METHOD FOR PREPARING CHIRAL NITRO DERIVATIVES USING ORGANIC CHIRAL CATALYST COMPOUNDS AND ECO-FRIENDLY SOLVENTS
20240076263 · 2024-03-07
Inventors
Cpc classification
C07C205/45
CHEMISTRY; METALLURGY
C07C201/12
CHEMISTRY; METALLURGY
B01J2231/32
PERFORMING OPERATIONS; TRANSPORTING
B01J31/0271
PERFORMING OPERATIONS; TRANSPORTING
C07C201/12
CHEMISTRY; METALLURGY
C07D333/22
CHEMISTRY; METALLURGY
C07D307/46
CHEMISTRY; METALLURGY
International classification
C07C201/12
CHEMISTRY; METALLURGY
C07C205/45
CHEMISTRY; METALLURGY
C07D307/46
CHEMISTRY; METALLURGY
C07D333/22
CHEMISTRY; METALLURGY
Abstract
Provided are a method for preparing chiral nitro derivatives using organic chiral catalyst compounds and water as an eco-friendly solvent, and the like. The catalyst is an organic catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN), and can prepare nitro derivatives having enantioselectivity and diastereoselectivity in excellent yield through a hydrophobic hydration effect. In particular, the preparation method of the present disclosure can stabilize a transition state through an interfacial reaction between the catalyst and water. In addition, indole derivatives can be synthesized using the chiral nitro derivatives prepared according to the present disclosure to be usefully used for the prevention or treatment of brain-nervous system diseases including depression and muscular diseases including cachexia.
Claims
1. A method for preparing chiral nitro derivatives comprising: preparing a compound represented by Chemical Formula 3 by reacting a compound represented by Chemical Formula 1 with a compound represented by Chemical Formula 2 in water, wherein a catalyst compound represented by Chemical Formula 4 is used in the reaction: ##STR00028## in Chemical Formulas 1 and 3, R.sub.1 is hydrogen, a C.sub.1-C.sub.7 acyclic alkyl group, or a C.sub.4-C.sub.10 aryl group, and R.sub.2 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, or the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and R.sub.3 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when R.sub.1, R.sub.2, and R.sub.3 are all hydrogens), in Chemical Formulas 2 and 3, R.sub.4 is a C.sub.4-C.sub.10 aryl group or C.sub.4-C.sub.10 heteroaryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a hydroxyl group, a nitro group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof, and in Chemical Formula 4, R.sub.5 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, and R.sub.6 may be a C.sub.4-C.sub.10 aryl group or C.sub.1-C.sub.7 acyclic alkyl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a cyano group, a nitro group, a trifluoromethyl group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.
2. The method for preparing the chiral nitro derivatives of claim 1, wherein the reaction is an asymmetric Michael addition reaction.
3. The method for preparing the chiral nitro derivatives of claim 1, wherein the compound represented by Chemical Formula 1 is at least one selected from the group consisting of compounds represented by Chemical Formulas 1-1 to 1-11 below: ##STR00029##
4. The method for preparing the chiral nitro derivatives of claim 1, wherein the compound represented by Chemical Formula 2 is at least one selected from the group consisting of compounds represented by Chemical Formulas 2-1 to 2-14 below: ##STR00030## ##STR00031##
5. The method for preparing the chiral nitro derivatives of claim 1, wherein the compound represented by Chemical Formula 3 is at least one selected from the group consisting of compounds represented by Chemical Formulas 3-1 to 3-36 below: ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037##
6. The method for preparing the chiral nitro derivatives of claim 1, wherein the compound represented by Chemical Formula 4 is at least one selected from the group consisting of compounds represented by Chemical Formulas 4-1 to 4-9 below: ##STR00038## ##STR00039##
7. The method for preparing the chiral nitro derivatives of claim 1, wherein the compound represented by Chemical Formula 1 and the compound represented by Chemical Formula 2 react with each other by further adding 4-nitrophenol, phenol, or 4-chlorophenol.
8. The method for preparing the chiral nitro derivatives of claim 1, wherein the reaction is performed in one reactor at room temperature.
9. The method for preparing the chiral nitro derivatives of claim 1, wherein 5 to 15 equiv. of the compound represented by Chemical Formula 1 and 0.5 to 2 equiv. of the compound represented by Chemical Formula 2 react with each other.
10. The method for preparing the chiral nitro derivatives of claim 1, wherein 1 to 10 mol % of the catalyst compound represented by Chemical Formula 4 is added.
11. A chiral nitro derivative prepared by the preparation method according to claim 1.
12. A method for preparing chiral indole derivatives comprising: (1) preparing a compound represented by Chemical Formula 3 by reacting a compound represented by Chemical Formula 1 with a compound represented by Chemical Formula 2 in water using a catalyst compound represented by Chemical Formula 4; and (2) preparing a compound represented by Chemical Formula 5 from the compound represented by Chemical Formula 3: ##STR00040## in Chemical Formulas 1, 3, and 5, R.sub.1 is hydrogen, a C.sub.1-C.sub.7 acyclic alkyl group, or a C.sub.4-C.sub.10 aryl group, and R.sub.2 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, or the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and R.sub.3 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when R.sub.1, R.sub.2, and R.sub.3 are all hydrogens), in Chemical Formulas 2, 3, and 5, R.sub.4 is a C.sub.4-C.sub.10 aryl group or C.sub.4-C.sub.10 heteroaryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a hydroxyl group, a nitro group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof, and in Chemical Formula 4, R.sub.5 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, and R.sub.6 may be a C.sub.4-C.sub.10 aryl group or C.sub.1-C.sub.7 acyclic alkyl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a cyano group, a nitro group, a trifluoromethyl group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.
13. The method for preparing the chiral indole derivatives of claim 12, wherein when R.sub.1 and R.sub.2 form a cyclohexyl group together with the carbons to which the R.sub.1 and R.sub.2 are attached and the carbons marked with asterisks (*), the compound represented by Chemical Formula 5 is a compound represented by Chemical Formula 5: ##STR00041##
14. The method for preparing the chiral indole derivatives of claim 12, wherein the compound represented by Chemical Formula 3 is added with Zn powder and NH.sub.4Cl.
15. A chiral indole derivative prepared by the preparation method according to claim 12.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] These and/or other aspects, features, and advantages of the invention will become apparent and more readily appreciated from the following description of embodiments, taken in conjunction with the accompanying drawings of which:
[0039]
[0040]
[0041]
[0042]
[0043]
[0044]
[0045]
[0046]
[0047]
DETAILED DESCRIPTION
[0048] The present inventors applied a thiourea catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) to an asymmetric Michael addition reaction of nitroalkene and aldehyde or ketone in water to prepare chiral nitro derivatives having a high level of enantioselectivity (76 to 99% syn ee) and diastereoselectivity (syn/anti=9/1) in an eco-friendly manner in a high yield of 88% to 99% (
[0049] Specifically, a primary amine moiety of DPEN reacts with carbonyl to form enamine and is activated through the formation of hydrogen bonds between nitro groups of ?,?unsaturated nitroalkene and thiourea. That is, an asymmetric Michael product was obtained by 1,4-adding enamine to alkene to form a new carbon-carbon bond. At this time, nitro derivatives as a product may have high stereoselectivity through double activation by hydrogen bonds between nitro groups and thiourea.
[0050] As an embodiment of the present disclosure, in the case of the Michael addition reaction using isobutyraldehyde and ?,?-unsaturated nitroalkene, the hydrogen of a thiourea moiety of the catalyst forms a hydrogen bond with the oxygen atom of the nitroalkene, and an amine moiety of the catalyst reacts with aldehyde to form enamine. Subsequently, the enamine, which is a nucleophile, approaches the rear surface of the ?,?-unsaturated nitroalkene to produce a compound with predominant stereoselectivity for an (R)-product (
[0051] Accordingly, the present disclosure provides a method for preparing chiral nitro derivatives including preparing a compound represented by Chemical Formula 3 by reacting a compound represented by Chemical Formula 1 and a compound represented by Chemical Formula 2 in water using a catalyst compound represented by Chemical Formula 4:
##STR00015##
[0052] In Chemical Formulas 1 and 3, R.sub.1 is hydrogen, a C.sub.1-C.sub.7 acyclic alkyl group, or a C.sub.4-C.sub.10 aryl group, and R.sub.2 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, or the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with the carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and R.sub.3 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when R.sub.1, R.sub.2, and R.sub.3 are all hydrogens), in Chemical Formulas 2 and 3, R.sub.4 is a C.sub.4-C.sub.10 aryl group or C.sub.4-C.sub.10 heteroaryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a hydroxyl group, a nitro group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof, and in Chemical Formula 4, R.sub.5 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, and R.sub.6 may be a C.sub.4-C.sub.10 aryl group or C.sub.1-C.sub.7 acyclic alkyl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a cyano group, a nitro group, a trifluoromethyl group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.
[0053] In the present disclosure, the term substitution is a reaction in which atoms or atom groups included in molecules of a compound are replaced with other atoms or atom groups.
[0054] In the present disclosure, the term acyclic alkyl group refers to a group derived from straight-chain or branched-chain saturated aliphatic hydrocarbon having a specified number of carbon atoms and having at least one valency. Examples of these alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, and the like, but are not limited thereto.
[0055] In the present disclosure, the term cycloalkyl group is also referred to as a cyclic alkyl group, and refers to a monovalent group having at least one saturated ring in which all ring members are carbons. Examples of such a cycloalkyl group include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like, but are not limited thereto.
[0056] In the present disclosure, the term heterocycloalkyl group usually refers to saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may optionally be unsubstituted, monosubstituted, or polysubstituted, and in its structure, at least one is selected from the group consisting of heteroatoms of N, O, or S.
[0057] In the present disclosure, the term aryl group refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (e.g., phenyl) or a plurality of condensed rings (e.g., naphthyl). Examples of such aryl include phenyl, naphthyl, and the like, but are not limited thereto.
[0058] In the present disclosure, the term heteroaryl group refers to a single ring or a plurality of condensed rings in which at least one among atoms constituting the ring has a heteroatom of N, O, or S. Examples of such a heteroaryl group include a furyl group, a thiophenyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, an oxazolyl group, and the like, but are not limited thereto.
[0059] In the present disclosure, the term alkoxy group refers to an atom group C.sub.nH.sub.2n+1O.sup.? formed by bonding an oxygen atom to an alkyl group, and examples of such an alkoxy group include methoxy, ethoxy, propoxy, phthaloxy, and the like, but are not limited thereto.
[0060] In the present disclosure, the term halogen group may be fluorine (F), chloride (C.sub.1), bromine (Br), iodine (I), or the like, as elements belonging to Group 17 of the periodic table.
[0061] In addition, since the chiral nitro derivatives of the present disclosure may be economically prepared without using expensive metal catalysts unlike conventional preparation methods and use water as an eco-friendly solvent under mild reaction conditions, the chiral indole derivatives prepared using the chiral nitro derivatives may be included in pharmaceutical compositions used for the treatment or prevention of various diseases.
[0062] Although the type of the disease is not limited, the chiral indole derivatives of the present disclosure may be used as an antidepressant and a cancer cachexia therapeutic agent, so that the present disclosure provides a composition for the prevention or treatment of brain-nervous system diseases including depression and muscular diseases including cachexia, including derivatives represented by Chemical Formula 5 below as an active ingredient.
