Novel cyclic allene precursor, and method for preparing same by using chiral auxiliary agent

Abstract

A novel cyclic allene precursor, and a method for preparing same by using a chiral auxiliary agent are disclosed. The novel cyclic allene precursor according to the present invention is structured such that a first position is double-bonded to a second position, a leaving group is bonded to the second position, and a silyl group is bonded to a third position.

Description

A novel cyclic allene precursor and a method for preparing the same using a chiral auxiliary agent

[0001] The present invention relates to a novel cyclic allene precursor and a method for preparing the same using a chiral auxiliary agent.

[0002] Allene is a structure containing two consecutive double bonds (C=C), characterized by orthogonal π orbitals that can form unique chirality. This chirality plays a crucial role in asymmetric synthesis and the synthesis of complex compounds. Therefore, allene has long been of interest in natural product synthesis and organic chemistry research. In particular, allene's structural characteristics offer chemical uniqueness not found in existing compounds.

[0003] Among these, cyclic allene refers to a compound with a ring structure and a narrower internal angle around the central carbon than linear allene. This structural feature exhibits high reactivity due to ring strain and possesses unique chemical properties with non-orthogonal twisting of π orbitals. This unique structure can be useful for stereochemical synthesis based on chirality or for constructing complex molecular structures. However, due to the high ring strain energy, cyclic allene is difficult to exist alone and is usually produced from precursor forms.

[0004] In particular, chiral cyclic allenes can exhibit highly useful reactivity in asymmetric synthesis due to the non-orthogonality of their π orbitals and structural distortion. This can serve as a valuable tool in the synthesis of natural products or stereochemically complex compounds. However, the preparation of these compounds typically requires high costs and complex experimental conditions, making mass production difficult. Therefore, the development of a more efficient and economical technique for preparing chiral cyclic allenes is necessary.

[0005] Meanwhile, a chiral auxiliary agent is a compound introduced to induce reaction selectivity in an asymmetric reaction of a specific compound. These auxiliary agents have the advantage of being removable or recyclable after the reaction and serve as important tools for the economical and selective synthesis of chiral compounds. In particular, the use of chiral auxiliary agents offers the potential to reduce the cost and complexity of conventional chiral separation processes.

[0006] The development of precursors for producing chiral cyclic allenes is crucial because these precursors can control the reactivity of cyclic allenes and enable stereochemically complex synthetic pathways. Specifically, efficiently designed precursors enable not only mass production but also highly selective reactions, increasing their potential for use in diverse applications, including synthetic chemistry and drug development. Furthermore, precursor design utilizing chiral auxiliaries has the potential to improve the economic efficiency of existing processes and reduce their environmental impact.

[0007] The present invention aims to alleviate the complexity of existing synthetic processes and enhance stereochemical precision through an economical and selective manufacturing method. Furthermore, by expanding the potential for mass production of cyclic allene precursors, it can contribute to increasing the utility of subsequent chemical reactions, such as stereoconservative reactions. This offers the potential to improve efficiency and accessibility in diverse application areas, such as natural product synthesis, drug development, and the production of high-value-added compounds.

[0008] In one aspect, the present invention provides a cyclic allene precursor having a double bond at position 1 and position 2, a leaving group -Z bonded to position 2, and -SiR3 bonded to position 3.

[0009] Here, the leaving group -Z is -F, -Cl, -Br, -I, -N2+, -OSO2(alkyl), -OSO2(aryl), -OSO2CF3, -OCO(alkyl), -OCO(aryl), -O(alkyl), -O(aryl), -OH, -SCN, -I+(aryl) X - (X is Cl, Br or I), -Br + (aryl) X - (X is one selected from the group containing Cl, Br or I), and the -SiR3 may be one selected from the group containing -Si(alkyl)3, -Si(alkyl)2(aryl), -Si(alkyl)(aryl)2, -Si(aryl)3, -Si(H)2(alkyl), -Si(H)(alkyl)2, -Si(H)2(aryl), -Si(H)(aryl)2, -Si(H)(alkyl)(aryl).

