ - methoxy- 1 , 1 -biphenyl; 2-dicyclohexylphosphino-2’ -diphenylphosphino-4,4’ ,6,6’ - tetramethyl-5, 5’ -dimethoxy- 1, l’-biphenyl; 2, 2’-bis(diphenylphosphino)-6,6’-dimethyl-l, l’- biphenyl; 2,2’ -bis(diphenylphosphino)-4,4’ ,6,6 ’ -tetramethyl- 1,1’ -biphenyl; 2,2’ - bis(diphenylphosphino)-3,3’ ,6,6’ -tetramethyl- 1,1’ -biphenyl); 2,2’ -bis(diphenylphosphino)- 4,4’ -difluoro-6,6’ -dimethyl- 1,1’ -biphenyl; 2,2’ -bis(diphenylphosphino)-4,4’ - bis(dimethylamino)-6, 6’ -dimethyl- 1,1’ -biphenyl; 2,2’ -bis(di-p-tolylphosphino)-6,6’ - dimethyl-1, l’-biphenyl; 2,2’-bis(di-o-tolylphosphino)-6,6’-dimethyl-l,l’- biphenyl; 2,2’- bis(di-m-fluorophenylphosphino)-6,6’ -dimethyl- 1,1’ -biphenyl; 1,11 -bis(diphenylphosphino)- 5,7-dihydrobenzo[c,e]oxepin; 2, 2’ -bis(diphenylphosphino)-6,6’-dimethoxy-l, l’-biphenyl; 2,2’ -bis(diphenylphosphino)-5,5 ’ ,6,6’ -tetramethoxy- 1 ,1’ -biphenyl; 2,2’ -bis(di-p- tolylphosphino)-6,6’ -dimethoxy- 1,1’- biphenyl; 2,2’ -bis(diphenylphosphino)-4,4’ ,5,5 ’ ,6,6’ - hexamethoxy- 1, l’-biphenyl; and the like In some embodiments, the optically active bisphosphine is (R)-(+)-5,5’-bis(diphenylphosphino)-4,4’-bi-l,3-benzodioxole ((R)-(+)- SEGPHOS®)). Other iridium dimers, optically active bisphosphines and complexes formed from the reaction of such that can be used in the present methods are found in US 7,624,357, US 2014/0213792, and limuro et al., Adv. Synth. Catal. 2016, 358, 1929 -1933.

[0038] In some embodiments, the asymmetric iridium catalyzed hydrogenation described above is performed in the presence of a solvent. In some embodiments, the asymmetric iridium catalyzed hydrogenation described above is performed in the presence of an aprotic solvent. In some embodiments, the asymmetric iridium catalyzed hydrogenation described above is performed in the presence of a dipolar aprotic solvent. In some embodiments, the asymmetric iridium catalyzed hydrogenation described above is performed in the presence of a dipolar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP). In some embodiments, the asymmetric iridium catalyzed hydrogenation described above is performed in the presence of N-methyl- 2-pyrrolidone (NMP). [0039] In one embodiment, provided is a method of preparing a compound having the structure:

said method comprising: reacting a compound having the structure:

Br Br

suitable base and a compound having the structure:

[0040] In some embodiments, the suitable base is one that is capable of deprotonating the alcohol on the cyclohexyl ring. In some embodiments, the suitable base is one that is capable of deprotonating the alcohol on the cyclohexyl ring without disturbing the integrity of the benzyl protection group of the phenol. In some embodiments, the suitable base is n- butyllithium (BuLi). In some embodiments, the suitable base is added prior to the addition of the 3-bromo-2-(bromomethyl)pyridine. In some embodiments, the suitable base is added concurrently with or after addition of the 3-bromo-2-(bromomethyl)pyridine.

[0041] In some embodiments, the reaction above is performed in the presence of a solvent. In some embodiments, the reaction above is performed in the presence of an aprotic solvent. In some embodiments, the reaction above is performed in the presence of THF.

[0042] In one embodiment, provided is a method of preparing a compound having the structure:

said method comprising: reacting a compound having the structure:

with an oxidoreductase. In some embodiments, the oxidoreductase is an NADPH-dependent oxidoreductase. NADPH-dependent oxidoreductase are known in the art and include e.g., KRED-Y1, KRED-NADPH-P1A04, KRED-NADPH-P2H07, KRED -NADPH-P1B10, KRED-NADPH-107, KRED-NADPH-135, KRED-NADPH-136, KRED-NADPH-147, KRED-NADH-110, KRED-NADH-124, ES-KRED-120, KRED-NADPH-104, KRED- NADPH-130, KRED-NADPH-148, KRED-Y2, KRED-NADH-117, KRED-NADH-126, and KRED-NADPH-162C. See e.g., WO 2015/086495, WO 2011/005527, and WO 2022/016195, each of which are incorporated herein by reference.

EXEMPLIFICATION

[0043] Compounds having the Formula I can be prepared following the procedures described below.

[0044] The following abbreviations are used in the synthetic examples below.

AcOH = acetic acid

ACN = acetonitrile

B-NMR = boron nuclear magnetic resonance n-BuLi = n-butyllithium

BINAP = (2,2'-bis(diphenylphosphino)-l,l'-binaphthyl)

BnBr = benzyl bromide

DIPEA or DIEA = N,N-diisopropylethylamine

EtOAc = ethyl acetate

EtOH = ethanol eq = equivalent g = grams

GC = gas chromatography h = hours

HBr = hydrogen bromide

HPLC = high-performance liquid chromatography

KF = Karl Fischer titration kg = kilograms

LOD = limit of detection MeOH = methanol mins = minutes

MPa = MegaPascal

MTBE = methyl tert-butyl ether

NADPH = Nicotinamide adenine dinucleotide phosphate

ND = no detection

NMP = N-methylpyrrolidone

Pd/C = palladium on carbon

(R)-(+)-SEGPHOS® = (7?)-(+)-5,5’-Bis(diphenylphosphino)-4,4’-bi-l,3-benzodioxole

TEA = trimethylamine

TFAA - trifluoro acetic acid

THF = tetrahydrofuran

V = volume

HATU = 2-(7-azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluoropho sphate

Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium

[0045] Scheme 1

%

( steps)

%

[0046] Scheme 1 - Continued

[0047] Step 1:

