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WO2024034767A1 - Procédé de production d'un produit de réaction d'aldol chiral sélectif à l'azote d'un composé nitroso à l'aide d'un composé catalyseur chiral organique - Google Patents

Procédé de production d'un produit de réaction d'aldol chiral sélectif à l'azote d'un composé nitroso à l'aide d'un composé catalyseur chiral organique Download PDF

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WO2024034767A1
WO2024034767A1 PCT/KR2023/003846 KR2023003846W WO2024034767A1 WO 2024034767 A1 WO2024034767 A1 WO 2024034767A1 KR 2023003846 W KR2023003846 W KR 2023003846W WO 2024034767 A1 WO2024034767 A1 WO 2024034767A1
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formula
chiral
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Korean (ko)
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심재호
김현수
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Korea University Research and Business Foundation
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

Definitions

  • the present invention relates to a method for producing a nitrogen-selective chiral aldol reaction product of a cyclic ketone and a nitroso compound using an organic chiral catalyst compound.
  • Organic catalysts generally contain carbon, hydrogen, nitrogen, and sulfur and are structurally different from metal catalysts, which include a metal core and ligands.
  • the Aldol reaction is the main reaction that forms carbon-carbon bonds and is an important reaction used to synthesize a wide range of natural products or complex compounds that exhibit biological activity.
  • the asymmetric nitroso aldol reaction is a powerful synthetic tool that can introduce nitrogen to carbonyl groups and can be used to construct optically active ⁇ -hydroxyamino carbonyl compounds.
  • the present inventors achieved high yield by using a (R,R)-1,2-diphenylethylenediamine (DPEN)-based catalyst that can effectively catalyze the nitroso aldol reaction and control the stereochemistry of the product. And the present invention was completed by developing a method for producing a reaction product with optical purity.
  • DPEN diphenylethylenediamine
  • the purpose of the present invention is to provide a method for producing chiral nitroso derivatives through an asymmetric aldol reaction using a chiral diamine catalyst.
  • Another object of the present invention is to provide a chiral nitroso derivative prepared by the above production method.
  • the present invention includes the step of reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] to prepare a compound represented by [Formula 3], and in the reaction [
  • a method for producing a chiral nitroso derivative is provided, characterized by using a catalyst compound represented by Formula 4.
  • R 1 and R 2 may form a C 5 -C 8 cycloalkyl group or heterocycloalkyl group together with the carbon to which they are attached and the carbon marked with an asterisk (*),
  • R 3 is substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an unsubstituted aryl group of C 5 -C 8 ,
  • R 4 may be a C 1 -C 9 chain alkyl group or a cycloalkyl group.
  • the reaction may be an asymmetric aldol reaction.
  • the reaction involves reacting a compound represented by [Formula 1] with a catalyst compound represented by [Formula 4] to form an enamine intermediate, and then reacting with a compound represented by [Formula 2].
  • a compound represented by [Formula 3] may be produced through a nitrogen-selective aldol reaction.
  • nitroso aldol reactions use enolate as a nucleophile, pre-activate a carbonyl compound, or directly use an enamine compound and show oxygen selectivity, but the present invention forms an enamine intermediate during the reaction. By doing so, a nitrogen-selective nitroso aldol reaction can be induced.
  • the nitrogen-selective nitroso derivative represented by [Compound 3] can be used in the main reactions of various synthetic intermediates and thus can be utilized in the field of pharmaceutical organic synthesis.
  • the compound represented by [Formula 1] may be a compound represented by the following [Formula 1-1].
  • the compound represented by [Formula 2] may be a compound represented by the following [Formula 2-1].
  • the compound represented by [Formula 3] may be a compound represented by the following [Formula 3-1].
  • the compound represented by [Formula 4] may be any one or more selected from the compounds represented by [Formula 4-1] to [Formula 4-5] below.
  • the catalyst compound may be a salt form of the compound represented by [Formula 4], and preferably may be hydrochloride (HCl).
  • the reaction may be performed in a polar protic solvent, a polar aprotic solvent, or a non-polar solvent.
  • the solvent may be water, brine ( brine), dimethyl sulfoxide (DMSO), nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), ethanol (EtOH), acetone, cyclohexanone, chloroethane (EtCl 2 ), Dichloromethane (CH 2 Cl 2 ), tetrahydrofuran (THF), aniline, chlorobenzene, chloroform (CHCl 3 ), diethyl ether (Et 2 O), toluene, benzene, carbon tetrachloride (CCl 4 ), cyclohexane, heptane. It may be, but is not limited to this.
  • the reaction may be carried out in a polar solvent having a dielectric constant of 30 or more, more preferably water, brine, dimethyl sulfoxide (DMSO), It may be performed in one or more solvents selected from the group consisting of nitromethane (CH 3 NO 2 ), acetonitrile (CH 3 CN), methanol (MeOH), and combinations thereof, but is not limited thereto.
  • a polar solvent having a dielectric constant of 30 or more more preferably water, brine, dimethyl sulfoxide (DMSO)
  • DMSO dimethyl sulfoxide
  • the reaction may be performed by reacting the compound represented by [Formula 1] with the compound represented by [Formula 2] at an equivalence ratio of 2:1 to 1:2, preferably 2:1.