##STR00016##
[0063] In Chemical Formula 5, R.sub.1 is hydrogen, a C.sub.1-C.sub.7 acyclic alkyl group, or a C.sub.4-C.sub.10 aryl group, and R.sub.2 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group, or the R.sub.1 and R.sub.2 may form a C.sub.4-C.sub.10 cycloalkyl group or heterocycloalkyl group together with the carbons to which the R.sub.1 and R.sub.2 are attached and carbons marked with asterisks (*), and R.sub.3 is hydrogen or a C.sub.1-C.sub.7 acyclic alkyl group (however, except when R.sub.1, R.sub.2, and R.sub.3 are all hydrogens), and R.sub.4 is a C.sub.4-C.sub.10 aryl group or C.sub.4-C.sub.10 heteroaryl group unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a hydroxyl group, a nitro group, a C.sub.1-C.sub.7 acyclic alkyl group, a C.sub.1-C.sub.7 alkoxy group, and combinations thereof.
[0064] The pharmaceutical composition according to the present disclosure may include a pharmaceutically acceptable carrier in addition to the active ingredients. The pharmaceutically acceptable carrier is generally used in preparation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but is not limited thereto. Further, the pharmaceutical composition may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the ingredients.
[0065] The pharmaceutical composition of the present disclosure may be administered orally or parenterally (e.g., applied intravenously, subcutaneously, intraperitoneally, or topically) according to a desired method, and a dose thereof varies depending on the condition and body weight of a patient, the severity of a disease, a drug form, and route and time of administration, but may be appropriately selected by those skilled in the art.
[0066] The pharmaceutical composition of the present disclosure is administered in a pharmaceutically effective dose. The pharmaceutically effective dose used herein refers to an amount enough to treat diseases at a reasonable benefit/risk ratio applicable to medical treatment. The effective dose level may be determined according to factors including the type and severity of a disease, the activity of a drug, the sensitivity to a drug, a time of administration, a route of administration, an excretion rate, duration of treatment, and simultaneously used drugs in patients, and other factors well-known in the medical field. The pharmaceutical composition according to the present disclosure may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to administer an amount capable of obtaining a maximum effect with a minimal amount without side-effects by considering all the factors, which may be easily determined by those skilled in the art.
[0067] Specifically, the effective dose of the pharmaceutical composition of the present disclosure may vary depending on the age, sex, condition, and body weight of a patient, absorption rate, inactivity rate, and excretion rate of active ingredients in the body, a disease type, and combined drugs.
[0068] As another aspect of the present disclosure, the present disclosure provides a method for the prevention or treatment of brain-nervous system diseases including depression and muscular diseases including cachexia, including administering the pharmaceutical composition to a subject. The subject used herein refers to a subject in need of treatment or prevention for diseases, and more particularly, refers to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cattle.
[0069] The terms used in embodiments are used for the purpose of description only, and should not be construed to be limited. The singular expression includes the plural expression unless the context clearly dictates otherwise. In the present specification, it should be understood that term comprising or having indicates that a feature, a number, a step, an operation, a component, a part, or the combination thereof described in the specification is present, but does not exclude a possibility of presence or addition of one or more other features, numbers, steps, operations, components, parts, or combinations thereof, in advance.
[0070] Unless otherwise contrarily defined, all terms used herein including technological or scientific terms have the same meanings as those generally understood by a person with ordinary skill in the art to which embodiments pertain. Terms which are defined in a generally used dictionary should be interpreted to have the same meaning as the meaning in the context of the related art, and are not interpreted as ideal or excessively formal meanings unless otherwise defined in the present application.
[0071] In describing the components of the embodiments of the present disclosure, terms including first, second, A, B, (a), (b), and the like may be used. These terms are just intended to distinguish the components from other components, and the terms do not limit the nature, sequence, or order of the components. When it is disclosed that any component is connected, coupled, or linked to other components, it should be understood that the component may be directly connected or linked to other components, but another component may be connected, coupled, or linked between the respective components.
[0072] Hereinafter, embodiments will be described in detail with reference to the accompanying drawings. However, since various modifications may be made to the embodiments, the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, and substitutes for the embodiments are included in the scope of the present disclosure.
[0073] In addition, in the description with reference to the accompanying drawings, like components designate like reference numerals regardless of reference numerals and a duplicated description thereof will be omitted. In describing the embodiments, a detailed description of related known technologies will be omitted if it is determined that they unnecessarily make the gist of the embodiments unclear.
[0074] The present disclosure may have various modifications and various embodiments and specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, this does not limit the present disclosure within specific embodiments, and it should be understood that the present disclosure covers all the modifications, equivalents, and replacements within the idea and technical scope of the present disclosure. In the interest of clarity, not all details of the relevant art are described in detail in the present specification in so much as such details are not necessary to obtain a complete understanding of the present disclosure.
EXAMPLE 1
Synthesis of chiral nitro Derivatives of Present Disclosure
[0075] 1.1. Instruments and Reagents
[0076] IR spectra were recorded using a NICOLET 380 FT-IR spectrophotometer (Thermo Fisher Scientific Inc., Waltham, MA, USA), and optical rotation was measured using an automatic digital polarimeter (model name: A20766 APV/6w, Rudolph Research Analytical, Hackettstown, NJ, USA). .sup.1H NMR and .sup.13C NMR spectra were obtained based on the internal standard of TMS using Varian Gemini 300 (300, 75 MHz, Agilent, Santa Clara, CA, USA), Varian Mercury 400 (400, 100 MHz, Agilent, Santa Clara, CA, USA), and Bruker Avance 500 (500, 125 MHz, Bruker BioSpin GmbH, Silberstreifen 4, 76287 Rheinstetten, Billerica, MA, USA). Chiral HPLC analysis was performed using a Jasco LC-1500 Series HPLC system (JASCO, 4-21, Sennin-cho 2-chome, Hachioji, Tokyo 193-0835, Japan). All reactions were performed under an argon environment in a flask well-dried in an oven. Toluene (CaH.sub.2), THF (Na, benzophenone), and CH.sub.2Cl.sub.2 (CaH.sub.2) reaction solvents were purified before use. Reagents used herein were products from Aldrich (Louis, MO, USA), TCI (Tokyo, Japan), etc., and purified or dried by known methods, if necessary. Merck's silica gel 60 (230 to 400 mech) was used as a stationary phase for column chromatography.
1.2. Synthesis of thiourea Catalyst
[0077] (R,R)-1.2-diphenylethylenediamine (200 mg, 0.942 mmol) was dissolved in toluene (1.00 mL), and then added with isothiocyanate (0.140 mL, 0.942 mmol) and stirred at 0? C. for 1 hour. After completion of the reaction with distilled water, the mixture was extracted with dichloromethane (20 mL?3 times), dehydrated with MgSO.sub.4, filtrated, and concentrated under reduced pressure, and then a product (Chemical Formula 4, however, R.sub.5?H) was isolated using column chromatography (SiO.sub.2, EtOAc:CH.sub.2Cl.sub.2=1:6) (Reaction Formula 1).
##STR00017##
[0078] In addition, an N-monoalkylated thiourea catalyst was synthesized according to Reaction Formula 2 below.
##STR00018##
[0079] (R,R)-1,2-diphenylethylenediamine (1.0 equiv.) was dissolved in toluene (0.1 M), added with MgSO.sub.4 and 3-pentanone (1.0 equiv.), and then heated and refluxed. After 48 hours, CH.sub.2Cl.sub.2 and MgSO.sub.4 were filtered and removed, and the produced diaminoacetal was dissolved in ethanol, added with an excess of NaBH.sub.4, and then stirred at room temperature for 3 hours. After the reaction was terminated with a 1 N NaOH aqueous solution, the mixture was extracted with CH.sub.2Cl.sub.2 three times. The extract was dehydrated with anhydrous MgSO.sub.4, filtrated, and concentrated under reduced pressure, and then the residue thereof was subjected to column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2:MeOH:NH.sub.3=300:10:1) to obtain a product. Mono-alkylated (R,R)-1,2-diphenylethylenediamine (1.0 equiv.) was dissolved in CH.sub.2Cl.sub.2 (0.2 M) under argon, added with isothiocyanate (1.1 equiv.), and then stirred at room temperature. After 2 hours, the mixture was transferred to water and extracted three times with 100 mL of CH.sub.2Cl.sub.2. The combined organic layers were dehydrated with anhydrous MgSO.sub.4, filtered, and concentrated under reduced pressure, and the residue thereof was subjected to column chromatography (SiO.sub.2, EA:hexane=1:5) to obtain a desired product (Chemical Formula 4, however, R.sub.5=3-pentyl).
[0080] Non-limiting examples of the thiourea catalyst according to an embodiment of the present disclosure were as follows:
(1) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-isopropylthiourea (Chemical Formula 4-1)
[0081] [?].sub.D.sup.25+62.3 (c 1.0, CHCl.sub.3); .sup.1H-NMR (500 MHZ, CDCl.sub.3) ?7.37-7.21 (m, 11H), 6.04 (br s, 1H), 5.09 (br s, 1H), 4.30 (s, 1H), 4.15 (br s, 1H), 1.73 (s, 2H), 1.09-1.03 (m, 6H) ppm; .sup.13C-NMR (125 MHz, CDCl.sub.3) ?180.68, 142.06, 129.00, 128.75, 127.88, 126.91, 64.12, 60.55, 46.39, 22.70 ppm; IR (KBr) 3335, 2966, 1527, 1326, 1273, 966, 695, 514 cm.sup.?1; HRMS (ESI+) for C.sub.18H2.sub.3N.sub.3S [M+H].sup.+ Calcd: 314.1691, Found: 314.1627;
(2) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-[3,5-bis(trifluoromethyl)phenyl]thiourea (Chemical Formula 4-2)
[0082] [?].sub.D.sup.25+13.5 (c 1.0, CH.sub.3Cl); .sup.1H-NMR (500 MHz, DMSO-d6) ?8.25 (s, 2H), 7.78 (s, 1H), 7.32-7.15 (m, 13H), 5.99 (d, J=3 Hz, 1H), 4.77 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (125 MHz, DMSO-d6) ?180.51, 143.26, 142.48, 130.82, 130.56, 128.51, 128.29 127.66, 127.55, 127.38, 124.78, 122.62, 121.34, 116.08, 63.66, 59.94 ppm; IR (KBr) 3305, 3032, 2963, 1652, 1601, 1557, 1383, 1277, 1262, 803, 700 cm.sup.?1; HRMS (FAB.sup.+) for C.sub.23H.sub.19F.sub.6N.sub.3S [M+H].sup.+ Calcd: 484.1282, Found: 484.1254;
(3) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-phenylthiourea (Chemical Formula 4-3)
[0083] [?].sub.D.sup.20=+62.0 (c=0.02, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?7.76 (s, 1 H), 7.54-7.19 (m, 15H), 5.54 (s, 1H), 4.42 (d, 1H, J=5Hz), 1.35 (br s, 1H); .sup.13C-NMR (100 MHz, DMSO-d6) ?182.09, 134.48, 133.93, 129.89, 128.70, 128.10, 127.91, 127.15, 126.94, 126.82, 126.74, 126.23, 125.59, 125.24, 122.98, 63.07, 59.09; IR (KBr) 3287.86, 3027.84, 1521.63, 1241.99, 1072.28, 939.20, 698.13 cm.sup.?1; HRMS (FAB+) for C.sub.21H.sub.22N.sub.3S [M+H].sup.+ Calcd: 348.4918, Found: 348.1534.