[0010] In one embodiment, the third position may be a chiral position.

[0011] In one embodiment, the cyclic allene precursor may have an enantiomeric excess other than 0%.

[0012] In one embodiment, the cyclic allene precursor may have a hexagonal ring.

[0013] In one embodiment, the fourth or fifth position of the cyclic allene precursor may be one selected from the group consisting of CH2, N, O, and SO2 bonded with a protecting group.

[0014] Here, the protecting group may be one selected from the group comprising -(alkyl), -(aryl), -CO(alkyl), -CO(aryl), -COO(alkyl), -COO(aryl), -SO2(alkyl), and -SO2(aryl).

[0015] In one embodiment, a substituent Y may be additionally bonded to at least one of the first, fifth, and sixth positions of the cyclic allene precursor.

[0016] Here, the substituent Y may be one selected from the group including -H, -(alkyl), -(aryl), -F, -Cl, -Br, -I, -CF3, -NO2, -CN, -CO2H, -COO(alkyl), -COO(aryl), -O(alkyl), -O(aryl), -OH, -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2, -N(aryl)2, -SO2(alkyl), -SO2(aryl), -S(alkyl), -S(aryl), and -PO4H2.

[0017] In one embodiment, the cyclic allene precursor may have a chemical formula (S1), (S2), (S3), (S4), (S5), (S6), (R1), (R2), (R3), (R4), (R5), or (R6).

[0018] (S1)

[0019] (S2)

[0020] (S3)

[0021] (S4)

[0022] (S5)

[0023] (S6)

[0024] (R1)

[0025] (R2)

[0026] (R3)

[0027] (R4)

[0028] (R5)

[0029] (R6)

[0030] Here, the X may be one selected from the group including CH2, N, O, and SO2 combined with a protecting group.

[0031] Here, the protecting group may be one selected from the group comprising -(alkyl), -(aryl), -CO(alkyl), -CO(aryl), -COO(alkyl), -COO(aryl), -SO2(alkyl), and -SO2(aryl).

[0032] Here, the substituent Y may be one selected from the group including -H, -(alkyl), -(aryl), -F, -Cl, -Br, -I, -CF3, -NO2, -CN, -CO2H, -COO(alkyl), -COO(aryl), -O(alkyl), -O(aryl), -OH, -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2, -N(aryl)2, -SO2(alkyl), -SO2(aryl), -S(alkyl), -S(aryl), and -PO4H2.

[0033] In another aspect, the present invention provides a method for producing a cyclic allene precursor, comprising: a hydrazone bonding step of reacting a chiral auxiliary agent having the following chemical formula (CA) with a raw material which is a cyclic compound having a carbonyl bond (C=O) at the second position to form a hydrazone bond (C=NNR2) at the second position; a silylation step of performing silylation at the third position to bond -SiR3; a hydrazonolysis step of decomposing the hydrazone bond at the second position to form a ketone group at the second position; and a leaving group conversion step of converting the functional group bonded at the second position to a leaving group Z.

[0034] (CA)

[0035] Here, the above R 1 and the above R 2 can each independently be alkyl or aryl.

[0036] Here, the above R 1 or the above R 2 can have chirality.

[0037] Here, the -SiR3 may be one selected from the group including -Si(alkyl)3, -Si(alkyl)2(aryl), -Si(alkyl)(aryl)2, -Si(aryl)3, -Si(H)2(alkyl), -Si(H)(alkyl)2, -Si(H)2(aryl), -Si(H)(aryl)2, -Si(H)(alkyl)(aryl).

[0038] Here, the leaving group -Z is -F, -Cl, -Br, -I, -N2+, -OSO2(alkyl), -OSO2(aryl), -OSO2CF3, -OCO(alkyl), -OCO(aryl), -O(alkyl), -O(aryl), -OH, -SCN, -I + (aryl) X - (X is Cl, Br or I), -Br + (aryl) X - (X may be one selected from the group containing Cl, Br or I).

