Chiral Synthesis of Tertiary Alcohols

Abstract

Disclosed herein is a method for preparing tertiary alcohols from optionally substituted phenyl ketones or optionally substituted pyridinyl ketones, comprising the use of chiral ligands and boron trifluoride diethyl etherate. The tertiary alcohols can be used to prepare synthetic versions of natural products and / or pharmaceuticals.

Description

[Technical Field]

[0001] (Incorporation by reference of any priority application) Any application in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application, including, for example, U.S. Provisional Application No. 62 / 935,894, filed November 15, 2019, and U.S. Provisional Application No. 62 / 037,761, filed June 11, 2020, is incorporated herein by reference under 37 CFR § 1.57 and Rules 4.18 and 20.6.

[0002] FIELD OF THE INVENTION This application relates to the fields of chemistry and medicine. More specifically, disclosed herein are methods for preparing tertiary alcohols. Also disclosed herein are methods for using tertiary alcohols in the preparation of compounds that can be used as anti-cancer agents. [Background technology]

[0003] New methods for preparing chiral compounds with high enantiomeric purity while minimizing undesired by-products would be highly valuable. Chiral secondary and tertiary alcohols are often used in the preparation of synthetic versions of natural products and pharmaceuticals. Many methods exist for preparing chiral secondary alcohols. However, methods for providing chiral tertiary alcohols with high enantiomeric purity and high yields remain a challenge. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2019 / 173082 [Non-patent literature]

[0005] [Non-Patent Document 1] Biochem.11:942-944(1972) [Non-patent document 2] Remington's Pharmaceutical Sciences,20thed., Lippincott Williams & Wilkins,Philadelphia Pa.,173(2000) [Non-patent document 3] The United States Pharmacopeia,37thed.,503-509(2014) Summary of the Invention

[0006] Some embodiments disclosed herein relate to a method for preparing a tertiary alcohol or a salt thereof, the method comprising: providing a phenyl ketone and a pyridinyl ketone that is substituted with a halogen, an unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 an optionally substituted phenyl ketone or an optionally substituted pyridinyl ketone, or a salt of any of the foregoing, substituted with one or more substituents selected from the group consisting of alkoxy; a zinc reagent selected from EtZn, MeZn, and PhZn; and a compound having the structure

[0007] [ka]

[0008] wherein each Ar can independently be unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl, and when Ar is substituted phenyl or naphthyl, the phenyl or naphthyl can independently be halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 The method may comprise combining BF3·OEt2 with a chiral ligand, which may be substituted with one or more substituents selected from alkoxy.

[0009] Some embodiments disclosed herein relate to a compound of the following formula (G1-a) having the following structure or a salt thereof:

[0010] [ka]

[0011] wherein X is Cl, Br, or I. In some embodiments, X is Cl. In some embodiments, X is Br. In some embodiments, X is I. [Brief explanation of the drawings]

[0012] [Figure 1] 1 provides a representative X-ray powder diffraction (XRPD) pattern of Form A of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol. [Figure 2] 1 provides a representative X-ray powder diffraction (XRPD) pattern of form B of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition 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. All patents, applications, published applications, and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] As used herein, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4b , R 5b , R 1g , R 2g , R 3g , R1h , R 2h , R 3h , R 1j , R 2j , R 3j , R 1k , R 2k , R 3k , R 4k , R 5k , R 1l , R 2l , R 3l , R 4l , R 5l , R 1m , R 2m , R 3m , R 4m , R 5m , X 1a , X 2a , X 3a , X 4a , X 1g , X 1h , X 1j , X 2g , X 3g , X 4g , X 2h , X 3h , X 4h , X 2j , X 3j , and X 4j Any "R" and "X" groups, such as, but not limited to, the indicated atom, represents a substituent that can be attached to a group. Such R and / or X groups may be referred to generally herein as an "R" or "X" group. When two "R" groups are described as being "together," the R groups and the atoms to which they are attached can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycle. For example, without limitation, NR a R b Group R a and R b When are shown to be "together," it is meant that they are covalently linked to each other to form a ring.

[0015] [ka]

[0016] Additionally, alternatively, when two "R" groups are described as "together" with the atoms to which they are attached to form a ring, the R groups are not limited to the variables or substituents defined above.

[0017] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b " refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in a ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not specified with respect to an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclyl group, the broadest range described by those definitions is assumed.

[0018] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms. (Whenever a numerical range such as "1 to 20" appears herein, it refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on up to 20 carbon atoms; however, this definition also encompasses the term "alkyl" without a specified numerical range.) The alkyl group can also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0019] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include allenyl, vinylmethyl, and ethenyl. Alkenyl groups can be unsubstituted or substituted.

[0020] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. Examples of alkynyl include ethynyl and propynyl. Alkynyl groups can be unsubstituted or substituted.

[0021] As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined by fusion. As used herein, the term "fused" refers to two rings that share two atoms and one bond. A cycloalkyl group can contain 3 to 30 atoms in the ring, 3 to 20 atoms in the ring, 3 to 10 atoms in the ring, 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring. A cycloalkyl group can be unsubstituted or substituted. Typical mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl, and tetradecahydroanthracenyl.

[0022] As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring, provided that if more than one is present, the double bonds cannot form a completely delocalized π-electron system throughout all rings (otherwise the group is an "aryl" as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. When consisting of more than one ring, the rings may be joined by fusion. Cycloalkenyl groups may be unsubstituted or substituted.

[0023] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbon rings share a chemical bond) having a completely delocalized pi-electron system throughout all rings. The number of carbon atoms in an aryl group can vary. For example, an aryl group can be any of C6 to C6. 14 Aryl groups, C6-C 10The aryl group may be an aryl group or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0024] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized π-electron system) containing one, two, three, or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. The number of atoms in the rings of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings share at least one chemical bond, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings. Examples of heteroaryl rings include, but are not limited to, those described herein and the following: furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0025] As used herein, "heterocyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with 1 to 5 heteroatoms, comprise the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned as such, but a completely delocalized π-electron system does not occur throughout all rings. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, to define them as including oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of more than one ring, the rings may be joined together in a fused or spiro fashion, as described herein for "cycloalkyl." Additionally, any nitrogen in a heterocyclyl may be quaternized. A heterocyclyl or heteroalicyclic group can be substituted or unsubstituted.Examples of such "heterocyclyl" groups include those described herein as well as the following: 1,3-dioxine, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3,4-oxadiazol-2(3H)-one, 1,2,3-oxadiazol-5(2H)-one, 1,3-oxathiolane, 1,3-dithiol, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 1,3-thiazinane, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, These include, but are not limited to, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and benzo-fused analogs thereof (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0026] As used herein, "cycloalkyl(alkyl)" refers to a cycloalkyl group bonded as a substituent via a lower alkylene group. The lower alkylene and cycloalkyl groups of cycloalkyl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, cyclohexyl(methyl), cyclopentyl(methyl), cyclohexyl(ethyl), and cyclopentyl(ethyl).

[0027] As used herein, "aryl(alkyl)" refers to an aryl group bonded as a substituent via a lower alkylene group. The lower alkylene and aryl groups of the aryl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

[0028] As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group bonded as a substituent via a lower alkylene group. The lower alkylene and heteroaryl groups of a heteroaryl(alkyl) can be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and benzo-fused analogs thereof.

[0029] "Heterocyclyl(alkyl)" refers to a heterocyclyl group attached as a substituent via a lower alkylene group. Heteroalicyclyl(alkyl) refers to a heterocyclic group having a substituted or unsubstituted alkylene group. The lower alkylene and heterocyclyl of heteroalicyclyl(alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0030] A "lower alkylene group" is a straight-chain -CH- linking group that forms a bond to connect molecular fragments through their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), and butylene (-CHCHCHCHCH-). A lower alkylene group can be substituted by replacing one or more hydrogens of the lower alkylene group with a substituent listed in the definition of "substituted."

[0031] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy(isopropoxy), cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, phenoxy, and benzoxy. Alkoxy can be substituted or unsubstituted.

[0032] As used herein, "acyl" refers to alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), and heterocyclyl(alkyl) bonded as a substituent through a carbonyl group. Examples include acetyl, propanoyl, benzoyl, and acryl. Acyl can be substituted or unsubstituted.

[0033] As used herein, the term "halogen atom" or "halogen" means any one of the radiostable atoms in column 7 of the periodic table of the elements, such as fluorine, chlorine, bromine, and iodine.

[0034] "Phenyl ketone" refers to monocyclic and bicyclic phenyl ketones. Monocyclic phenyl groups have a "-C(=O)R" bonded to the phenyl ring. a1 " moiety, wherein R a1can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Bicyclic phenyl ketones have a phenyl fused to a 4-8 membered monocyclic hydrocarbon ring with a carbonyl moiety attached to one of the ring carbons of the hydrocarbon ring, where one or two ring carbons of the hydrocarbon ring can be independently replaced with a heteroatom selected from oxygen (O) and sulfur (S).

