New process for phenylephrine and salbutamol and related compounds via asymetric transfer hydrogenation of unprotected amino ketones

Abstract

Methods for the preparation of asymmetrically reduced compounds such as (R)- phenylephrine and (R)- salbutamol) are provided. The methods comprise two steps: 1) nucleophilic substitution of a halogenated starting material to form an unprotected amino ketone, followed by 2) asymmetric transfer hydrogenation of the unprotected amino ketone. The methods are advantageously performed under mild conditions, e.g. at ambient pressure.

Description

[0001]NEW PROCESS FOR PHENYLEPHRINE AND SALBUTAMOL AND RELATED COMPOUNDS VIA ASYMETRIC TRANSFER HYDROGENATION OF UNPROTECTED AMINO KETONES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims benefit of United States provisional patent application 65 / 538,562, filed September 15, 2023. BACKGROUND OF THE INVENTION Technical Field The present invention relates to synthetic methods for the preparation of asymmetrically hydrogenated compounds via a nucleophilic substitution of halogenated starting materials to form unprotected amino ketones, followed by asymmetric transfer hydrogenation of the unprotected amino ketone. Description of Related Art (R)-Phenylephrine is an α1-adrenergic receptor agonist used as a decongestant, a pupil dilator and to increase blood pressure. Phenylephrine is used as a substitute for pseudoephedrine (e.g., Pfizer's Sudafed®) and is a selectiveα-adrenergic receptor agonist that does not cause the release of endogenous noradrenaline. Phenylephrine is less likely to cause side-effects such as central nervous system stimulation, insomnia, anxiety, irritability, and restlessness. Various chemical reaction methods have been described for the synthesis of phenylephrine. U.S. Pat. No. 6,900,203 describes a synthetic route to phenylephrine that includes a chiral addition of cyanide to a ring-fluorinated phenaldehyde intermediate using hydroxynitrile lyase enzyme and U.S. Pat. No. 12031159 describes engineered ketoreductase polypeptides for the preparation of phenylephrine. Salbutamol, also known as albuterol and sold under the brand name Ventolin® among others, is a short-acting β2 adrenergic receptor agonist that causes relaxation of airway smooth muscle. It is used to treat asthma, including asthma attacks and exercise- induced bronchoconstriction, as well as chronic obstructive pulmonary disease (COPD). It is also one of the most common medicines used in rescue inhalers and may also be used to treat high blood potassium levels. Salbutamol is on the World Health Organization's List of Essential Medicines. In 2022, it was the seventh most commonly prescribed medication in the United States. Although sold as a racemic mixture, the (R)-(−)-enantiomer is responsible for the pharmacologic activity; the (S)-(+)-enantiomer blocks metabolic pathways associated with elimination of itself and of the pharmacologically active enantiomer (R). The slower metabolism of the (S)-(+)-enantiomer also causes it to accumulate in the lungs, which can cause airway hyperreactivity and inflammation. Potential formulation of the R form as an enantiopure drug is complicated by the fact that the stereochemistry is not stable, but rather the compound undergoes racemization within a few days to weeks, depending on pH. Methods of manufacturing this drug are described in the prior art, e.g. in U.S. Pat. No. US3705233. Several related compounds are known to have beneficial physiological activities and are in need of improvements in manufacturing processes. Examples include Tembaamide, Acgeline, Pipratecol, Denopamine, Deterenol, Octopamine, Colterol and Levisoprenaline. There remains a need for novel processes for synthesizing phenylephrine and salbutamol and related compounds with improved yield and chiral purity, especially for synthesizing pure enantiomeric forms such as R enantiomers. SUMMARY OF THE INVENTION Other features and advantages of the present invention will be set forth in the description of invention that follows, and in part will be apparent from the description or may be learned by practice of the invention. The invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof. In some aspects, the invention provides methods to reduce an amino ketone via asymmetric transfer hydrogenation, not hydrogenation. Asymmetric transfer hydrogenation is applying a hydride source (e.g. using HCOOH and Et3N) using regular (unpressurized) reactors. This is in contrast to prior art asymmetric hydrogenation, which is performed by applying hydrogen under pressurized hydrogenation conditions, which requires special reactors. It is an object of this invention to provide a method of preparing an asymmetrically reduced compound, comprising reacting a halogenated starting material with an amine nucleophile under conditions suitable for nucleophilic substitution of the halogenated starting material to form a substituted unprotected amino ketone; and reacting the substituted unprotected amino ketone with a tethered ligand transition metal catalyst under conditions suitable for asymmetric transfer-hydrogenation to produce an enantiomerically pure amino alcohol compound. In some aspects, the halogenated starting material is a brominated starting material. In further aspects, the tethered ligand transition metal catalyst is a tethered ruthenium catalyst. In additional aspects, the tethered ruthenium catalyst is selected from the group consisting of [(S,S)-Teth-TsDpen RuCl], RuCl[(R,R)-Ts DPEN](p-cymene), RuCl[(R,R)-Ms DPEN](p-cymene), RuCl[(R,R)-Fs DPEN](p-cymene), RuCl[(R,R)-Ts DACH](p-cymene), RuCl[(R,R)-Nitro DACH](p-cymene), and [(S,S)-Teth-TsDENEB RuCl]. In other aspect, the amine nucleophile is selected from the group consisting of NH3,CH3NH2, isopropylamine, butylamine, tert-butyl amine, methylamine, hexamethylenetetramine, (2-(3,4-dimethoxyphenyl)ethan-1-amine ), 1-(2- methoxyphenyl)piperazine, morpholine, N-benzylmethylamine, 1-(m-tolyl) piperazine, and 1-(3-methylphenyl)piperazine. In additional aspects, the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution at a temperature of 0-75°C. In additional aspects, the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile. In further aspects, the solvent is selected from the group consisting of methanol, water, isopropyl alcohol, acetonitrile, dioxane, acetone and dichloromethane. In yet further aspects, the conditions suitable for nucleophilic substitution comprise a reaction time of 0.5-24 hours. In certain aspects, the method further comprises reacting the substituted unprotected amino ketone with a protic acid. In some aspects, the protic acid is aqueous HCl or methanolic HCl. In other aspects, the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation at a temperature of 60-65°C. In additional aspects, the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile. In further aspects, the solvent is methanol. I certain aspects, the conditions suitable for transfer-hydrogenation comprise a reaction time of 3-5 hours. In yet further aspects, the method is performed at ambient pressure. Other aspects include that the halogenated starting material is 2-bromo-1-(4-methoxyphenyl)ethan- 1-one the amine nucleophile is hexamethylenetetramine, and the unprotected amino ketone is (R)-2-amino-1-(4-methoxyphenyl)ethan-1-ol , and wherein the method further comprises, after the step of reacting, a step of amide bond formation with cinnamoyl chloride to form acgeline; and / or amide formation with benzoyl chloride o form tembaamide. In further aspects, the asymetrically reduced compound is selected from the group consisting of (R)- phenylephrine and (R)-salbutamol). Also provided is a method of preparing a salt of an asymmetrically hydrogenated compound, comprising performing the method of claim 1 to produce the asymmetrically hydrogenated compound, and forming a salt of the asymmetrically hydrogenated compound. In some aspects, the salt is selected from the group consisting of tartrate salt, maleate salt, fumarate salt, and hydrochloride salt. In certain aspects, the methods also comprise isolating the salt. DETAILED DESCRIPTION Provided herein are new methods of synthesizing pharmacologcally useful compounds such as (R)-phenylephrine and (R)-salbutamol (albuterol), and several compounds related thereto. These compounds are collectively referred to herein as enantiomerically enriched 1,2-amino alcohol-containing compounds. These compounds are synthesized utilizing highly enantioselective ruthenium-catalyzed asymmetric transfer hydrogenation of unprotected α-keto amines. The methods are advantageously facile without the need of protection and deprotection steps on the amino groups, and the protocol can be executed in any part of the world without the need of pressurized reactors. The methods generally utilize the starting material where X is a halogen, typically Br or Cl or I and W is a 5 or 6 membered cyclic moiety which is optionally substituted and optionally has attached reactive groups. In some aspects, W is where n is 0 or 1; Y is OH, MeO-, a halogen or absent; and Z is OH, MeO- or absent; with the caveat that at least one of Y or Z is present. Y and Z may both be present and when this is the case, they are independently the same or different. In some aspects, W is . The synthesis begins with a nucleophilic substitution of a leaving group, e.g., a halogen such as bromine, by the R group of an amine nucleophile RNH2, where R=a group desired to be present in the product. A subsequent step of the method involves establishment of the chiral center [e.g., an (R) isomer] via an asymmetric transfer hydrogenation reaction, typically catalyzed, e.g. by a tethered Ru catalyst. In some aspects, the methods thus comprise two reaction steps including 1) a nucleophilic substitution followed by 2) an asymmetric transfer hydrogenation reaction, to yield the target molecules in excellent yield and stereoselectivity. The work-up and purification may also entail the formation of a salt of a corresponding product (or intermediate) which may or may not be isolated. However, some reactions are more complex. For example, the syntheses of (S)-2- (benzyl(methyl)amino)-1-(thiophen-2-yl)ethan-1-ol), phenylephrine, (R)-tembaamide and (R)-acgeline involve more complex reactions, as depicted in the Examples below. Accordingly, embodiments provide a method of preparing an asymmetrically hydrogenated compound comprising reacting a suitable halogenated (e.g. brominated) starting material (a chemical compound) with an amine nucleophile under conditions suitable for nucleophilic substitution of the starting material (dehalogenation, the halogen is displaced and replaced or substituted) to form a substituted starting material, i.e. a substituted unprotected amino ketone, and reacting the substituted unprotected amino ketone with a catalyst under conditions suitable for asymmetric transfer hydrogenation, thereby forming the desired product, an asymmetrically hydrogenated compound. In the first step of the process, a molar ratio of the halogenated starting material to the amine nucleophile is at least about 1:2, e.g. about 1:2 to about 1:50, such as bout 1:1, 1:5, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45 or 1:50. A nucleophile is a chemically reactive group which is attracted to, and then attacks, a positive or slightly positive part of another molecule or ion. All amines contain an active lone pair of electrons on the very electronegative nitrogen atom. It is these electrons which