(4) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-p-tolythiourea (Chemical Formula 4-4)
[0084] [?].sub.D.sup.22+0.27 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) ?9.79 (s, 1H), 7.13-7.38 (m, 15H), 5.50(s, 1H), 4.32 (d, J=3 Hz, 1H), 2.27(s, 3H) ppm; .sup.13C-NMR (100 MHz, DMSOd6) ?180.90, 143.72, 142.20, 137.14, 134.32, 129.86, 128.82 128.59, 127.68, 127.61, 127.46, 127.39, 123.97, 63.88, 60.00, 21.23 ppm; IR (KBr) 3301.69, 2861.98, 1889.99, 1527.42, 1342.28, 964.28, 701.99, 524.56 cm.sup.?1; HRMS (FAB+) for C.sub.22H.sub.24N.sub.3S [M+H].sup.+ Calcd: 362.1691, Found: 362.2188
(5) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(4-methoxyphenyl)thiourea (Chemical Formula 4-5)
[0085] [?].sub.D.sup.22+0.327 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) ?9.55 (s, 1H), 8.17 (s, 1H), 7.12-7.22 (m, 12H), 6.87(d, J=6.0 Hz, 3H), 5.94 (s, 1H), 3.72 (s, 3H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) ?180.72, 156.54, 139.70, 131.67, 128.09, 127.97, 127.19, 125.61, 113.93, 62.38, 59.81. 55.24 ppm; IR (KBr) 3303.63, 3027.84, 1733.78, 1510.06, 1297.92, 1243.92, 1029.85, 831.21, 700.07, 568.93 cm.sup.?1; HRMS (FAB+) for C.sub.22H.sub.24N.sub.3OS [M+H].sup.+ Calcd: 378.1640, Found: 378.1563
(6) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(4-fluorophenyl)thiourea (Chemical Formula 4-6)
[0086] [?].sub.D.sup.22+0.132 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) ?9.93 (s, 1H), 7.08-7.46 (m, 15H), 5.52(s, 1H), 4.34 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) ?181.28, 160.71, 143.73, 142.10, 136.32, 128.79, 128.58, 127.70, 127.59, 127.49, 127.39, 125.79, 115.94, 115.71, 63.88, 60.06 ppm; IR (KBr) 3301.69, 3029.77, 1874.56, 1527.42, 1342.27, 1218.85, 840.85, 701.99 cm.sup.?1; HRMS (FAB+) for C.sub.21H.sub.21FN.sub.3S [M+H].sup.+ Calcd: 366.1440, Found: 366.1440
(7) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(4-cyanophenyl)thiourea (Chemical Formula 4-7)
[0087] [?].sub.D.sup.22+1.50 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) ?10.50 (s, 1H), 7.07-7.88 (m, 15H), 5.56 (d, J=3 Hz, 1H), 4.39 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) ?180.47, 145.05, 143.34, 141.61, 133.36, 128.83, 128.64 127.74, 127.68, 127.59, 127.50, 121.37, 119.85, 105.11, 63.74, 60.04 ppm; IR (KBr) 3263.1, 2219.7, 1646.9, 1592.9, 1361.5, 1091.5 cm.sup.?1; HRMS (FAB+) for C.sub.22H.sub.20N.sub.4S [M+H].sup.+ Calcd: 372.1487, Found: 372.1400
(8) 1-(4-Nitrophenyl)-3-[(1R,2R)-2-(pentan-3-ylamino)-1,2-diphenylethyl]thiourea (Chemical Formula 4-8)
[0088] [?].sub.D.sup.20+37.7 (c 0.20, CHCl.sub.3); .sup.1H-NMR (300 MHz, DMSO-d6) ?10.5 (s, 1H), 8.16 (m, 2H), 7.90 (d, J=9.1 Hz, 2H), 7.37-7.15 (m, 10H), 5.54 (br s, 1H), 4.16 (d, J=5.5 Hz, 1H), 2.07 (m, 1H), 1.30-1.15 (m, 4H), 0.75 (t, J=7.4 Hz, 3H), 0.50 (t, J=7.4 Hz, 3H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) ?179.85, 146.27, 141.82, 141.25, 140.25, 128.00, 127.86, 127.04, 126.98, 126.87, 124.60, 124.46, 120.28, 63.71, 63.14, 55.72, 26.04, 23.36, 10.32, 7.97 ppm; IR (KBr) 3330.5, 2960.2, 2599.6, 2456.4, 2345.0, 1951.6, 1743.3, 1496.5, 1346.1, 1110.8, 1072.2, 852.4, 700.0, 586.3 cm.sup.?1; HRMS (FAB+) for C.sub.26H.sub.31N.sub.4O.sub.2S [M+H].sup.+ Calcd: 463.2168, Found: 463.2186.
(9) 1-[(1R,2R)-2-Amino-1,2-diphenylethyl]-3-(naphthalene-1-yl)thiourea (Chemical Formula 4-9)
[0089] [?].sub.D.sup.25+0.157 (c 1.00, CH.sub.3Cl); .sup.1H-NMR (300 MHz, DMSO-d6) ?9.93 (s, 1H), 7.22-7.99 (m, 18H), 5.51(s, 1H), 4.34 (d, J=3 Hz, 1H) ppm; .sup.13C-NMR (100 MHz, DMSO-d6) ?182.70, 143.47, 142.08, 135.06, 134.65, 130.66, 128.84, 128.55, 127.69, 127.61, 127.45, 126.99, 126.32, 126.00, 123.65, 64.01, 59.88 ppm; IR (KBr) 3340.26, 3116.55, 1951.70, 1511.99, 1249.70, 941.13, 701.99, 632.56 cm.sup.?1; HRMS (FAB+) for C.sub.25H.sub.24N.sub.3S [M+H].sup.+ Calcd: 398.1691, Found: 398.551
[0090] 1.3. Asymmetric Michael Addition Reaction Between Chiton and ?,?-Unsaturated Nitroalkene
[0091] 1.3.1. In Case of Ketone
[0092] A thiourea catalyst (Chemical Formula 4, 7.3 mg, 0.020 mmol), 4-nitrophenol (5 mol %), and ?,?-unsaturated nitroalkene (Chemical Formula 2, 30 mg, 0.20 mmol) were added to a reaction container at room temperature and dissolved in water (1.0 mL) under an air condition. Subsequently, ketone (Chemical Formula 1, however, except for R.sub.1=H, 0.21 mL, 2.0 mmol) was added and stirred for 5 hours. After completion of the reaction with distilled water, the mixture was extracted with dichloromethane (20 mL?3 times), dehydrated with MgSO.sub.4, filtrated, and concentrated under reduced pressure, and then a product (Chemical Formula 3) was isolated using column chromatography (SiO.sub.2, EtOAc:hexane=5:1).
[0093] 1.3.2. In Case of Aldehyde
[0094] A thiourea catalyst (Chemical Formula 4, 5 mol %) and ?,?-unsaturated nitroalkene (Chemical Formula 2, 0.3 mmol) were added to a reaction container at room temperature under an air condition and dissolved in water (1.0 mL) under the air condition. Then, aldehyde (Chemical Formula 1, however, R.sub.1=H, 5 equiv.) was added and stirred for 4 to 12 hours. After completion of the reaction with distilled water, the mixture was extracted with dichloromethane (20 mL?3 times), dehydrated with MgSO.sub.4, filtrated, and concentrated under reduced pressure, and then a product (Chemical Formula 3) was isolated using column chromatography (SiO.sub.2, EtOAc:hexane=5:1).
[0095] Non-limiting examples of the chiral nitro derivatives prepared by the asymmetric Michael addition reaction between the ketone or aldehyde and the ?,?-unsaturated nitroalkene according to an embodiment of the present disclosure were as follows:
(1) (S)-5-Nitro-4-phenylpentan-2-one (Chemical Formula 3-1)
[0096] [?]D.sup.20+4.5 (c 1.0, CHCl.sub.3); .sup.1H NMR (400 MHz, CDCl.sub.3) ?7.35-7.21 (m, 5H), 4.72-4.67 (dd, J=12.3, 7.0 Hz, 1H), 4.63-4.58 (dd, J=12.3, 7.6 Hz, 1H), 4.05-3.98 (m, 1H), 2.92 (d, J=7.0 Hz, 2H), 2.13 (s, 3H) ppm; .sup.13C NMR (100 MHz, CDCl.sub.3) ?205.67, 138.99, 129.30, 128.14, 127.59, 79.67, 46.33, 39.23, 30.65 ppm; IR (KBr) 3064, 3035, 2968, 2948, 2919, 2902, 1714, 1548, 1384, 1361, 1163, 758, 696, 548 cm.sup.?1; LRMS (FAB+) for C.sub.11H.sub.13NO.sub.3 [M+H].sup.+ Calcd: 208, Found: 208; HPLC [Chiralcel AD-H, hexane/2-propanol=4/96, flow rate=1.0 mL/min, ?=254 nm, retention times: (major) 28.2 min, (minor) 38.3 min];
(2) (R)-2-[(S)-2-Nitro-1-phenylethyl]cyclohexanone (Chemical Formula 3-2)
[0097] [?].sub.D.sup.26+37.5 (c 0.100, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.34-7.23 (m, 3H), 7.16 (d, J=7 Hz, 2H), 4.95 (dd, J=12, 5 Hz, 1H), 4.63 (dd, J=12, 10 Hz, 1H), 3.76 (dt, J=10, 5 Hz, 1H), 2.68 (m, J=11, 9, 8 Hz, 1H), 2.49-2.33 (m, 2H), 2.10-2.04 (m, 1H), 1.79-1.52 (m, 4H), 1.52-1.19 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 211.9, 137.6, 128.8, 128.1, 127.7, 78.8, 52.4, 43.8, 42.7, 33.1, 28.5, 24.9, IR(KBr) 3855.1, 3650.7, 3448.2, 2921.1, 1700.9, 1552.4, 1382.7, 1243.9, 1130.1, 696.2, 561.2 cm.sup.?1; LRMS(FAB+) for C.sub.14H.sub.17NO.sub.3[M+H].sup.+ Calcd:247, Found: 247; chiral-phase HPLC, AS-H column (i-PrOH/hexane=20:80), 254 nm, flow rate=0.5 ml/min, tr (major)=19.74 min, tr (minor)=27.57 min.
(3) (R)-2-[(S)-2-Nitro-1-phenylethyl]cyclopentanone(Chemical Formula 3-3)
[0098] [?].sub.D.sup.23+12.1(c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.34-7.23 (m, 3H), 7.20-7.15 (m, 2H), 5.37-5.30 (m, 1H), 4.71 (dd, J=13, 10 Hz, 1H), 3.76-3.65 (m, 1H), 2.44-2.31 (m, 2H), 2.19-2.06 (m, 1H) , 1.94-1.83 (m, 2H), 1.76-1.66 (m, 1H), 1.55-1.41 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 218.5, 137.6, 128.8, 127.9, 78.2, 50.4, 44.1, 38.6, 28.3, 20.2, IR (KBr) 3363.4, 2921.7, 1731.8, 1552.4, 1378.9, 1124.3 cm.sup.?1; LRMS(FAB+) for C.sub.13H.sub.15NO.sub.3[M+H].sup.+ Calcd: 234, Found: 234; chiral-phase HPLC, AS-H column (i-PrOH/hexane=20:80), 254 nm, flow rate=0.5 ml/min, tr (major)=22.74 min, tr (minor)=30.47 min.