[0035] "Pyridinyl ketone" refers to monocyclic and bicyclic pyridinyl ketones. Monocyclic pyridinyl groups have a "-C(=O)R" bonded to the phenyl ring. b1 " moiety, wherein R b1 can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). Bicyclic pyridinyl ketones have a pyridinyl fused to a 4-8 membered monocyclic hydrocarbon ring with a carbonyl moiety attached to one of the ring carbons of the hydrocarbon ring, where one or two ring carbons of the hydrocarbon ring can be independently replaced with a heteroatom selected from oxygen (O) and sulfur (S).

[0036] Where the number of substituents is not specified (e.g., alkoxyphenyl), one or more substituents may be present. For example, "alkoxyphenyl" may include one or more of the same or different alkoxy groups. As another example, "C1-C3 alkoxyphenyl" may include one or more of the same or different alkoxy groups containing 1, 2, or 3 atoms.

[0037] As used herein, the abbreviations for any protecting groups, amino acids, and other compounds are consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Non-Patent Document 1), unless otherwise specified.

[0038] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic or sulfonic acid, for example, formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium or potassium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0039] Unless otherwise specified, as used herein, the term "crystalline" and related terms, when used to describe a substance, component, product, or form, means that the substance, component, product, or form is substantially crystalline, for example, as determined by X-ray diffraction (see, e.g., J. Chem. Soc. 1999, 144:111-112; J. Chem. Soc. 1999, 144:111-112).

[0040] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, such as a particular temperature or temperature range (e.g., those describing melting, dehydration, desolvation, or glass transition temperatures), mass change (e.g., mass change as a function of temperature or humidity), solvent or water content (e.g., mass or percentage), or peak position (e.g., in analysis by IR or Raman spectroscopy or XRPD), indicate that the value or range of values ​​may be deviated from to an extent that would be reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffraction, vibrational spectroscopy (e.g., infrared (IR), Raman spectroscopy), solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility testing, and dissolution testing. In some embodiments, the terms "about" and "approximately" are used interchangeably. As used in this context, the terms "about" and "approximately" indicate that a numerical value or range of values ​​may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. In the context of molar ratios, "about" and "approximately" indicate that a numerical value or range of values ​​may vary within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. Because the numerical values ​​of peaks in X-ray powder diffraction patterns can vary from instrument to instrument or sample to sample, quoted numerical values ​​should not be construed as absolute, but should be understood to be subject to acceptable variability, such as ±0.2 degrees 2-theta (°20) or more. For example, in some embodiments, XRPD peak position values ​​can vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak.

[0041] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," etc. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring" and is inclusive or open-ended, not excluding additional, unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including, but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, should not be understood to imply that a particular feature is critical, essential, or even important to its structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be synonymous with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0042] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope thereof.

[0043] In any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. Additionally, in any compound described herein having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof.

[0044] Likewise, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0045] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0046] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood as being present in the compound. At any position in a compound where a hydrogen atom can be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0047] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0048] Compounds and Preparation Methods

[0049] Some embodiments described herein relate to a method for preparing a tertiary alcohol or a salt thereof, the method comprising reacting an optionally substituted phenyl ketone, or an optionally substituted pyridinyl ketone, or a salt of any of the foregoing, with a zinc reagent selected from EtZn, MeZn, and PhZn, and a tertiary alcohol having the structure:

[0050] [ka]

[0051] wherein R 1 can be -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3, and R 2 can be H or R 1 and R 2 However, each R 1 and R 2may be taken together with the carbon to which Ar is attached to form an unsubstituted cyclohexyl ring, and each Ar may independently be unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl, and when Ar is substituted phenyl or substituted naphthyl, the phenyl or naphthyl may independently be selected from the group consisting of halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 alkoxy, and b may be 1 or 2, and may comprise combining a chiral ligand with BF3·OEt2.

[0052] Some embodiments described herein relate to a method for preparing a tertiary alcohol or a salt thereof, the method comprising reacting an optionally substituted phenyl ketone, or an optionally substituted pyridinyl ketone, or a salt of any of the foregoing, with a zinc reagent selected from EtZn, MeZn, and PhZn, and a tertiary alcohol having the structure:

[0053] [ka]

[0054] wherein each Ar can independently be unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl, and when Ar is substituted phenyl or naphthyl, the phenyl or naphthyl can independently be halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 The method may comprise combining BF3·OEt2 with a chiral ligand, which may be substituted with one or more substituents selected from alkoxy.

[0055] Optionally substituted phenyl ketones can have a variety of structures. For example, the optionally substituted phenyl ketones can be bicyclic, having a carbonyl bonded to a ring carbon of a 4- to 8-membered monocyclic hydrocarbon ring, the hydrocarbon ring fused to a phenyl group, and one to two carbons of the hydrocarbon ring can be independently replaced with a heteroatom selected from O (oxygen) and S (sulfur). As another example, the optionally substituted phenyl ketones can be monocyclic, and an acyl can be bonded to the phenyl group.

[0056] In some embodiments, the optionally substituted phenyl ketone can have a structure selected from a compound of formula (A) and a compound of formula (B):

[0057] [ka]

[0058] wherein m1 can be 0, 1, 2, 3, or 4; n1 can be 0, 1, 2, 3, 4, or 5; m2 can be 1 or 2; and X 1a can be -CH2-, and X 2a can be —CH—, —CH(CH)—, —C(CH)—, or O (oxygen), and each R 1a and each R 1b are independently halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 alkoxy, and R 2b is the unsubstituted C 1~4 Non-limiting examples of optionally substituted ketones include:

[0059] [ka]

[0060] [ka]

[0061] Examples include:

[0062] Various optionally substituted pyridinyl ketones can also be used in the methods described herein. As described herein, the optionally substituted pyridinyl ketones can be monocyclic or bicyclic. When the optionally substituted pyridinyl ketone is bicyclic, the carbonyl can be bonded to a ring carbon of a 4- to 8-membered monocyclic hydrocarbon ring, and the carbonyl can be bonded to a ring carbon of a 4- to 8-membered monocyclic hydrocarbon ring. The hydrogen ring may have 1 to 2 ring carbons independently replaced with heteroatoms selected from O (oxygen) and S (sulfur), and the hydrocarbon ring is fused to a pyridinyl group. When the optionally substituted pyridinyl ketone is monocyclic, an acyl group may be added to the pyridinyl group.

[0063] In some embodiments, the optionally substituted pyridinyl ketone can have a structure selected from a compound of formula (G), a compound of formula (H), a compound of formula (J), a compound of formula (K), a compound of formula (L), and a compound of formula (M):

[0064] [ka]

[0065] wherein t1, u1, and v1 can independently be 0, 1, 2, or 3; w1, x1, and y1 can independently be 0, 1, 2, 3, or 4; t2, u2, and v2 can independently be 1 or 2; and X 1g , X 1h , and X 1j may each be -CH2-, and X 2g , X 2h , and X 2j may independently be -CH-, -CH(CH)-, -C(CH)-, or O; R 1g , R 1h , R 1j , R 1k , R 1l , and R 1m are independently halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4alkoxy, and R 2k , R 2l , and R 2m are independently unsubstituted C 1~4 A non-limiting list of optionally substituted pyridinyl ketones includes the following:

[0066] [ka]

[0067] [ka]

[0068] [ka]

[0069] Examples include:

[0070] As described herein, optionally substituted phenyl ketones and / or optionally substituted pyridinyl ketones can be used to provide tertiary alcohols. For example, optionally substituted phenyl ketones and / or optionally substituted pyridinyl ketones can be used in the methods described herein to provide chiral tertiary alcohols in high yield and / or high enantiomeric purity. Examples of tertiary alcohols that can be obtained by the methods described herein include, but are not limited to, compounds of formula (A1) and (B1):

[0071] [ka]

[0072] wherein m3 can be 0, 1, 2, 3, or 4; n2 can be 0, 1, 2, 3, 4, or 5; m4 can be 1 or 2; and X 3a can be -CH2-, and X 4acan be —CH—, —CH(CH)—, —C(CH)—, or O (oxygen), and each R 2a and each R 3b are independently halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 alkoxy, and R 4b is the unsubstituted C 1~4 R may be alkyl; 3a and R 5b can be independently -CH3, -CH2CH3, or -Ph. Additional examples of tertiary alcohols that may be obtained by the methods described herein include, but are not limited to, having a structure selected from a compound of formula (G1), a compound of formula (H1), a compound of formula (J1), a compound of formula (K1), a compound of formula (L1), and a compound of formula (M1):

[0073] [ka]

[0074] wherein t3, u3, and v3 can independently be 0, 1, 2, or 3; w2, x2, and y2 can independently be 0, 1, 2, 3, or 4; t4, u4, and v4 can independently be 1 or 2; and X 3g , X 3h , and X 3j may each be -CH2-, and X 4g , X 4h , and X 4j can independently be —CH—, —CH(CH)—, —C(CH)—, or O (oxygen), and R 2g , R 2h , R 2j , R 3k , R 3l , and R 3m are independently halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 alkoxy, and R 4k , R 4l , and R 4m are independently unsubstituted C 1~4 R 3g , R3h , R 3j , R 5k , R 5l , and R 5m can independently be -CH3, -CH2CH3, or -Ph.