are attracted to positive parts of other molecules or ions. Nucleophilic reactions include those in which the nucleophile contains an amino group (aminolysis). Examples of suitable amine nucleophiles that are used in the reactions described herein include but are not limited to: NH3,CH3NH2,isopropylamine, butylamine (e.g. Na butylamine), tert-butyl amine, methylamine, hexamethylenetetramine (“hexamine”), 2-(3,4-dimethoxyphenyl)ethan-1-amine ), 1-(2- methoxyphenyl)piperazine, morpholine, N-benzylmethylamine, 1-(m-tolyl) piperazine, and 1-(3-methylphenyl)piperazine. As shown in the Examples presented below, each amine has a different structure and imparts a portion of its structure to the final product via the substitution reaction. The nucleophilic substitution occurs in the present of a solvent, e.g. a solvent for example, an alcoholic solvent, ether, polar amide, chlorinated solvent, water, etc. In some embodiments, the solvent is selected from the group consisting of methanol, water, isopropyl alcohol, acetonitrile, dioxane, acetone, dichloromethane, etc. The choice of solvent or solvent mixtures varies depending on the nature of the reactants and is readily determined by combining extant knowledge and the detailed teachings in the Examples presented herein. An exemplary generic scheme for a synthesis process described above is depicted below (it being understood that the solvents, temperatures, and times can vary). In some embodiments, the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution at a temperature of about 0-100°C, such as at about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95oC; e.g., from about 0-75oC. The choice of temperature varies depending on the nature of the reactants and is readily determined by combining extant knowledge and the detailed teachings in the Examples presented herein. In some embodiments, the conditions suitable for nucleophilic substitution comprise a reaction time of about 0.5-24 hours, e.g. about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours, including 0.5-hour increments in between these values. The choice of the reaction time varies depending on the nature of the reactants and is readily determined by combining extant knowledge and the detailed teachings in the Examples presented herein. In other aspects, the nucleophilic substitution is performed under N2. The first step of the process generally yields an unprotected amino ketone. In the second step of the process, the substituted starting material (unprotected amino ketone) is reacted with a catalyst in the presence of a hydride source under conditions suitable for asymmetric transfer hydrogenation. Suitable hydride sources include H2 gas or hydrogen donor compounds such as formic acid, dihydroanthracene, or alcohols (e.g. methanol, isopropanol, propanol, etc.). In some aspects, the hydrogen donor is formic acid. The conditions suitable for asymmetric transfer-hydrogenation generally comprise performing the reaction at a temperature of about 55-75°C, e.g. about 55, 60, 65, 70 or 75oC, A typical reaction is performed at about 62-65o. In some embodiments, the conditions suitable for asymmetric transfer hydrogenation comprise a reaction time of about 1-10 hours, e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours, such as 3-5 hours or longer, e.g., up to 9 hours. In some embodiments, the conditions suitable for asymmetric transfer hydrogenation comprise performing the asymmetric transfer hydrogenation in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and / or acetonitrile. In some embodiments, the solvent is MeOH. The tethered ligand transition metal catalyst may be a tethered ruthenium, titanium, vanadium, iron, cobalt, nickel, zinc, zirconium, rhodium, or palladium catalyst. In some embodiments, the tethered ligand transition metal catalyst is selected from the group consisting of [(S,S)-Teth-TsDpen RuCl], RuCl[(R,R)-Ts DPEN](p-cymene), RuCl[(R,R)- Ms DPEN](p-cymene), RuCl[(R,R)-Fs DPEN](p-cymene), RuCl[(R,R)-Ts DACH](p- cymene), RuCl[(R,R)-Nitro DACH](p-cymene), and [(S,S)-Teth-TsDENEB RuCl]. A tethered catalyst may refer to a catalyst in a polymer-bound form, e.g. immobilized on a solid support. In some embodiments, non-tethered catalysts may be used alternatively or in addition to tethered catalysts. In exemplary aspects, the tethered catalyst that is employed is a Ru catalyst in formic acid / TEA (5:2) in MeOH, and the reaction is performed for 3 hours at 62-65oC. The resulting product may then be isolated / purified by known methods. The method may further comprise an optional step in between the nucleophilic substitution and the transfer-hydrogenation. In this step, the substituted starting material may be reacted with a protic acid. In some embodiments, the protic acid 5 is aqueous HCl or methanolic HCl. The reaction may occur at 0-100°C, e.g. 20-40°C, for about 1 minute to 12 hours, e.g. 2-60 minutes. A molar ratio of the substituted starting material to the protic acid is at least about 1:1, e.g. about 1:2 to 1:20 In some aspects, e.g. the synthesis of acgeline and tembaamide, additional steps are required to form the final product. In this case, the compound (R)-2-amino-1-(4- methoxyphenyl)ethan-1-ol (“1k”) is prepared by ruthenium catalyzed asymmetric transfer hydrogenation and then further transformed via amide bond formation with acid chloride e.g., under basic conditions (NaOH in DCM) to yield acgeline, or in NaOH / DCM in the presence of benzoyl chloride and triethylamine (TEA) to yield tembaamide (also amide bond formation). The details of this reaction are provided in the Examples section below. The synthesis of (R)-Phenylephrine requires two steps to form the unprotected amino ketone. The first step is nucleophilic substitution and the second step is salt formation. The details of these reactions are shown in the Examples section below. Further embodiments provide a method of preparing a salt of an asymmetrically hydrogenated compound produced by the methods disclosed herein. In some aspects, the salt is selected from the group consisting of tartrate salt, maleate salt, fumarate salt, and hydrochloride salt. In some embodiments, the method further comprises isolating / purifying the salt. Suitable methods for forming and isolating / purifying salts are known in the art. The methods set forth herein allow the synthesis and manufacturing of the disclosed compounds with improved yield and chiral purity. Purification advantageously does not require chiral resolution since the final product is an R-enantiomer. The hydrogenation can be run under normal pressure and does not require pressurized conditions. In some embodiments, any or all steps of the method is performed at ambient pressure, e.g. about 0.5-2 bars. Performing a method as described herein, the resulting compounds can be obtained in a total yield of 75% or more, e.g. 80%, 85%, 90%, or 95% or more, with an optical purity of 98% or more and a chemical purity of 98% or more. The described process is very efficient and easily scalable for adaptation to large scale production. The process avoids the use of hydrogen gas and pressure as was needed in previous methods of high- pressure hydrogenation. Embodiments also avoid the use of protecting groups. In other words, in some aspects, protecting groups are not present on (are absent from) the reactants, i.e. the reactants do not comprise protecting groups. Further embodiments provide compounds prepared by the methods as described herein. Compounds that are made using the present methods include but are not limited to the exemplary compounds: (R)-salbutamol [(R)-4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol, (R)-phenylephrine [3-[(1R)-1-Hydroxy-2-(methylamino)ethyl]phenol], (R)-levisoprenaline [(R)-4-(1-hydroxy-2-(isopropylamino)ethyl)benzene-1,2-diol], (R)- colterol [(R)-4-(2-(tert-butylamino)-1-hydroxyethyl)benzene-1,2-diol], (R)-octopamine [(R)-4-(2-amino-1-hydroxyethyl)phenol], (R)-deterenol [(R)-4-(1-hydroxy-2-(isopropylamino)ethyl)phenol], (R)-denopamine [(R)-4-(2-((2,3-dimethoxyphenethyl)amino)-1-hydroxyethyl)phenol], (R)-pipratecol [(R)-4-(1-hydroxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)benzene- 1,2- diol], (R)-acgeline, which is used to treat rheumatic fever, neuralgia, gout, headache, muscular aches and pains, (R)-tembamide in synthetic form (tembamide is a natural product) (R)-2-amino-1-(3-fluorophenyl)ethan-1-ol; (R)-2-amino-1-(3-chlorophenyl)ethan-1-ol; (R)- 2-amino-1-(4-methoxyphenyl)ethan-1-ol; (R)-4-(2-(benzyl(methyl)amino)-1-hydroxyethyl) benzene-1,2-diol; (R)-3-(2-(benzyl(methyl)amino)-1-hydroxyethyl) phenol; (R)-4-(1- hydroxy-2-morpholinoethyl)phenol; (R)-2-(benzyl(methyl)amino)-1-(3-chlorophenyl) ethan- 1-ol; (S)-2-(benzyl(methyl)amino)-1-(thiophen-2-yl)ethan-1-ol; (R)-1-(3-methoxyphenyl)-2- (4-(m-tolyl) piperazin-1-yl) ethan-1-ol; and (R)-4-(1-hydroxy-2-(4-(m-tolyl)piperazin-1- yl)ethyl)benzene-1,2-diol. Further embodiments provide a composition comprising the compounds prepared as described herein. In some embodiments, the composition is a pharmaceutical composition which further comprises a pharmaceutically acceptable excipient. The preparation of pharmacologically suitable compositions for use as medicaments is well known to those of skill in the art. Typically, such compositions are prepared either as liquid solutions or suspensions, however solid dry forms such as tablets, pills, powders and the like are also contemplated. The liquid may be an aqueous liquid. Solid forms suitable for solution in, or suspension in, liquids prior to administration may also be prepared. The preparation may also be emulsified. The active ingredients may be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredients. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like, or combinations thereof. In addition, the composition may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like. If it is desired to administer an oral form of the composition, various thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders and the like may be added. The composition of the present invention may contain any such additional ingredients so as to provide the composition in a form suitable for administration. The final amount of compound in the formulations may vary. However, in general, the amount in the formulations will be from about 1% to about 99%. Dosage forms of the compounds are also encompassed, including but not limited to capsules, pills, patches impregnated with the compound, implants, metered dose inhalers (mist or dry powder), and the like, depending on the intended use. The compounds synthesized by the methods described herein may be used in any of a variety of methods of treatment. For example, descriptions of the uses of selected compounds is as follows: Salbutamol is used to relieve symptoms of asthma and chronic obstructive pulmonary disease (COPD) such as coughing, wheezing and feeling breathless. It works by relaxing the muscles of the airways into the lungs, which makes it easier to breathe. Levisoprenaline (l-isoproterenol) is a β1- and β2-adrenoreceptor agonist. In Japan, continuous inhalation of levisoprenaline is a recommended treatment for pediatric patients with acute severe exacerbation of asthma. Compared with salbutamol, l-isoproterenol reduced modified pulmonary index score more rapidly. Most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma due to worsening asthma control. Colterol is a short-acting β2-adrenoreceptor agonist. It is used in the management of bronchospasm