(4) (S)-3-[(S)-2-Nitro-1-phenylethyl]tetrahydropyran-4-one (Chemical Formula 3-4)
[0099] [?].sub.D.sup.23+14.4 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.37-7.26 (m, 3H), 7.21-7.16 (m, 2H), 4.96 (dd, J=12, 5 Hz, 1H), 4.64 (dd, J=12, 10 Hz, 1H), 4.20-4.10 (m, 1H), 3.87-3.68 (m, 2H), 3.70 (dd, J=11, 5 Hz, 1H), 3.27 (dd, J=11, 10 Hz, 1H), 2.93-2.83 (m, 1H), 2.73-2.61 (m, 1H), 2.60-2.53 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 207.4, 136.1, 128.9, 127.8, 78.6, 71.5, 68.9, 53.2, 42.9, 41.2, 29.6; IR (KBr) 3278.5, 2923.7, 2291.1, 1735.7, 1457.9, 1243.9, 1087.7 cm.sup.?1; chiral-phase HPLC, AS-H column (i-PrOH/hexane=50:50), 254 nm, flow rate=0.5 ml/min, tr (major)=19.29 min, tr (minor)=25.53 min.
(5) (R)-3-[(S)-2-Nitro-1-phenylethyl]tetrahydrothiopyran-4-one (Chemical Formula 3-5)
[0100] [?].sub.D.sup.23+21.9 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.37-7.26 (m, 3H), 7.21-7.16 (m, 2H), 4.96 (dd, J=12, 5 Hz, 1H), 4.64 (dd, J=12, 10 Hz, 1H), 4.20-4.10 (m, 1H), 3.87-3.68 (m, 2H), 3.70 (dd, J=11, 5 Hz, 1H), 3.27 (dd, J=11, 10 Hz, 1H), 2.93-2.83 (m, 1H), 2.73-2.61 (m, 1H), 2.60-2.53 (m, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3) 209.5, 136.5, 129.3, 128.3, 128.2, 78.6, 55.0, 44.6, 53.5, 35.1, 31.6; IR (KBr) 3367.2, 1646.9, 1376.9, 1093.4 cm.sup.?1; chiral-phase HPLC, AS-H column (i-PrOH/hexane=50:50), 254 nm, flow rate=0.5 ml/min, tr (major)=18.40 min, tr (minor)=26.84 min.
(6) (S)-4-Nitro-1,3-diphenyl-butan-1-one (Chemical Formula 3-6)
[0101] [?].sub.D.sup.20?18.5 (c 1.0, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) ?7.91-7.92 (m, 2H), 7.59-7.26 (m, 8H), 4.85-4.81 (dd, J=12.5, 6.7 Hz, 1H), 4.71-4.67 (dd, J=12.5, 7.8 Hz, 1H), 4.26-4.20 (m, 1H), 3.51-3.46 (dd, J=17.7, 6.4 Hz, 1H), 3.45-3.40 (dd, J=17.7, 7.5 Hz, 1H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?196.87, 139.15, 136.39, 133.60, 129.09, 128.77, 128.04, 127.90, 127.48, 79.58, 41.54, 39.30 ppm; IR (KBr) 3058, 3029, 2920, 1687, 1544, 1440, 1367, 1268, 1224, 1084, 988, 764, 703, 623, 559 cm.sup.?1; LRMS (ESI+) for C.sub.16H.sub.15NO.sub.3 [M+Na].sup.+ Calcd: 292.1, Found: 292.1; HPLC [Chiralcel AD-H, hexane/2-propanol=90/10, flow rate=1.0 mL/min, ?=254 nm, retention times: (major) 12.8 min, (minor) 17.4 min];
(7) (S)-5-Nitro-4-(p-tolyl)pentan-2-one (Chemical Formula 3-7)
[0102] [?].sub.D.sup.20+4.7 (c 1.5, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) ?7.13-7.08 (m, 4H), 4.68-4.64 (dd, J=12.3, 6.9 Hz, 1H), 4.58-4.54 (dd, J=12.1, 7.7 Hz, 1H), 3.99-3.93 (m, 1H), 2.89 (d, J=7.7 Hz, 1H), 2.31 (s, 3H), 2.10 (s, 3H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?205.57, 137.62, 135.76, 129.74, 127.24, 79.63, 46.22, 38.76, 30.41, 21.05 ppm; IR (KBr) 3056, 3029, 2976, 2944, 2924, 1717, 1551, 1378, 1365, 1163, 816, 544 cm.sup.?1; LRMS (ESI+) for C.sub.12H.sub.15NO.sub.3 [M+Na].sup.+ Calcd: 244.1, Found: 244.2; HPLC [Chiralcel AS-H, hexane/2-propanol=80/20, flow rate=1.0 mL/min, ?=213 nm, retention times: (major) 13.1 min, (minor) 20.4 min];
(8) (S)-4-(4-Methoxyphenyl)-5-nitropentan-2-one (Chemical Formula 3-8)
[0103] [?].sub.D.sup.20?5.7 (c 1.0, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) ?7.13 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.67-4.63 (dd, J=12.3, 6.8 Hz, 1H), 4.57-4.53 (dd, J=12.3, 7.8 Hz, 1H), 3.98-3.92 (m, 1H), 3.78 (s, 3H), 2.88 (d, J=7.0, 2H), 2.11 (s, 3H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?205.55, 159.13, 130.67, 128.45, 114.44, 79.73, 55.26, 46.29, 38.42, 30.43 ppm; IR (KBr) 3028, 3002, 2960, 2901, 1715, 1550, 1517, 1260, 1180, 1033, 813,544 cm.sup.?1; LRMS (ESI+) for C.sub.12H.sub.15NO.sub.4 [M+Na].sup.+Calcd: 260.1, Found: 260.1; HPLC [Chiralcel AS-H, hexane/2-propanol=80/20, flow rate=1.4 mL/min, ?=213 nm, retention times: (major) 16.2 min, (minor) 37.9 min];
(9) (S)-4-(4-Chlorophenyl)-5-nitropentan-2-one (Chemical Formula 3-9)
[0104] [?].sub.D.sup.20?2.9 (c 1.0, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) ?7.32-7.29 (m, 2H), 7.17-7.15 (m, 2H), 4.70-4.66 (dd, J=12.4, 6.7 Hz, 1H), 4.59-4.55 (dd, J=12.4, 7.9 Hz, 1H), 4.02-3.96 (m, 1H), 2.94-2.90 (dd, J=18.5, 7.0 Hz, 1H), 2.89-2.85 (dd, J=19.0, 7.0 Hz, 1H), 2.12 (s, 3H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?205.03, 137.35, 133.79, 129.26, 128.82, 79.19, 45.97, 38.40, 30.39 ppm; LRMS (ESI+) for C.sub.11H.sub.12ClNO.sub.3 [M+Na].sup.+ Calcd: 264.0, Found: 264.1; HPLC [Chiralcel AD-H, hexane/2-propanol=5/95, flow rate=1.0 mL/min, ?=254 nm, retention times: (major) 14.1 min, (minor) 21.9 min]; Rf (SiO.sub.2, EtOAc/n-hexane=1/5)=0.22
(10) (S)-4-(4-Bromophenyl)-5-nitropentan-2-one (Chemical Formula 3-10)
[0105] [?].sub.D.sup.20?0.6 (c 0.4, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) ?7.45 (d, J=7.0 Hz, 2H), 7.10 (d, J=7.0 Hz, 2H), 4.69-4.66 (dd, J=12.5, 6.5 Hz, 1H), 4.59-4.55 (dd, J=12.7, 7.5 Hz, 1H), 4.0-3.95 (m, 1H), 2.88 (d, J=7.5 Hz, 2H), 2.12 (s, 3H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?205.04, 137.91, 132.20, 129.18, 121.85, 79.10, 45.91, 38.46, 30.38 ppm; LRMS (ESI+) for CH.sub.12BrNO.sub.3 [M+Na].sup.+ Calcd: 308.0, Found: 308.0; HPLC [Chiralcel AD-H, hexane/2-propanol=80/20, flow rate=1.0 mL/min, ?=210 nm, retention times: (major) 10.9 min, (minor) 12.5 min];
(11) (S)-4-(2-Methoxyphenyl)-5-nitropentan-2-one (Chemical Formula 3-11)
[0106] [?].sub.D.sup.20+16.4 (c 1.6, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) ?7.26-7.23 (m, 1H), 7.15-7.13 (m, 1H), 6.92-6.87 (m, 2H), 4.76-4.69 (m, 2H), 4.25-4.19 (m, 1H), 3.86 (s, 3H), 3.05-3.0 (dd, J=18.0, 7.5 Hz, 1H), 2.98-2.93 (dd, J=18.0, 7.0 Hz, 1H), 2.13 (s, 3H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?206.16, 157.09, 129.31, 129.01, 126.44, 120.94, 110.99, 77.85, 55.35, 44.52, 35.33, 30.25 ppm; LRMS(ESI+) for C.sub.12H.sub.15NO.sub.4[M+Na] Calcd: 260.1, Found: 260.1; HPLC [Chiralcel AD-H, hexane/2-propanol=5/95, flow rate=1.0 mL/min, ?=254 nm, retention times: (major) 14.1 min, (minor) 21.9 min];
(12) (S)-4-(Furan-2-yl)-5-nitropentan-2-one (Chemical Formula 3-12)
[0107] [?].sub.D.sup.20?8.1 (c 1.0, CHCl.sub.3); .sup.1H NMR (500 MHz, CDCl.sub.3) ?7.34-7.33 (dd, J=1.8, 0.7 Hz, 1H), 6.30-6.29 (dd, J=3.2, 1.8 Hz, 1H), 6.14 (d, J=3.2 Hz, 1H), 4.71-4.68 (dd, J=12.6, 6.6 Hz, 1H), 4.67-4.64 (dd, J=12.6, 6.6 Hz, 1H), 4.13-4.07 (m, 1H), 3.00-2.95 (dd, J=16.7, 5.2 Hz, 1H), 2.93-2.87 (dd, J=16.7, 6.0 Hz, 1H), 2.18 (s, 3H) ppm; .sup.13C NMR (125 MHz, CDCl.sub.3) ?205.11, 151.69, 142.31, 110.50, 107.10, 77.07, 43.49, 32.89, 30.22 ppm; IR (flim) 3151, 3124, 2920, 1714, 1552, 1430, 1377, 1165, 1015, 741 cm.sup.?1; LRMS (ESI+) for C.sub.9H.sub.11NO.sub.4 [M+Na].sup.+ Calcd: 220.1, Found: 220.1; HPLC [Chiralcel AD-H, hexane/2-pro panol=94/6, flow rate=1.0 mL/min, ?=213 nm, retention times: (major) 10.5 min, (minor) 11.6 min];
(13) (R)-2-[(S)-1-(3-Methylphenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-13)
[0108] [?].sub.D.sup.23+10.8 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.12 (d, J=8 Hz, 2H), 7.04 (d, J=8 Hz, 2H), 4.91 (dd, J=12, 5 Hz, 1H), 4.60 (dd, J=12, 10 Hz, 1H), 3.72 (dt, J=10, 5 Hz, 1H), 2.71-2.62 (m, 1H), 2.50-2.37 (m, 2H), 2.10 (s, 3H), 2.08 (m, 1H), 1.81-1.53 (m, 5H); .sup.13C NMR (75 MHz, CDCl.sub.3) ?212.0, 137.4, 134.5, 129.5, 127.9, 78.9, 52.5, 43.5, 42.7, 33.1, 28.5, 24.9, 21.0; IR (KBr) 3286.2, 2925.6, 1704.8, 1552.4, 13789, 1130.1, 819.6 cm.sup.?1; LRMS(FAB+) for C.sub.15H.sub.19NO.sub.3 [M+H].sup.+ Calcd: 262, Found: 262 chiral-phase HPLC, AD-H column (i-PrOH/hexane=5:95), 254 nm, flow rate=1 ml/min, tr (major)=10.54 min, tr (minor)=12.98 min.