[0075] Various structures of tertiary alcohols that can be obtained by the methods described herein include the following:

[0076] [ka]

[0077] [ka]

[0078] [ka]

[0079] [ka]

[0080] [ka]

[0081] In particular, the following compounds are included: 3a , R 3g , R 3h , R 3j , R 5b , R 5k , R 5l , and / or R 5m are described herein. In some embodiments, including those in this paragraph, R 3a , R 3g , R 3h , R 3j , R 5b , R 5k , R 5l , and / or R 5mis the unsubstituted C 1~4 In some embodiments, including those in this paragraph, R 3a , R 3g , R 3h , R 3j , R 5b , R 5k , R 5l , and / or R 5m can be —CH2CH3.

[0082] structure

[0083] [ka]

[0084] wherein R 1 can be -CH3, -CH2CH3, -CH(CH3)2, or -C(CH3)3, and R 2 can be H or R 1 and R 2 However, each R 1 and R 2 may be taken together with the carbon to which Ar is attached to form an unsubstituted cyclohexyl ring, and each Ar may independently be unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl, and when Ar is substituted phenyl or substituted naphthyl, the phenyl or naphthyl may independently be selected from the group consisting of halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 Chiral ligands may be used in the methods described herein, wherein the chiral ligand is substituted with one or more substituents selected from alkoxy, and b may be 1 or 2. In some embodiments, the chiral ligand is

[0085] [ka]

[0086] wherein each Ar can be unsubstituted phenyl. In other embodiments, the chiral ligand has the structure

[0087] [ka]

[0088] wherein each Ar is independently selected from halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 In yet other embodiments, the chiral ligand may have the structure

[0089] [ka]

[0090] In still other embodiments, the chiral ligand has the structure

[0091] [ka]

[0092] wherein each Ar is independently selected from halogen, unsubstituted C 1~4 Alkyl and unsubstituted C 1~4 It may be a substituted naphthyl substituted with one or more substituents selected from the group consisting of alkoxy.

[0093] Substituent R 1 is C 1~4 C can be a variety of saturated hydrocarbons, such as alkyl. 1~4 The alkyl can be linear or branched. In some embodiments, R 1 can be methyl (-CH). In other embodiments, R 1 can be ethyl (-CH2CH3). In still other embodiments, R 1 can be isopropyl (-CH(CH)). In still yet other embodiments, R 1 can be tert-butyl (-C(CH3)3). 1~4Alkyl includes n-propyl, n-butyl, sec-butyl, and iso-butyl. R 1 But C 1~4 If it is alkyl, R 2 can be hydrogen. A saturated carbocyclic ring is 1 and R 2 can be formed by taking each R 1 and R 2 In some embodiments, R 1 and R 2 is each R 1 and R 2 may be taken together with the carbon to which R is attached to form an unsubstituted cyclohexyl ring. 1 But C 1~4 If it is alkyl, R 1 It is understood that the carbon to which is attached may be a chiral center. For example, a chiral ligand may have the structure

[0094] [ka]

[0095] Similarly, R 1 and R 2 However, each R 1 and R 2 When R is taken together with the carbon to which it is attached to form an unsubstituted cyclohexyl ring, R 1 and R 2 Each of the carbons to which is attached can be a chiral center.

[0096] [ka]

[0097] may have:

[0098] Suitable chiral ligands include:

[0099] [ka]

[0100] In some embodiments, the chiral ligand has the structure

[0101] [ka]

[0102] may have:

[0103] Obtaining tertiary alcohols in high yield and / or high enantiomeric purity can be advantageous for preparing synthetic versions of natural products and / or pharmaceutical compounds. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥30%. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥40%. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥50%. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥60%. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥70%. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥80%. In some embodiments, tertiary alcohols can be obtained using the methods described herein with an enantiomeric purity of ≥90%. In some embodiments, tertiary alcohols can be obtained in ≧95% enantiomeric purity using the methods described herein.

[0104] In some embodiments, including those in the preceding paragraph, tertiary alcohols may be obtained in a yield of ≥ 50% using the methods described herein. In some embodiments, including those in the preceding paragraph, tertiary alcohols may be obtained in a yield of ≥ 60% using the methods described herein. In some embodiments, including those in the preceding paragraph, tertiary alcohols may be obtained in a yield of ≥ 70% using the methods described herein. In some embodiments, including those in the preceding paragraph, tertiary alcohols may be obtained in a yield of ≥ 80% using the methods described herein. In some embodiments, including those in the preceding paragraph, tertiary alcohols may be obtained in a yield of ≥ 90% using the methods described herein.

[0105] A variety of solvents can be used in the methods described herein. For example, the solvent can be hexane, heptane, dichloromethane, toluene, and combinations thereof. A variety of temperatures can also be used in the methods described herein. In some embodiments, the methods described herein can be carried out at a temperature ranging from about -78°C to about 25°C. In some embodiments, the methods described herein can be carried out at a temperature ranging from about -50°C to about 25°C.

[0106] The methods described herein may utilize BF3·OEt2. BF3·OEt2 may function as a Lewis acid. In some embodiments, the amount of BF3·OEt2 used in the methods described herein may be present in a catalytic amount. For example, the amount of BF3·OEt2 used in the methods described herein may range from about 0.05 equivalents to about 1 equivalent per equivalent of optionally substituted phenyl ketone or optionally substituted pyridinyl ketone (BF3·OEt2:optionally substituted phenyl ketone, or BF3·OEt2:optionally substituted pyridinyl ketone). In some embodiments, the amount of BF3·OEt2 used in the methods described herein can range from about 0.08 equivalents to about 0.25 equivalents per equivalent of optionally substituted phenyl ketone or optionally substituted pyridinyl ketone (BF3·OEt2:optionally substituted phenyl ketone, or BF3·OEt2:optionally substituted pyridinyl ketone). In some embodiments, the amount of BF3·OEt2 used in the methods described herein can be about 0.1 equivalents per equivalent of optionally substituted phenyl ketone or optionally substituted pyridinyl ketone.

[0107] Some examples of tertiary alcohols that may be obtained from the methods described herein include the following:

[0108] [ka]

[0109] These include, but are not limited to:

[0110] Additional examples of tertiary alcohols that may be obtained by the methods described herein include, but are not limited to, compounds having the structure of formula (G1-a):

[0111] [ka]

[0112] wherein X can be Cl, Br, or I. In some embodiments, X can be Cl (chlorine). In some embodiments, X can be Br (bromine). In some embodiments, X can be I (iodine).

[0113] The compound of Formula (G1-a) where X is Cl may be obtained in various polymorphs, such as Form A and Form B. Various methods may be used to characterize the polymorphs of the compound of Formula (G1-a) where X is Cl. In some embodiments, Form A may be characterized by one or more peaks in an X-ray powder diffraction pattern, the one or more peaks may be selected from a peak in the range of about 15.7 degrees 2θ to about 16.7 degrees 2θ, a peak in the range of about 20.5 degrees 2θ to about 21.5 degrees 2θ, a peak in the range of about 23.7 degrees 2θ to about 24.7 degrees 2θ, and a peak in the range of about 26.0 degrees 2θ to about 27.0 degrees 2θ ... In some embodiments, Form B may be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks may be selected from about 16.2 degrees 2θ ± 0.2 degrees 2θ, about 21.0 degrees 2θ ± 0.2 degrees 2θ, about 24.2 degrees 2θ ± 0.2 degrees 2θ, and about 26.5 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, Form B may be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks may be selected from a peak in the range of about 13.5 degrees 2θ to about 14.5 degrees 2θ, a peak in the range of about 17.1 degrees 2θ to about 18.1 degrees 2θ, a peak in the range of about 19.6 degrees 2θ to about 20.6 degrees 2θ, a peak in the range of about 24.3 degrees 2θ to about 25.3 degrees 2θ, and a peak in the range of about 25.0 degrees 2θ to about 26.0 degrees 2θ. In some embodiments, Form B may be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks may be selected from about 14.0 degrees 2θ ± 0.2 degrees 2θ, about 17.6 degrees 2θ ± 0.2 degrees 2θ, about 20.1 degrees 2θ ± 0.2 degrees 2θ, about 24.8 degrees 2θ ± 0.2 degrees 2θ, and about 25.5 degrees 2θ ± 0.2 degrees 2θ. In some embodiments, Form A may be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks may be selected from the peaks in Table 5. In some embodiments, Form B may be characterized by one or more peaks in an X-ray powder diffraction pattern, wherein the one or more peaks may be selected from the peaks in Table 6. In some embodiments, Form A may exhibit an X-ray powder diffraction pattern as shown in FIG. 1. In some embodiments, Form B may exhibit an X-ray powder diffraction pattern as shown in FIG. 2. All XRPD patterns provided herein are measured on the degree 2-theta (2θ) scale. Because the numerical values ​​of peaks in X-ray powder diffraction patterns can vary from instrument to instrument or sample to sample, it is understood that quoted numerical values ​​should not be construed as absolute, but rather as being subject to an allowable variability, such as ±0.5 degrees two-theta (2θ) or more. For example, in some embodiments, XRPD peak position values ​​can vary by up to ±0.2 degrees 2θ while still describing a particular XRPD peak.