in asthma and chronic obstructive pulmonary disease (COPD). Octopamine is an organic chemical closely related to noradrenaline. Octopamine plays important roles as a neurotransmitter and hormone in invertebrates. Denopamine (INN) is a cardiotonic drug which acts as a β1 adrenergic receptor agonist. It is used in the treatment of angina and may also have potential uses in the treatment of congestive heart failure and for clearing pulmonary oedema. Phenylephrine is an alpha-1 adrenergic agonist that mediates vasoconstriction and mydriasis depending on the route and location of administration and is used as a decongestant. Systemic exposure to phenylephrine also leads to agonism of alpha-1 adrenergic receptors, raising systolic and diastolic pressure as well as peripheral vascular resistance. Increased blood pressure stimulates the vagus nerve, causing reflex bradycardia. Phenylephrine also has an indirect effect by releasing norepinephrine from its storage sites. Deterenol is a stimulant drug which acts as a beta agonist and is used for weight loss, to increase energy, improve athletic performance, etc. Pipratecol is a peripheral vasodilator and has been used in conjunction with raubasine in the treatment of cerebrovascular disorders. Pipradrol is also a central nervous stimulant to treat functional fatigue and as an antiulcerative agent. Methods of using the compounds made by the methods described herein are provided. For example: Methods of treating and / or preventing and / or relieving symptoms of sinus congestion in a subject in need thereof are provided and comprise administering to the subject a therapeutically effective dose of phenylephrine made by the methods disclosed herein. In addition, methods of treating and / or preventing and / or relieving at least one symptom of asthma or chronic obstructive pulmonary disease (COPD) (such as coughing, wheezing, bronchospasm, feeling breathless, etc.), in a subject in need thereof comprises administering to the subject a therapeutically effective dose of salbutamol and / or colterol and / or levisoprenaline made by the methods disclosed herein. Methods of treating and / or preventing and / or relieving at least one symptom of angina, congestive heart failure and / or pulmonary oedema in a subject in need thereof are provided and comprise administering to the subject a therapeutically effective dose of denopamine made by the methods disclosed herein. It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention. Unless defined otherwise, 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 invention belongs. Representative illustrative methods and materials are herein described; methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual dates of public availability and may need to be independently confirmed. It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as support for the recitation in the claims of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitations, such as "wherein [a particular feature or element] is absent", or "except for [a particular feature or element]", or "wherein [a particular feature or element] is not present (included, etc.)...". Herein, a weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. For example if a particular element or component in a composition or article is said to have 30 wt. %, it is understood that this percentage is in relation to a total compositional percentage of 100%. Further, with respect to the compositions, the dry weight basis is used. That is, the wt. % is based on a total weight of dried material so that a weight of water does not significantly contribute to the total weight of material, unless stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated. As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should they be interpreted to, limit the scope of the invention. EXAMPLES Synthesis of Compound 2 and Asymmetric transfer hydrogenation to synthesize (R)- Salbutamol (compound 4): Synthesis of 2-(tert-butylamino)-1-[4-hydroxy-3-(hydroxymethyl)phenyl] ethan-1-one hydrogen chloride, 2: A 100 ml 3 neck RB flask equipped with an internal thermometer, addition funnel, and N2 line was charged with 2-Bromo-1-[4-hydroxy-3-(hydroxymethyl) phenyl]ethan-1-one(1) (1.0 g, 4.08 mmol) and acetonitrile (8V). The reaction mixture was treated with dropwise addition of t-butylamine (1.29 mL, 12.24 mmol, 3.0 equiv) over a period of 10 min at 0-5oC. The slurry was warmed to rt and stirred at rt for 4 h. The reaction mixture was filtered, and washed with acetone (2V). The cake was suction dried and dried under vacuum oven at 30oC for 12 h. The product 2 was collected as a yellow solid: crude 1.34 g (containing mixture of compound 2 and t-butylaminehydrobromide salt). A 50 ml 3-neck RBF equipped with an internal thermometer, addition funnel and N2line was charged with 2 (Crude 1.34 g (mixture of compound 2 and t-butylaminehydrobromide salt), 4.08 mmol, 1.0 equiv) and MeOH (10V). The reaction mixture was treated with dropwise addition of 4N HCl (2.4 mL, 9.6 mmol, 2.0 equiv) at 0-5oC over a period of 5 min. The reaction mixture was stirred at rt for 1 h. Isolation protocol: The reaction mixture distilled to remove MeOH (the pressure was reduced gradually from 1000 mbar to 550 mbar; internal temperature: 40-45oC). The remaining crude reaction mixture in water (~2.5 mL) was cooled to 0-5oC and stirred for 1 h. The product was filtered and washed with IPA (1V). The solid was suction filtered and dried in a vacuum oven at 35oC for 12 h to afford pure 2 (0.85 g, 76%) as pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.96 (t, J = 6.4 Hz, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.91 (dd, J = 8.5, 2.4 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 4.61 – 4.54 (m, 2H), 4.52 (s, 2H), 3.67 – 3.19 (m, 4H), 1.37 (s, 9H);13C NMR (101 MHz, DMSO-d6) δ 191.1, 160.9, 129.9, 129.9, 128.4, 125.4, 114.9, 58.2, 56.7, 46.9, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 25.6. Synthesis of (R)-Salbutamol, 4: A sample vial equipped with stir bar and N2line was charged with compound 2 (100 mg, 0.36 mmol, 1.0 equiv), MeOH (1 mL, 10V), Ru catalyst (0.15 mol%) and formic acid / TEA (5:2) (1V). The reaction mixture was stirred at 62oC. After 16h, the reaction mixture was cooled to rt. Isolation protocol: After 16 h, the reaction mixture was cooled to room temperature, neutralized with aq. NH4OH (1V). The reaction mixture was filtered and washed with H2O (1 ml), followed by MeOH (5 ml). Filtrate was evaporated to dryness, to the crude MeOH (1 ml) and EtOAc(5 ml) were added, heated to 70-75oC and additional EtOAc (10 ml) added dropwise. Crude mixture was slowly cooled to rt. Crystallized material was filtered and washed with EtOAc (2 ml). The cake was dried via vacuum suction and then dried under vacuum oven at 35oC for 16 h (Yield: 71 mg, 82%), er ratio: >99.9:0.1.1H NMR (400 MHz, CD3OD_SPE) δ 7.36 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.3, 2.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.84 – 4.79 (m, 1H), 4.65 (s, 2H), 3.13 – 2.96 (m, 2H), 1.38 (s, 9H).;13C NMR (101 MHz, CD3OD_SPE) δ 154.9, 131.6, 127.6, 125.7, 125.6, 114.6, 69.2, 59.4, 56.7, 48.4, 48.3, 48.1, 47.8, 47.6, 47.4, 47.2, 47.0, 24.4. Enantiomeric ratio was determined by SFC: Chiralpak® IC-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: CO2, B: ethanol with 0.1% of diethylamine, isocratic: A / B,82 / 18 v / v, flow rate 0.8 mL / min. Synthesis of Compound 1c and Asymmetric transfer hydrogenation to Levisoprenaline: Synthesis of 1-(3,4-dihydroxyphenyl)-2-(isopropylamino) ethan-1-one hydrogen chloride, 1c: 2-Chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (5.03 g, 26.95 mmol) in ACN (25.0 mL) was treated with the dropwise addition of isopropylamine (6.55 mL, 80.4 mmol). The reaction mixture was heated to 65oC. After 2h, LCMS indicated reaction completion. The reaction was treated with IPA (50 mL) and concentrated to ~ 35 mL. The precipitate was suction filtered, washed with H2O (6V). NMR showed residual isopropylamine. The cake was washed with H2O (10 V) and IPA (10 V). NMR indicated <1% isopropylamine remaining. The yellow solid was suspended in IPA (5V) and treated with 12 M HCl (2 eq; 4.5 mL). After stirring for 1h, the suspension was filtered, washed with Acetone (10V) and heptane (5V). The cake was transferred to the vacuum oven for further drying (35oC, 14h). The aminoketone salt 1c (1.61 g, 24%) was collected as an off-white solid.1H NMR (400 MHz; DMSO-d6) δ 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 3.48 (sept, J = 6.6 Hz, 1H), 1.33 (d, J = 6.6 Hz, 1H);13C NMR (101 MHz; DMSO-d6) δ 191.5, 151.3, 144.2, 125.8, 123.2, 115.7, 115.2, 50.9, 49.4, 18.1. Synthesis of (R)-4-(1-hydroxy-2-(isopropylamino)ethyl)benzene-1,2-diol, 2c: A 3-neck RBF was charged with compound 1c (0.250 g, 1.02 mmol) and MeOH (10V, 2.5 mL). The suspension was treated with Ru cat (0.20 mol%, 1.26 mg) in formic acid / TEA (5:2) (1V, 0.25 mL). The reaction mixture was stirred at 62oC under N2sparging for 19 h. After cooling to rt, the reaction mixture was treated with NH4OH (1V; 0.25 mL) and H2O (5 V; 1.0 mL) and stirred for 20 min. The precipitate was filtered and rinsed with MTBE (5 V). The amino alcohol 2c (165 mg, 77% yield) was collected as a beige solid, er ratio: >99.9:0.1.1H NMR (400 MHz; DMSO-d6): δ 6.73 (d, J = 2.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.56 (dd, J = 8.0, 2.0 Hz, 1H), 4.42 (dd, J = 8.6, 4.0 Hz, 1H), 2.77 (sept, J = 6.2 Hz, 1H), 2.63-2.52 (m, 2H), 0.98 (app t, J = 6.6 Hz, 6H);13C NMR (101 MHz; DMSO-d6): δ 144.9, 144.2, 135.3, 116.7, 115.1, 113.5, 71.1, 54.9, 48.1, 22.5, 22.4. Enantiomeric ratio was determined by SFC: Chiralpak® IC-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 40 ºC, A: CO2, B: ethanol with 0.05% of diethylamine, isocratic: A / B: 88 / 12, v / v, flow rate 1.5 mL / min. Synthesis of Compound 1d and Asymmetric transfer hydrogenation to Colterol: Synthesis of 2-(tert-butylamino)-1-(3,4-dihydroxyphenyl) ethan-1-one hydrogen chloride, 1d: To a sealed tube 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (2.0 g, 10.72 mmol, 1.0 equiv) and Dioxane (2V) were charged. The reaction mixture was treated with the dropwise addition of t-Butylamine (9.01 mL, 85.75 mmol, 8.0 equiv) over a period of 10 min at rt. The slurry was heated to 70-75 ºC for 4 h. The reaction mixture was cooled, diluted with acetone (40 mL) and filtered, and washed with 2 V Acetone. The crude filtrate was dried, and acetone (50 mL) was added. After stirring for 1h, the filtered solid compound was vacuum oven dried at 25 ºC for 12 h. The product 2-(tert-butylamino)-1- (3,4- dihydroxyphenyl)ethan-1-one (Crude Yield: 2.25 g, 94%) was collected as a brown-colored solid. A 50 mL 3-neck RBF equipped with an internal thermometer, addition funnel, and N2line was charged with 2-(tert-butylamino)-1- (3,4-dihydroxyphenyl)ethan-1-one (1.0 g, 4.48 mmol, 1.0 equiv) and MeOH (6V). The reaction mixture was treated with the dropwise addition of 3M HCl in MeOH (2.98 mL, 8.96 mmol 2.0 equiv) at 0-5 ºC over a period of 5 min. The reaction mixture was stirred at rt for 1 h. The crude reaction mixture MTBE (100 mL) was added and stirred for 3 h. The crystallized salt was filtered and washed with MTBE (20 mL) and dried in a vacuum oven at rt for 12 h to afford 1d (0.97 g, 84%).1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.54 (s, 1H), 8.92 (t, J = 6.6 Hz, 2H), 7.54 (dd, J = 8.3, 2.2 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.53 (t, J = 6.2 Hz, 2H), 3.36 (s, 2H), 1.35 (s, 