  • the reaction may involve adding 5 to 10 mol% of a catalyst compound represented by [Formula 4].
  • benzoic acid may be added and reacted with the compound represented by [Formula 1] and the compound represented by [Formula 2].
  • the reaction may be performed in a single reactor at room temperature.
  • the reaction may be completed within 15 minutes to 24 hours.
  • the reaction may be performed at -10 to 25°C. Preferably, it may be performed at a temperature of 0 to -10°C.
  • the present invention provides a chiral nitroso derivative prepared by the above-described production method.
  • the method for producing a chiral nitroso derivative uses a diamine catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) to form a cyclic ketone and an enamine. And, the enamine reacts with the nitroso compound to produce a nitroso derivative with high yield and enantioselectivity.
  • the catalyst is an organic catalyst that can be easily synthesized and can increase electrophilicity by activating nitroso compounds through hydrogen bonding.
  • the method for producing a chiral nitroso derivative according to an embodiment of the present invention is environmentally friendly by using water or brine as a solvent, and can improve the yield of the asymmetric nitroso aldol reaction product by stabilizing the transition state.
  • the method for producing a chiral nitroso derivative according to an embodiment of the present invention induces a nitrogen-selective nitroso aldol reaction by forming a transition state in the direction of minimizing steric hindrance, thereby increasing optical purity.
  • the chiral nitroso derivative prepared according to an embodiment of the present invention has nitrogen selectivity and can be used in the main reactions of various synthetic intermediates, so it can be used in the field of pharmaceutical organic synthesis.
  • Figure 1 is a reaction scheme of a method for producing a chiral nitroso derivative according to a nitrogen-selective nitroso aldol reaction as an example of the present invention.
  • Figure 2 shows the catalytic cycle of the nitroso aldol reaction including the proposed transition state.
  • Figure 3 shows the relative free energy diagram representing the catalytic transition state of catalysts 1a and 1b (Formulas 4-1 and 4-2 ) based on the B3LYP/6-31G(d,p) method in the gas phase and aqueous phase. Calculations were performed. At this time, 1 is cyclohexanone, 2 is nitrosobenzene, 3 is catalyst 1a , and 4 is catalyst 1b .
  • Figure 4 shows the effect of solvent on the transition state of the asymmetric nitroso aldol reaction. Calculations were performed based on the B3LYP/6-31G(d,p) method under various solvent conditions.
  • Figure 5 shows B3LYP/6-31G(d,p) calculations and relative free energies of (R,R)-1,2-diphenylethylenediamine (DPEN)-iminium salt catalyzed enantioselective nitroso aldol reaction.
  • the proposed catalytic mechanism is shown based on the diagram, and calculations were performed in the aqueous phase. At this time, 1 is cyclohexanone, 2 is nitrosobenzene, and 3 is catalyst 1a .
  • the present inventors discovered that the enamine formed by the reaction of a catalyst based on (R,R)-1,2-diphenylethylenediamine (DPEN) and a cyclic ketone is the oxygen of the nitroso compound activated through hydrogen bonding with the acid catalyst. It was confirmed that it attacks and induces a nitrogen-selective nitroso aldol reaction (Figure 1).
  • the present invention involves preparing a compound represented by [Formula 3] by reacting a compound represented by [Formula 1] with a compound represented by [Formula 2] using a catalyst compound represented by [Formula 4]. It provides a method for producing a chiral nitroso derivative, including:
  • a nitroso aldol reaction product with a high level of enantioselectivity can be produced in excellent yield.
  • R 1 and R 2 may form a C 5 -C 8 cycloalkyl group or heterocycloalkyl group together with the carbon to which they are attached and the carbon marked with an asterisk (*),
  • R 3 is substituted with one or more selected from the group consisting of a halogen group, cyano group, nitro group, hydroxy group, C 1 -C 9 chain alkyl group, and combinations thereof. It is an unsubstituted aryl group of C 5 -C 8 ,
  • R 4 may be a C 1 -C 9 chain or cyclic alkyl group.
  • substitution refers to a reaction in which an atom or atomic group contained in a molecule of a compound is replaced with another atom or atomic group.
  • chain alkyl group refers to a group derived from a straight-chain or branched-chain saturated aliphatic hydrocarbon having a specified number of carbon atoms and a valency of at least one.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, etc.
  • cycloalkyl group also referred to as a cyclic alkyl group, refers to a monovalent group having one or more saturated rings in which all ring members are carbon.
  • examples of such cycloalkyl groups include, but are not limited to, cyclobutyl groups, cyclopentyl groups, and cyclohexyl groups.
  • heterocycloalkyl group typically refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, mono-substituted or poly-substituted, and in its structure At least one is selected from heteroatoms of N, O or S.
  • aryl group refers to an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (eg, phenyl) or a plurality of condensed rings (eg, naphthyl). Examples of such aryl include, but are not limited to, phenyl, naphthyl, etc.
  • halogen group refers to elements belonging to group 17 of the periodic table and may include fluorine (F), chloride (Cl), bromine (Br), or iodine (I).
  • first, second, A, B, (a), and (b) may be used. These terms are only used to distinguish the component from other components, and the nature, sequence, or order of the component is not limited by the term.