[0114] The methods described herein for preparing tertiary alcohols include:

[0115] [ka]

[0116] The method described herein may include the use of NaHSO3 on a tertiary alcohol, such as, where the use of NaHSO3 may increase the enantiomeric excess (ee%) of the tertiary alcohol compared to the ee% before the use of NaHSO3.

[0117] [ka]

[0118] The recrystallization may include recrystallization of a tertiary alcohol, including, where the recrystallization may increase the enantiomeric excess (ee%) of the tertiary alcohol compared to the ee% before recrystallization. In some embodiments, the recrystallization may utilize hexane. In other embodiments, the recrystallization may utilize heptane.

[0119] Use of the compound

[0120] Those skilled in the art will recognize that the compounds described herein can be used in a variety of ways to produce compounds of interest. In some embodiments, the compounds described herein can be used to produce compounds that act as WEE1 inhibitors, as WEE1 has been found to be overexpressed in various cancer types. Examples of WEE1 inhibitors include those described in U.S. Patent Application Publication No. 2019 / 0129992, published September 12, 2019, which is incorporated herein by reference in its entirety for all purposes. Those skilled in the art will recognize that certain compounds described herein can be used as intermediates in the synthesis of WEE1 inhibitors. In some embodiments, compounds described herein, such as compounds of Formula (G1-a), can be used as intermediates in the synthesis of enantiomerically pure or substantially enantiomerically pure WEE1 inhibitors. [Example]

[0121] Further embodiments, which in no way limit the scope of the claims, are disclosed in more detail in the examples below.

[0122] Example A

[0123] (R)—N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (63.8 mg, 0.179 mmol) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, and filled with N (3×), then cooled to −50° C. 1 M diethylzinc in hexanes (2.39 mL, 2.39 mmol) was added at −50° C., and the mixture was stirred for 30 minutes. A Lewis acid (0.1 equiv., Table 1) was added, and the mixture was stirred at −50° C. for 30 minutes. 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (100 mg, 0.597 mmol) in DCM (2.5 mL) was added over 30 minutes via syringe pump (5 mL / h). The mixture was stirred at −50° C. for 5 hours and then warmed to room temperature (RT) overnight. The mixture was cooled to 0° C., and the reaction was slowly quenched with saturated NH4Cl (5 mL). The mixture was poured into a mixture of EtOAc (25 mL) and saturated NH4Cl (25 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried (Na2SO4). The crude residue was purified by column chromatography (SiO2, EtOAc:hexane) to give the alcohol listed below as Example 1. The enantiomeric purity was determined by chiral LCMS. As shown in Table 1, BF3·OEt2 showed the best yield and ee% compared to the other listed Lewis acids.

[0124] [ka]

[0125] [Table 1]

[0126] Example B

[0127] (R)-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (63.8 mg, 0.179 mmol) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, and backfilled with N (3x), then cooled to -78 °C. 1 M diethylzinc in hexane (2.98 mL, 2.98 mmol) was added at -78 °C, and the mixture was stirred for 30 min. To this mixture was added BF OEt via syringe (see Table 2), and the mixture was stirred at -78 °C for 30 min. 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (100 mg, 0.597 mmol) in DCM (2.5 mL) was added over 30 min (5 mL / h) using a syringe pump at −78° C. The mixture was stirred at −78° C. for 2 h, slowly warmed to room temperature, and then stirred for 20 h. The mixture was cooled to 0° C., and the reaction was quenched by the slow addition of saturated NH4Cl (5 mL) with stirring. The reaction was poured into a mixture of EtOAc (20 mL) and saturated NH4Cl (20 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried (Na2SO4). The solvent was evaporated, and the crude residue was analyzed by chiral LCMS. As shown in Table 2, 0.1 equiv of BF3·OEt2 provided the highest ee%.

[0128] [ka]

[0129] [Table 2]

[0130] Example C

[0131] The ligand (0.3 equiv., Table 3) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, and backfilled with N (3x), then cooled to -50 °C. 1 M diethylzinc in hexane (2.39 mL, 2.39 mmol) was added at -50 °C, and the mixture was stirred for 30 min. To this mixture was added 100 μL of BF3·OEt2 solution [prepared by diluting 70 μL of BF3·OEt2 (0.007 mL, 0.060 mmol) with 930 μL of DCM], and the mixture was stirred at -50 °C for 30 min. 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (100 mg, 0.597 mmol) in DCM (2.5 mL) was added over 30 min (5 mL / h) using a syringe pump at −50° C. The mixture was stirred at −50° C. for 5 h, slowly warmed to room temperature, and then stirred for 20 h. The mixture was cooled to 0° C., and the reaction was quenched by the slow addition of saturated NH4Cl (5 mL) with stirring. The reaction was poured into a mixture of EtOAc (20 mL) and saturated NH4Cl (20 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried (Na2SO4). The solvent was evaporated, and the crude residue was analyzed by chiral LCMS. Ligand 1 provides a high ee% and ≦10% survival of the starting ketone. Ligands 4 and 5 provide a high ee% and ≦20% survival of the starting ketone.

[0132] [ka]

[0133] [Table 3]

[0134] For each entry, the solvent was DCM.

[0135] Ena1 has the structure

[0136] [ka]

[0137] and Ena2 has the structure

[0138] [ka]

[0139] It has.

[0140] General Procedure for Examples 1-21

[0141] (R)-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (0.160 g, 0.450 mmol) was added to a flame-dried 40 mL vial. The vial was sealed with a septum cap, evacuated, and backfilled with N (3x), then cooled to -50 °C. 1 M diethylzinc in hexanes (6.00 mL, 6.00 mmol) was added, and the mixture was stirred for 30 min. BF3·OEt2 solution [prepared by diluting 100 μL of 190 μL of BF3·OEt2 (0.019 mL, 0.150 mmol) with 810 μL of DCM] was added to the reaction, and the mixture was stirred at -50 °C for 30 min. The ketone (1.5 mmol) in DCM (2.5 mL) was added via syringe pump over 30 min. The mixture was stirred at -50 °C for 5 h and then warmed to RT overnight. The mixture was cooled to 0 °C, and the reaction was slowly quenched with saturated NH4Cl (5 mL). The mixture was poured into a mixture of EtOAc (25 mL) and saturated NH4Cl (25 mL) with stirring. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (1 × 75 mL) and dried (Na2SO4). The crude residue was purified by column chromatography (SiO2, EtOAc:hexanes) to give the desired alcohol. Enantiomeric purity was determined by chiral LCMS, HPLC, or chiral SFC. The absolute stereochemistry for Example 1 was determined by X-ray crystallography of a later compound in the synthesis provided in WO 2014 / 02390. The absolute stereochemistry of Examples 2-21 is arbitrarily assigned.

[0142] Example 1 (R)-2-Chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0143] [ka]

[0144] Example 1: 908 mg, (77%), colorless oil. 1H NMR (400MHz, CDCl3) δ7.50(d, J=7.9Hz, 1H), 7.17(d, J=8.1Hz, 1H), 2.99-2.90(m, 1H), 2.82-2.71(m, 1H), 2.33(ddd, J=4.3, 8 .7, 13.4Hz, 1H), 2.19(ddd, J=6.8, 9.0, 13.5Hz, 1H), 2.04-1.89(m, 1H), 1.81(qd, J=7.3, 14.1Hz, 1H), 0.94(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ166.90, 150.07, 135.67, 134.94, 123.10, 81.98, 36.03, 32.37, 26.47, 8.13. LCMS(APCI)m / z198.1[M+H] + 97% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 x 150) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 1 eluted as peak 1 (t1 = 8.16 min), and the enantiomer eluted as peak 2 (t1 = 8.54 min). As provided in Patent Document 1, the compound of Example 1 can be used to prepare compounds that have been shown to inhibit the activity of WEE1 in cells and therefore may be effective as anticancer agents.