9H);13C NMR (101 MHz, DMSO-d6) δ 190.9, 152.7, 146.1, 126.0, 122.7, 115.8, 115.5, 56.7, 46.9, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 25.6. Synthesis of (R)-4-(2-(tert-butylamino)-1-hydroxyethyl)benzene-1,2-diol, 2d: A sample vial equipped with a stir bar and N2line was charged with compound 1d (200 mg, 0.81 mmol), MeOH (2 mL, 10 V), Ru catalyst (0.15 mol%) and formic acid / TEA (5:2) (1 V). The reaction mixture was stirred at 62 ºC. After 20 h, the reaction mixture was cooled to rt (100% conversion). The reaction mixture was cooled to rt, neutralized with aq. NH4OH (1 V). The reaction mixture was filtered and washed with H2O (1 ml), followed by MeOH (5 ml). The filtrate was evaporated to dryness, and the crude compound was treated with MeOH (2 ml) and EtOAc(10 ml), followed by heating at 70-75 ºC. The crude compound was slowly cooled to rt. The crystallized material was filtered and washed with EtOAc (2 ml). The filtrate was dried under vacuum oven at 45 ºC for 16 h (Yield: 132 mg, 76%), er ratio: >99.9:0.1.1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 1.7 Hz, 1H), 6.77 – 6.67 (m, 2H), 4.73 (dd, J = 10.1, 3.1 Hz, 1H), 3.08 – 2.88 (m, 2H), 1.34 (s, 9H);13C NMR (101 MHz, DMSO-d6) δ 145.2, 145.2, 132.5, 117.1, 115.0, 112.8, 69.2, 56.7, 48.5, 48.3, 48.0, 47.8, 47.6, 47.4, 47.2, 47.0, 24.4. Enantiomeric ratio was determined by SFC: Chiralpak® IC-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: CO2, B: ethanol with 0.1% of diethylamine, isocratic: A / B,82 / 18 v / v, flow rate 0.8 mL / min. Synthesis of Compound 1e and Asymmetric transfer hydrogenation to Octopamine: Synthesis of 2-amino-1-(4-hydroxyphenyl)ethan-1-one hydrogen chloride, 1e: A 3-neck RBF was charged with bromoketone (4.0 g, 0.014 mol), HMTA (3.0 g, 0.016 mol), IPA (4 V) and ACN (4 V). An immediate formation of creamy white solid was observed. The reaction was stirred for 2 h. The cake was washed with IPA (90 mL) and dried under vacuum to afford hexamine salt 6.4 g (96% yield). A 25 mL single-neck RBF equipped with a stirrer, internal thermometer, and N2 line was charged with hexamine salt (3.0 g, 8.5 mmol) and MeOH (6V). The reaction mixture was treated with the dropwise addition of 12M HCl (2 mL, 2.0 equiv) at rt over a period of 5 min. During the addition, the slurry changed from pale white to a light-yellow solution over a period of 24 hours. The solvent was evaporated, and the solid was washed with cold MeOH to give 1.5 g of compound 1e in 98 % yield.1H NMR (400 MHz, D2O) δ 7.96 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.65 (s, 2H);13C NMR (101 MHz, DMSO-d6) δ 190.7, 163.4, 130.8, 125.1, 115.6, 44.1. Synthesis of (R)-4-(2-amino-1-hydroxyethyl)phenol, 2e: A 10 mL vial equipped with a stirrer and N2 line was charged with compound 1e (0.1 mg, 0.54 mmol), MeOH (3 mL), Ru catalyst (0.5 mg, 0.15 mol%) and formic acid / TEA (5:2) (1 V). The reaction mixture was stirred at 62oC. After 24 h, the reaction mixture was cooled to room temperature, and the solvent was reduced and neutralized with aq. NH4OH (1 V). The slurry was stirred for 15 min, filtered, and dried under vacuum oven at 45 ºC for 16 h to give 78.0 mg (94%) of compound 2e as a white solid, er ratio: >99.9:0.1.1H NMR (400 MHz, CD3OD) δ 7.19 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 4.69 (dd, J = 8.9, 4.0 Hz, 1H), 3.00 – 2.81 (m, 2H);13C NMR (101 MHz, CD3OD) δ 157.1, 132.0, 126.9, 115.0, 70.1, 46.5. Enantiomeric ratio was determined by SFC: Chiralpak® AD-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 40 ºC, A: CO2, B: Isopropyl alcohol with 0.1% of diethylamine,, isocratic: A / B: 85 / 15, v / v, flow rate 1.0 mL / min. Synthesis of Compound 1f and Asymmetric transfer hydrogenation to Deterenol: Synthesis of 1-(4-hydroxyphenyl)-2-(isopropylamino)ethan-1-one hydrogen chloride, 1f: A 25 mL single-neck RBF equipped with a stirrer, internal thermometer, and N2line was charged with 1-(4-hydroxyphenyl)-2-(isopropylamino)ethan-1-one (0.3 g, 4.8 mmol) and MeOH (12V). The reaction mixture was treated with dropwise addition of 12M HCl (0.260 mL, 2.0 equiv) in H2O (3V) at rt over a period of 5 min. During the addition, the slurry changed from dark orange to a pale-yellow solution. The slurry was stirred at rt for 1h. The solvent was evaporated, and the solid was washed with cold MeOH to give 325.0 mg (92%) of compound 1f as a pale-yellow solid. The solid is carried forward for the next steps.1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.99 (s, 2H), 7.93 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 4.61 (d, J = 5.8 Hz, 2H), 1.29 (d, J = 6.5 Hz, 6H);13C NMR (101 MHz, DMSO-d6) δ 190.4, 163.5, 163.5, 131.0, 130.9, 125.1, 115.6, 49.7, 49.1, 49.0, 18.5. Synthesis of (R)-4-(1-hydroxy-2-(isopropylamino)ethyl)phenol, 2f: A 10 mL reactor equipped with a stirrer and N2 line was charged with compound 1f (150 mg, 0.66 mmol), MeOH (2 mL), Ru catalyst (0.69 mg, 0.15 mol%) and formic acid / TEA (5:2) (1 V). The reaction mixture was stirred at 62 ºC. After 20 h, the reaction mixture was cooled to room temperature, and the solvent was reduced and neutralized with aq. NH4OH (1V). The slurry was stirred for 15 min, filtered, and dried under vacuum oven at 45 ºC for 16 h to give 115.0 mg (90%) of compound 2f as a white solid, er ratio: > 99.9:0.1.1H NMR (400 MHz, D2O) δ 7.33 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 4.95 (dd, J = 7.3, 5.9 Hz, 1H), 3.50 (hept, J = 6.6 Hz, 1H), 3.27 (d, J = 7.2 Hz, 2H), 1.34 (dd, J = 6.6, 2.2 Hz, 6H);13C NMR (101 MHz, D2O) δ 155.9, 131.5, 127.7, 115.7, 68.8, 51.0, 50.1, 18.3, 17.9. Enantiomeric ratio was determined by SFC: Chiralpak® AD-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 40 ºC, A: CO2, B: Isopropyl alcohol with 0.1% of diethylamine, Isocratic A / B: 85 / 15, v / v, flow rate 1.0 mL / min. Synthesis of Compound 1g and Asymmetric transfer hydrogenation to Denopamine: Synthesis of 2-((2,3-dimethoxyphenethyl)amino)-1-(4-hydroxyphenyl)ethan-1-one hydrogen chloride, 1g: To a stirred solution of 2-bromo-1-(4-hydroxyphenyl) ethan-1-one (3.0 g, 1.0 equiv) in THF (27.0 mL) was added 2-(3,4-dimethoxyphenyl)ethan-1-amine (5.057 g, 2.0 equiv) at 0 ºC over a period of 1h and stirred at the same temperature for 2h. The resulting precipitate was filtered and solid was washed with THF (3.0 mL), and filtrate was concentrated. The residue was dissolved in acetone (60.0 mL), treated with 2N HCl in Et2O (15 mL) at 0ºC, and stirred for 30min. The precipitated solid was filtered and washed with acetone (3 x 5 mL) to obtain compound 1g as white color solid with 2.7 g with 55% isolated yield.1H NMR (400 MHz, DMSO-d6) δ 10.89 (brs, 1H), 9.31 (brs, 2H), 7.89 (d, J = 9.2 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.92-6.88 (m, 2H), 6.78 (dd J = 8, 2.5 Hz, 1H), 4.7 (s, 2H), 3.7 (s, 3H), 3.73 (s, 3H), 3.22-3.16 (m, 2H), 3.02-2.96 (m, 2H);13CNMR (100 MHz, DMSO- d6) δ 190.7, 164.1, 149.3, 148.2, 131.4, 130.0, 125.5, 121.0, 116.2, 113.0, 112.6, 56.0, 55.9, 52.1, 48.5, 31.4. Synthesis of (R)-4-(2-((2,3-dimethoxyphenethyl)amino)-1-hydroxyethyl)phenol, 2g: To a stirred solution of 1g (0.2 g, 0.568 mmol) in MeOH (2.0 mL) was added Ru catalyst (0.71 mg, 0.00113 mmol) followed by a mixture of HCO2H / TEA (0.2 mL) at rt. The reaction mixture was warmed to 65 ºC and stirred for 12 h. MeOH was evaporated from the reaction mixture and the residue was neutralized with aq. NH4OH solution and extracted with DCM (3 x 2 mL). The combined organic layer was dried over Na2SO4and concentrated under reduced pressure to afford crude compound 2g. The crude compound was recrystallized with MeOH to afford desired product 2g as an off-white solid with 91% isolated yield, er ratio: >99.9:0.1.1HNMR (400 MHz, DMSO-d6) δ 9.28 (brs, 1H), 7.16 (d, J = 7.1 Hz, 2H), 6.90-6.82 (m, 2H), 6.72-6.70 (m, 3H), 5.09 (brs, 1H), 4.574.51 (m, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.84-2.72 (m, 2H), 2.71-2.60 (m, 4H);13CNMR (100 MHz, DMSO- d6) δ 156.7, 149.1, 147.5, 135.3, 133.4, 127.5, 120.8, 115.1, 113.0, 112.3. 71.7, 58.1, 56.0, 55.8., 51.4, 36.0. Enantiomeric ratio was determined by SFC: Chiralpak® IC-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: CO2, B: Methanol with 0.1% of diethylamine, isocratic: A / B: 8 / 155, v / v, flow rate 1.2 mL / min. Synthesis of Compound 1h and Asymmetric transfer hydrogenation to (R)- Phenylephrine: Synthesis of 1-(3-hydroxyphenyl)-2-(methylamino)ethan-1-one hydrogen chloride 1h: To the cooled solution of MeNH2in THF (35.0 mL, 70.0 mmol, 3.0 equiv), was added 2- bromo-1-(3-hydroxyphenyl)ethan-1-one (5.0 g, 23.2 mmol, 1.0 equiv) in THF (15.0 mL) slowly at 0oC under nitrogen. After the resulting solution was stirred at this temperature for 30-60 min, reaction mixture was filtered to remove MeNH2.HBr salt, THF solution was cooled to 0oC and 3M HCl in MeOH was added slowly and stirred for 1h at rt. After this time, the crude reaction was filtered and cake was washed with MTBE (5 mL) and dried under vacuum to afford HCl salt 1h (1.7g, 36% over 2 steps).1H NMR (400 MHz, CD3OD) δ 7.48 (m, 1H), 7.43-7.33 (m, 3H), 7.12 (m, 1H), 4.69 (s, 2H), 2.81 (s, 3H);13CNMR (100 MHz, CD3OD) δ 192.8, 159.4, 136.2, 131.3, 123.0, 120.5, 115.3, 55.4, 33.5. Synthesis (R)-3-(1-hydroxy-2-(methylamino)ethyl)phenol, 2h: A 40 mL vial was charged with compound 1h (0.3 g, 1.49 mmol), catalyst Ru-TsDPEN (1.42 mg, 0.15 mol%) and MeOH (10 V). To the above reaction flask HCOOH / TEA mixture (0.3 mL) was added at RT and stirred at 60-65 ºC for 5 h. The reaction was completed (monitored by TLC & HPLC). [TLC condition- DCM:MeOH:NH4OH = 80:18:2]. After completion of starting material, the reaction mixture was neutralized with NH4OH (1 V). The organic solvent (MeOH) was concentrated, and the crude was dissolved in DCM (1.0 mL). The crude compound was directly purified by column chromatography, providing 2h as an off white solid (206 mg, 82% yield, off-white solid), er ratio:>99.9:0.1.1H NMR (400 MHz, CD3OD) δ 7.16 (t, J = 7.8 Hz, 1H), 6.87-6.79 (m, 2H), 6.73-6.66 (m, 1H) 4.75 (dd, J = 5.03 Hz, 1H), 2.88-2.77 (m, 2H), 2.49 (s, 3H);13C NMR (101 MHz, CD3OD) δ 158.8, 145.5, 130.5, 118.0, 115.7, 113.8, 72.2, 59.0, 35.3. Enantiomeric ratio was determined by SFC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 40 ºC, A: CO2, B: Isopropyl alcohol with 0.5% DEA, isocratic: A / B: 78 / 22, v / v, flow rate 1.4 mL / min. Synthesis of Compound 1s and Asymmetric transfer hydrogenation to (R)-Pipratecol: Synthesis of 1-(3,4-dihydroxyphenyl)-2-(4-(2-methoxy phenyl)piperazin-1-yl)ethan- 1- one hydrochloride, 1s: To a solution of 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (2g, 10.7 mmol, 1.0 equiv) in MeCN (10 mL, 5 V) and DMF (4 mL, 2 V) was added a solution of 1-(2- methoxyphenyl)piperazine (6.2 g, 31.2 mmol, 3.0 equiv) in MeCN (10 mL, 5 V) at rt. The reaction mixture was heated to 60 ºC and stirred under nitrogen for 3 h. Then the reaction mixture was cooled to rt and filtered to remove insoluble salts. The filter cake was rinsed with MeCN (10 mL × 2, 5 V × 2). Then combined organic solutions were concentrated under reduced pressure to afford crude product. The crude product was purified by flash column chromatography (EtOAc:Hexanes=20:80 to 80:20) to afford 1-(3,4-dihydroxyphenyl)-2-(4- (2-methoxy phenyl)piperazin-1-yl)ethan-1-one as brown solid (3.17 g, 86%). To a slurry of 1-(3,4-dihydroxyphenyl)-2-(4-(2-methoxy phenyl)piperazin-1-yl)ethan-1-one (1.03 g, 3 mmol, 1.0 equiv) in MeOH (5 mL, 5 V) was added conc. HCl (0.55 mL, 6.6 mmol, 2.2 equiv) at rt. The slurry was dissolved immediately after HCl