[0048] To a reactor was added THF (5V), 2-iodophenol, and 1 (1.0 eq., 230 kg) under stirring. The solution was cooled to -5 to 0 °C and i-PrMgCl.LiCl (3.0 eq.) solution was added dropwise over a period of at least 4 hours at 0 ± 5 °C. After the addition, the reaction was stirred for at least 6 h at 0 ± 5 °C. l,4-dioxaspiro[4.5]decan-8-one (1.0 eq.) in THF (3.0 V) was then added to the reactor at 0 ± 5 °C and the reaction was stirred for at least 1 h at 0 ± 5 °C. [0049] The reaction was quenched with 5% ammonium chloride aqueous (5.0 V) at 5 ± 5 °C and the mixture was stirred for at least 30 min, and then warmed to 25 ± 5 °C. EtOAc (10.0 V) and soften water (15.0 V) was added at 25 ± 5 °C, and the mixture was stirred for at least 1 hour, and then allowed to stand for at least 1 hour. The organic phase was separated and washed with 20% sodium chloride solution. Under a nitrogen atmosphere, 20% sodium chloride solution (10.0 V) was added to the organic phase. The temperature was adjusted to 25 ± 5 °C and the mixture was allowed to stir for at least 30 min and then allowed to stand for at least 30 min. The organic phase was separated and transferred to a concentration reactor through filter. The organic phase was concentrated to approximately 4 to 5 V under vacuum while controlling the internal temperature no more than 45 °C or to a jacket temperature no more than 55 °C.

[0050] The temperature was adjusted to 25 ± 5 °C. Under a nitrogen atmosphere n- heptane (10.0 V) was added to the reactor at 25 ± 5°C over a period of at least 2 h. The organic phase was concentrated 8 to 9 V under vacuum while controlling the internal temperature to no more than 45 °C or to a jacket temperature no more than 55 °C. N-heptane (5.0 V) was again added to the reactor and the organic phase was concentrated to 8 to 9 V under vacuum while controlling the internal temperature to no more than 45 °C or a jacket temperature no more than 55 °C. The resultant mixture was cooled to 20 ± 5 °C, and stirred for at least 1 h at 20 ± 5 °C. The slurry was centrifuged and the cake was washed with heptane (1.0 V), and dried under vacuum at 40 + 5 °C for at least 16 hours to give 291 kg (77% yield) of 2.

[0051] Step 2:

[0052] MTBE (10.0 V) was added to a reactor under stirring. 2 (1.0 eq., 144 kg) was added along with TEA (4.0 eq.) at 20 + 10 °C. The reaction was cooled to 0 + 5 °C, and TFAA (1.5 eq.) was added over a period of at least 3 h at 0 + 5 °C. The reaction was stirred for at least 16 h at 0 + 5 °C and quenched with soften water (10.0 V) at 5 + 5 °C. The mixture was warmed to 25 + 5 °C, stirred for at least 30 min and then allowed to stand for at least 30 min. The organic phase was separated. 0.2 mol/L hydrochloric acid solution (10.0 V) was added to the organic phase and the temperature was adjusted to 25 + 5 °C. The mixture was stirred for at least 30 min and then allowed to stand for at least 30 min. The organic phase was separated. 0.2 mol/L hydrochloric acid solution (5.0 V) was added to the organic phase and the temperature was adjusted to 25 + 5 °C. The mixture was stirred for at least 30 min and then allowed to stand for at least 30 min. The organic phase was separated [0053] 20% sodium chloride solution (10.0 V) was added to the organic phase and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min and then allowed to stand for at least 30 min. The organic phase was separated and transferred to a concentration reactor through filter. The organic phase was concentrated to approximately 2 to 3 V under vacuum while controlling the internal temperature to no more than 45 °C or to a jacket temperature no more than 55 °C. MeOH (10.0 V) was added and the organic phase was concentrated to 5-6 V under vacuum while controlling the internal temperature to no more than 45 °C or to a jacket temperature no more than 55 °C. MeOH (10.0 V) was again added and the organic phase was concentrated to 5-6 V under vacuum while controlling the internal temperature to no more than 45 °C or to a jacket temperature no more than 55 °C. The solution was transferred though filter to drum containing 3.

[0054] Step 3:

[0055] The solution of 3 in MeOH (5 V) was placed in an autoclave and Pd/C (5% w/w) was successively added. The autoclave was heated to 25 ± 5°C slowly and hydrogen was slowly charged to maintain a pressure to 0.5-1.2 MPa every time. This procedure was repeated until the system pressure change was less than 0.1 MPa in one hour. The reaction was cooled to 20 ± 5 °C and filtered. The cake was washed with with MeOH (2.0 v) and the filtrate was collected. The organic phase was concentrated to approximately 5 to 6 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature no more than 55 °C. After cooling to the temperature to 20 ± 5 °C, the reactor was charged with the Hydrochloric acid solution (10.0) dropwise at 20 ± 5 °C. After the addition, the reactor was stirred for at least 16 h at 20 ± 5 °C.

[0056] The reaction was cooled to 0 ± 5 °C and stirred for at least 5 h. The mixture was centrifuged and the cake was washed with softened water (1.0 V). The cake was dried under vacuum at 50+5 °C for at least 24 hours to give 4. Isolated 95.3 kg (87% yield over two steps).

[0057] Step 4:

[0058] A reactor was charged with THF (9.5 V) and stirred. The reactor was then charged with 4 (1.0 eq., 95 kg) followed by THF (0.5 V) to rinse the solid feeding port. The reactor was cooled to approximately -75 to -70°C and lithium tri-sec-butylborohydride (1.1 eq.) solution was added dropwise over a period of at least 8 h at -70 + 5 °C. After the addition, the reaction was stirred for Ih at -70 + 5 °C. Then, lithium tri-sec-butylborohydride (0.1 eq.) solution was added dropwise over a period of at least 1 h at -70 + 5 °C. After the addition, the reaction was stirred for Ih at -70 + 5 °C. [0059] MeOH (1.0 V) was then added dropwise at -65 ± 10 °C and the reaction was warmed to 0 ± 5 °C and stirred for at least 2 hours while bubbling N2 to remove H2. The reactor was charged with acetic acid (1.5 V) dropwise at 0 ± 5 °C. After stirring for at least 1 hour, the system was transferred to an enamel reactor, and the eluent was combined with the system in a tetrahydrofuran (1.0 V) eluent reactor. The reaction was warmed to 50 ± 5 °C and stirred for at least 20 h at 50 ± 5 °C. The reaction was then cooled to 0 ± 5 °C, charged with acetic acid (0.5 V) dropwise at 0 ± 5 °C, and then the reaction was warmed to 50 ± 5 °C and stirred for at least 5 h at 50 ± 5 °C. The reaction was then cooled to 20 ± 5 °C and stirred for at least 2 hours while bubbling nitrogen to remove butane and H2.