[0039] In one embodiment, the chiral auxiliary agent may be one of the substances having the following chemical formula (CA-SAMP) or the following chemical formula (CA-RAMP).

[0040] (CA-SAMP)

[0041] (CA-RAMP).

[0042] In one embodiment, the hydrazone decomposition step can be performed by ozonolysis or hydrolysis.

[0043] In one embodiment, the hydrolysis may be acid-catalyzed hydrolysis.

[0044] In one embodiment, in the hydrazone decomposition step, a carbonyl bond (C=O) may be formed at the second position.

[0045] In one embodiment, the leaving group conversion step can convert the oxygen of the carbonyl bond (C=O) into a leaving group Z.

[0046] In one embodiment, in the leaving group conversion step, the bond between the first position and the second position can be converted into a double bond.

[0047] In one embodiment, in the hydrazone decomposition step, a carbonyl bond (C=O) may be formed at the second position.

[0048] In one embodiment, the method for preparing the cyclic allene precursor may further include, prior to the leaving group conversion step, an acylation step of bonding an ester to the first position, converting the oxygen of the carbonyl bond (C=O) at the second position into a hydroxyl group (-OH), and converting the bond between the first position and the second position into a double bond.

[0049] In one embodiment, in the leaving group conversion step, the oxygen of the hydroxyl group (-OH) can be converted into a leaving group Z.

[0050] In one embodiment, the raw material has a hexagonal ring, and the method for producing the cyclic allene precursor may further include, prior to the hydrazone bonding step, an enone forming step of bonding a halogen to the first position of the raw material and then converting the bond between the first position and the sixth position into a double bond through removal.

[0051] The effects of the present invention can contribute to reducing the cost of reagents used in the synthetic process and simplifying reaction conditions. Furthermore, it can open up new possibilities for solving scale-up and mass production challenges previously difficult with existing synthetic methods. These effects can broaden the range of applications utilizing cyclic allene precursors and further enhance their industrial utility.

[0052] Figure 1 illustrates an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0053] FIG. 2 illustrates another example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0054] FIG. 3 illustrates another example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0055] FIG. 4a is an overall schematic diagram of an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0056] FIG. 4b is an overall schematic diagram of an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0057] FIG. 4c is an overall schematic diagram of an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0058] Figure 5a shows the hydrazone binding step.

[0059] Figure 5b shows the silylation step.

[0060] Figure 5c shows the ozone decomposition reaction.

[0061] Figure 5d shows the triflation step.

[0062] Figure 5e shows the acylation step.

[0063] Figure 5f shows the acylation step.

[0064] Figure 5g shows the bromination reaction.

[0065] Figure 5h shows the enone formation step.

[0066] Figure 5i shows the hydrazone binding step.

[0067] Figure 5j shows the silylation step.

[0068] Figure 5k shows the ozone decomposition reaction.

[0069] Figure 5l shows the transition stage of the leaving group.

[0070] Figure 6a shows the 1H NMR spectrum of cyclohexanone.

[0071] Figure 6b shows the 13C NMR spectrum of cyclohexanone.

[0072] Figure 6c shows the 1H NMR spectrum of (S)-N-cyclohexylidene-2-(methoxymethyl)pyrrolidin-1-amine.

[0073] Figure 6d shows the 13C NMR spectrum of (S)-N-cyclohexylidene-2-(methoxymethyl)pyrrolidin-1-amine.

[0074] Figure 6e shows the 1H NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-(triethylsilyl)cyclohexylidene)pyrrolidin-1-amine.

[0075] Figure 6f shows the 13C NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-(triethylsilyl)cyclohexylidene)pyrrolidin-1-amine.

[0076] Figure 6g shows the 1H NMR spectrum of (R)-2-(triethylsilyl)cyclohexanone.