[0145] Example 2 (R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0146] [ka]

[0147] Example 2: 235 mg (65%) colorless oil. 1H NMR (400MHz, CDCl3) δ7.41(d, J=7.9Hz, 1H), 7.32(d, J=7.9Hz, 1H), 2.98-2.89(m, 1H), 2.80-2.71(m, 1 H), 2.36-2.29(m, 2H), 2.22-2.21(m, 1H), 2.02-1.92(m, 1H), 1.86-1.76(m, 1H), 0.95(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ167.65, 140.74, 135.51, 135.27, 126.89, 82.02, 35.95, 32.49, 26.56, 8.16. LCMS(APCI)m / z242.7[M+H] + 96.4% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 2 eluted as peak 1 (t = 8.73 min) and the enantiomer eluted as peak 2 (t = 9.17 min).

[0148] Example 3 (R)-7-Ethyl-2-iodo-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0149] [ka]

[0150] Example 3: 114 mg (32%), colorless oil. 1 H NMR (400 MHz, CDCl 3) δ7.54(d, J=7.8Hz, 1H), 7.20(d, J=7.8Hz, 1H), 2.96-2.87(m, 1H), 2.78-2.68(m, 1H), 2.42(brs, 1H), 2.29(ddd, J=4 .2, 8.7, 13.3Hz, 1H), 2.15(ddd, J=7.0, 9.0, 13.5Hz, 1H), 2.04-1.87(m, 1H), 1.83-1.73(m, 1H), 0.94(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ168.53, 135.66, 134.78, 133.50, 115.94, 81.93, 35.75, 32.38, 26.58, 8.13. LCMS(APCI)m / z290.0[M+H] + 92% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 3 eluted as peak 1 (t = 9.63 min) and the enantiomer eluted as peak 2 (t = 10.09 min).

[0151] Example 4 (R)-7-Ethyl-2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0152] [ka]

[0153] Example 4: 80 mg (27%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.43(d, J=8.3Hz, 1H), 6.60(d, J=8.3Hz, 1H), 3.94(s, 3H), 2.88(ddd, J=3.9, 9.0, 15.7Hz, 1H), 2.71(td, J=7. 7, 15.5Hz, 1H), 2.33(ddd, J=4.0, 8.3, 13.4Hz, 2H), 2.23-2.10(m, 1H), 2.00-1.87(m, 1H), 1.84-1.74(m, 1H), 0.96(t, J=7.5Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.38, 162.83, 135.63, 127.84, 109.68, 82.16, 53.41, 36.64, 32.48, 26.31, 8.22. LCMS (APCI) m / z 194.0 [M+H]. 96.7% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® IG-3 column (4.6 × 150 mm) eluted with 10% (0.5% DEA in methanol) at 30 °C and 3 g / min. Under these conditions, the enantiomer eluted as peak 1 (t = 1.45 min) and Example 4 eluted as peak 2 (t = 1.83 min).

[0154] Example 5 (R)-7-Ethyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0155] [ka]

[0156] Example 5: 55 mg (23%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.42 (d, J=7.8Hz, 1H), 6.99 (d, J=7.8Hz, 1H), 2.92(ddd, J=3.8, 9.1, 16.1Hz, 1H), 2.81-2.69(m, 1H), 2.66(s, 1H), 2.56-2.53(m, 3H), 2.33(ddd, J=3.9, 8.3, 13.4Hz, 1H), 2.15(ddd, J=7.3, 9.0, 13.4Hz, 1H), 2.05-1.89(m, 1H), 1.86-1.74(m, 1H), 0.95(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ165.47, 156.77, 133.19, 132.87, 122.24, 82.02, 36.34, 32.51, 26.64, 23.83, 8.24. LCMS(APCI)m / z178.0[M+H] +93.0% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® IF-3 column (4.6 × 150 mm) eluted with 15% (0.5% DEA in methanol) at 30 °C and 3 g / min. Under these conditions, the enantiomer eluted as peak 1 (t = 1.23 min) and Example 5 as peak 2 (t = 1.40 min).

[0157] Example 6 (R)-7-Ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0158] [ka]

[0159] Example 6: 47 mg (19%), colorless oil. 1 H NMR (400MHz, CDCl3) δ8.47-8.42(m, 1H), 7.55(dd, J=1.2, 7.6Hz, 1H), 7.14(dd, J=4.9, 7.6Hz, 1H), 3.04-2.93(m, 1H) , 2.86-2.76(m, 1H), 2.37-2.30(m, 1H), 2.30-2.11(m, 1H), 2.05-1.91(m, 1H), 1.91-1.79(m, 1H), 0.99-0.93(m, 3H). 13 C NMR (101MHz, CDCl3) δ166.14, 147.96, 136.21, 133.14, 122.64, 82.04, 36.10, 32.55, 27.03, 8.30. LCMS(APCI)m / z164.6[M+H] + 80% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® AD-3 column (4.6 × 150 mm) eluted with 10% (0.5% DEA in methanol) at 30 °C and 3 g / min. Under these conditions, the enantiomer eluted as peak 1 (t = 1.71 min) and Example 6 as peak 2 (t = 2.44 min).

[0160] Example 7 (R)-2-Chloro-7-ethyl-4-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0161] [ka]

[0162] Example 7: 219 mg (69%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.01 (s, 1H), 2.87 (ddd, J=4.3, 9.1, 16.4Hz, 1H), 2.71-2.62(m, 1H), 2.41-2.30(m, 1H), 2.26(s, 3H), 2.24-2.13(m, 1H), 2.04-1.88(m, 1H), 1.85-1.71(m, 1H), 0.92(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ166.00, 150.35, 147.14, 134.41, 123.67, 82.24, 35.51, 32.62, 25.20, 18.47, 8.24. LCMS(APCI)m / z212.7[M+H] + 92% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 7 eluted as peak 1 (t = 9.43 min) and the enantiomer eluted as peak 2 (t = 9.77 min).

[0163] Example 8 (R)-2-Bromo-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0164] [ka]

[0165] Example 8: 175 mg (60%), colorless oil. 1H NMR (400MHz, CDCl3) δ7.35 (d, J=7.8Hz, 1H), 7.11 (d, J=8.1Hz, 1H), 3.04 (brs, 1H) , 2.84-2.66(m, 2H), 2.12-1.96(m, 1H), 1.96-1.62(m, 5H), 0.93(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ161.65, 148.44, 139.73, 130.02, 122.66, 72.58, 34.22, 32.09, 28.07, 18.98, 7.68. LCMS(APCI)m / z212.1[M+H] + 88% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 8 eluted as peak 1 (t = 10.41 min) and the enantiomer eluted as peak 2 (t = 10.75 min).

[0166] Example 9 (R)-2-Bromo-8-ethyl-5,6,7,8-tetrahydroquinolin-8-ol

[0167] [ka]

[0168] Example 9: 193 mg (50%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.26(s, 2H), 3.06(s, 1H), 2.81-2.67(m, 2H), 2.13-2.03(m, 1H), 1.95-1.75(m, 5H), 0.94(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ=162.44, 139.46, 138.92, 130.42, 126.43, 72.59, 34.25, 32.04, 28.11, 18.93, 7.67. LCMS(APCI)m / z256.7[M+H] + 85% ee. Chiral analysis was performed using Lux Cellulose-4 column. Analysis was performed by LCMS on a column (4.6 x 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 9 eluted as peak 1 (t = 10.9 min) and the enantiomer eluted as peak 2 (t = 11.3 min).

[0169] Example 10 (R)-8-Ethyl-2-iodo-5,6,7,8-tetrahydroquinolin-8-ol

[0170] [ka]

[0171] Example 10: 298 mg (66%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.52-7.46(m, 1H), 7.05-6.99(m, 1H), 3.15(s, 1H), 2.79-2.65(m, 2H), 2.17-1.71(m, 6H), 0.93(t, J=7.4Hz, 3H). LCMS(APCI)m / z304.0[M+H] + 71% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 10 eluted as peak 1 (t = 11.79 min) and the enantiomer eluted as peak 2 (t = 12.12 min).

[0172] Example 11 (R)-8-Ethyl-2-methyl-5,6,7,8-tetrahydroquinolin-8-ol

[0173] [ka]

[0174] Example 11: 117 mg (41%), colorless oil. 1H NMR (400MHz, CDCl3) δ7.27(d, J=8.0Hz, 1H), 6.94(d, J=7.8Hz, 1H), 3.76(s, 1H), 2.81- 2.69(m, 2H), 2.49(s, 3H), 2.20-2.10(m, 1H), 1.93-1.73(m, 5H), 0.94(t, J=7.4Hz, 3H). 13 C NMR (101MHz, CDCl3) δ160.03, 155.16, 136.98, 127.35, 121.61, 72.29, 34.24, 32.30, 27.91, 23.93, 19.16, 7.67. LCMS(APCI)m / z192.0[M+H] + 84.6% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® IG-3 column (4.6 × 150 mm) eluted with 10% (0.5% DEA in methanol) at 30 °C and 3 g / min. Under these conditions, the enantiomer eluted as peak 1 (t = 1.98 min) and Example 11 eluted as peak 2 (t = 2.46 min).