[0060] The pH was adjusted to 8-9 with 10% aqueous sodium carbonate at 20 ± 5 °C and stirred for 15 minutes. The pH was retested, stirred for at least 30 min, and then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was transferred to the concentration reactor through a filter. The organic phase was concentrated to approximately 4 to 5 V under vacuum controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The reactor was then charged with n-heptane (10.0 V) and the organic phase was concentrated to 4-5 V under vacuum controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The reactor was then charged with n-heptane (10.0 V), and the organic phase was concentrated to 4-5 V under vacuum, controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The temperature was adjusted to 20 ± 5 °C and the reactor was charged with 10% sodium hydrate aqueous at 20 ± 5 °C. The mixture was stirred until the system was clear and then allowed to stand for at least 30 min. The layers were separated and the aqueous phase was collected. The pH of aqueous phase was adjusted to 2-3 with 2N hydrochloric acid solution at 20 ± 5 °C, and stirred for 15 minutes. The pH was retested, and the mixture was stirred for at least for 1 h at 20 + 5 °C. The resulting mixture was centrifuged and the cake was washed with softened water (1.0 V).

[0061] The cake was dried under vacuum at 50 + 5 °C for at least 24 hours to afford 5. Isolated 88.2 kg (91% yield).

[0062] Step 5:

[0063] A reactor was charged with NMP (5.0 V) and stirred. Then, 5 (1.0 eq., 88 kg) was charged to the reactor, followed by anhydrous potassium phosphate (1.5 eq.) and BnBr (1.02 eq.) at 25 + 5 °C. The reactor was heated to 50 + 5 °C and stirred for at least 4 h at 50 + 5 °C. [0064] Softened water (3.0 V) at 20 ± 10°C was added and the mixture was transferred to another reactor, which was charged with softened water (22.0 V). The reactor was charged with MTBE (10.0 V) and the mixture was stirred for at least 30 min. The mixture was then allowed to stand for at least 30 min, the layers were separated and the organic phase was collected. Softened water (5.0 V) was added to the organic phase, stirred for at least 30 min and then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. Under a nitrogen atmosphere, 20% sodium chloride solution (5.0 V) was added to the organic phase and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min and allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was transferred to the concentration reactor through a filter. The reaction was slowly charged with n-heptane (10.0 V) at 25 ± 5°C over a period of at least 4 hours. The organic phase was concentrated to approximately 9 to 10 V under vacuum, controlling the internal temperature to no more than 45 °C or a jacket temperature to no more than 55 °C. The reactor was charged with n-heptane (10.0 V). The organic phase was concentrated to 9-10 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The temperature was adjusted to 25 ± 5 °C and the mixture was stirred for at least 2 h. The mixture was centrifuged and the cake was washed with n-heptane (1.0 V). The wet cake was transferred to the reactor at 25 ± 5 °C and the feeding gate was flushed with MTBE (0.5V). The system was stirred until it is clear. Then, n-heptane (10.0 V) was slowly charged to the reactor at 25 ± 5°C over a period of at least 4 hours. The organic phase was concentrated to 9- 10 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. Under a nitrogen atmosphere, n-heptane (10.0 V) was charged to the reactor. The organic phase was concentrated to 9-10 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The temperature was adjusted to 25 ± 5 °C and stirred for at least 2 h. The mixture was centrifuged and the cake was washed with n-heptane (1.0 V). The wet cake was slurried with heptane (10 V) and MTBE (1 V) for 4 h at 25 ± 5 °C. The mixture was centrifuge and the cake was washed with n-heptane (1.0 V).

[0065] The cake was dried under vacuum at 40 ± 5°C for at least 16 hours to afford 6. Isolated 85.8 kg (67% yield).

[0066] Step 6:

[0067] Reactor A was charged THF (5.0 V) and stirred. Reactor A was then charged with 6 (1.0 eq., 70 kg), the temperature was adjusted to 25 ± 5°C, and stirred for at least 30 mins until clear. Then, n-BuLi (1.0 eq.) solution was added dropwise over a period of at least 2 hours at 25 ± 5°C. After the addition, the reaction was stirred for 1 h at 25 ± 5°C. Then, THF (10.0 V) was charged to reactor B under nitrogen protection and agitated. Then, 7 (0.9 eq.) was charged into the reactor and the reaction was warmed to 65 ± 5 °C. The solution of 7 lithium salt was transferred to the reactor B at 65 ± 5°C over a period of at least 6 hours. The mixture was stirred for at least 16 h at 65 ± 5°C and then cooled to below 30 °C.

[0068] The reactor was cooled to 25 ± 5 °C. Under a nitrogen atmosphere, 10% ammonium chloride solution (10.0 V) was charged to reactor B at 25 ± 5 °C and stirred for at least 30 min. The mixture was allowed to stand for at least 30 min, the layers were separated and the organic phase was collected. The organic phase was washed with 20% sodium chloride solution (5.0 V) and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min and then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was concentrated to approximately 4 to 5 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The temperature was adjusted to 25 ± 5°C and MeOH (10.0 V) was charged to the reactor B at 25 ± 5°C. The organic phase was concentrated to 4-5 V under vacuum, controlling the internal temperature to no more than 45 °C or jacket temperature no more than 55 °C. MeOH (10.0 V) was charged to reactor B, and the organic phase was concentrated to 4-5 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C.

[0069] The reactor was cooled to 20 ± 5 °C, charged with MTBE (7.0 V), and stirred for 30 mins. The reactor was then charged with HBr in acetic acid (1.0 eq.) at 20 ± 5 °C, warmed to 45 ± 5 °C, then charged with 8 (0.05% wt/wt.), and stirred for at least 2 h at 45 ± 5 °C. The reactor was then cooled to 20 ± 5 °C and stirred for at least 16 h at 20 ± 5 °C. The reactor was then cooled to 5 ± 5 °C and stirred for at least 2 h at 5 ± 5 °C. The mixture was centrifuged and the cake was washed with MTBE (1.0V).