addition and then precipitate formed after about stirring at rt for 20 seconds. The slurry was continually stirred for an additional 1h and then filtered. The filter cake was washed with MeOH (2.0 mL, 2V), dried overnight under vacuum at 40oC to afford hydrochloride salt 1s (1.06 g, 85%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 10.65 (broad s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 -6.97 (m, 4H), 6.92 (td, J = 7.2, 1.4 Hz, 1H), 6.36 (broad s, 3H), 5.04 (s, 2H), 3.79 (s, 3H), 3.34 (broad s, 2H), 3.63-3.50 (m, 4H), 3.40-3.26 (m, 4H).13C NMR (101 MHz, DMSO-d6) 189.3, 152.5, 152.0, 145.8, 138.6, 125.6, 124.3, 121.9, 121.0, 118.8, 115.6, 115.0, 112.3, 59.8, 55.6, 52.1, 48.7, 46.9. Synthesis of (R)-4-(1-hydroxy-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)benzene- 1,2-diol, 2s: To a mixture of hydrochloride salt 1s (208 mg, 0.5 mmol, 1 eq.), Ru catalyst (0.62 mg, 1.0 μmol, 0.2 mol%) in MeOH (1.1 mL, 5 V) was added formic acid / triethyl amine complex (5:2) (0.2 mL, 1 V). The reaction mixture was stirred at 60oC for 4 h. Then the reaction mixture was treated with formic acid / TEA (5:2) (0.06 mL, 0.3 V) again and stirred at 60oC for 4 h. The reaction mixture was cooled to rt, basified with aq. NH4OH (0.2 mL, 1 V), and concentrated under reduced pressure. The crude product was dissolved in CH2Cl2(2 mL, 10 V) and washed with water (2 mL, 10 V). The reaction mixture was concentrated under reduced pressure and purified by column chromatography (CH2Cl2:MeOH = 98:2 to 94:6) to afford 2s (100 mg, 58%) as an off-white solid, e.r: 99.6:0.4.1H NMR (400 MHz, CD3OD) δ 7.03-6.88 (m, 4H), 6.84 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 6.70 (dd, J = 8.2, 2.0 Hz, 1H), 4.89 (broad s, 3H), 4.72 (dd, J = 9.3, 3.6 Hz, 1H), 3.84 (s, 3H), 3.07 (broad s, 4H), 2.80-2.79 (m, 2H), 2.72 (broad s, 2H), 2.68 (partially obscured dd, J = 13.0, 9.2 Hz, 1H), 2.51 (dd, J = 12.8, 3.5 Hz, 1H).13C NMR (101 MHz, CD3OD): 153.9, 146.3, 145.8, 142.3, 136.2, 124.6, 122.2, 119.4, 118.7, 116.1, 114.4, 112.8, 71.5, 67.5, 55.9, 54.6, 51.7; HRMS (ESI) [M+H]+ m / z calcd for [C19H25N2O4]+ 329.1809, found 345.1847. Enantiomeric ratio was determined by HPLC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: n-heptane with 0.1% diethylamine, B: Isopropyl alcohol with 0.1% diethylamine, Isocratic A / B, 70 / 30 v / v, flow rate 1.0 mL / min. Synthesis of Compound 2k and Asymmetric transfer hydrogenation to (R)-Acgeline (4) and (R)-Tembaamide (5): Synthesis of 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrogen chloride, 1k: A 3-neck round-bottom-flask was charged with urotropine (6.12 g, 43.65 mmol), dichloromethane (150 mL, 15 V), and then 2-bromo-1-(4-methoxyphenyl)ethan-1-one (10 g, 43.65 mmol) was added portion wise. Immediate formation of creamy white solid was observed, and the reaction mixture was stirred at room temperature for 24 h. The reaction mass was filtered through a sintered funnel, washed with DCM (2 x 20 mL), MTBE (2 x 50 mL), and dried under vacuum to give an off-white hexamine salt (11.0 g, 68.5% yield). A 100 mL three-neck round-bottom-flask equipped with a stirrer, internal thermometer, was charged with hexamine salt (5.0 g, 13.58 mmol) and MeOH (25 mL, 5 V). The reaction mixture was treated with the dropwise addition of 12 M HCl (2.26 mL, 2.0 equiv) at room temperature over a period of 5 min. During the addition, the mixture changed from off-white slurry to light-yellow solution over a period of 24 hours. The solvent was evaporated, and the solid was washed with cold MeOH (5 mL, 1 V). The solid 1k (2.0 g, 73% yield) was carried forward for the next step.1HNMR (400 MHz, DMSO-d6) δ ppm 8.25 (brs, 3H), 7.95 - 8.04 (m, 2H), 7.03 - 7.14 (m, 2H), 4.53 (s, 2H), 3.88 (s, 3H);13C {H} NMR (101MHz, DMSO-d6) δ 191.7, 164.6, 131.1, 127.0, 114.7, 56.2, 44.9. Synthesis of (R)-2-amino-1-(4-methoxyphenyl)ethan-1-ol, 2k: A stirred solution of 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrochloride 1k (1.0 g, 4.97 mmol, 1.0 equiv) in MeOH (8.0 V, 8.0 mL) was treated with Ru cat (0.15 mol%, 4.83 mg) followed by formic acid / TEA (5:2) (1.0 V, 1.0 mL). The reaction mixture was stirred at 60oC under N2sparging for 8h. After cooling to rt, the reaction mixture was treated with NH4OH (2.0 V; 2.0 mL) and stirred at RT for 30 min. Most of the MeOH was evaporated under vacuum in rotavapor and the reaction mass was extracted with EtOAc (3 X 10 mL). The combined organic layer was washed with H2O (1 X 5 mL), brine (1 X 5 mL) and evaporated to dryness to get the desired amino alcohol 2k (780 mg, 94%) as a brown solid, er ratio: > 99.9:0.1.1H NMR (400 MHz, DMSO-d6) δ 7.25-7.19 (m, 2H), 6.90-6.84 (m, 2H), 4.53-4.38 (m, 1H), 3.73 (s, 3H), 3.16-2.94 (m, 1H), 2.66-2.54 (m, 1H);13CNMR (100 MHz, DMSO-d6): δ 158.5, 136.0, 127.3, 113.6, 73.2, 55.2, 49.4. Enantiomeric ratio was determined by HPLC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: n-Hexane with 0.1% Isopropylamine, B: Isopropyl alcohol, Gradient: 0 min-20%, 10 min-55% v / v, flow rate 1.2 mL / min. Synthesis of (R)-Acgeline, 4: A 40 mL reaction vial equipped with stirrer bar, and N2line was charged with compound 1k (0.5 g, 2.479 mmol), MeOH (5 mL), Ru catalyst (2.31 mg, 0.15 mol%) and formic acid / TEA (5:2) (0.5 mL, 1V). The reaction mixture was stirred at 62oC. After 16 h, the reaction mixture was cooled to room temperature, neutralized with aq. NH4OH (1V) and the solvent was removed under reduced pressure and extracted in IPAc (2X 10 mL). The crude 2k was carried for used in next step to couple with cinnamoyl chloride. To a solution of 2k (0.2 g, 1.196 mmol) in dry CH2Cl2 (4 mL), a solution of NaOH (0.143g, 3.59 mmol) in water (3.3 mL) was added at ice bath temperature. The mixture was stirred vigorously for 10 min. A solution of cinnamoyl chloride (0.239 mg, 1.43 mmol) in anhydrous toluene (1.0 mL) was added dropwise to the reaction mixture, while vigorously stirring. After the addition was complete, the reaction mixture was stirred for a further 5h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was separated and washed with brine. The solvent was evaporated and then the resulting solid was recrystallized from ethanol / water (v / v = 80:20) to afford the natural product (R)-(-)-Acgeline, 4, in 61% yield.1H NMR (400 MHz, DMSO-d6) δ 8.14 (t, J = 5.8 Hz, 1H), 7.54 (d, J = 6.5 Hz, 2H), 7.45-7.33 (m, 4H) 7.27 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 15.8 Hz, 1H), 5.44 (d, J = 3.0 Hz, 1H), 4.61 (m ,1H), 3.73 (s, 3H), 3.47-3.36 (m, 1H), 3.28-3.17 (m, 1H);13C NMR (101 MHz, DMSO-d6) δ 165.1, 158.3, 138.5, 135.7, 134.9, 129.4, 128.9, 127.5, 127.1, 122.4, 113.4, 70.9, 55.0, 47.0. Synthesis of (R)-Tembaamide, 5: To a stirred solution of 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrochloride 1k (1.0 g, 4.97 mmol, 1.0 equiv) in MeOH (8.0 V, 8.0 mL), Ru cat (0.15 mol%, 4.83 mg) followed by formic acid / TEA (5:2) (1.0 V, 1.0 mL)were added. The reaction mixture was stirred at 60oC under N2sparging for 8h. After cooling to rt, the reaction mixture was treated with NH4OH (2.0 V; 2.0 mL) and stirred at RT for 30 min. Next, most of the MeOH was evaporated under vacuum in rotavapor and reaction mass was extracted with EtOAc (3 X 10 mL). The combined organic layer was washed with H2O (1 X 5 mL), brine (1 X 5 mL) and evaporated to dryness to get the desired amino alcohol 2k (870 mg) as a brown semi solid. To the crude compound 2k, Toluene (20 mL) and aq. NaOH (10%, 4 mL, 4.0 eq) were added and cooled to 0 °C with an ice bath. Benzoyl chloride (0.635 mL, 5.467mmole, 1.1 equiv) in toluene (2 mL) were added dropwise at 0°C and the reaction mass was stirred for 2h at 0-10 °C. Reaction progress was monitored by TLC, and after confirming complete consumption of amino alcohol, the reaction mass was diluted with EtOAc (15 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1 X 5 mL). The combined organic layers were washed with H2O (1 X 5 mL) and brine (1 X 5 mL), and then dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude product was purified by silica gel column chromatography to afford 5 as an off-white solid (900 mg, 67% yield).1HNMR (400 MHz, CDCl3) δ ppm 7.67 (d, J = 7.3 Hz, 2H), 7.41 (d, J = 7.3 Hz, 1H), 7.28 - 7.38 (m, 2H), 7.19 - 7.28 (m, J =8.5 Hz, 2H), 6.72 - 6.90 (m, J = 8.6 Hz, 2H), 6.61 (brs., 1H), 4.81 (dd, J = 7.9, 3.3 Hz, 1H), 3.78 (ddd, J = 10.5, 7.0, 3.4 Hz, 1H), 3.73 (s, 3H), 3.36 - 3.48 (m, 1H), 3.27 (brs., 1H);13C NMR (101 MHz, CDCl3) δ 168.6, 159.3, 134.1, 133.9, 131.7, 128.6, 127.1, 127.0, 114.0, 73.3, 55.3, 47.8. Synthesis of 2-amino-1-(3-fluorophenyl)ethan-1-one hydrogen chloride, 1i: To a 100 mL RBF, 2-bromo-1-(3-fluorophenyl)ethan-1-one (4.2 g, 19.53 mmol) and CHCl3 (10 V) were charged, followed by HMTA (2.73 g, 19.53 mmol). The reaction mixture was stirred for 2h at 50oC, filtered, and the solid was washed with CHCl3(10 V) and dried under vacuum to afford hexamine salt 1i as a white solid (6.4 g, 92%). The product contains NH4Cl as a byproduct (observed by1H NMR).1H NMR (600 MHz, DMSO-d6) δ 8.52 (s, 3H), 7.89-7.83 (m, 2H), 7.68-7.59 (m, 2H), 7.38 (t, J = 51 Hz, 3H, NH4+), 4.61 (d, J = 5.4 Hz, 2H);13C NMR (150 MHz, DMSO-d6) 192.4, 163.4, 161.7, 136.2,132.3, 132.2, 132.1, 131.4, 131.3, 131.2, 131.1, 125.4, 125.3, 124.6, 124.4, 122.4, 122.2, 121.4, 121.3, 121.2, 115.8, 115.6, 114.8, 114.6, 45.5, 45.4, 44.7, 44.6. Synthesis of (R)-2-amino-1-(3-fluorophenyl)ethan-1-ol, 2i: A 100 mL RBF was charged with compound 1i (1.0 g, 5.27 mmol, qNMR: 62.6%) and MeOH (10 V). The catalyst (TsDPEN: 6.53 mg, 0.2 mol%) and HCOOH / TEA mixture (1 mL) were added to the reaction mixture at RT. The reaction mixture was stirred at 60-65oC for 7 h. The starting material was not completely consumed, then 0.3 mL of HCOOH / TEA was added and continued the reaction overnight. The reaction was completed (monitored by HPLC). The reaction mixture was cooled to rt, neutralized with NH4OH (1 V), and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford crude compound. The crude compound was purified by column chromatography (on SiO2, 15 to 20% MeOH in DCM) to afford 2i as a tan color solid (425 mg (qNMR: 90%), corrected yield: 74.7%). er ratio: 99.6:0.4.1H NMR (600 MHz, DMSO-d6) δ 7.37-7.33 (m, 1H), 7.16-7.12 (m, 2H), 7.04 (t, J = 8.4 Hz, 1H), 4.48-4.46 (m, 1H), 2.70-2.67 (m, 1H), 2.59-2.56 (m, 1H);13C NMR (150 MHz, DMSO- d6) δ 163.4, 161.8, 148.1, 130.2, 122.4, 113.8, 113.7, 113.0,112.9, 74.3, 50.4. Enantiomeric ratio was determined by SFC: Chiralpak® IA-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 25 ºC, A: CO2, B: Methanol with 0.1% of DEA, Gradient: 10% Methanol v / v, flow rate 2.0 mL / min. Synthesis of 2-amino-1-(3-chlorophenyl)ethan-1-one hydrogen chloride 1j: A 3-neck RBF was charged with 2-bromo-1-(3-chlorophenyl)ethan-1-one (4g, 0.014 mol), HMTA (3 g, 0.016 mol), IPA (4V), and ACN (4V). Immediate formation of a creamy white solid was observed. The reaction was stirred for 2 h and the cake was washed with IPA (90 mL). The cake was dried under vacuum to afford hexamine salt 3.0g (94% yield). A 25 mL single-neck RBF equipped with a stirrer, internal thermometer, and N2line was charged with the above hexamine salt (3.0 g, 8.5 mmol) and MeOH (6V). The reaction mixture was treated with the dropwise addition of 12M HCl (2 mL, 2.0 eq) at rt over a period of 5 min. During the addition, the slurry changed from pale white to a light-yellow solution over a period of 24 h. After 24 h, the solvent was evaporated, and the solid was washed with cold MeOH and filtered, dried to give 1j (1.1g, 