(14) (R)-2-[(S)-1-(4-Isopropylphenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-14)
[0109] [?].sub.D.sup.23+16.9 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.16 (d, J=8 Hz, 2H), 7.07 (d, J=8 Hz, 2H), 4.91 (dd, J=12, 4 Hz, 1H), 4.62 (dd, J=12, 10 Hz, 1H), 3.76-3.70 (m, 1H), 2.88-2.85 (m, 1H), 2.71-2.65 (m, 1H), 2.49-2.38 (m, 2H), 2.09-2.04 (m, 1H), 1.81-1.58 (m, 5H), 1.22 (d, J=7 Hz, 6H); .sup.13C NMR (75 MHz, CDCl.sub.3) 212.2, 148.2, 134.8, 127.9, 126.9, 78.9, 52.5, 43.4, 33.6, 29.6, 28.5, 24.9, 23.8; IR (KBr) 3853.2, 3357.6, 2925.6, 2345.1, 1706.7, 1552.4, 1378.9, 1089.6 cm.sup.?1, chiral-phase HPLC, AD-H column (i-PrOH/hexane=3:97), 254 nm, flow rate=1 ml/min, tr (major)=10.19 min, tr (minor)=12.15 min.
(15) (R)-2-[(S)-1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-15)
[0110] [?].sub.D.sup.23+29.2 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.14-7.17 (m, 2H), 7.03-6.99 (m, 2H), 4.95 (dd, J=8, 5 Hz, 1H), 4.59 (dd, J=12, 10 Hz, 1H), 3.80-3.74 (m, 1H), 2.67-2.65 (m, 1H), 2.49-2.32 (m, 2H), 2.12-2.04 (m, 1H), 1.81-1.56 (m, 4H), 1.26-1.20 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 211.6, 163.3, 160.8, 133.3, 129.7, 115.9, 78.8, 52.5, 43.2, 42.7, 33.1, 28.4, 25.0; IR (KBr) 3266.9, 2923.7, 2279.5, 1708.7, 1550.5, 1376.9, 1093.4, 853.0 cm.sup.?1; LRMS(FAB+) for C.sub.14H.sub.16FNO.sub.3 [M+H].sup.+ Calcd: 266, Found: 266; chiral-phase HPLC, AS-H column (i-PrOH/hexane=10:90), 254 nm, flow rate=1 ml/min, tr (major)=17.62 min, tr (minor)=23.07 min.
(16) (R)-2-[(S)-1-(4-Chlorophenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-16)
[0111] [?].sub.D.sup.23+24.6 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.31 (d, J=8 Hz, 2H), 7.13 (d, J=8 Hz, 2H), 4.96 (dd, J=12, 4 Hz, 1H), 4.62 (dd, J=12, 10 Hz, 1H), 3.78 (dt, J=10, 4 Hz, 1H), 2.69-2.60 (m, 1H), 2.51-2.34 (m, 2H), 2.15-2.05 (m, 1H), 1.83-1.52 (m, 4H), 1.28-1.23 (m, 1H), .sup.13C NMR (75 MHz, CDCl.sub.3) 211.6, 136.3, 133.7, 129.6, 129.2, 78.6, 52.4, 43.4, 42.8, 33.2, 28.5, 25.1; IR (KBr) 3252.2, 2897.7, 1721.7, 1555.0, 1087.5 cm.sup.?1; chiral-phase HPLC, AS-H column (i-PrOH/hexane=10:90), 254 nm, flow rate=1 ml/min, tr (major)=14.96 min, tr (minor)=21.15 min.
(17) (R)-2-[(S)-1-(4-Bromophenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-17)
[0112] [?].sub.D.sup.25+16.4 (c 0.80, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.46 (d, J=8 Hz, 2H), 7.06 (d, J=8 Hz, 2H), 4.93 (dd, J=12, 4 Hz, 1H), 4.60 (dd, J=12, 10 Hz, 1H), 3.75 (dt, J=10, 4 Hz, 1H), 2.69-2.60 (m, 1H), 2.51-2.32 (m, 2H), 2.15-2.05 (m, 1H), 1.85-1.58 (m, 4H), 1.30-1.16 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 211.4, 136.7, 132.0, 129.8, 121.7, 78.4, 52.3, 43.4, 42.7, 33.1, 28.4, 25.0; IR (KBr) 3373.0, 2927.5, 1706.7, 1550.5, 1376.9, 1087.7, 827.3 cm.sup.?1; LRMS(FAB+) for C.sub.14H.sub.16BrNO.sub.3 [M+H].sup.+ Calcd: 326, Found: 326; chiral-phase HPLC, AS-H column (i-PrOH/hexane=10:90), 254 nm, flow rate=0.5 ml/min, tr (major)=20.22 min, tr (minor)=29.08 min.
(18) (R)-2-[(S)-1-(3-Chlorophenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-18)
[0113] [?].sub.D.sup.23+17.2 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.26-7.24 (m, 2H), 7.17 (s, 1H), 7.09-7.06 (m, 1H), 4.94 (dd, J=13, 4 Hz, 1H), 4.61 (d, J=13, 10 Hz, 1H), 3.75 (dt, J=10, 4 Hz, 1H), 2.69-2.64 (m, 1H), 2.62-2.34 (m, 2H), 2.13-2.07 (m, 1H), 1.82-1.57 (m, 4H), 1.23-1.19 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 211.4, 139.8, 134.7, 130.1, 128.2, 128.0, 126.4, 78.3, 52.2, 43.6, 42.7, 33.2, 28.4, 25.0; IR (KBr) 3284.3, 2929.4, 2362.4, 1706.7, 1552.4, 1378.9, 1130.1, 794.5 cm.sup.?1; chiral-phase HPLC, AS-H column (i-PrOH/hexane=10:90), 254 nm, flow rate=1 ml/min, tr (major)=16.09 min, tr (minor)=22.16 min.
(19) (R)-2-[(R)-1-(Furan-2-yl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-19)
[0114] [?].sub.D.sup.23+12.4 (c 2.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.35 (m, 1H), 6.28 (dd, J=3, 2 Hz, 1H), 6.18 (d, J=3 Hz, 1H), 4.83-4.63 (m, 2H), 3.97 (dt, J=10, 5 Hz, 1H), 2.80-2.71 (m, 1H), 2.50-2.31 (m, 2H), 2.14-2.04 (m, 1H), 1.88-1.56 (m, 4H), 1.35-1.21 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 211.0, 150.9, 142.3, 110.3, 109.0, 77.1, 51.1, 42.6, 37.6, 32.5, 28.2, 25.1; IR (KBr) 3392., 2941.0, 1706.7, 1552.4, 1430.9, 1376.9, 1130.1, 1014.4, 916.0, 740.5 cm.sup.?1; HRMS(FAB+) for C.sub.12H.sub.15NO.sub.4 [M+H].sup.+ Calcd: 238.1079, Found: 238.1080; chiral-phase HPLC, AD-H column (i-PrOH/hexane=5:95), 254 nm, flow rate=0.7 ml/min, tr (minor)=26.50 min, tr (major)=33.60 min.
(20) (R)-2-[(S)-1-Thien-2-yl-2-nitroethyl]cyclohexanone (Chemical Formula 3-20)
[0115] [?].sub.D.sup.23+20.1 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.22-7.21 (m, 1H), 6.93 (dd, J=5, 3 Hz, 1H), 6.88-6.87 (m, 1H), 4.89 (dd, J=12, 5 Hz, 1H), 4.65 (dd, J=12, 9 Hz, 1H), 4.13 (dt, J=9, 5 Hz, 1H), 2.73-2.64 (m, 1H), 2.50-2.32 (m, 2H), 2.14-2.06 (m, 1H), 1.95-1.82 (m, 2H), 1.69-1.58 (m, 2H), 1.39-1.29 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 3392.3, 3110.7, 2939.1, 2285.3, 1704.8, 1552.4, 1378.9, 1253.5, 1128.2, 850.4, 705.8 cm.sup.?1; HRMS(FAB+) for C.sub.12H.sub.15NO.sub.3S [M+H].sup.+ Calcd: 254.0851, Found: 254.0853; chiral-phase HPLC, AS-H column (i-PrOH/hexane=4:96), 254 nm, flow rate=0.5 ml/min, tr (minor)=29.95 min, tr (major)=35.16 min.
(21) (R)-2-[(S)-1-Naphthalen-2-yl-2-nitroethyl]cyclohexanone (Chemical Formula 3-21)
[0116] [?].sub.D.sup.23+15.6 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.84-7.78 (m, 3H), 7.64 (s, 1H), 7.50-7.46 (m, 2H), 7.29 (dd, J=11, 2 Hz, 1H), 5.03 (dd, J=12, 4 Hz, 1H), 4.74 (dd, J=12, 10 Hz, 1H), 3.95 (dt, J=10, 4 Hz, 1H), 2.83-2.74 (m, 1H), 2.54-2.36 (m, 2H), 2.11-2.04 (m, 1H), 1.79-1.62 (m, 4H), 1.32-1.29 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 211.8, 135.0, 133.2, 128.8, 127.7, 126.4, 126.1, 125.1, 78.8, 52.4, 44.0, 42.7, 33.3, 28.5, 25.0; IR (KBr) 3376.9, 2923.7, 1700.9, 1550.5, 1382.7, 1091.5, 825.4 cm.sup.?1; LRMS(FAB+) for C.sub.18H.sub.19NO.sub.3 [M].sup.+ Calcd: 297, Found: 297; chiral-phase HPLC, ASH column (i-PrOH/hexane=50:50), 254 nm, flow rate=0.7 ml/min, tr (major)=9.14 min, tr (minor)=13.12 min.
(22) (R)-2-[(S)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-22)
[0117] [?].sub.D.sup.23+10.8 (c 1.00, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.08 (d, J=9 Hz, 2H), 6.85 (d, J=9 Hz, 2H), 4.91 (dd, J=12, 4 Hz, 1H), 4.58 (dd, J=12, 10 Hz, 1H), 3.78 (s, 3H), 3.71 (dt, J=10, 4 Hz, 1H), 2.69-2.60 (m, 1H), 2.52-2.32 (m, 2H), 2.13-2.03 (m, 1H), 1.83-1.51 (m, 4H), 1.30-1.16 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 212.2, 15809, 129.4, 129.1, 114.2, 79.0, 55.1, 52.6, 43.1, 42.7, 33.1, 28.5, 24.9; IR (KBr) 3380.7, 2950.7, 2360.5, 1700.9, 1552.4, 1388.5, 1255.4, 1089.6, 831.2 cm.sup.?1; HRMS(FAB+) for C.sub.15H.sub.19NO.sub.4 [M].sup.+ Calcd: 278.1392, Found: 278.1390; chiral-phase HPLC, AD-H column (i-PrOH/hexane=20:80), 254 nm, flow rate=0.5 ml/min, tr (major)=18.59 min, tr (minor)=23.72 min.