[0070] The cake was dried under vacuum at 40 ± 5 °C for at least 24 hours to afford 8. Isolated 100.5 kg (75% yield).

[0071] Step 7:

[0072] Toluene (14.5 V) was charged to a reactor under nitrogen protection and agitated. The reactor was then charged with 8 (1.0 eq., 95 kg), sodium tert-butoxide (2.5 eq.), benzylamine (1.2 eq.), and stirred for at least 1 hour while bubbling N2 to remove O2. Then, 2, 2’ -bis(diphenylphosphino)-l,l’ -binaphthyl (0.025 eq.) and tris(dibenzylideneacetone)dipalladium (0.0125 eq.) were charged into the reactor and the reaction was stirred for at least 1 hour while bubbling N2 to remove O2.

[0073] The reaction was cooled to 25 ± 5°C, charged with softened water (10 V) at 25 ± 5 °C, and stirred for at least 30 min. Diatomite was charged into a filter tank and wet with toluene (2 V). The organic phase was filtered through the diatomite and the cake was washed with toluene (2 V). The filtrate was collected in a drum and transferred to a reactor containing toluene (0.5 V), stirred for at least 30 min, and then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected.

[0074] The organic phase was charged with oxone solution (0.1 wt/wt., 5.0 V) at 20 ± 5 °C, and stirred for at least 6 h. 10% sodium sulfite solution (5.0 V) at 20 ± 5 °C was added and the mixture was stirred for at least 2 h. The filter tank was charged with diatomite and wetted with toluene (2 V). The organic phase was filtered through the diatomite and the cake was washed with toluene (2 V). The filtrate was collected and stirred for at least 30 min and allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was washed with softened water (5.0 V), and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min and allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was washed with 20% Sodium chloride solution (5.0 V), and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min and allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The filter and pipeline were washed with toluene (1.0 V). The organic phase was transferred into the drum through an activated carbon filter, and concentrated to 4~5 V under vacuum while controlling the internal temperature to no more than 65 °C or a jacket temperature to no more than 70 °C. EtOH (10.0 V) was added to the reactor and the organic phase was concentrated to 4-5 V under vacuum while controlling the internal temperature to no more than 65 °C or a jacket temperature to no more than 70 °C. The organic phase was diluted with EtOH (10.0 V), and concentrated to 4-5 V under vacuum while controlling the internal temperature to no more than 65 °C or a jacket temperature to no more than 70 °C. The system was stirred and heated to 80 ± 5 °C, until the system was clear at 80 ± 5 °C. The system was then cooled to 30 ± 5 °C and stirred for at least 8 h at 30 ± 5 °C, before cooling to 20 ± 5 °C. The system was stirred for at least 2 h at 20 ± 5 °C and then the mixture was centrifuged and the cake was washed with EtOH (0.5 V). The cake was dried under vacuum at 40 ± 5 °C to afford 9. Isolated 67 kg (78% yield).

[0075] Step 8: [0076] A reactor was charged with NMP (3.0 V) and 9 (1.0 eq., 62 kg), and the funnel was washed with NMP (1.0 V). The temperature was adjusted to 25 ± 5 °C and stirred for at least 30 mins. Then, ammonium formate (2.0 eq.) was added and the funnel was washed with NMP (1.0 V). The reactor was charged with Pd/C(5% w/w) and the funnel was washed with NMP (0.5 V). The autoclave was heated to 40 ± 5°C slowly under N2, and the reaction was monitored via HPLC analysis after stirring for at least 4 hours at 40 ± 5°C. The reaction was then cooled to 20 ± 5 °C and filtered. The cake was washed with NMP (0.5 v) and the filtrate was collected and combined to afford a solution containing 10..

[0077] Step 9:

[0078] A reactor was charged with the solution of 10 in NMP (5V) through the filter and stirred. Cesium carbonate (2.0 eq.) was added at 25 ± 5 °C, followed by isopropyl bromoacetate (1.1 eq.) dropwise to reactor B at 25 ± 5 °C. The reaction was stirred for at least

4 h at 25 ± 5 °C.

[0079] MTBE (10.0 V) and softened water (10.0 V) were added into the system at 20 ± 10°C and the mixture was stirred for at least 30 min. The mixture was then allowed to stand for at least 30 min, the layers were separated and the organic phase was collected. The organic phase was washed with 10% ammonium chloride solution (10 V) and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min, allowed to stand for at least 30 min, the layers were separated and the organic phase was collected. The organic phase was charged with softened water (5.0 V), stirred for at least 30 min and then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was charged with 20% Sodium chloride solution (4.00 V), and the temperature was adjusted to 25 ± 5 °C. The mixture was stirred for at least 30 min, then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was concentrated to approximately 4 to 5 V under vacuum, controlling the internal temperature to no more than 45 °C or a jacket temperature to no more than 55 °C. The organic phase was charged with MTBE (10.0 V) and concentrated the organic phase to approximately 4 to 5 V under vacuum, controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C twice to afford a solution of 11.

[0080] Step 10:

[0081] A reactor was charged with the solution of 11 in MTBE (5V) and stirred. TFAA (2.0 eq.) was added dropwise at 25 ± 5 °C and the reaction was stirred for at least 4 h at 25 ±

5 °C. The system was charged with 5% sodium bicarbonate solution (15.0 V) at 20 ± 10°C and the mixture was stirred for at least 30 min then allowed to stand for at least 30 min. The layers were separated and the organic phase was collected. The organic phase was charged with 20% Sodium chloride solution (5.0 V), stirred for at least 30 mins, then allowed to stand for at least 30 mins. The layers were separated and the organic phase was collected. Using MTBE (1.0 V), a filter and a pipeline were washed and the organic phase was transferred through an activated carbon filter into a drum. The reactor was rinsed with MTBE (1.0 V) and then transferred through an activated carbon filter into the drum. The reactor was rinsed with softened water and MTBE and the organic phase was transferred to the concentration reactor through a filter. The organic phase was concentrated to approximately 4 to 5 V under vacuum, controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The organic phase was charged with heptane (10.0 V) and concentrated to 4-5 V under vacuum, controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. Reactor B was charged with heptane (10.0 V) and the organic phase was concentrated to 9-10 V under vacuum while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The reaction was then cooled to 30 ± 5 °C, then charged with 12, and stirred for at least 10 h at 30 ± 5 °C. The reaction was then cooled to 0 ± 5 °C and stirred for at least 4 h at 0 ± 5 °C. The mixture was centrifuged and the cake was washed with heptane (I V).