[0175] Example 12 (R)-8-Ethyl-2-methoxy-5,6,7,8-tetrahydroquinolin-8-ol

[0176] [ka]

[0177] Example 12: 150 mg (48%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.29(d, J=8.4Hz, 1H), 6.57(d, J=8.3Hz, 1H), 3.92(s, 3H), 3.28( s, 1H), 2.76-2.63 (m, 2H), 2.14-2.04 (m, 1H), 1.92-1.73 (m, 5H), 0.94 (t, J=7.5Hz, 3H). 13C NMR (101MHz, CDCl3) δ162.05, 157.15, 139.93, 123.13, 109.38, 72.46, 53.16, 34.21, 32.41, 27.59, 19.32, 7.83. LCMS(APCI)m / z208.0[M+H] + 90.0% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® AD-3 column (4.6 × 150 mm) eluted with 15% (0.5% DEA in methanol) at 30 °C and 3 g / min. Under these conditions, the enantiomer eluted as peak 1 (t = 1.31 min) and Example 12 as peak 2 (t = 1.47 min).

[0178] Example 13 (R)-8-Ethyl-5,6,7,8-tetrahydroquinolin-8-ol

[0179] [ka]

[0180] Example 13: 81 mg (30%), colorless oil. 1 H NMR (400MHz, CDCl3) δ8.40(d, J=4.8Hz, 1H), 7.40(d, J=7.7Hz, 1H), 7.10(dd, J=4.8, 7.7Hz, 1H) , 3.52(s, 1H), 2.87-2.74(m, 2H), 2.23-2.01(m, 1H), 1.99-1.75(m, 5H), 0.93(t, J=7.4Hz, 3H). 13 C NMR (101MHz, CDCl3) δ160.89, 146.51, 136.92, 131.21, 122.10, 72.53, 34.35, 32.43, 28.50, 19.06, 7.77. LCMS(APCI)m / z178.7[M+H] +74% ee. Chiral analysis was performed by chiral SFC on a CHIRALPAK® IG-3 column (4.6 × 150 mm) eluted with 15% (0.5% DEA in methanol) at 3 g / min. Under these conditions, Example 13 eluted as peak 1 (t = 2.35 min) and the enantiomer eluted as peak 2 (t = 3.07 min).

[0181] Example 14 (R)-6-chloro-4-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol

[0182] [ka]

[0183] Example 14: 122 mg (38%) colorless oil. 1 H NMR (400MHz, CDCl3) δ7.11(d, J=1.5Hz, 2H), 4.31-4.20(m, 2H), 2.52(brs, 1H), 2.20-2.01(m, 3H), 1.88(qd, J=7.4, 14.4Hz, 1H), 0.93(t, J=7.5Hz, 3H). LCMS(APCI)m / z214.1[M+H] + 79% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 14 eluted as peak 1 (t = 6.85 min) and the enantiomer eluted as peak 2 (t = 7.04 min).

[0184] Example 15 (S)-2-(6-chloropyridin-2-yl)butan-2-ol

[0185] [ka]

[0186] Example 15: 218 mg (78%), colorless oil.1 H NMR (400MHz, CDCl3) δ7.66(t, J=7.8Hz, 1H), 7.28-7.26(m, 1H), 7.22(dd, J=0.6, 7.8Hz, 1H), 1.88-1.66(m, 2H), 1.52(s, 3H), 0.77(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ166.60, 149.83, 139.42, 122.22, 117.76, 74.35, 35.90, 28.49, 8.03. LCMS(APCI)m / z186.1[M+H] + 40% ee. Chiral analysis was performed by chiral SFC on a CHIRALPAK IG-3 (4.6 x 150 mm) eluted with 15% (0.5% DEA in methanol) at 3 g / min. Under these conditions, Example 15 eluted as peak 1 (t = 1.25 min) and the enantiomer eluted as peak 2 (t = 1.51 min).

[0187] Example 16 (S)-2-(6-bromopyridin-2-yl)butan-2-ol

[0188] [ka]

[0189] Example 16: 229 mg (66%), colorless oil, 1 H NMR (400MHz, CDCl3) δ7.59-7.53(m, 1H), 7.38(dd, J=0.7, 7.8Hz, 1H), 7.31(dd, J =0.6, 7.7Hz, 1H), 4.19(s, 1H), 1.83(dq, J=1.5, 7.4Hz, 2H), 1.51(s, 3H), 0.78(t , J = 7.5 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ167.09, 140.40, 139.08, 126.00, 118.08, 74.28, 35.86, 28.42, 7.99. LCMS(APCI)m / z230.6[M+H] +84% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® IG-3 column (4.6 × 150 mm) eluted with 20% (0.5% DEA in methanol) at 30 °C and 3 g / min. Under these conditions, Example 16 eluted as peak 1 (t = 1.44 min) and the enantiomer eluted as peak 2 (t = 1.76 min).

[0190] Example 17 (S)-2-(6-fluoropyridin-2-yl)butan-2-ol

[0191] [ka]

[0192] Example 17: 111 mg (44%), colorless oil. 1 H NMR (400MHz, CDCl3) δ7.80(q, J=7.9Hz, 1H), 7.27-7.24(m, 1H), 6.82(dd, J=2.7, 8.1Hz, 1H), 1.89-1.80(m, 2H), 1.53(s, 3H), 0.78(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ165.09(d, J=10.3Hz), 162.42(d, J=241.4Hz), 141.72(d, J =7.3Hz), 116.40(d, J=4.4Hz), 107.06(d, J=35.9Hz), 74.38, 35.83, 28.31, 7.97. LCMS(APCI)m / z170.0[M+H] + 54% ee. Chiral analysis was performed by chiral SFC on a Chiralpak® IF-3 column (4.6 × 150 mm) eluted with 10% methanol at 3 g / min at 30° C. Under these conditions, Example 17 eluted as peak 1 (t = 1.13 min) and the enantiomer eluted as peak 2 (t = 1.31 min).

[0193] Example 18 (S)-2-(pyridin-2-yl)butan-2-ol

[0194] [ka]

[0195] Example 18: 116 mg (51%), colorless oil. 1 H NMR (400MHz, CDCl3) δ8.51 (td, J=0.8, 4.9Hz, 1H), 7.70 (dt, J=1.7, 7.7Hz, 1H), 7.31 (d, J=7.9Hz, 1H), 7 .19(ddd, J=1.0, 4.9, 7.5Hz, 1H), 5.17(brs, 1H), 1.90-1.55(m, 2H), 1.50(s, 3H), 0.73(t, J=7.4Hz, 3H). 13 C NMR (101MHz, CDCl3) δ164.79, 147.14, 136.89, 121.69, 119.23, 73.85, 36.02, 28.81, 7.97. LCMS(APCI)m / z152.6[M+H] + Chiral analysis was performed by chiral SFC on a CHIRALPAK AD-3 column (4.6 x 150 mm) eluted with 20% DEA in methanol (0.5% DEA in methanol) at 3 g / min. Under these conditions, Example 18 eluted as peak 1 (t1 = 1.17 min) and the enantiomer eluted as peak 2 (t2 = 1.32 min).

[0196] Example 19 (S)-2-(2-chloropyridin-4-yl)butan-2-ol

[0197] [ka]

[0198] Example 19: 139 mg (50%), colorless oil. 1H NMR (400MHz, CDCl3) δ8.33(d, J=5.3Hz, 1H), 7.41(d, J=1.6Hz, 1H), 7.26(s, 1H), 7 .24(dd, J=1.6, 5.3Hz, 1H), 1.88-1.74(m, 2H), 1.53(s, 3H), 0.81(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ160.52, 151.68, 149.26, 120.97, 119.20, 74.19, 36.18, 29.34, 7.89. LCMS(APCI)m / z186.1[M+H] + 75% ee. Chiral analysis was performed by chiral HPLC on a CHIRALPAK IF column (4.6 x 250 mm) using ethanol and n-hexane as eluents at 1.0 mL / min. Under these conditions, Example 19 eluted as peak 1 (t = 9.78 min) and the enantiomer eluted as peak 2 (t = 10.28 min).