(23) (R)-2-[(S)-1-(2-Methoxyphenyl)-2-nitroethyl]cyclohexanone (Chemical Formula 3-23)
[0118] [?].sub.D.sup.23+7.2 (c 0.10, CHC.sub.13); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.28-7.22 (m, 1H), 7.09 (dd, J=7, 2 Hz, 1H), 6.91-6.86 (m 2H), 4.84 (dd, J=10, 5 Hz, 1H), 4.00-3.90 (m, 1H), 3.84 (s, 3H), 2.99 (dt, J=10, 5 Hz, 1H), 2.50-2.34 (m, 2H), 2.10-2.04 (m, 1H), 1.80-1.54 (m, 4H), 1.12-1.18 (m, 1H); .sup.13C NMR (75 MHz, CDCl.sub.3) 212.5, 157.5, 130.9, 128.8, 125.2, 120.8, 110.9, 76.6, 55.3, 50.5, 42.6, 33.2, 28.5, 25.1; IR (KBr) 3293.9, 2935.2, 2345.1, 1706.7, 1550.5, 1378.9, 1245.8, 1122.4, 755.9 cm.sup.?1; HRMS(FAB+) for C.sub.15H.sub.19NO.sub.4 [M+H].sup.+ Calcd: 278.1392, Found: 278.1390; chiral-phase HPLC, AS-H column (i-PrOH/hexane=10:90), 254 nm, flow rate=0.5 ml/min, tr (major)=26.35 min, tr (minor)=36.10 min.
(24) (R)-2-[(S)-2-Nitro-1-(2-nitrophenyl)ethyl)cyclohexanone (Chemical Formula 3-24)
[0119] [?].sub.D.sup.23+9.8 (c 0.80, CHCl.sub.3); .sup.1H NMR (300 MHz, CDCl.sub.3) 7.83 (dd, J=8, 2 Hz, 1H), 7.64-7.58 (m, 1H), 7.49-7.41 (m, 2H), 4.98-4.83 (m, 2H), 4.38 (dt, J=9, 4 Hz, 1H), 2.98-2.87 (m, 1H), 2.50-2.34 (m, 2H), 2.17-2.07 (m, 1H), 1.85-1.61 (m, 5H); .sup.13C NMR (75 MHz, CDCl.sub.3) 211.1, 150.7, 133.1, 132.8, 129.1, 128.6, 124.9, 77.6, 52.1, 42.8, 38.6, 33.2, 28.3, 25.3; IR (film) 2944, 2864, 1707, 1552, 1527, 1358, 855, 781 cm.sup.?1; HRMS(FAB+) for C.sub.14H.sub.16N.sub.205 [M+H].sup.+ Calcd: 293.1137, Found: 293.1141; chiral-phase HPLC, AD-H column (i-PrOH/hexane=15:85), 254 nm, flow rate=1 ml/min, tr (major)=14.45 min, tr (minor)=22.22 min.
(25) (R)-2,2,-Dimethyl-4-nitro-3-phenylbutanal (Chemical Formula 3-25)
[0120] [?].sub.D.sup.20+11.26 (c 0.3, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.50 (s, 1H), 7.18-7.34 (m, 5H), 4.81-4.89 (dd, J=9.0, 12 Hz, 1H), 4.66-4.71 (dd, J=3.0, 12 Hz, 1H), 3.76-3.81 (dd, J=3.0 12 Hz, 1H) 1.10 (s, 3H), 0.97 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?204.25, 135.30, 129.06, 128.71, 128.15, 76.30, 48.45, 48.22, 21.70, 18.88 ppm; IR(neat) 3033, 2974, 2933, 2819, 2721, 1725, 1555, 1496, 1455, 1379, 882, 750, 705 cm.sup.?1; HRMS (FAB+) for C.sub.12H.sub.15NO.sub.3 [M+Na].sup.+ Calcd: 244.0950 Found: 244.0950; HPLC [Chiralcel ODH, hexane/2-propanol=80/20, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 18.3 min, (minor) 31.1 min].
(26) (R)-3-(4-Chlorophenyl)-2,2-dimethyl-4-nitrobutanal (Chemical Formula 3-26)
[0121] [?].sub.D.sup.22?5.83 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.50 (s, 1H), 7.31 (d, J=6.0 Hz, 2H), 7.15 (d, J=6.0 Hz, 2H), 4.79-4.85 (dd, J=6.0, 9.0 Hz, 1H), 4.67-4.71 (dd, J=3.0, 9.0 Hz, 1H), 3.75-3.79 (dd, J=3.0, 9.0 Hz, 1H), 1.12 (s, 3H), 1.00 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?204.07, 134.34, 134.20, 130.61, 129.16, 76.35, 48.39, 48.07, 21.95, 19.10 ppm; IR (KBr) 2926, 1728, 1556, 1494, 1378, 1094, 835 cm.sup.?1; HRMS (FAB+) for C.sub.12H.sub.14ClNO.sub.3 [M+Na].sup.+ Calcd: 278.0560 Found: 278.0562; HPLC [Chiralcel OD-H, hexane/2-propanol=80/20, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 16.1 min, (minor) 25.4 min].
(27) (R)-3-(4-Bromophenyl)2,2-dimethyl-4-nitrobutanal (Chemical Formula 3-27)
[0122] [?].sub.D.sup.23?14.86 (c 0.1, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.49 (s, 1H), 7.47 (d, J=6.0 Hz, 2H), 7.09 (d, J=6.0 Hz, 2H), 4.79-4.85 (dd, J=9.0, 9.0 Hz, 1H), 4.67-4.71 (dd, J=3.0, 9.0 Hz, 1H), 3.74-3.78 (dd, J=3.0, 9.0 Hz, 1H), 1.12 (s, 3H), 1.01 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?204.04, 134.73, 132.12, 130.95, 122.49, 76.28, 48.33, 48.15, 21.98, 19.11 ppm; IR (KBr) 2924, 2857, 1727, 1555, 1457, 1377, 1009 cm.sup.?1; HRMS (FAB+) for C.sub.12H.sub.14BrNO.sub.3 [M+Na].sup.+ Calcd: 322.0055 Found: 322.0053; HPLC [Chiralcel OD-H, hexane/2-propanol=80/20, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 21.9 min, (minor) 31.7 min].
(28) (R)-2,2-Dimethyl-4-nitro-3-p-tolylbutanal (Chemical Formula 3-28)
[0123] [?].sub.D.sup.22?15.07 (c 0.4, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.50 (s, 1H), 7.05-7.12 (m, 4H), 4.78-4.84 (dd, J=9.0, 12.0 Hz, 1H), 4.63-4.67 (dd, J=3.0, 9.0 Hz, 1H) 2.29 (s, 3H), 1.09 (s, 3H), 0.97 (s, 3H); .sup.13C-NMR (100 MHz, CDCl.sub.3) ?204.65, 138.07, 132.38, 129.60, 129.13, 76.60, 48.46, 48.34, 21.75, 21.23, 19.05 ppm; IR (KBr) 2973, 2925, 1726, 1556, 1516, 1381, 1120, 824 cm.sup.?1; HRMS (FAB+) for C.sub.13H.sub.17NO.sub.3 [M+Na].sup.+ Calcd: 258.1106 Found: 258. 1107; HPLC [Chiralcel OD-H, hexane/2-propanol=80/20, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 14.2 min, (minor) 21.1 min].
(29) (R)-3-(Furan-2-yl)-2,2-dimethyl-4-nitrobutanal (Chemical Formula 3-29)
[0124] [?].sub.D.sup.22?12.06 (c 0.3, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.51 (s, 1H), 7.37 (d, J=0.6 Hz, 1H), 6.31-6.32 (dd, J=3.0, 3.3 Hz, 1H), 6.23 (d, J=3.0 Hz, 1H), 4.73-4.79 (dd, J=9.0, 12 Hz, 1H), 4.58-4.62 (dd, J=3.0, 9.0 Hz, 1H), 3.91-3.95 (dd, J=3.0, 9.0 Hz, 1H), 1.17 (s, 3H), 1.04 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?203.76, 150.02, 142.92, 110.62, 109.82, 75.09, 48.36, 42.39, 21.31, 19.21 ppm; IR (KBr) 2925, 1728, 1557, 1376, 1148, 740 cm.sup.?1; HRMS (FAB+) for C.sub.10H.sub.13NO+[M+Na].sup.+ Calcd: 234.0742 Found: 234.0742; HPLC [Chiralcel OD-H, hexane/2-propanol=90/10, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 14.7 min, (minor) 21.2 min].
(30) (R)-3-(4-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal (Chemical Formula 3-30)
[0125] [?].sub.D.sup.22?9.55 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.51 (s, 1H), 7.12 (d, J=9.0 Hz, 2H), 6.85 (d, J=6.0, 2H), 4.78-4.84 (dd, J=9.0, 12 Hz, 1H), 4.64-4.68 (dd, J=3.0, 9.0 Hz, 1H), 3.77 (s, 3H), 3.71-3.75 (dd, J=3.0, 9.0 Hz, 1H), 1.11 (s, 3H), 0.98 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) 8204.73, 159.47, 130.32, 127.30, 114.26, 76.69, 55.41, 48.57, 47.98, 21.71, 19.10 ppm; IR (KBr) 2927, 1725, 1611, 1556, 1514, 1465, 1380, 1252, 1033, 836 cm.sup.?1; HRMS(FAB+) for C.sub.13H.sub.17NO+[M+Na].sup.+ Calcd: 274.1055 Found: 274.1055; HPLC [Chiralcel OD-H, hexane/2-propanol=80/20, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 18.2 min, (minor) 25.7 min].
(31) (R)-3-(2-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal (Chemical Formula 3-31)
[0126] [?].sub.D.sup.20?14.39 (c 0.3, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.50 (s, 1H), 7.23-7.29 (m, 1H), 7.11-7.14 (dd, J=3.0, 9.0 Hz, 1H), 6.87-6.95 (m, 2H), 4.86-4.94 (dd, J=12, 15 Hz, 1H), 4.69-4.75 (dd, J=3.0, 12 Hz, 1H), 4.22 (d, J=9.0 Hz, 1H), 3.81 (s, 3H), 1.09 (s, 3H), 1.05 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?204.13, 157.36, 129.79, 129.28, 124.00, 120.76, 111.29, 75.81, 55.34, 48.37, 21.00, 19.96 ppm; HRMS (FAB+) for C.sub.13H.sub.17NO.sub.4 [M+Na].sup.+ Calcd: 274.1055 Found: 274.1056; IR (KBr) 2927, 1725, 1611, 1556, 1514, 1465, 1380, 1252, 1033, 836 cm.sup.?1; HPLC [Chiralcel OD-H, hexane/2-propanol=90/10, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 15.4 min, (minor) 25.2 min].
(32) (R)-3-(4-Hydroxyphenyl)-2,2-dimethyl-4-nitrobutanal (Chemical Formula 3-32)
[0127] [?].sub.D.sup.22?13.37 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.52(s, 1H), 7.04-7.07 (m, 2H), 6.74-6.77 (m, 2H), 5.47 (br s, 1H), 4.77-4.85 (dd, J=12, 12 Hz, 1H), 4.64-4.69 (dd, J=3.0, 12.0 Hz, 1H), 3.69-3.75 (dd, J=6.0, 12.0 Hz), 1.12 (s, 3H), 1.00 (s, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) 8205.71, 155.80, 130.47, 127.07, 115.8, 76.71, 48.67, 48.01, 21.40, 19.07 ppm; IR (KBr) 2925, 1726, 1638, 1556, 1456, 1380, 705 cm.sup.?1; HRMS (FAB+) for C.sub.12H.sub.15NO.sub.4 [M+Na].sup.+ Calcd: 260.0899 Found: 260.0899; HPLC [Chiralcel ODH, hexane/2-propanol=80/20, flow rate=0.7 mL/min, ?=254 nm, retention times: (major) 16.1 min, (minor) 24.9 min].