[0082] The cake was dried under vacuum at 40 ± 5 °C for at least 16 hours to afford 12. Isolated 62.3 kg (82% yield for three steps).

[0083] Step 11:

[0084] N-methyl-2-pyrrolidone (4.0 V) was charged to a glass reactor under the protection of nitrogen and stirred. Charged 12 (1.0 eq.) to the reactor and rinsed the reactor with NMP(1 V). The temperature was adjusted to 25±5°C and stirred for at least 30 minutes until the system was dissolved. Charged hydrogen chloride 1, 4-dioxane solution (1.0 eq.) to the reactor at 25+5 °C and stirred for at least 2 h at 25+5 °C. Charged D-camphor- 10- sulfonic acid (l.Oeq.) to the reactor at 25+5°C, rinsed the reactor with NMP (1 V) and stirred for at least 2 h.

[0085] To a reactor was added, NMP (2.0V) under the protection of nitrogen and stirred, followed by di-p-chlorotetrakis(cyclooctene)diiridium (0.0125 eq.) and (R)-(+)-SEGPHOS® (0.025 eq.). The reactor was rinsed with NMP (I V) and the temperature was adjusted to 25 + 5°C. The reaction was stirred for at least 2 hours, then 1, 4-dioxane solution (0.2 eq.) of hydrogen chloride was added to the reactor at a temperature of 25 + 5 °C and stirred for at least 2 h at 25 + 5 °C. [0086] A solution of 12 (30 kg) in drum was added to the autoclave under N2 protection, followed by NMP (12.0 V), and the Ir complex solution. NMP (0.5 V) was transferred to the drum to transfer the eluent to autoclave. The autoclave was then pressurized under hydrogen to 2.0-2.5 MPa and heated slowly (maintaining the hydrogen pressure to 2.0-2.5 MPa every time) until the temperature reached 70 + 5 °C.

[0087] The reaction of 13 was transferred to the reactor and the temperature was adjusted to 20 + 10 °C. The reactor was charged with MTBE (20.00 V), 5% sodium bicarbonate solution (10.00 V) at 20 + 10 °C, and stirred for at least 30 mins. The pH was monitored in 30 minute intervals. The reactor was charged with softened water (10.00 V) at 20 + 10 °C, stirred for at least 30 min, and then prepared for filtration. The filter tank was charged with diatomite and wetted with MTBE (2.00 V). The organic phase was filtered through the diatomite and the cake was washed with MTBE (2.00 V). The filtrate was collected in reactor A and prepared to separate by stirring the filtrate for at least 30 min, allowing it to stand for at least 30 min, allowing the layers to separate, and then transferring the aqueous to a new reactor while the organic remained in the reactor. The aqueous phase was charged with MTBE (10.00 V), stirred for at least 30 min, and then allowed to stand for at least 30 min. The layers were separated, and the aqueous phase was discharged, while the organic phase was transferred to the reactor. The organic phase was charged with softened water (10.00 V) and the temperature was adjusted to 25 + 5 °C. The mixture was stirred for at least 30 min, allowed to stand for at least 30 min at 25 + 5 °C, where the layers were separated and the organic phase was collected twice. The organic phase was charged with 20% sodium chloride solution (5.0 V) and the temperature was adjusted to 25 + 5 °C. The mixture was stirred for at least 30 min, allowed to stand for at least 30 min at 25 + 5 °C, where the layers were separated and the organic phase was collected. A filter was prepared and MTBE (2.00V) was used to wash the filter and the pipeline. The organic phase was transferred into the drum, through the activated carbon filter, and the reactor was rinsed with MTBE (2.00V) and transferred into the drum through the activated carbon filter. The organic phase was then transferred to the reactor through a filter and charged with sulfhydryl silica (0.25 w/w). The mixture was warmed to 50 + 5°C and stirred for at least 20 h, then filtered and the cake was washed with MTBE (2.0 V). The organic phase was transferred and concentrated to 5-10 V under vacuum, controlling the internal temperature to no more than 45 °C or a jacket temperature to no more than 55 °C. The organic phase was charged with MeOH (10.00 V) and concentrated to 5-10 V under vacuum, while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The organic phase was then charged with MeOH (10.00 V) and concentrated to 9-10 V under vacuum, while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The temperature was adjusted to 25±5°C and maintained for the next step.

[0088] Step 12:

[0089] The solution of 13 (57 kg) in MeOH (10 V) was charged with THF (10.00 V) and the temperature was adjusted to 20-25 °C, followed by dropwise addition of the 3% lithium hydroxide solution at 25 ± 5 °C. After addition, the reaction was stirred for at least 4 h at 25 ± 5 °C.

[0090] The reaction system was concentrated to 4.5-5.5 V under vacuum, controlling the internal temperature to no more than 45 °C or a jacket temperature to no more than 55 °C. The temperature was adjusted to 20 ± 5 °C and then the reactor was charged with softened water until the system volume was 10.00 V. The system was transferred to another reactor, and MeOH (20.00 V) was added to reactor A. The pH was adjusted to 7-8 with IN hydrochloric acid aqueous at 20 ± 5 °C, stirring for 15 minutes and testing the pH until the desired pH was maintained. The system was stirred for at least for 2 h at 20 ± 5 °C and then concentrated to 15-20 V under vacuum, while controlling the internal temperature to no more than 45 °C or jacket temperature to no more than 55 °C. The temperature was adjusted to 20 ± 5 °C and stirred for at least for 2 h. The organic phase was then cooled to 20 ± 5 °C, stirred for at least for 2 h. The cake was dried under vacuum at 50 ± 5 °C for at least 16 hours to afford 14. Isolated 36.4 kg (82% over two steps).

[0091] Step 13:

[0092] A reactor was charged with ACN (20.0 V) and stirred. The reactor was then charged with 2-(7-azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (1.5 eq.) and the temperature was adjusted to 0 ± 5 °C. Then, DIEA (2.0 eq.) and 1,8- diazabicyclo[5.4.0]undec-7-ene (1.0 eq) were added and stirred for at least 1 h at 0 ± 5 °C. A solution of 14 (79 kg) in NMP (5 V) was then added drop wise (controlling the charging time to at least 10 h) and the reaction was stirred for at least 1 h. The reaction was monitored via HPLC.