[0077] Figure 6h shows the 13C NMR spectrum of (R)-2-(triethylsilyl)cyclohexanone.

[0078] Figure 6i shows the 1H NMR spectrum of (R)-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0079] Figure 6j shows the 13C NMR spectrum of (R)-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0080] Figure 6k shows the 1H NMR spectrum of (R)-methyl 2-hydroxy-3-(triethylsilyl)cyclohex-1-enecarboxylate.

[0081] Figure 6l shows the 13C NMR spectrum of (R)-methyl 2-hydroxy-3-(triethylsilyl)cyclohex-1-enecarboxylate.

[0082] Figure 6m shows the 1H NMR spectrum of (R)-methyl 3-(triethylsilyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-enecarboxylate.

[0083] Figure 6n shows the 13C NMR spectrum of (R)-methyl 3-(triethylsilyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-enecarboxylate.

[0084] Figure 6o shows the 1H NMR spectrum of 2-methylcyclohexanone.

[0085] Figure 6p shows the 13C NMR spectrum of 2-methylcyclohexanone.

[0086] Figure 7a shows the 1H NMR spectrum of 2-bromo-2-methylcyclohexanone.

[0087] Figure 7b shows the 13C NMR spectrum of 2-bromo-2-methylcyclohexanone.

[0088] Figure 7c shows the 1H NMR spectrum of 2-methylcyclohex-2-enone.

[0089] Figure 7d shows the 13C NMR spectrum of 2-methylcyclohex-2-enone.

[0090] Figure 7e shows the 1H NMR spectrum of (S,E)-2-(methoxymethyl)-N-(2-methylcyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0091] Figure 7f shows the 13C NMR spectrum of (S,E)-2-(methoxymethyl)-N-(2-methylcyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0092] Figure 7g shows the 1H NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-methyl-6-(triethylsilyl)cyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0093] Figure 7h shows the 13C NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-methyl-6-(triethylsilyl)cyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0094] Figure 7i shows the 1H NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-2-enone.

[0095] Figure 7j shows the 13C NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-2-enone.

[0096] Figure 7k shows the 1H NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0097] Figure 7l shows the 13C NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0098] Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. The present invention may be modified in various ways and may take various forms. Therefore, specific embodiments are illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to a specific disclosed form, but should be understood to include all modifications, equivalents, and substitutes included in the spirit and technical scope of the present invention. In describing each drawing, similar reference numerals are used to indicate similar components. In the attached drawings, the dimensions of structures are shown larger than actual size to ensure clarity of the present invention.

[0099] The terminology used in this application is only used to describe specific embodiments and is not intended to limit the present invention. The singular expression includes plural expression unless the context clearly indicates otherwise. In this application, it should be understood that the terms "comprise" or "have" are intended to specify the presence of a feature, number, step, operation, component, or combination thereof described in the specification, but do not exclude in advance the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, or combinations thereof. In the context of this specification, the term "about" or the like can mean about ± 1%, about ± 2%, about ± 3%, about ± 4%, about ± 5%, about ± 6%, about ± 7%, about ± 8%, about ± 9%, or about ± 10% of a numerical value described in the specification.

[0100] Additionally, the description of one aspect of the present invention may be applied identically or similarly to the same or similar configurations or terms in the description of other aspects.

[0101] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and will not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0102] The cyclic allene precursor according to an embodiment of the present invention has a double bond at the first and second positions, a leaving group -Z can be bonded to the second position, and -SiR3 can be bonded to the third position.

[0103] In the context of this specification, the term "allene" refers to a compound with a cumulene structure containing two consecutive double bonds. This structure is characterized by orthogonal π orbitals around the central carbon atom, which can induce unique chirality. These structural characteristics make allene compounds potentially useful in asymmetric synthesis or the synthesis of complex compounds.

[0104] In the context of this specification, the term "cyclic" or "cyclic material" refers to a compound that forms a ring structure. This may include not only the structural characteristics of a simple ring-shaped backbone, but also unique chemical or physical properties resulting from the ring structure. For example, cyclic materials may exhibit higher reactivity, specific stereochemical control, or unique reaction mechanisms compared to linear compounds.