71% yield) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.63-8.38 (s, 3H), 8.04 (t, J = 1.85 Hz, 1H), 7.97 (m, 1H), 7.8 (m, 1H), 7.62 (m, 1H), 4.61 (s, 2H);13CNMR (100 MHz, DMSO-d6) δ 192.1, 135.5, 134.1, 133.9, 131.0, 127.9, 126.8, 44.9. Synthesis of (R)-2-amino-1-(3-chlorophenyl)ethan-1-ol, 2j: A 40 mL vial was charged with compound 1j (0.3 g, 1.456 mmol), catalyst Ru-TsDPEN (1.39 mg, 0.15 mol%) and MeOH (10 V). To the above reaction flask, HCOOH / TEA mixture (0.3 mL) was added at RT and stirred at 60-65oC for 5 h. The reaction was completed (monitored by TLC & HPLC). [TLC condition- DCM: MeOH: NH4OH = 90:9:1]. After completion of the reaction, the reaction mixture was neutralized with NH4OH (1 V). The organic solvent (MeOH) was concentrated, and crude product was dissolved in DCM (1.0 mL). The crude compound was directly purified by column chromatography, providing 2j (226 mg, 90% yield) as an off white solid, er ratio: 99.6:0.4.1H NMR (400 MHz, DMSO-d6) δ 7.39-7.31 (m, 2H), 7.30-7.23 (m, 2H), 4.46 (dd, J = 4.3 Hz, 1H), 2.69 (m, 1H), 2.58 (m, 1H);13C NMR (101 MHz, DMSO-d6) δ 147.0, 132.7, 129.8, 126.6, 125.8, 124.6, 73.6, 49.8. er ratio: 99.6:0.4. Enantiomeric ratio was determined by SFC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 25 ºC, A: CO2, B: Isopropyl alcohol with 0.1% diethylamine, gradient: A / B: 0 min-5%, 3 min-5% and 10 min- 30%, v / v, flow rate 2.0 mL / min. Synthesis of 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrogen chloride, 1k: This compound was synthesized as previously described. A 3-neck RBF was charged with urotropine (6.12 g, 43.65 mmol), dichloromethane (150 mL, 15 V), and then 2-bromo-1-(4- methoxyphenyl)ethan-1-one (10 g, 43.65 mmol) was added portion wise. Immediate formation of creamy white solid was observed, and the reaction mixture was stirred at room temperature for 24 h. The reaction mass was filtered through a sintered funnel, washed with DCM (2 X 20 mL), MTBE (2 X 50 mL), and dried under vacuum to give off white hexamine salt 11.0 g (68.5 % yield). A 100 mL single-neck RBF equipped with a stirrer, internal thermometer, was charged with hexamine salt (5.0 g, 13.58 mmol) and MeOH (25 mL, 5 Volume). The reaction mixture was treated with the dropwise addition of 12M HCl (2.26 mL, 2.0 eq) at room temperature over a period of 5 min. During the addition, the slurry changed from off-white to a light-yellow solution over a period of 24 hours. The solvent was evaporated, and the solid was washed with cold MeOH (5 mL, 1.0 volume). The solid 1k (2.0 g, 73%) was carried forward for the next steps.1HNMR (400 MHz, DMSO-d6) δ ppm 8.25 (brs, 3H), 7.95 - 8.04 (m, 2H), 7.03 - 7.14 (m, 2H), 4.53 (s, 2H), 3.88 (s, 3H);13C NMR (101MHz, DMSO-d6) δ 191.7, 164.6, 131.1, 127.0, 114.7, 56.2, 44.9. Synthesis of (R)-2-amino-1-(4-methoxyphenyl)ethan-1-ol, 2k: A stirred solution of 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrochloride 1k (1.0 g, 4.97 mmol, 1.0 equiv) in MeOH (8.0 V, 8.0 mL) was treated with Ru cat (0.15 mol%, 4.83 mg) followed by formic acid / TEA (5:2) (1.0 V, 1.0 mL). The reaction mixture was stirred at 60oC under N2sparging for 8h. After cooling to rt, the reaction mixture was treated with NH4OH (2.0 V; 2.0 mL) and stirred at RT for 30 min. Most of the MeOH was evaporated under vacuum in rotavapor and the reaction mass was extracted with EtOAc (3 X 10 mL). The combined organic layer was washed with H2O (1 X 5 mL), brine (1 X 5 mL) and evaporated to dryness to get the desired amino alcohol 2k (780 mg, 94%) as a brown solid, er ratio: > 99.9:0.1.1H NMR (400 MHz, DMSO-d6) δ 7.25-7.19 (m, 2H), 6.90-6.84 (m, 2H), 4.53-4.38 (m, 1H), 3.73 (s, 3H), 3.16-2.94 (m, 1H), 2.66-2.54 (m, 1H);13CNMR (100 MHz, DMSO-d6): δ 158.5, 136.0, 127.3, 113.6, 73.2, 55.2, 49.4. Enantiomeric ratio was determined by HPLC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: n-Hexane with 0.1% Isopropylamine, B: Isopropyl alcohol, Gradient: 0 min-20%, 10 min-55% v / v, flow rate 1.2 mL / min. Compound 1l is commercially available and was purchased. Synthesis of (R)-4-(2-(benzyl(methyl)amino)-1-hydroxyethyl) benzene-1,2-diol, 2l: A 3-neck RBF was charged with compound 1l (5.0 g, 16.26 mmol), catalyst (14.5 mg, 0.13 mol%), and MeOH (100 mL, 10V). This solution was charged with formic acid and TEA (5:2) (10.5 mL). The reaction mixture was stirred at reflux for 20 h. The reaction mixture was cooled to RT and treated with 15 mL of NH4OH. The slurry was stirred for 15 min, treated with water (150 mL), and stirred for another 30 min. The slurry was filtered, washed with water (20 V), and dried under vacuum. The product 2l (3.74 g, 85% isolated yield, er ratio: 93.2:6.8) was obtained as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 7.30-7.20 (m, 5H), 6.72 (s, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 7.6 Hz, 1H), 4.55 (dd, J = 7.6, 4.6 Hz, 1H), 2.52-2.47 (m, 1 H), 2.37 (dd, J = 12.5, 4.4 Hz, 1H), 2.17 (s, 3 H);13CNMR (100 MHz, DMSO-d6) δ 144.9, 144.2, 139.1, 135.6, 128.8, 128.1, 126.8, 117.0, 115.1, 113.7, 70.1, 65.4, 61.9, 42.4, 39.5. Enantiomeric ratio was determined by SFC: Chiralpak® AD-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 30 ºC, A: CO2, B: Isopropyl alcohol with 0.1% diethylamine, isocratic: A / B: 70 / 30, v / v, flow rate 1.5 mL / min. Compound 1m is commercially available and was purchased. Synthesis of (R)-3-(2-(benzyl(methyl)amino)-1-hydroxyethyl) phenol, 2m: A 3-neck RBF was charged with 2-(benzyl(methyl)amino)-1-(3-hydroxyphenyl)ethan-1-one hydrochloride salt (1.0 g, 3.4 mmol), MeOH (10 mL), Ru catalyst (2.7 mg, 0.13 mol%), and HCO2H / TEA (5:2, 1 ml), and heated to 60 °C for 18 h. The crude mixture was analyzed by HPLC, which showed 100A% conversion of stating material, cooled, and filtered through charcoal / celite and washed the bed with methanol. To this crude mixture was charged aq. NH3(2.0 mL) and water (5 mL). The solvent was removed under reduced pressure, passed through silica gel bed, and evaporated to dryness to obtain 2m (0.620 g, 71% isolated yield, >99.9:0.1 er ratio) as an off-white solid.1H NMR (600 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.29-7.23 (m, 5H), 7.09 (dd, J = 6.7, 3.8 Hz, 1H), 6.76 (s, 1H), 6.73 (s, 1H), 6.63 – 6.62 (m, 1H), 4.94 (s, 1H), 4.65 (s, 1H), 3.56 (s, 2H), 2.51 (s, 1H), 2.44 – 2.42 (m, 1H), 2.21 (d, J = 2.5 Hz, 3H);13C NMR (151 MHz, DMSO-d6) δ 157.5, 146.7, 139.5, 129.2, 129.2, 128.5, 127.2, 117.2, 114.1, 113.4, 70.72.65.7, 62.3, 42.8. Enantiomeric ratio was determined by SFC: Chiralpak® IK, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 30 ºC, A: CO2, B: Methanol with 0.1% of DEA, Gradient: 10% of Methanol with 0.1% of DEA, v / v, flow rate 2.5 mL / min. Synthesis of 1-(4-hydroxyphenyl)-2-morpholinoethan-1-one, 1n: To a mixture of 2-bromo-1-(4-hydroxyphenyl)ethan-1-one (4.0 g, 18.6 mmol) in acetonitrile was added morpholine (3 equiv.) at room temperature. The mixture was allowed to stir at room temperature for 1 h. The formation of a white precipitate was observed during the course of the reaction. The precipitate was filtered and the cake was washed with water followed by acetonitrile and dried under air followed by vacuum over to obtain the product as white solid (3.8 g, 92%). To a suspension of 1-(4-hydroxyphenyl)-2-morpholinoethan-1- one (3.7 g, 16.7 mmol) in MeOH (5 V) at room temperature was added a solution of 3M HCl in MeOH (11.15 mL, 33 mmol). The resulting suspension was stirred at room temperature for 3 h and filtered, and the cake was washed with MeOH and dried to obtain 1n in 91% (3.9 g) yield.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.74 (br s, 1H), 7.87 (d, J = 8 Hz, 2H), 6.98 (d, J = 12 Hz, 2H), 5.02 (s, 2H), 3.95-3.92 (br m, 4H), 3.45-3.25 (m overlapping with the water peak, 7 H).13C NMR (100 MHz, DMSO-d6) δ 189.6, 164.2, 132.3, 125.6, 116.2, 63.4, 60.5, 52.6. Synthesis of (R)-4-(1-hydroxy-2-morpholinoethyl)phenol, 2n: To a mixture of hydrochloride salt 1n (500 mg, 1.94 mmol, 1 eq.), Ru catalyst (1.8 mg, 2.9 μmol, 0.15 mol%) in MeOH (10 V) was added formic acid / triethyl amine complex (5:2) (1 V). The reaction mixture was stirred at 60oC for 14 h, while a slow stream of N2 bubbling through the reaction mixture. HPLC after 14 h indicated the presence of 73A% of the product along with unreacted starting material. The mixture was then charged additional catalyst (0.15 mol%) followed by the formic acid / TEA (5:2) (1 V) and stirred at 60oC for 14h. HPLC showed the complete consumption of the starting material. Then the reaction mixture was cooled to room temperature and MeOH was evaporated. The crude mixture was then treated with aq. NH4OH and stirred. The resulting suspension was filtered and obtained the product 2n as a light brown solid (220 mg, 51%) and the presence of additional material (not quantified) was observed in the mother liquor. er ratio: 99.6:0.4.1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.06 (d, J = 8 Hz, 2H), 6.63 (d, J = 8 Hz, 2H), 4.78 (s, H), 4.55-4.53 (m, 1H), 3.51-3.49 (m, 4H), 2.44-2.26 (overlapping m, 6H);13C NMR (100 MHz, DMSO-d6) δ 156.7, 135.2, 127.6, 115.1, 69.6, 67.2, 66.6, 54.1; HRMS (ESI) [M+H]+ m / z calcd for [C12H18NO3]+224.1287, found 224.1308. Enantiomeric ratio was determined by HPLC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: n-heptane with 0.1% diethylamine, B: Isopropyl alcohol with 0.1% of DEA, isocratic: A / B: 30 / 70, v / v, flow rate 1.0 mL / min. Synthesis of 2-(benzyl(methyl)amino)-1-(3-chlorophenyl) ethan-1-one hydrochloride, 1o: A single-neck RBF equipped with a magnetic stir bar was charged with N,N- dimethylacetamide (11 mL, 10 V) and 2-chloro-1-(3-chlorophenyl)ethan-1-one (a) (1.1 g, 5.82 mmol) at 10 °C. N-Benzylmethylamine (0.79 mL, 6.11 mmol, 1.05 equiv.) was charged dropwise over 5 min resulting in a clear brown color solution, followed by the dropwise addition of triethylamine (0.85 mL, 6.11 mmol, 1.05 equiv.) resulting in thickening of the reaction mixture. Cooling was removed and the reaction mixture was heated to 35 °C using a water bath. The reaction mixture was stirred at this temperature for 2.5 h until a complete conversion of the starting material was confirmed by TLC. Afterwards, the reaction mixture was diluted with 30 mL of water and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were then washed with water, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography using 5-40% ethyl acetate / hexane solvent system to give 2-(benzyl(methyl)amino)-1-(3-chlorocyclohexa- 1,5- dien-1-yl)ethan-1-one (1.1 g, 4.02 mmol, 69%) as a yellow oil. A single neck RBF equipped with a magnetic stir bar was charged with methanol (10 mL, 10 V) and 2-(benzyl(methyl)amino)-1-(3-chlorocyclohexa-1,5-dien-1-yl)ethan-1-one (1.0 g, 3.65 mmol) at room temperature. 