  • a component is described as being “connected,” “coupled,” or “connected” to another component, that component may be directly connected or connected to that other component, but there is no need for another component between each component. It should be understood that may be “connected,” “combined,” or “connected.”
  • Optical rotation was measured using an automated digital polarimeter, and FT-IR spectra were recorded using a NICOLET 380 FT-IR spectrophotometer from Thermo Electron Corporation (Thermo Fisher Scientific Inc., Waltham, MA, USA). . using Varian Gemini 300 (300, 75 MHz) and Varian Mercury 400 (400, 100 MHz, Agilent, Santa Clara, CA, USA) with TMS (300, 75 MHz, Agilent, Santa Clara, CA, USA) as internal standard. 1 H NMR and 13 C NMR spectra were obtained.
  • the reagents and conditions are as follows: (a) 1.0 eq. Carbonyl compound, MgSO 4 , toluene (0.1 M), reflux, 48 hours. (b) Ethanol (0.1 M), NaBH 4 excess, 3 h (overall yield 81-90%).
  • a protic solvent In the case of a protic solvent, it can greatly contribute to stabilizing the transition state during a catalytic reaction by contributing to stabilizing the cation of the catalyst.
  • the reactivity of the catalyst increases in a polar solvent, and as the polarity of the catalyst increases, the binding force of the nucleophile increases and the free energy of the transition state is stabilized, showing relatively excellent yield and enantioselectivity.
  • polar aprotic solvents also showed relatively low yields because the interference of hydrogen bonding was more important than the activation of nitrosobenzene by the solvent. Therefore, from the solvent screening results in Table 1, the brine with the best yield and enantioselectivity for N-nitroso aldol reaction was determined as the reaction solvent.
  • the amount of reagent was changed to determine how the ratio of cyclic ketone (Formula 1 ) to nitroso compound (Formula 2 ) affects the nitroso aldol reaction.
  • the ratio of cyclohexanone:nitrosobenzene was 1:1 (entry 1)
  • the yield and enantioselectivity decreased compared to when the ratio was 2:1 (entry 1 in Table 2)
  • the amount of nitrosobenzene reagent was increased.
  • yield and enantioselectivity decreased (entries 6 and 7).
  • benzoic acid promotes amine catalysis and imine formation through activation of cyclohexanone.
  • the chiral diamine catalyst (Formula 4 ) reacts with cycloketone (Formula 1 ) to form an imine, which in turn forms an enamine.
  • Alkylated chiral diamine and nitroso compounds (Formula 2 ) activate the electrophile through hydrogen bonding with the acid catalyst. Afterwards, the activated electrophile and enamine react to produce a nitroso aldol reaction product (Formula 3 ).
  • the nitroso aldol reaction product forms a more stable enamine when dehydrated at room temperature.
  • process A which includes enamine synthesis through the reaction of a chiral diamine catalyst and cycloketone, proceeds slowly, resulting in a decrease in the reaction rate. Without brine, process A proceeded quickly, but after the reaction between the enamine and the nitroso compound, the hydrolysis (C) of the imine to the ⁇ -hydroxyamino compound was slow, resulting in a side reaction.
  • toluene was used as a solvent (entry 8 in Table 1)
  • the reaction time was short, but side reactions proceeded quickly and several by-products were produced.
  • benzoic acid was added (entry 8 in Table 3)
  • self-aldol condensation was prevented, by-products were minimized, and cycloketone was activated.
  • Density Functional Theory (DFT) calculations were intended to demonstrate the mechanisms of substrates and catalysts and were performed using Gaussian 16 and Gauss-View 6.0 programs.
  • the optimized shape was described using the Becke three-parameter Lee-Yang-Parr (B3LYP) level. Afterwards, single point calculations were performed on the optimized shape using the 6-31G(d,p) basis set. After the shapes of reactants, intermediates (IM), transition states (TS), and products are fully optimized, the thermodynamic functions and parameters (Gibbs free energy) of the reactants are determined through calculation of vibrational frequencies. was obtained. Minimum or transition state energies were obtained at the same level of theory. Enthalpy correction and temperature-dependent entropy were calculated at 298 K and 1 atm.
  • thermodynamic analysis was performed to confirm the solvent effect on the nitroso aldol reaction. To this end, based on the results confirmed in Figure 3, the thermodynamic energies of various solvents for the transition state of catalyst 1a were compared ( Figure 4).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de production d'un dérivé nitroso chiral à l'aide d'un composé catalyseur chiral organique à base de (R,R)-1,2-diphényléthylènediamine (DPEN), et analogues. Selon le procédé de production, un dérivé nitroso chiral ayant une énantiosélectivité élevée par une réaction aldol asymétrique entre une cétone cyclique et un composé nitroso peut être produit avec un rendement élevé. En particulier, dans le procédé de production selon la présente invention, le composé catalyseur forme une liaison hydrogène avec le composé nitroso pour activer un électrophile et former un état de transition de telle sorte que l'encombrement stérique est réduit au minimum, ce qui permet de produire un produit stable. De plus, un dérivé nitroso chiral produit selon la présente invention peut être utilisé dans la réaction principale de divers intermédiaires synthétiques, et peut ainsi être utilisé dans le domaine de la synthèse organique pharmaceutique.
PCT/KR2023/003846 2022-08-11 2023-03-23 Procédé de production d'un produit de réaction d'aldol chiral sélectif à l'azote d'un composé nitroso à l'aide d'un composé catalyseur chiral organique Ceased WO2024034767A1 (fr)