[0105] In the context of this specification, the term "precursor" refers to a starting material used to produce a target compound in a subsequent reaction. This means that a precursor not only serves as an intermediate for the reaction, but the structure and properties of the compound can also play a crucial role in determining the selectivity and efficiency of the subsequent reaction. Therefore, a precursor can be understood as a starting material with the potential to promote a subsequent reaction or control the reaction pathway.

[0106] In the context of this specification, the term "n-th position" refers to a specific, relatively defined position along the ring skeleton. This numbering is simply based on adjacency or bonding relationships and is independent of any atomic arrangement or numbering scheme defined externally to this specification. For example, "position 1" and "position 2" may refer to two adjacent positions, while "position 3" may refer to a position opposite position 1 and connected to position 2.

[0107] In the context of this specification, the term "leaving group" refers to a functional group that can be separated at a specific position during a subsequent reaction of a precursor. This group is separated or removed depending on the reaction conditions, and the leaving process itself can determine the efficiency or selectivity of the subsequent chemical transformation. However, the leaving group itself does not limit the scope of the present invention or be limited to a specific function, and can be understood as a part of the precursor.

[0108] Here, the leaving group -Z is -F, -Cl, -Br, -I, -N2 + , -OSO2(alkyl), -OSO2(aryl), -OSO2CF3, -OCO(alkyl), -OCO(aryl), -O(alkyl), -O(aryl), -OH, -SCN, -I + (aryl) X - (X is Cl, Br or I), -Br + (aryl) X - (X may be one selected from the group containing Cl, Br or I).

[0109] Here, the -SiR3 may be one selected from the group including -Si(alkyl)3, -Si(alkyl)2(aryl), -Si(alkyl)(aryl)2, -Si(aryl)3, -Si(H)2(alkyl), -Si(H)(alkyl)2, -Si(H)2(aryl), -Si(H)(aryl)2, -Si(H)(alkyl)(aryl).

[0110] In one embodiment, the third position may be a chiral position. In the context of this specification, the term "chiral position" refers to a structural feature in which the entire molecule has mirror-image asymmetry due to a substituent bonded to a specific position or a chemical environment. This means that the arrangement of the substituents present at that position can determine the stereochemical properties of the molecule, i.e., optical activity or stereochemical selectivity. The chiral position can play an important role in forming a specific stereoisomer in a subsequent reaction or in controlling the selectivity of the reaction.

[0111] In one embodiment, the cyclic allene precursor may have an enantiomeric excess that is not 0%. In the context of this specification, the term enantiomeric excess refers to a ratiometric measure of how much more one enantiomer is present relative to the other enantiomer. This can be an indicator of the optical purity of a molecule. Therefore, a value other than 0% indicates that a particular enantiomer is predominantly present relative to the other enantiomer. This may indicate that an asymmetric reaction occurred during the synthesis, or conditions were applied to selectively produce a particular stereoisomer.

[0112] In one embodiment, the cyclic allene precursor may have a hexagonal ring. Hexagonal rings typically have internal angles close to 120 degrees, forming ideal bond angles. Therefore, they are likely to exhibit relatively low ring strain compared to other cyclic structures. This structural feature may contribute to enhancing reaction selectivity or promoting specific reaction pathways. Furthermore, hexagonal rings are a common structure in natural product synthesis and drug development, which may help expand the applicability of the present invention to various chemical or biological fields.

[0113] In one embodiment, the 4th or 5th position of the cyclic allene precursor may be one selected from the group consisting of CH2, N, O, and SO2 bonded to a protecting group. Here, the meaning of the 4th or 5th position being an element or group may mean that the element constituting the skeleton of the ring itself is the element or group. On the other hand, the meaning of the 4th or 5th position being a group may mean that one of the elements constituting the group is an element constituting the skeleton of the ring itself. That is, the 4th or 5th position may be C, N, O, or S, and further, the 4th and 5th positions may each independently be C, N, O, or S.