(33) (2R,3S)-2-Methyl-4-nitro-3-phenylbutanal (Chemical Formula 3-33)
[0128] [?].sub.D.sup.20?9.00 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.71 (s, 1H), 7,15-7.36 (m, 5H), 4.77-4.83 (dd, J=6.0, 12 Hz, 1H), 4.64-4.71 (dd, J=9.0, 12 Hz, 1H), 3.77-3.87 (m, 1H), 2.72-2.83 (m, 1H), 1.00 (d, J=9.0 Hz, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?202.53, 136.75, 129.30, 128.35, 128.28, 78.33, 48.65, 44.24, 12.36 ppm; IR (neat) 3031, 2975, 2933, 2827, 2729, 1724, 1603, 1551, 1496, 1433, 1459, 1380, 1203, 914, 853, 757, 702 cm.sup.?1; LRMS (FAB+) for C.sub.1H.sub.13NO.sub.3 [M+Na].sup.+ Calcd: 230.1 Found: 230.1; HPLC [Chiralcel OD-H, hexane/2-propanol=90/10, flow rate=1.0 mL/min, ?=254 nm, retention times: (major) 35.4 min, (minor) 25.4 min].
(34) (2R,3S)-2-Ethyl-4-nitro-3-phenylbutanal (Chemical Formula 3-34)
[0129] [?].sub.D.sup.20+8.10 (c 0.4, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.72 (d, J=3.0 Hz, 1H), 7.28-7.35 (m, 3H), 7.16-7.20 (m, 2H), 4.74-4.81 (dd, J=9.0, 18 Hz), 4.63-4.71 (dd, J=3.0, 15 Hz), 3.75-3.83 (m, 1H), 2.64-2.72 (m, 1H), 1.46-1.56 (m, 2H), 0.83 (t, J=9.0 Hz, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) 8203.32, 136.75, 129.11, 128.21, 127.99, 78.55, 54.98, 42.68, 20.36, 10.66 ppm; IR (neat) 3031, 2969, 2878, 2738, 1719, 1551, 1496, 1456, 1432, 1379, 1206, 757, 702 cm.sup.?1; LRMS (FAB+) for C.sub.12H.sub.15NO.sub.3 [M+Na].sup.+ Calcd: 244.1 Found: 244.1; HPLC [Chiralcel OD-H, hexane/2-propanol=90/10, flow rate=0.8 mL/min, ?=215 nm, retention times: (major) 34.5 min, (minor) 29.9 min].
(35) (R)-2-[(S)-2-Nitro-1-phenylethyl]pentanal (Chemical Formula 3-35)
[0130] [?].sub.D.sup.20+15.40 (c 0.2, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.70 (d, J=3.0 Hz, 1H), 7.27-7.37 (m, 3H), 7.16-7.19 (m, 3H), 4.60-4.81 (m, 2H), 3.73-3.81 (m, 3H), 2.60-2.74 (m, 3H), 1.12-1.55 (m, 4H), 0.79 (t, J=6.0 Hz, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?203.28, 136.77, 129.11, 128.22, 127.98, 78.42, 53.78, 43.13, 29.44, 19.75, 13.93 ppm; IR (neat) 2968, 1719, 1553, 1379 cm.sup.?1; LRMS (FAB+) for C.sub.13H.sub.17NO.sub.3 [M+Na].sup.+ Calcd: 258.1 Found: 258.1; HPLC [Chiralcel OD-H, hexane/2-propanol=80/20, flow rate=1.0 mL/min, ?=254 nm, retention times: (major) 19.3 min, (minor) 14.1 min].
(36) (2R,3S)-2-Isopropyl-4-nitro-3-phenylbutanal (Chemical Formula 3-36)
[0131] [?].sub.D.sup.20+19.81 (c 0.5, CH.sub.2Cl.sub.2); .sup.1H-NMR (300 MHz, CDCl.sub.3) ?9.93 (d, J=1.8 Hz, 1H), 7.28-7.37 (m, 3H), 7.15-7.20 (m, 2H), 4.65-4.69 (dd, J=3.0, 9.0 Hz, 1H), 4.55-4.60 (dd, J=6.0, 9.0 Hz, 1H), 3.87-3.93 (m, 1H), 2.75-2.80 (m, 1H), 1.68-1.76 (m, 1H), 1.11 (d, J=6.0 Hz, 3H), 0.89 (d, J=6.0 Hz, 3H) ppm; .sup.13C-NMR (100 MHz, CDCl.sub.3) ?204.59, 137.26, 129.37, 128.32, 128.16, 79.21, 58.95, 42.13, 28.13, 21.88, 17.18 ppm; IR (neat) 2964, 1717, 1553, 1379 cm.sup.?1; HRMS (FAB+) for C.sub.13H.sub.17NO.sub.3 [M+H].sup.+ Calcd: 236.1208 Found: 236.1287; HPLC [Chiralcel AD-H, hexane/2-propanol=99.5/0.5, flow rate=0.3 mL/min, ?=254 nm, retention times: (major) 24.1 min, (minor) 29.6 min]
EXAMPLE 2
Synthesis of chiral indole Derivatives of Present Disclosure
[0132] A solution of (R)-2-((S)-1-(4-methoxyphenyl)-2-nitroethyl)cyclohexan-1-one (Chemical Formula 3-22, 300 mg, 1.08 mmol) in THF (5 mL) was added with zinc powder (707 mg, 10.8 mmol) and added with a solution of NH.sub.4Cl (57 mg, 1.08 mmol) in water (2 mL). The mixture was vigorously stirred at room temperature for 6 hours and filtered. A residual solid was washed with THF and the combined filtrate was concentrated. The residue was purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH, 95/5) on a silica gel to obtain 197 mg (95%) of 3-arylhexahyroindole 1-oxides (Chemical Formula 5-1) as a white solid (Reaction Formula 3).
##STR00019##
(3R,3aS)-3-(4-Methoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H-indole-1-Oxide (Chemical Formula 5-1)
[0133] .sup.1H NMR (500 MHz, CDCl.sub.3): 7.16 (d, 2H, J=8.7, ArH), 6.89 (d, 2H, J=8.7, ArH), 4.27-4.24 (br m, 1H, NCH.sub.2), 4.15-4.10 (br m, 1H, NCH2), 3.81 (s, 3H, OCH.sub.3), 3.25-3.15 (m, 2H, ArCH, NCCH2), 2.8-2.7 (ArCHCH), 2.12-1.84 (m, 3H, CH.sub.2), 1.85 (br d, 1H, J=12.8, CH.sub.2), 1.45-1.18 (m, 4H, CH.sub.2); .sup.13C NMR (125 MHz, CDCI3): ?158.9, 148.6, 131.7, 128.3, 114.4, 68.4, 55.3, 50.6, 45.3, 32.3, 24.3, 23.8, 23.5; LRMS(ESI+): m/z 246.1 (M+H);
[0134] In the presence of zinc powder, since a chiral nitro derivative (Chemical Formula 3-22) was easily hydrogenated to the corresponding chiral indole derivative to exhibit a yield of 95%, the reaction was potentially very useful in association with organic synthesis for forming carbon-carbon bonds.
EXPERIMENTAL EXAMPLE 1
Optimization of thiourea catalyst
[0135] In order to examine an effect of a catalyst on an enantioselective Michael addition reaction of nitroalkene and aldehyde, the reaction was performed using isobutyraldehyde and trans-beta-nitrostyrene. The basic skeleton of DPEN was used as a catalyst, and a catalyst in which one amine was unsubstituted or substituted with 3-pentyl group and the other amine was substituted with thiourea was used.
##STR00020##
[0136] In order to examine the effect of the catalyst, first, a thiourea catalyst in which one amine group was substituted with an alkyl group was used. Toluene was used as the solvent, and the reaction was performed at room temperature (Table 1).
##STR00021##
TABLE-US-00001 TABLE 1 Temp Yield.sup.a Entry Catalyst (? C.) Equiv. mol % (%) ee.sup.b (%) 1 1a rt 10 10 50 92 2 1b rt 10 10 91 97 3 1c rt 10 10 67 93 4 1d rt 10 10 70 93 5 1e rt 10 10 50 92 6 1f rt 10 10 68 97 7 1g rt 10 10 86 94 8 1h rt 10 10 N.R 9 1i rt 10 10 45 94 10 1b 10 10 74 97 11 1b rt 7 10 86 97 12 1b rt 5 10 85 97 13 1b rt 10 5 83 96 .sup.aisolated yields, .sup.bThe ee values were determined by chiral-phase HPLC using OD-H column.
[0137] A case of using a thiourea catalyst without an alkyl group in amine was more effective than a case of using a catalyst (Chemical Formula 4-8) in which amine was substituted with an alkyl group. As a result of comparing yields and stereoselectivities of a thiourea catalyst substituted with a paramethoxy group (Chemical Formula 4-5) as an electron donating group (EDG) and a thiourea catalyst substituted with a parafluoro group (Chemical Formula 4-6) as an electron withdrawing group (EWG), the catalyst substituted with the parafluoro group (Chemical Formula 4-6) as the EWG showed higher yield and stereoselectivity. The catalyst substituted with the EWG was higher likely to participate in hydrogen bonds than the catalyst in which hydrogen of thiourea involved in hydrogen bonds was substituted with the EDG, and thus, the stereoselectivity of the product was higher. In particular, the catalyst (Chemical Formula 4-2) substituted with 3,5-bis(trifluoromethyl-1) showed the highest yield and stereoselectivity.
[0138] In order to further increase the effect of the catalyst, the reaction was performed at a lower temperature. The reaction at low temperature showed stereoselectivity similar to the reaction at room temperature, but had a lower yield therethan. That is, it was confirmed that the catalyst provided the highest reactivity and stereoselectivity at room temperature.
[0139] Meanwhile, the stereoselectivity did not depend on an equivalent of aldehyde and an amount of catalyst, but did affect the reaction yield. As the amount of aldehyde decreased from 10 equiv. to 7 equiv. and 5 equiv., the stereoselectivity was not changed, but the yield was decreased. Subsequently, when 5 mol % of the catalyst was added after fixing 10 equiv. of aldehyde, both the yield and stereoselectivity were decreased compared to the case of using 10 mol % of the catalyst. Accordingly, both yield and optical purity were excellent when 10 equiv. of aldehyde and 10 mol % of the catalyst were used.
EXPERIMENTAL EXAMPLE 2
Optimization of Solvent
[0140] An experiment was conducted using a catalyst (Chemical Formula 4-2) substituted with 3,5-bis(trifluoromethyl-1), which was the most active in Experimental Example 1. The reaction was performed in all solvents, and a desired yield was obtained in all the solvents except hexane and tetrahydrofuran (THF). The stereoselectivity of 96% or more was obtained in all the solvents. In particular, when water was used as a solvent, the reaction was performed for 12 hours, which was 8 times shorter than other solvents (96 hours), and 5 mol %, which was half the used amount (10 mol %) of catalyst. Therefore, water, which provided the highest yield and stereoselectivity and enabled a Michael addition reaction even at a short reaction time and a small amount of catalyst, was selected as a solvent.
##STR00022##
TABLE-US-00002 TABLE 2 Entry Solvent Yield (%) .sup.a ee (%) .sup.b 1 n-hexane 52 97 2 CHCl.sub.3 80 97 3 THF 60 96 4 benzene 87 97 5 EtOH 58 97 6 toluene 85 97 7.sup.c water 99 99 8 CH.sub.2Cl.sub.2 85 97 .sup.a isolated yields, .sup.b The ee values were determined by HPLC using OD-H column. .sup.cThe reactions were run with catalyst of 5 mol %, 12 h
EXPERIMENTAL EXAMPLE 3
Reaction Depending on Type of carbonyl Compound
[0141] 3.1. In Case of Ketone
[0142] Various ketones and phenyl-substituted nitroalkenes were reacted in the presence of catalysts, solvents, and phenol derivatives (Table 3).