[0199] Example 20 (S)-2-(2-Bromopyridin-4-yl)butan-2-ol

[0200] [ka]

[0201] Example 20: 170 mg (49%), white solid. 1 H NMR (400MHz, CDCl3) δ8.31(d, J=5.3Hz, 1H), 7.58(d, J=1.6Hz, 1H), 7.28(dd, J=1.6, 5.3Hz, 1H), 1.87-1.76(m, 2H), 1.53(s, 3H), 0.82(t, J=7.5Hz, 3H). 13 C NMR (101MHz, CDCl3) δ160.06, 149.82, 142.52, 124.74, 119.54, 74.19, 36.21, 29.42, 7.91. LCMS(APCI)m / z230.6[M+H] +80% ee. Chiral analysis was performed by chiral HPLC on a Lux Cellulose-4 column (4.6 x 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 20 eluted as peak 1 (t = 6.56 min) and the enantiomer eluted as peak 2 (t = 6.75 min).

[0202] Example 21 (R)-2-Bromo-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0203] [ka]

[0204] Example 21: This reaction was carried out according to the general procedure using 10% Me2Zn instead of Et2Zn. 54 mg (16%), white solid. 1 H NMR (400MHz, CDCl3) δ7.42(td, J=0.9, 7.9Hz, 1H), 7.33(d, J=7.9Hz, 1H), 2.99-2.90(m, 1H), 2.81-2.69(m, 1H), 2.34-2.18(m, 2H), 1.59(s, 3H). 13 C NMR (101MHz, CDCl3) δ168.09, 140.69, 135.66, 134.61, 126.89, 79.27, 39.27, 26.69, 26.33. LCMS(APCI)m / z227.9[M+H] + 94% ee. Chiral analysis was performed by LCMS on a Lux Cellulose-4 column (4.6 × 150 mm) eluted with CHCN / water 0.1% formic acid at 1.2 mL / min. Under these conditions, Example 21 eluted as peak 1 (t = 7.49 min) and the enantiomer eluted as peak 2 (t = 7.78 min).

[0205] [Table 4-1]

[0206] [Table 4-2]

[0207] As shown in Table 4, the methods described herein can be used to prepare tertiary alcohols in high yield, high enantiomeric purity, and / or both. Additionally, as described herein, tertiary alcohols can be used to prepare synthetic versions of natural products and pharmaceuticals.

[0208] Example D Scale-up synthesis of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol

[0209] [ka]

[0210] (R)-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (16.0 kg, 44.9 mol) was suspended in n-heptane (125 L, 5V) in a 1000 L reactor under N2. The suspension was heated to -65 °C. The mixture was cooled to an internal temperature of -65°C. 2.0 M diethylzinc (265 kg, 597 mol) in hexanes was added via a peristaltic pump at an average rate of 100 L / h. The total addition time was 3 h with a target internal temperature of -60 ± 5°C. The solution was then stirred at -65°C for 45 min. BF3·OEt2 (2.13 kg, 14.9 mol) was added over 10 min, and the mixture was stirred at -65°C for 60 min. 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (25.0 kg, 149 mol) in DCM (250 L, 10 V) was added via a peristaltic pump over 3 h. The internal temperature was maintained at -65 ± 5°C. The solution was stirred at -65°C for 1 h. The temperature was allowed to rise slowly to 14°C over 13 h. The mixture was transferred to another vessel containing saturated NH4Cl (20% w / w, 125 L, 5V) initially cooled to 0 °C. The internal temperature of the quench was maintained at 10-25 °C. The mixture was filtered, and the residue was washed with MTBE. The aqueous phase was separated and extracted with MTBE (62.5 L, 2.5 V). 125 L of NaHSO3 (1% w / w, 5 V) was added to the combined organic layers. The mixture was stirred for 30 minutes and then separated. Silica gel (30 kg, 1.2 wt) and activated carbon (2.5 kg) were added to the organic layer. The mixture was stirred for 60 minutes and then filtered. The filter cake was washed with MTBE (200 L, 8 V). The filtrate was concentrated. Recrystallization was performed as follows: (1) the residue was dissolved in n-heptane (100 L, 4V), (2) the mixture was heated to 60°C and then slowly cooled to 30°C, (3) seed crystals of (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (1 wt%) were added, (4) the mixture was slowly cooled to 10°C and stirred at that temperature for 1 hour. The solid was collected by filtration and then triturated with 125 L of NaHSO (1% w / w, 5V). The slurry was stirred for 1 hour and then collected by filtration. The filter cake was washed with water (125 L, 5 V) and dried under a stream of N for 15 h to give (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol (22.4 kg, 76% yield, 97.3% ee) as a white solid. 1H NMR (400MHz, CDCl3) δ7.50(d, J=7.9Hz, 1H), 7.17(d, J=8.1Hz, 1H), 2.99-2.90(m, 1H), 2.82-2.71(m, 1H), 2.33(ddd, J=4.3, 8 .7, 13.4Hz, 1H), 2.19(ddd, J=6.8, 9.0, 13.5Hz, 1H), 2.04-1.89(m, 1H), 1.81(qd, J=7.3, 14.1Hz, 1H), 0.94(t, J=7.5Hz, 3H), 13 C NMR (101MHz, CDCl3) δ=166.90, 150.07, 135.67, 134.94, 123.10, 81.98, 36.03, 32.37, 26.47, 8.13. LCMS(APCI)198.1[M+H] + .

[0211] Example E (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol Form A

[0212] (R)-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (6.38 kg, 17.9 mol) was suspended in n-heptane (32 L, 3.2 V) in a reaction vessel under N. The suspension was cooled to an internal temperature of -65 °C. 1.0 M diethylzinc in heptane (238.7 L, 238.7 mol) was added via a peristaltic pump over 2 h. The internal temperature was maintained between -48 °C and -55 °C. The solution was then stirred at -65 °C for 45 min. BF OEt (847 g, 5.97 mol) was added over 15 min, and the mixture was stirred at -65 °C for 60 min. 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (10 kg, 59.7 mol) in DCM (100 L, 10 V) was added via peristaltic pump over 2 h. The internal temperature was maintained at -65±5°C. The solution was stirred at -65°C for 4 h. The temperature was allowed to rise slowly to 20°C over 24 h. The mixture was transferred to another vessel containing saturated NH4Cl (100 L, 10 V) initially cooled to -5°C. Citric acid was added to the mixture. The internal temperature of the flask was maintained at 10-25°C. The mixture was stirred for 30 min and filtered. The residue was washed with DCM (25 L, 2.5 V) and the layers were separated. The organic phase was washed with water (50 L). The aqueous phase was extracted with DCM (50 L, 5 V). The combined organic layers were concentrated. The crude residue was purified by column chromatography (SiO2) using the following petroleum ether:ethyl acetate gradient: (10:1, 200 L), (5:1, 800 L), (1.5:1, 200 L). The eluent was concentrated. The residue was diluted with heptane (10 L, 1 V) and the mixture was heated to 60°C. The mixture was slowly cooled to 30°C and seed crystals (1 wt%) were added. The slurry was cooled to 10°C and stirred for 1 h. The solid was collected by filtration and dried under a stream of N to give (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol Form A (7 kg, 59% yield, 92.1% ee). The XRPD pattern of Form A is provided in Figure 1, and a partial listing of the XRPD peaks is provided in Table 5.

[0213] [Table 5]

[0214] Example F (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol Form B

[0215] (R)-N-(3-methyl-1-(pyrrolidin-1-yl)butan-2-yl)-P,P-diphenylphosphinamide (9.57 kg, 26.9 mol) was suspended in hexane (75 L, 5 V) in a reaction vessel under N. The suspension was cooled to an internal temperature of -65 °C. 1.0 M diethylzinc in hexane (358 L, 358 mol) was added via a peristaltic pump over 2 h. The internal temperature was maintained at -60 ± 5 °C. The solution was then stirred at -65 °C for 45 min. BF OEt (1.27 kg, 8.95 mol) was added over 30 min, and the mixture was stirred at -65 °C for 60 min. 2-Chloro-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (15.0 kg, 89.5 mol) in DCM (150 L, 10 V) was added via a peristaltic pump over 3 h. The internal temperature was maintained at −65±5°C. The solution was stirred at −65°C for 1 h. The temperature was allowed to slowly rise to 20°C over 17 h. The mixture was transferred to a separate vessel containing saturated NH4Cl (150 L, 10 V) initially cooled to 0°C. The internal temperature of the quench was maintained between 10 and 25°C. The mixture was filtered and the layers separated. The aqueous phase was extracted with MTBE (100 mL). 75 L of NaHSO3 (1% w / w, 5 V) was added to the combined organic layers. The mixture was stirred for 30 min and then separated. To the organic layer, silica gel (30 kg, 2 wt) and activated carbon (3 kg) were added. The mixture was stirred for 60 minutes and then filtered. The filter cake was washed with MTBE (120 L, 8 V). The filtrate was concentrated and the residue was dissolved in n-heptane (30 L, 2 V). The mixture was heated to 60°C and then slowly cooled to 30°C. Seed crystals (1 wt%) were added. The mixture was slowly cooled to 10°C and stirred at that temperature for 1 hour. The solid was collected by filtration and then triturated with 70 L of NaHSO3 (1% w / w, 5 V). The slurry was stirred for 2 hours and then collected by filtration. Trituration with 1% NaHSO3 was repeated four times. The filter cake was washed with water (45 L, 3 V) and dried under a stream of N for 3 days to give (R)-2-chloro-7-ethyl-6,7-dihydro-5H-cyclopenta[b] as a white solid. Pyridin-7-ol Form B (6.76 kg, 38% yield, 99.3% ee) was obtained. The XRPD pattern of Form B is provided in FIG. 2 and a partial listing of the XRPD peaks is provided in Table 6.