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* Cited by examiner, † Cited by third party
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CN104860939A (zh) * 2015-04-10 2015-08-26 昆明理工大学 一种金鸡纳碱类化合物及其制备方法

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KR102261108B1 (ko) * 2018-02-28 2021-06-04 고려대학교 산학협력단 입체 선택성이 우수한 이 작용성 유기 키랄 촉매 화합물, 이의 제조 방법 및 이를 이용한 나이트로 화합물로부터의 비천연 감마-아미노산의 제조 방법

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CN104860939A (zh) * 2015-04-10 2015-08-26 昆明理工大学 一种金鸡纳碱类化合物及其制备方法

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MOMIYAMA NORIE, YAMAMOTO HISASHI: "Brønsted Acid Catalysis of Achiral Enamine for Regio- and Enantioselective Nitroso Aldol Synthesis", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 127, no. 4, 1 February 2005 (2005-02-01), pages 1080 - 1081, XP093139954, ISSN: 0002-7863, DOI: 10.1021/ja0444637 *
MOMIYAMA NORIE, YAMAMOTO HISASHI: "Enantioselective O - and N -Nitroso Aldol Synthesis of Tin Enolates. Isolation of Three BINAP−Silver Complexes and Their Role in Regio- and Enantioselectivity", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 126, no. 17, 1 May 2004 (2004-05-01), pages 5360 - 5361, XP093139955, ISSN: 0002-7863, DOI: 10.1021/ja039103i *
N. MOMIYAMA ET AL.: "o-nitroso aldol synthesis:catalytic enantioselective route to alfa-aminooxy carbonyl compounds via enamine intermediate", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, vol. 101, no. 15, 13 April 2004 (2004-04-13), pages 5374 - 5378, XP002449131, ISSN: 0027-8424, DOI: 10.1073/pnas.0307785101 *
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KR102823284B1 (ko) 2025-06-23

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