3M HCl in MeOH (4.9 mL, 14.61 mmol, 4.0 equiv.) was charged in one portion and the reaction mixture was stirred at room temperature for 1 h. TLC confirmed a complete consumption of the starting material. Afterwards, the reaction mixture was evaporated to dryness to get yellow oil. Heptane (10 mL, 10 V) was charged to the flask and evaporated again to get a yellow solid. Finally, the yellow solid was recrystallized with Ethyl acetate / heptane solvent system to get 1o (1.11 g, 3.58 mmol, 98%) as an off-white solid.1H NMR (600 MHz, CD3OD) δ 8.03 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.66 – 7.56 (m, 3H), 7.51 (s, 3H), 5.10 (d, J = 17.7 Hz, 1H), 4.97 (d, J = 17.8 Hz, 1H), 4.57 (d, J = 12.8 Hz, 1H), 4.29 (d, J = 12.8 Hz, 1H), 2.96 (s, 3H);13C NMR (150 MHz, CD3OD) δ 191.4, 136.6, 136.4, 135.9, 132.4, 131.9, 131.5, 130.6, 130.5, 129.2, 127.8, 61.9, 41.9 (one carbon merging). Synthesis of (R)-2-(benzyl(methyl)amino)-1-(3-chlorophenyl) ethan-1-ol, 2o: A 50 mL 3-neck round bottom flask, equipped with a magnetic stir bar, nitrogen line and a reflux condenser, was charged with MeOH (5 mL, 10 V) and 3-chloro N-Benzylmethyl adrenalone hydrochloride 1o (0.5 g, 1.61 mmol). The reaction mixture was purged with N2 for 10 mins before charging Ru-catalyst (1.3 mg, 0.002 mmol, 0.0013 equiv.), followed by charging formic acid / triethylamine (5:2) complex (0.65 mL, 1.3 V). The reaction mixture was refluxed at 65-70 °C for 9 h, in which 98.7% conversion was observed. The reaction mixture was stirred for another hour and then cooled to room temperature. Charged water (2.5 mL, 5 V) and ammonium hydroxide (1 mL, 2 V) to see oiling out of the reaction mixture. The reaction mixture was concentrated to dryness and diluted with water. Extracted with EtOAc (3 X 10 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography using 25-30% ethyl acetate / hexane solvent to give (R)-2-(benzyl(methyl)amino)-1-(3-chlorophenyl)ethan- 1-ol 2o (0.28 g, 1.02 mmol, 63%) as colorless oil. er ratio: 98.0: 2.0.1H NMR (600 MHz, CDCl3) δ 7.30 – 7.25 (m, 3H), 7.25 – 7.19 (m, 3H), 7.19 – 7.12 (m, 3H), 4.63 (dd, J = 9.1, 5.0 Hz, 1H), 3.66 (d, J = 13.1 Hz, 1H), 3.46 (d, J = 13.1 Hz, 1H), 2.54 – 2.39 (m, 2H), 2.24 (s, 3H);13C NMR (150 MHz, CDCl3) δ 144.5, 138.1, 134.4, 129.7, 129.2, 128.6, 127.7, 127.6, 126.2, 124.1, 68.9, 65.4, 62.5, 41.9; HRMS (ESI) [M+H]+ m / z calcd for [C16H19ClNO]+ 276.1150, found 276.1138; Enantiomeric ratio was determined by SFC: Chiralpak® IA, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 30 ºC, A: CO2, B: Methanol, Gradient: 5% of Methanol, v / v, flow rate 2.0 mL / min; 2-(benzyl(methyl)amino)-1-(thiophen-2-yl)ethan-1-one hydrogen chloride, 1p: To 1.0 g of Bromo compound dissolved in anhydrous toluene (10 mL) was added dropwise N-Methylbenzylamine (2.0 equiv) at 0 ºC. The reaction was brought to ambient temperature and stirred at the same temperature for 2h. The solids were filtered and the filtrate was concentrated under vacuum to afford 1.2 g of 2-(benzyl(methyl)amino)- 1-(thiophen-2- yl)ethan-1-one crude thick brown liquid.1.0 g of crude 2-(benzyl(methyl)amino)-1-(thiophen- 2-yl)ethan-1-one was dissolved in 10.0 mL of MTBE and 5.0N HCl in IPA (1.5 equiv) was added dropwise. Solid material was observed, and reaction was allowed to stir at ambient temperature for 1h. The solid material was filtered, washed with MTBE, dried under vacuum to afford 1.0 g of crude 1p that was carried to the next step with no further purification.1H NMR (400 MHz, CD3OD) δ 8.04 (dd, J = 4.9, 1.0 Hz, 1H), 8.00 (dd, J = 3.9, 1.0 Hz, 1H), 7.62-7.58 (m, 2H), 7.51-7.44 (m, 4H), 7.28 (dd, J = 4.9, 3.9 Hz, 1H), 5.02 (d, J = 17.4 Hz, 1H), 4.88 (d, J = 17.2 Hz, 1H), 4.57 (d, J = 12.8 Hz, 1H), 4.33 (d, J = 12.8 Hz, 1H), 2.96 (s, 3H). Synthesis of (S)-2-(benzyl(methyl)amino)-1-(thiophen-2-yl)ethan-1-ol, 2p A 10.0 mL sealed tube was charged compound 1p (250 mg, 1.0 mmol), MeOH (2.5 mL, 10V), Ru catalyst (0.15 mol%) and formic acid / TEA (5:2) (1V) with nitrogen bubbling. The reaction mixture was stirred at 62 ℃ under nitrogen bubbling. After 3 h, the reaction mixture was monitored for conversion by LC-MS / HPLC. Both showed completion of SM. After 3 h, the reaction mixture was cooled to room temperature, neutralized with aq. NH4OH (1 V). The volatiles were removed under vacuum and diluted with DCM (20 mL). The organic layer was washed with water (2 X 5 mL). The organic layer was dried over anhydrous Na2SO4 and reduced under vacuum to afford crude which was purified using Biotage® with eluent as: DCM / MeOH (10%) to afford 2p (150 mg, 89% isolated yield) as a brown viscous oil. er ratio: 98.8:1.2.1H NMR (400 MHz, DMSO-d6) δ 7.23 – 7.40 (m, 6H), 6.94 – 7.06 (m, 2H), 5.11 (m, 1H), 4.94 (brs, 1H), 3.65 (q, 2H, J = 18.32 Hz), 2.66-2.86 (m, 2H), 2.34 (s, 3H);13CNMR (100 MHz, DMSO-d6): δ 138.9, 130.0, 120.9, 119.7, 118.7, 117.9, 115.8, 115.3, 58.9, 56.6, 54.0, 33.4. Enantiomeric ratio was determined by SFC: Chiracel IC-3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 35 ºC, A: CO2, B: Methanol with 0.1% diethylamine, Isocratic: A / B: 88 / 12, v / v, flow rate 1.0 mL / min. Synthesis of 1-(3-methoxyphenyl)-2-(4-(m-tolyl) piperazin-1-yl)ethan-1-one hydrochloride, 1q: To a stirred solution of 1-(m-tolyl) piperazine (750 mg, 4.26 mmol, 1.0 equiv) in acetonitrile (18 mL, 24V) was added K2CO3 (706 mg, 5.11 mmol, 1.2 equiv) under N2 atmosphere at 0°C. The mixture was stirred for 5 min at 0°C before the addition of 2-bromo-1-(3-methoxyphenyl) ethan-1-one (975 mg, 4.26 mmol, 1.0 equiv). After complete consumption of the starting materials, the reaction mixture was quenched by the addition of H2O (4.5 mL, 6V) and diluted with DCM (4.5 mL, 6V). The aqueous layer was extracted with DCM (2 x 4.5 mL, 12V) and the collected organic layers were washed with brine (4.5 mL, 6V), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude product was purified by silica gel column chromatography to afford 1.22 g of the expected product as a colorless oil (88.4% yield). A solution of 1-(3-methoxyphenyl)-2-(4-(m-tolyl)piperazin-1-yl)ethan-1-one (158 mg, 0.49 mmol, 1.0 equiv) in MeOH (5.6 mL, 36V) was treated with the dropwise addition of 12 M HCl (0.10 mL, 1.22 mmol, 2.5 equiv) in H2O (0.47 mL, 3V) over a period of 5 min at 22°C. The resulting mixture was stirred for 1h at 22 °C. Upon completion, the reaction mixture was filtered through a charcoal bed and solka floc. The collected filtrate was distilled to remove MeOH, charged IPA (0.96 mL, 6V), and the distillation was continued. The product suspension in IPA was filtered and washed with IPA (0.16 mL, 1V). The solid was suction filtered and dried in a vacuum oven at 35°C for 18 h to afford 150 mg of the expected product 1q as a red solid (89.3% yield).1H NMR (400 MHz, CD3OD) δ 7.67 (dt, J = 7.6, 1.2 Hz, 1H), 7.60 (dd, J = 2.6, 1.5 Hz, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.0, 2.6 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 1.9 Hz, 1H), 7.06 (dd, J = 8.1, 2.4 Hz, 1H), 6.95 (d, J = 7.5 Hz, 1H), 5.16 (s, 2H), 3.91 (s, 3H), 3.82 – 3.59 (m, 8H), 2.38 (s, 3H);13C NMR (101 MHz, CD3OD) δ 190.3, 160.3, 147.7, 139.5, 134.8, 130.0, 129.2, 124.0, 120.8, 120.5, 118.3, 114.7, 112.4, 60.9, 54.7, 52.2, 47.5, 20.3. Synthesis of (R)-1-(3-methoxyphenyl)-2-(4-(m-tolyl) piperazin-1-yl) ethan-1-ol, 2q: To a stirred solution of 1-(3-methoxyphenyl)-2-(4-(m-tolyl) piperazin-1-yl) ethan-1-one hydrochloride (1q) (80 mg, 0.2318 mmol, 1.0 eq.) in MeOH (0.8 mL, 10V) were added (S.S)- Teth-TsDpen RuCl catalyst (0.22 mg, 0.3477 µmol, 0.15 mol%) and a 5:2 mixture (by volume) of formic acid and triethyl amine (0.08 mL, 1V) under N2atmosphere at 22°C. The reaction mixture was heated to 62°C and agitated for 6 h at the same temperature. After 6 h of stirring at 62°C (reaction progress was monitored by HPLC), the reaction mixture was cooled to 22°C and neutralized by addition of aq. NH4OH (0.08 mL, 1V). The resulting slurry was filtered, and the wet cake was successively washed with HPLC grade H2O (0.48 mL, 6V), MeOH (0.40 mL, 5V), and n-heptane (0.16 mL, 2 V). The cream-colored wet cake was first dried via vacuum suction and then under vacuum oven at 35 ºC for 48 h to afford 2q (65.0 mg, 86.0% yield) as a white solid, er ratio: 99.6:0.4.1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.9 Hz, 1H), 7.11 – 7.04 (m, 1H), 6.92 – 6.84 (m, 2H), 6.74 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 6.70 – 6.59 (m, 3H), 4.68 (dd, J = 9.8, 4.1 Hz, 1H), 3.73 (s, 3H), 3.13 (pt, J = 7.4, 3.3 Hz, 4H), 2.81 (ddd, J = 10.7, 6.4, 3.4 Hz, 2H), 2.56 – 2.45 (m, 4H), 2.24 (s, 3H);13C NMR (101 MHz, CDCl3) δ 159.8, 151.3, 143.9, 138.9, 129.4, 129.0, 120.9, 118.2, 117.1, 113.4, 113.2, 111.3, 68.8, 66.2, 55.3, 53.1, 49.4, 21.8; HRMS (ESI) [M+H]+ m / z calcd for [C20H27N2O2]+ 327.2067, found 327.2058. Enantiomeric ratio was determined by SFC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 30 ºC, A: CO2, B: Isopropyl alcohol with 0.1% of diethylamine, gradient: A / B: 0 min: 20%, 8 min: 50%, 15 min: 50%, flow rate 0.5 mL / min. Synthesis of 1-(3,4-dihydroxyphenyl)-2-(4-(m-tolyl)piperazin-1-yl)ethan-1-one hydrochloride, 1r: A stirred solution of 2-chloro-1-(3,4-dihydroxyphenyl)ethan-1-one (0.514g, 2.68 mmol) in acetonitrile (6 V, 3 mL) was treated with 1-(3-methylphenyl)piperazine (0.582g, 2.68 mmol) and TEA (0.747 mL, 5.36 mmol). The reaction was stirred under N2 for 16 h at 46 ºC. LCMS was used to track reaction progress. The reaction mixture was cooled to RT, filtered, and rinsed with ACN (5V), and suction filtered. The solid collected was the triethylamine hydrochloride salt. The filtrate was concentrated and purified by flash column chromatography (0-10% MeOH in CH2Cl2). The collected fractions were dissolved in 3 mL of MeOH and treated with 12M HCl (0.5 ml). Upon stirring for 1h, the precipitate was filtered and rinsed with MeOH. The product 1r (725 mg, 75% yield) was collected as a cream-colored solid.1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.3, 2.1 Hz, 1H), 7.15 (app t, J = 7.76 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.85-6.81 (m, 2H), 6.70 (d, J = 7.4 Hz, 1H), 5.02 (s, 2H), 3.82-3.78 (m, 2H), 3.62-3.59 (m, 2H), 3.31-3.21 (m, 4H), 2.27 (s, 3H);13CNMR (100 MHz, DMSO-d6) δ 189.3, 152.5, 149.5, 145.7, 138.3, 129.0, 125.5, 121.8, 120.8, 116.6, 115.5, 114.9, 113.1, 59.7, 51.8, 45.1, 21.4. Synthesis of (R)-4-(1-hydroxy-2-(4-(m-tolyl)piperazin-1-yl)ethyl)benzene-1,2-diol, 2r: A solution of 1r (0.203 g, 0.560 mmol) in MeOH (10V;2.0 mL) was treated with Ru cat (0.30 mol%, 1.05 mg) in formic acid / TEA (5:2) (1V, 0.2 mL). The reaction mixture was stirred at 62oC under N2 sparging for 4 h, and more formic acid / TEA (5:2) (1V, 0.2 mL) was added. After an additional 4 h of stirring, HPLC indicated >98% conversion and the reaction mixture was cooled to rt and treated with NH4OH (1.5V; 0.3 mL). The solution was treated with brine (5 mL) and EtOAc (5 mL). The biphasic layers were stirred for 5 min, transferred to a separatory funnel, and separated. The aqueous layer was extracted with EtOAc (2 x 8 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by chromatography (on SiO2, 0-10% MeOH in CH2Cl2) and the amino alcohol 2r (154 mg, 82%) was collected as a white solid, er ratio: 99.3:0.7.1H NMR (400 MHz; CD3OD): δ 8.44 (s, 1 H), 7.15 (app t, J = 7.8 Hz, 1 H), 6.89-6.74 (m, 6 H), 4.93 (dd, J = 7.7, 3.3 Hz, 1 H), 3.45-3.23 (m, 8 H), 3.14 (dd, J = 13.0, 10.4 Hz, 1 H), 3.04 (dd, J = 13.0, 3.3 Hz, 1 H), 2.31 (s, 3 H).13C NMR (101 MHz; CD3OD): δ 151.7, 146.6, 146.5, 140.1, 134.2, 130.1, 122.9, 118.7, 118.6, 116.3, 115.0, 114.3, 69.2, 64.9, 53.7, 21.7; HRMS (ESI) [M+H]+ m / z calcd for [C19H25N2O3]+ 329.1860, found 329.1870. Enantiomeric ratio was determined by SFC: Chiralpak®-AD3, 4.6 mm x 150 mm, particle size: 3 µm, temperature: 50 ºC, A: CO2, B: Ethanol with 0.05% of DEA, Isocratic A / B: 68 / 32% v / v, flow rate 1.2 mL / min. While the invention has been described in terms of its several exemplary embodiments, those skilled in the art will recognize that the invention can be practiced with modification within the spirit and scope of the appended claims. Accordingly, the present invention should not be limited to the embodiments as described above but should further include all modifications and equivalents thereof within the spirit and scope of the description provided herein.