[0093] The reactor was then cooled to -10 ± 5 °C and stirred at least for 20 h. The mixture was centrifuged and the cake was washed with ACN (1.0 V). The cake was dried under vacuum at 45+5 °C for at least 16 hours to afford 15 as a crude solid. Dichloromethane was added and undissolved solid was filtered. The organic layer was washed with 1:1 saturated bicarbonate and brine wash of dichloromethane solution. The organic layer was decanted and evaporated under vacuum to afford the product. Isolated 42.2 kg (56% yield). [0094] Step 14:

[0095] An autoclave was charged with NMP (3.0 V) and agitated. The temperature was adjusted to 25 ± 5 C and 15 (1.0 eq.) was added. The charging port was rinsed with NMP (1.0 V) and then hydrochloric acid (0.8 eq.) was added. The reaction was stirred for at least 2 hours at 25 ± 5 °C and then hydroxide palladium carbon (5% w/w) was added. The charging port was rinsed with NMP (1.0 V) and the autoclave was heated slowly while pressurizing with hydrogen until heating the autoclave to 45 ± 5°C slowly. This procedure was repeated until the system pressure change is less than 0.1 MPa in one hour. The reaction was analyzed via HPLC every 6 hours after stirring for at least 16 hours.

[0096] The autoclave was cooled to 25 ± 5 °C, charged with ACN (10 V), and then stirred for at least 1 h. The reaction was filtered and the cake was washed with ACN (2 V) and the filtrate was collected. The filtrate was transferred to a reactor via a filter and the organic phase was concentrated to 5-6 V under vacuum, controlling the internal temperature to no more than 45 °C and a jacket temperature to no more than 55 °C. The temperature was adjusted to 25 ± 5 °C, then MTBE (10 V) was added and the mixture was stirred for at least 1 h. Then 2-Mercaptopropyl ethyl sulfide silica (0.2 w/w) was added and stirred for at least 16 h at 25 ± 5 °C. The reaction was filtered and the cake washed with ACN (2 V). The organic phase was diluted with ACN (10 V) and concentrated to 5-6 V under vacuum, controlling the internal temperature to no more than 45 °C and a jacket temperature to no more than 55 °C. The organic phase was then further concentrated to 4-6 V under vacuum, controlling the internal temperature to no more than 50 °C and a jacket temperature to no more than 60 °C to afford a solution of 16.

[0097] Step 15:

[0098] Step 15 is performed following the procedures set forth in WO 2022/232025, WO 2022/140316, and WO 2021/108628.

[0099] Alternative Synthesis of Intermediates 2, 5, and 6

[00100] Scheme 2

Step 1a 260 kg, 87%

NaOH, Water, THF,

[00101] Step la:

[00102] The reactor was charged with THF (2 V, 409 kg) and 2-bromomophenol (230 kg,

1 equiv.), and stirred. The temperature was adjusted to 10 + 5 °C. A solution of isopropylmagnesium chloride (z-PrMgCl, 2M, 665 kg, 1 equiv.) was added dropwise (controlling the charging time to at least 8 h) and the mixture was stirred for at least 1 h. A solution of zz-Butyllithium (zz-BuLi, 2.5M in hexanes, 796 kg, 2.2 equiv.) was added dropwise (controlling the charging time to a least 4 h) and the mixture was stirred for at least 1 h. The temperature was adjusted to 40 + 5 °C and the mixture was stirred for at least 2 h. An additional portion of z-PrMgCl (131.2 kg, 0.2 equiv.) was charged (controlling the charging time to at least 1 h) and stirring continued for at least 2 h. The temperature was adjusted to 0 + 5 °C. A solution of l,4-dioxaspiro[4.5]decan-8-one (259.8 kg, 1.25 equiv.) in THF (3 V, 715 kg) was charged and stirring continued for at least 1 h. Reaction was monitored by HPLC.

[00103] MTBE (5 V, 832.4 kg) was charged at 0 ± 5°C. Then the pH was adjusted to 7-8 with a 15 wt. % citric acid in water solution (1703.9 kg). The resulting mixture was warmed to 25 ± 5 °C and stirred for at least 1 h and let stand for at least 1 h. The aqueous layer was separated and discarded. The organic layer was charged with 20% aqueous sodium chloride solution (3 V, 795.3 kg) and the mixture was stirred for at least 30 min and let stand for at least 30 min. The aqueous phase was separated and discarded. The organic phase was concentrated to a volume of 700 L under vacuum maintaining an internal temperature of no more than 45 + 5 °C. //-Heptane (15 V, 2309.9 kg) was charged at 25 + 5 °C and the mixture was concentrated to a volume of 1900 L under vacuum maintaining an internal temperature of no more than 45 + 5 °C. The resulting mixture was cooled to 20 + 5 °C and stirred for at least 1 h. The product was collected by filtration, washed with heptane (IV) and dried under vacuum at no more than 40 + 5 °C. Isolated 259.7 kg of 2 (87%).

[00104] Step 4a: [00105] Suitable enzymatic reductions conditions known to those skilled in the art using

NADPH-dependent reductase were employed to afford 5 as a wet cake which was used directly in the next step.

[00106] Step 5a:

[00107] The reactor was charged with water (2.5 V, 804 kg), sodium hydroxide (134 kg, 2 equiv. based on 4 in the previous step), and 5 wet cake (372 kg, 1 equiv.) at 25 ± 10 °C. THF (5 V, 1421 kg) was charged to the reactor and the internal temperature was adjusted to 25 ± 5 °C. The mixture was then charged with tetrabutylammonium hydrogen sulfate (115 kg, 0.20 equiv) and benzyl bromide (BnBr, 275 kg, 0.95 equiv) at 25 ± 5 °C. The mixture is stirred for at least 8 h at 25 ± 5 °C. The reaction was monitored by HPLC.

[00108] MTBE (2392 kg, 10 V) was charged, and the resulting mixture was stirred for at least 1 h and then allowed to stand for at least Ih. The aqueous layer was separated and washed with water (4 x 5 V, total 6422 kg) and then 20% aqueous sodium chloride solution (3 V, 995 kg). The organic phase was concentrated to 1650 L at an internal temperature no more than 45 + 5 °C. Heptane (20 V, 4140 kg) was charged (controlling the charging time to at least 7 h). The organics were then concentrated to 2733 L under vacuum at an internal temperature no more than 45 + 5 °C. The reactor walls were then rinsed with heptane (2 V, 435 kg). The mixture was cooled 0 + 5 °C and stirred for at least 5 h. The mixture was centrifuged, and the cake was washed with heptane (1 V). The solids were dried for at least 16 h at 40 + 5 °C. Isolated 394 kg of 6 (81% over two steps).