##STR00023##
TABLE-US-00003 TABLE 3 ee (syn) .sup.c Entry R1 R2 Yield ? (%) syn/anti .sup.b (%) 1 .sup.d CH.sub.3 H 72 72 2 .sup.e CH.sub.3 H 81 98 3 .sup.f CH.sub.3 H 90 99 4 .sup.g CH.sub.3 H 98 99 5 C.sub.6H.sub.5 H 95 98 6 (CH.sub.2).sub.4 99 90/10 99 7 (CH.sub.2).sub.3 98 80/20 88 8 CH.sub.2CH.sub.2OCH.sub.2 87 82/18 66 9 CH.sub.2CH.sub.2SCH.sub.2 85 66/34 94 .sup.a isolated yields, .sup.b diastereoselectivities were determined by .sup.1H NMR analysis, .sup.c The ee values were determined by chiral-phase HPLC, .sup.d used 1 mol % of 1b catalyst, .sup.e used 5 mol % of phenol addictive, .sup.f used 5 mol % of 4-chlorophenol, .sup.g the reaction proceeded for 36 h.
[0143] The reaction including acetone (Chemical Formula 1-1) showed relatively high yield and enantioselectivity compared to cycloketone substituted with sulfur (Chemical Formula 1-6) and oxygen (Chemical Formula 1-5). This was because ketone reacted with an amino group of the catalyst to form enamine. In the case of aliphatic ketone, diastereoselectivity and enantioselectivity increased because steric hindrance was small and a nucleophile was easily accessible to nitroalkene.
[0144] Meanwhile, when 4-nitrophenol was added as an additive, relatively high yield and enantioselectivity were provided, whereas when phenol and 4-chlorophenol were added, a suitable yield was obtained.
[0145] 3.2. In Case of aldehyde
[0146] Various aldehydes and nitrostyrenes were reacted under optimized conditions (Table 4).
##STR00024##
TABLE-US-00004 TABLE 4 dr .sup.b Entry R1 R2 Yield (%) ? (syn:anti) ee (%) .sup.c 1 Me H 95 67:33 99 2 Et H 94 83:17 99 3 n-Pr H 94 83:17 98 4 i-Pr H 93 93:07 99 .sup.a isolated yields. .sup.b Determined by .sup.1H-NMR analysis. .sup.c The ee values were determined by HPLC using OD-H and AD-H columns.
[0147] Propionaldehyde (Chemical Formula 1-8) showed high enantioselectivity, butyraldehyde (Chemical Formula 1-9) and pentanal (Chemical Formula 1-10) showed higher diastereoselectivity than propionaldehyde, and 3-methylbutanal (Chemical Formula 1-11) showed the best diastereoselectivity and enantioselectivity. This means that the larger an alkyl group of aldehyde, the higher the diastereoselectivity due to steric hindrance.
EXPERIMENTAL EXAMPLE 4
Reaction Depending on Type of nitroalkene
[0148] 4.1. In Case of aliphatic ketone
[0149] To confirm the applicability of the reaction to aliphatic ketone, acetone (Chemical Formula 1-1) reacted with various ?,?-unsaturated nitroalkenes (Table 5).
##STR00025##
TABLE-US-00005 TABLE 5 Entry Ar Time (h) Yield (%) ? ee (%) .sup.b 1 4-MeC.sub.6H.sub.4 10 91 99 2 4-MeOC.sub.6H.sub.4 12 95 99 3 4-ClC.sub.6H.sub.4 9 96 99 4 4-BrC.sub.6H.sub.4 9 99 98 5 2-MeOC.sub.6H.sub.4 17 88 99 6 2-furyl 10 95 98 .sup.a Isolated yields, .sup.b the ee values were determined by chiral-phase HPLC.
[0150] Nitroalkenes (Chemical Formulas 2-4, 2-5, and 2-7) attached with phenyl rings substituted with electron withdrawing groups reacted better overall and had relatively shorter reaction time than nitroalkenes attached with phenyl rings substituted with electron donating groups (entry 3, 4, 6 of Table 2). In the case of the electron withdrawing groups, the reaction time was reduced because the nucleophiles did not prevent approach to electrophiles.
[0151] 4.2. In Case of cycloketone
[0152] The results of reacting cycloketone with various ?,?-unsaturated nitroalkenes were shown in Table 6 below.
##STR00026##
TABLE-US-00006 TABLE 6 Entry R Yield ? (%) syn/anti .sup.b ee (syn) .sup.c (%) 1 4-MeC.sub.6H.sub.4 98 86/14 99 2 4-i-PrC.sub.6H.sub.4 88 93/7 82 3 4-FC.sub.6H.sub.4 92 88/12 99 4 4-ClC.sub.6H.sub.4 99 81/19 99 5 4-BrC.sub.6H.sub.4 97 85/15 96 6 3-ClC.sub.6H.sub.4 93 91/9 96 7 2-furyl 92 92/8 96 8 2-thienyl 99 84/16 98 9 2-naphthyl 92 89/11 92 10 4-MeOC.sub.6H.sub.4 99 91/9 99 11 2-MeOC.sub.6H.sub.4 94 91/9 99 12 2-NO2C.sub.6H.sub.4 95 87/13 94 .sup.a Isolated yields, .sup.b diastereoselectivities were determined by .sup.1H NMR analysis, .sup.c the ee values were determined by chiral-phase HPLC
[0153] Trans-?-nitrostyrene (Chemical Formula 2-1) had similar or slightly higher enantioselectivity than nitroalkenes (Chemical Formulas 2-4, 2-5, and 2-9) having a halogen-substituted phenyl ring at a para position. Similarly, reactions using nitroalkenes substituted with 2-furyl (Chemical Formula 2-7), 2-thienyl (Chemical Formula 2-11), and 2-naphthyl (Chemical Formula 2-12) had relatively excellent enantioselectivities. In particular, the reaction with the 2-furyl derivative showed the highest yield. In addition, the nitroalkene (Chemical Formula 2-3) attached to a phenyl ring having a methoxy group as an electron donating group at the 4th position showed slightly higher yield and stereoselectivity than a nitro group as an electron withdrawing group at the 4th position.
[0154] 4.3. In Case of aldehyde
[0155] The reactions of isobutyraldehyde (Chemical Formula 1-7) and various ?,?-unsaturated nitroalkenes were performed under optimal conditions (Table 7).
##STR00027##
TABLE-US-00007 TABLE 7 Entry Ar Yield (%) .sup.a ee (%) .sup.b 1 Ph 99 99 2 4-ClPh 94 99 3 4-BrPh 94 98 4 4-MePh 94 99 5 2-Furyl 96 99 6 4-MeOPh 97 99 7 .sup.c 2-MeOPh 96 99 8 4-OHPh 96 99 .sup.a isolated yields, .sup.b The ee values were determined by HPLC using OD-H column.
[0156] As a result, the highest yield was obtained when unsubstituted nitrostyrene (Chemical Formula 2-1) was used. In addition, the reaction with nitrostyrenes substituted with an electron withdrawing group and an electron donating group also showed excellent stereoselectivity and yield.
EXPERIMENTAL EXAMPLE 5
Calculation of Transition State Energy Through DFT
[0157] 5.1. Experimental Method
[0158] Density functional theory (DFT) calculation showed a mechanism of a substrate and a catalyst and was performed using Gaussian 16 and Gauss-View 6.0 programs. An optimized shape was described using a B3LYP/6-31G(d,p) level. After the shapes of a reactant, an intermediate (IM), a transition state (TS), and a product were completely optimized, zero-point energy (ZPE) was obtained through vibrational frequency calculation at the same theoretical level, and a potential energy surface (PES) was obtained. Enthalpy correction and entropy according to a temperature were calculated at 298 K and 1 atm.
[0159] 5.2. In Case of ketone
[0160] A mechanism proposed for a Michael reaction between cyclohexanone and phenyl-substituted nitroalkene was illustrated in
[0161] 5.3. In Case of aldehyde
[0162] A mechanism proposed for a Michael reaction between propionaldehyde and phenyl-substituted nitroalkene was illustrated in
[0163] 5.4. Solvent Effect
[0164] The relative freedom of the solvent effect and thermal energy for each step of the Michael reaction were calculated via DFT.
[0165] When water as a polar protic solvent was used as a solvent, it was confirmed through experiments that the reactivity was higher than the reaction using other solvents. In addition, when water was used as a solvent, it was confirmed through quantum calculation that the reactivity was improved by stabilizing the transition state of the catalyst. According to the stabilized transition state, aldehyde reacted with an amino group of the catalyst to form enamine, and a thiourea moiety on the other side formed hydrogen bonds with two oxygen atoms of a nitro group. The enamine nucleophile formed by the catalyst attacked the electrophile from below.
[0166] In order to predict a solvent effect of the catalyst, the relative free energy of the transition state (TS) during an interfacial reaction between a hydrophobic substituent (CF.sub.3) of the catalyst 4-2 and H.sub.2O was compared with that of an aqueous binary mixture (H.sub.2O+solvent) and the result thereof was illustrated in
[0167] As a result, it was confirmed that when water was used as the solvent, the relative free energy in the transition state was the lowest. When water was used as the solvent in the Michael addition reaction, the reactivity increased as the polarity of the catalyst increased. This was because the reactivity increased due to the stabilization of the relative energy and the hydrophobic effect of the hydration reaction. In particular, in the case of the catalyst 4-2, the transition state was stabilized through hydrogen bonds between fluorine (F) atoms of the catalyst and hydrogen (H) atoms of water. In addition, when a contact between the catalyst and the water increased due to hydrogen bonds, the degree of stabilization varied according to the number of hydrogen bonds of water molecules (
[0168] Conventionally, hydrophobic non-polar solvents such as n-hexane and toluene have been widely used in Michael addition reactions. Since the solvent effect on the Michael addition reaction was confirmed in Experimental Example 2 of the present disclosure, thermodynamic analysis was performed to determine a factor affecting the Michael addition reaction of water. Quantum calculations were performed to predict thermophysical data for an interfacial reaction system in the transition state of the catalyst. Comparing an actual reaction (Table 2) and quantum calculation results, it was confirmed that non-polar solvents such as n-hexane and benzene exhibited the lowest reactivity. In addition, CHCl.sub.3, tetrahydrofuran (THF), CH.sub.2Cl.sub.2, and EtOH showed similar reactivity in the calculated results, and it was confirmed that water among these solvents showed the best reaction activity and stability (
[0169] In addition, in order to prove through nuclear magnetic resonance spectroscopy (NMR) that the reaction proceeded through hydrogen bonds between fluorine (F) atoms and hydrogen (H) atoms in a catalytic reaction when water was used as a solvent, as a result of measuring NMR by using DO instead of water, it was confirmed that the peaks for observing fluorine (.sup.19F) in the catalyst shifted depending on the presence or absence of D.sub.2O (
[0170] As described above, although embodiments have been described by the restricted drawings, various modifications and variations can be applied on the basis of embodiments by those skilled in the art. For example, even if the described techniques are performed in a different order from the described method, and/or components such as a system, a structure, a device, a circuit, and the like described above are coupled or combined in a different form from the described method, or replaced or substituted by other components or equivalents, an appropriate result can be achieved.
[0171] Therefore, other implementations, other embodiments, and equivalents to the appended claims fall within the scope of the claims to be described below.