Claims

CLAIMS We claim:

1. A method of preparing an asymmetrically reduced compound, comprising reacting a halogenated starting material with an amine nucleophile under conditions suitable for nucleophilic substitution of the halogenated starting material to form a substituted unprotected amino ketone; and reacting the substituted unprotected amino ketone with a tethered ligand transition metal catalyst under conditions suitable for asymmetric transfer-hydrogenation to produce an enantiomerically pure amino alcohol compound.

2. The method of claim 1, wherein the halogenated starting material is a brominated starting material.

3. The method of claim 1, wherein the tethered ligand transition metal catalyst is a tethered ruthenium catalyst.

4. The method of claim 3, wherein the tethered ruthenium catalyst is selected from the group consisting of [(S,S)-Teth-TsDpen RuCl], RuCl[(R,R)-Ts DPEN](p-cymene), RuCl[(R,R)-Ms DPEN](p-cymene), RuCl[(R,R)-Fs DPEN](p-cymene), RuCl[(R,R)-Ts DACH](p-cymene), RuCl[(R,R)-Nitro DACH](p-cymene), and [(S,S)-Teth-TsDENEB RuCl].

5. The method of claim 1, wherein the amine nucleophile is selected from the group consisting of NH3, CH3NH2, isopropylamine, butylamine, tert-butyl amine, methylamine, hexamethylenetetramine, (2-(3,4-dimethoxyphenyl)ethan-1-amine ), 1-(2- methoxyphenyl)piperazine, morpholine, N-benzylmethylamine, 1-(m-tolyl) piperazine, and 1-(3-methylphenyl)piperazine.

6. The method of claim 1, wherein the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution at a temperature of 0-75°C.

7. The method of claim 1, wherein the conditions suitable for nucleophilic substitution comprise performing the nucleophilic substitution in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile.

8. The method of claim 7, wherein the solvent is selected from the group consisting of methanol, water, isopropyl alcohol, acetonitrile, dioxane, acetone and dichloromethane.

9. The method of claim 1, wherein the conditions suitable for nucleophilic substitution comprise a reaction time of 0.5-24 hours.

10. The method of claim 1, further comprising reacting the substituted unprotected amino ketone with a protic acid.

11. The method of claim 10, wherein the protic acid is aqueous HCl or methanolic HCl.

12. The method of claim 1, wherein the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation at a temperature of 60-65°C.

13. The method of claim 1, wherein the conditions suitable for transfer-hydrogenation comprise performing the transfer-hydrogenation in a solvent selected from the group consisting of an alcoholic solvent, ether, polar amide, chlorinated solvent, water, and acetonitrile.

14. The method of claim 13, wherein the solvent is methanol.

15. The method of claim 1, wherein the conditions suitable for transfer-hydrogenation comprise a reaction time of 3-5 hours.

16. The method of claim 1, wherein the method is performed at ambient pressure.

17. A method of preparing a salt of an asymmetrically hydrogenated compound, comprising performing the method of claim 1 to produce the asymmetrically hydrogenated compound, and forming a salt of the asymmetrically hydrogenated compound.

18. The method of claim 17, wherein the salt is selected from the group consisting of tartrate salt, maleate salt, fumarate salt, and hydrochloride salt.

19. The method of claim 17, further comprising isolating the salt.

20. The method of claim 1, wherein the halogenated starting material is 2-bromo-1-(4- methoxyphenyl)ethan-1-one the amine nucleophile is hexamethylenetetramine, and the unprotected amino ketone is (R)-2-amino-1-(4-methoxyphenyl)ethan-1-ol , and wherein the method further comprises, after the step of reacting, a step of amide bond formation with cinnamoyl chloride to form acgeline; and / or amide formation with benzoyl chloride to form tembaamide.

21. The method of claim 1 wherein the asymetrically reduced compound is selected from the group consisting of (R)- phenylephrine and (R)-salbutamol).

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