[00109] Alternative Preparation of Intermediate 15

[00110] Scheme 3

[00111] Step 13a:

[00112] A reactor was charged with THF (10.0 V, 596 kg) and stirred. The reactor was then charged with diphenylphosphoryl chloride (53.6 kg, 1.35 equiv) and diisopropylethylamine (29.6 kg, 1.55 equiv). The temperature was adjusted to 0 ± 5 °C and the solution was stirred for at least 1 h at 0 ± 5 °C. A solution of 14 (66.5 kg, 1 equiv) and diazabicycloundecene (DBU, 26.8 kg, 1.2 equiv) in ACN (5 V, 265 kg) was then added drop wise (controlling the charging time to at least 10 h). Upon complete addition, the reaction was stirred for at least 1 h. The reaction was monitored via HPLC.

[00113] Water (0.1 V, 6.9 kg) was charged, and the temperature was adjusted to 20 ± 5 °C. It was stirred for at least 1 h, and the organics were concentrated by distillation to 815 L at not more than 45 °C. The temperature was adjusted to 20+5 °C and a small amount of 15 (0.334 kg, 0.5 wt%) was added as seed and stirring continued for at least 2 h. Water (10 V, 674 kg) was added (controlling the charging time to at least 2 h), and the mixture was stirred for an additional 2 h. The mixture was centrifuged and washed with THF:water (1:1, 2 V, 126 kg). The cake was slurred in ACN (5 V, 266 kg) and the mixture was centrifuged for the second time. The cake was washed with ACN (I V) and dried under vacuum at 45+5 °C for at least 16 hours to afford the product. Isolated 46.6 kg of 15 (72% yield).

[00114] Step 13a’:

[00115] A solution of 14 (200 g, 1 equiv), diazabicycloundecene (DBU, 87.5 g, 1.2 equiv) in acetonitrile (5 V, 1 L) was added to a solution of bis(2-oxo-3-oxazolidinyl)phosphinic chloride (135 g, 1.2 equiv) and diisopropylethylamine (45.7 g, 0.8 equiv) in DCM (10 V, 4 L) at 40 °C over at least 5 h. The reaction mixture was heated 40 °C for an additional 1 h. The reaction was cooled to 20 + 5 °C and 5% NaHCOa solution (10 V, 2 L) and 20% brine solution (5 V, 1 L) were added. The organic phase was collected and washed with 20% brine solution (5 V, 1 L). The washed solution was concentrated to 1 L. 2-MeTHF (10 V, 2 L) was added and the mixture was concentrated to 1 L. The process was repeated twice and the mixture was concentrated to a final volume of 2 L. The solution was heated to 50 + 5 °C for at least 2 h then cooled to 0 + 5 °C for at least 16 h. The resulting solids were collected by filtration, washed with 2-MeTHF (2 V, 0.4 L) and dried under vacuum to give 15 (142 g, 74%) as a solid.

[00116] Exemplary compounds made by the present methods include those described in WO 2022/232025, WO 2022/140316, and WO 2021/108628. In some embodiments, exemplary compounds made by the present methods are selected from:

[00117] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

1. A method of preparing a compound having the structure:

said method comprising: reacting a compound having the structure:

with an iridium dimer and an optically active bisphosphine in the presence of a hydrogen atmosphere.

2. The method of Claim 1, wherein the dimer is selected from di-p- chlorotetrakis(cyclooctene)diiridium ([IrCl(coe)2]2), di-p-bromotetrakis(cyclooctene) diiridium ([IrBr(coe)2]2), di-p -iodotetrakis(cyclooctene)diiridium ([Irl(coe)2]2), di-p- chlorobis(l,5-cyclooctadiene)diiridium, ([IrCl(cod)]2]2), di-p-bromobis(l,5- cyclooctadiene)diiridium, ([IrBr(cod)]2), di-p-iodobis(l,5-cyclooctadiene)diiridium, ([Irl(cod)]2), di-p-chlorobis(bicyclo[2,2,l]hepta-2,5-diene), diiridium([IrCl(nbd)]2), di-p- bromobis(bicyclo[2,2, l]hepta-2,5-diene)diiridium([IrBr(nbd)]2), and di-p-iodobis(bicyclo[2,

2. l]hepta-2,5-diene)diiridium ([Irl(nbd)]2)

3. The method of Claim 1 or 2, wherein the iridium dimer is di-p-chlorotetrakis- (cyclooctene)diiridium ( [IrCl(coe)2] 2) .

4. The method of any one of Claims 1 to 3, wherein the optically active bisphosphine is of the formula:

wherein

R², R³, R⁴, and R⁵ are each independently a phenyl or cycloalkyl group, each of which is optionally substituted with one or more (Ci-C4)alkyl or (Ci-C4)alkoxy groups; and

R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are each independently selected from hydrogen, (Ci- C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halogen, (Ci-C4)acyloxy, and -N[(Ci-C4)alkyl]2, or R⁷ and R⁸ and/or R⁹ and R¹⁰ are taken together to form an optionally substituted cycloalkyl, an optionally substituted aryl, or an optionally substituted oxygen containing heterocyclyl.

5. The method of any one of Claims 1 to 4, wherein the optically active bisphosphine is selected from 2, 2’ -bis-(diphenylphosphino)- 1,1’ -binaphthyl (BINAP®); 2,2,-bis-(di-p- tolylphosphino)- 1,1’ -binaphthyl; 2,2’ -bis-(di-m-tolylphosphino)- 1,1’ -binaphthyl, 2,2’ -bis(di- 3,5-xylylphosphino)- 1,1’ -binaphthyl; 2,2,-bis(di-p-tert-butylphenylphosphino)- 1,1’- binaphthyl; 2,2,-bis(di-p-methoxyphenylphosphino)- 1,1’ -binaphthyl, 2,2’ -bis(di-p- chlorophenylphosphino)- 1,1’ -binaphthyl; 2,2’ -bis(dicyclopentylphosphino)- 1,1’ -binaphthyl;