[0216] [Table 6]

[0217] Moreover, although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternatives consistent with the true scope and spirit of the present invention.

Claims

1. A method for preparing a tertiary alcohol or a salt thereof, comprising: an optionally substituted phenyl ketone, or an optionally substituted pyridinyl ketone, or a salt of any of the foregoing, and Et ２ Zn, Me ２ Zn, and Ph ２ a zinc reagent selected from the group consisting of Zn, a chiral ligand having the structure 【Chemical 1】 wherein, in the structural formula of the chiral ligand, BF ３ ・OEt ２ A method comprising combining: When the phenyl ketone or pyridinyl ketone is substituted, the phenyl ketone and pyridinyl ketone are substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy, is substituted with one or more substituents selected from the group consisting of R １ is -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , or -C(CH ３ ) ３ and R ２ is H or R １ and R ２ wherein each R １ and R ２ together with the carbon to which they are attached form an unsubstituted cyclohexyl ring, Each Ar is, independently, unsubstituted or substituted phenyl, or unsubstituted or substituted naphthyl, and when Ar is substituted phenyl or substituted naphthyl, the phenyl or the naphthyl is, independently, halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy and b is 1 or 2.

2. The optionally substituted phenyl ketone has a structure selected from the group consisting of wherein 【Chemical 2】 m1 is 0, 1, 2, 3, or 4; n1 is 0, 1, 2, 3, 4, or 5; m2 is 1 or 2.

3. The optionally substituted ketone is selected from the group consisting of X １ａ is -CH ２ -, and X ２ａ is -CH ２ -, -CH(CH ３ )-, -C(CH ３ ) ２ -, or O, and Each R １ａ and each R １ｂ is independently selected from the group consisting of halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy R ２ｂ is unsubstituted C １～４ alkyl, the method according to claim 1. The method according to claim 2.

4. [Chemical Formula 3] 【Chemical Formula 4】 The tertiary alcohol has a structure selected from the group consisting of wherein m3 is 0, 1, 2, 3, or 4; [Chemical Formula 5] n2 is 0, 1, 2, 3, 4, or 5; m4 is 1 or 2.

5. The optionally substituted pyridinyl ketone has a structure selected from the group consisting of wherein X ３ａ is -CH ２ -, and X ４ａ is -CH ２ -, -CH(CH ３ )-, -C(CH ３ ) ２ -, or O, and Each R ２ａ and each R ３ｂ is independently selected from the group consisting of halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy R ４ｂ is an unsubstituted C １～４ alkyl, R ３ａ and R ５ｂ each independently represents -CH ３ , -CH ２ CH ３ , or -Ph, the method according to any one of claims 1 to 3. t1, u1, and v1 are independently 0, 1, 2, or 3; w1, x1, and y1 are independently 0, 1, 2, 3, or 4; 【Chemical Formula 6】 t2, u2, and v2 are independently 1 or 2.

6. The optionally substituted pyridinyl is selected from the group consisting of The method according to claim 5.

7. X １ｇ 、 X １ｈ 、 and X １ｊ are each -CH ２ -. X ２ｇ 、X ２ｈ 、and X ２ｊ is independently —CH ２ —, —CH(CH ３ ), —C(CH ３ ), ２ —, or O, R １ｇ , R １ｈ , R １ｊ , R １ｋ , R １ｌ , and R １ｍ are each independently selected from the group consisting of halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy. R ２ｋ , R ２ｌ , and R ２ｍ are, independently, unsubstituted C １～４ alkyl, the method according to claim 1. The tertiary alcohol has a structure selected from the group consisting of wherein 【Chemical Formula 7】 【Chemical Formula 8】 【Chemical Formula 9】 t3, u3, and v3 are independently 0, 1, 2, or 3; w2, x2, and y2 are independently 0, 1, 2, 3, or 4; t4, u4, and v4 are independently 1 or 2. 【Chemical Formula 10】

8. The method according to any one of claims 1 to 7, wherein the tertiary alcohol is obtained with an enantiomeric purity of ≧ 50%.

9. The method according to any one of claims 1 to 7, wherein the tertiary alcohol is obtained with an enantiomeric purity of ≧ 90%.

10. X ３ｇ 、 X ３ｈ 、 and X ３ｊ are each -CH ２ -. X ４ｇ , X ４ｈ , and X ４ｊ are, independently, -CH ２ -, -CH(CH ３ ), -C(CH ３ ) ２ -, or O, and R ２ｇ 、 R ２ｈ 、 R ２ｊ 、 R ３ｋ 、 R ３ｌ 、 and R ３ｍ are, independently, halogen, non-substituted Replacement C １～４ alkyl, and unsubstituted C １～４ selected from the group consisting of alkoxy, R ４ｋ 、 R ４ｌ 、 and R ４ｍ are, independently, unsubstituted C １～４ alkyl, R ３ｇ , R ３ｈ , R ３ｊ , R ５ｋ , R ５ｌ , and R ５ｍ are, independently, -CH ３ , -CH ２ CH ３ , or -Ph, the method according to any one of claims 5 to 6. The method according to any one of claims 1 to 7, wherein the tertiary alcohol is obtained with an enantiomeric purity of ≧ 95%.

11. The chiral ligand has the structure

12. The chiral ligand has the structure wherein each Ar is unsubstituted naphthyl. The method according to any one of claims 1 to 10.

13. The chiral ligand has the structure 【Chemical Formula 11】 having, wherein each Ar is unsubstituted phenyl or, independently, substituted phenyl substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy, the method according to any one of claims 1 to 10.

14. ​ 【Chemical 12】 ​ ​ ​ 【Chemical Formula 13】 having, wherein each Ar is independently a substituted naphthyl substituted with one or more substituents selected from the group consisting of halogen, unsubstituted C １～４ alkyl, and unsubstituted C １～４ alkoxy, the method according to any one of claims 1 to 10. ​ The method according to any one of claims 1 to 13, wherein b is 1.

15. The method according to any one of claims 1 to 10, wherein the chiral ligand is selected from the group consisting of the structure 【Chemical 14】

16. The method according to any one of claims 1 to 15, wherein the tertiary alcohol is selected from the group consisting of 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical Formula 19】

17. The method according to any one of claims 1 to 16, wherein the obtained tertiary alcohol is selected from the group consisting of 【Chemical 20】

18. The method according to any one of claims 1 to 17, wherein the method increases the ee% of 【Chemical 21】 including further the use of NaHSO ３ and the use of said NaHSO ３ is, as compared with the enantiomeric excess (ee%) before the use of said NaHSO ３ ​ 【Chemical 22】

19. The method according to any one of claims 1 to 18, wherein the method further comprises recrystallization of 【Chemical 23】 and the recrystallization increases the ee% of 【Chemical 24】 as compared to the enantiomeric excess (ee%) before the recrystallization.

20. A compound of formula (G1-a) or a salt thereof, having the following structure 【Chemical 25】 wherein X is Cl or I, the compound or a salt thereof.

21. The compound or a salt thereof according to claim 20, wherein X is Cl.

22. The compound or a salt thereof according to claim 21, wherein the compound is obtained as a crystalline form selected from Form A or Form B, Form A is characterized by peaks in the X-ray powder diffraction pattern, the peaks including peaks at 16.2 degrees 2θ ± 0.2 degrees 2θ, 21.0 degrees 2θ ± 0.2 degrees 2θ, 24.2 degrees 2θ ± 0.2 degrees 2θ, 24.9 degrees 2θ ± 0.2 degrees 2θ, and 26.5 degrees 2θ ± 0.2 degrees 2θ, Form B is characterized by peaks in the X-ray powder diffraction pattern, the peaks including peaks at 14.0 degrees 2θ ± 0.2 degrees 2θ, 17.6 degrees 2θ ± 0.2 degrees 2θ, 20.1 degrees 2θ ± 0.2 degrees 2θ, 24.8 degrees 2θ ± 0.2 degrees 2θ, and 25.5 degrees 2θ ± 0.2 degrees 2θ, the compound or a salt thereof.

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