2,2’-bis(dicyclohexylphosphino)-l,l’-binaphthyl; 2,2’-bis(diphenylphosphino)-

5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(di-p-tolylphosphino)-

5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(di-m-tolylphosphino)-

5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(di-3,5-xylylphosphino)-

5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(di-p-tert-butylphenylphosphino)- 5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(di-p-methoxyphenylphosphino)- 5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(di-p-chlorophenylphosphino)- 5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(dicyclopentylphosphino)-

5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; 2,2’-bis(dicyclohexylphosphino)-

5, 5’, 6, 6’, 7, 7’, 8, 8’ -octahydro- 1,1’ -binaphthyl; (R)-(+)-5,5’-bis(diphenylphosphino)-4,4’-bi- 1,3-benzodioxole ((R)-(+)-SEGPHOS®)); (4,4’-bi-l,3-benzodioxole)-5,5’-diyl)bis(bis(3,5- xylyl)phosphine; (4,4’-bi-l,3-benzodioxole)-5,5’-diyl)bis(bis(3,5-di-t-butyl-4- methoxyphenyl)phosphine; (4,4’-bi-l,3-benzodioxole)-5,5’-diyl)bis(bis(4- methoxyphenyl)phosphine; (4,4’-bi-l,3-benzodioxole)-5,5’-diyl)bis(dicyclohexylphosphine; (4,4’-bi-l,3-benzodioxole)-5,5’-diyl)bis(bis(3,5-di-t-butylphenyl)phosphine; 4,4’-bi(2,2- difluoro-l,3-benzodioxole)-5,5’-diyl) bis(diphenylphosphine); 2,2’-bis(diphenylphosphino)- 4,4’,6,6’-tetramethyl- 5, 5 ’-dimethoxy- 1,1’ -biphenyl; 2,2’-bis(di-p- methoxyphenylphosphino)-4,4’ ,6,6’ -tetramethyl-5,5 ’ -dimethoxy- 1 , 1 ’-biphenyl; 2,2’ - bis(diphenylphosphino)-4,4’ ,6,6’ -tetra(trifluoromethyl)-5,5’ -dimethyl- 1 , l’-biphenyl; 2,2’ - bis(diphenylphosphino)-4,6-di(trifluoromethyl)-4’ ,6’ -dimethyl-5 ’ -methoxy- 1 , 1 -biphenyl; 2- dicyclohexylphosphino-2’-diphenylphosphino-4, 4’, 6, 6’-tetramethyl-5,5’-dimethoxy-l, l’- biphenyl; 2,2’ -bis(diphenylphosphino)-6, 6’ -dimethyl- 1,1’ -biphenyl; 2,2’ - bis(diphenylphosphino)-4,4’ ,6,6’ -tetramethyl- 1,1’ -biphenyl; 2,2’ -bis(diphenylphosphino)- 3, 3’, 6, 6’ -tetramethyl- 1, l’-biphenyl); 2,2’-bis(diphenylphosphino)-4,4’-difluoro-6,6’- dimethyl-1, l’-biphenyl; 2,2’-bis(diphenylphosphino)-4,4’-bis(dimethylamino)-6,6’-dimethyl- 1 , 1’ -biphenyl; 2,2’ -bis(di-p-tolylphosphino)-6,6 ’ -dimethyl-1,1’ -biphenyl; 2,2’ -bis(di-o- tolylphosphino)-6,6’ -dimethyl- 1,1’- biphenyl; 2,2’ -bis(di-m-fluorophenylphosphino)-6,6’ - dimethyl-1, l’-biphenyl; 1,1 l-bis(diphenylphosphino)-5,7-dihydrobenzo[c,e]oxepin; 2,2’ - bis(diphenylphosphino)-6,6’-dimethoxy-l, l’-biphenyl; 2,2’-bis(diphenylphosphino)- 5,5 ’ ,6,6’ -tetramethoxy- 1 ,1’ -biphenyl; 2,2’ -bis(di-p-tolylphosphino)-6,6’ -dimethoxy- 1,1’- biphenyl; and 2,2’ -bis(diphenylphosphino)-4,4’ ,5,5 ’ ,6,6’ -hexamethoxy- 1 ,1’ -biphenyl.

6. The method of any one of Claims 1 to 5, wherein the optically active bisphosphine is (R)-(+)-5,5 ’ -bis(diphenylphosphino)-4,4’ -bi- 1 ,3-benzodioxole.

7. The method of any one of Claims 1 to 6, wherein the reaction is performed in the presence of a solvent.

8. The method of any one of Claims 1 to 7, wherein the reaction is performed in the presence of an aprotic solvent.

9. The method of any one of Claims 1 to 8, wherein the reaction is performed in the presence of a dipolar aprotic solvent.

10. The method of any one of Claims 1 to 9, wherein the reaction is performed in the presence of a dipolar aprotic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP).

11. The method of any one of Claims 1 to 10, wherein the reaction is performed in the presence of N-methyl-2-pyrrolidone (NMP).

12. A method of preparing a compound having the structure:

said method comprising: reacting a compound having the structure:

suitable base and a compound having the structure

13. The method of Claim 12, wherein the suitable base is one that is capable of deprotonating the alcohol on the cyclohexyl ring.

14. The method of Claim 12 or 13, wherein the suitable base is one that is capable of deprotonating the alcohol on the cyclohexyl ring without disturbing the integrity of the benzyl protection group of the phenol.

15. The method of any one of Claim 12 to 14, wherein the suitable base is n-butyllithium.

16. The method of any one of Claim 12 to 15, wherein the suitable base is added prior to the addition of the 3-bromo-2-(bromomethyl)pyridine.

17. The method of any one of Claim 12 to 16, wherein the reaction is performed in the presence of THF.

18. A method of preparing a compound having the structure:

said method comprising: reacting a compound having the structure:

oxidoreductase.

19. The method of Claim 18, wherein the oxidoreductase is an NADPH-dependent oxidoreductase.

20. The method of Claim 18 or 19, wherein the oxidoreductase is selected from KRED- Yl, KRED-NADPH-P1A04, KRED-NADPH-P2H07, KRED -NADPH-P1B10, KRED- NADPH-107, KRED-NADPH-135, KRED-NADPH-136, KRED-NADPH-147, KRED- NADH-110, KRED-NADH-124, ES-KRED-120, KRED-NADPH-104, KRED-NADPH-130, KRED-NADPH-148, KRED-Y2, KRED-NADH-117, KRED-NADH-126, and KRED- NADPH-162C.