[0114] In the context of this specification, the term "protecting group" refers to a chemical substituent introduced to temporarily deactivate or protect a specific functional group during a chemical reaction. This can be used to prevent a specific functional group from undergoing undesirable side reactions under reaction conditions or to selectively induce reactions in other parts.

[0115] Here, the protecting group may be one selected from the group consisting of -(alkyl), -(aryl), -CO(alkyl), -CO(aryl), -COO(alkyl), -COO(aryl), -SO2(alkyl), and -SO2(aryl). For example, protecting groups such as Boc(t-butoxycarbonyl), Fmoc(9-fluorenylmethoxycarbonyl), Cbz(benzyloxycarbonyl), Benzyl, 2-Nosyl(2-nitrobenzenesulfonyl), 4-Nosyl(4-nitrobenzenesulfonyl), Moc(methoxycarbonyl), 1-Naphthyl, or 4-Nitrobenzoyl may be included.

[0116] In the context of this specification, the meaning of alkyl refers to a straight, branched, or cyclic hydrocarbon chain composed solely of carbon and hydrogen. It has a structure connected by single bonds and can include substituents ranging from simple structures such as methyl, ethyl, and propyl to more complex structures. In the context of this specification, the meaning of aryl refers to a hydrocarbon substituent containing one or more aromatic rings. This can include a single aromatic ring structure such as benzene or a multiple aromatic ring structure such as naphthalene.

[0117] In one embodiment, a substituent Y may be additionally bonded to at least one of the first, fifth, and sixth positions of the cyclic allene precursor. In the context of the present specification, the term "substituent" refers to an atom or functional group that replaces or additionally bonds an existing atom or group in the basic skeleton of a specific compound. A substituent can change the chemical and physical properties of a molecule, and can affect reactivity, stereochemical properties, electronic properties, etc. For example, a substituent has the potential to induce a specific reaction pathway or increase selectivity under reaction conditions.

[0118] Here, the substituent Y may be one selected from the group consisting of -H, -(alkyl), -(aryl), -F, -Cl, -Br, -I, -CF3, -NO2, -CN, -CO2H, -COO(alkyl), -COO(aryl), -O(alkyl), -O(aryl), -OH, -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2, -N(aryl)2, -SO2(alkyl), -SO2(aryl), -S(alkyl), -S(aryl), and -PO4H2. These substituents may contribute to adjusting the chemical and physical properties of the cyclic allene precursor or controlling the reactivity in subsequent reactions.

[0119] In one embodiment, the cyclic allene precursor may have a chemical formula (S1), (S2), (S3), (S4), (S5), (S6), (R1), (R2), (R3), (R4), (R5), or (R6).

[0120] (S1)

[0121] (S2)

[0122] (S3)

[0123] (S4)

[0124] (S5)

[0125] (S6)

[0126] (R1)

[0127] (R2)

[0128] (R3)

[0129] (R4)

[0130] (R5)

[0131] (R6)

[0132] Here, X may be one selected from the group comprising CH2, N, O, and SO2 to which a protecting group is bonded. Here, the protecting group may be one selected from the group comprising -(alkyl), -(aryl), -CO(alkyl), -CO(aryl), -COO(alkyl), -COO(aryl), -SO2(alkyl), and -SO2(aryl). Here, the substituent Y may be one selected from the group including -H, -(alkyl), -(aryl), -F, -Cl, -Br, -I, -CF3, -NO2, -CN, -CO2H, -COO(alkyl), -COO(aryl), -O(alkyl), -O(aryl), -OH, -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2, -N(aryl)2, -SO2(alkyl), -SO2(aryl), -S(alkyl), -S(aryl), and -PO4H2.

[0133] Meanwhile, a method for producing a cyclic allene precursor according to an embodiment of the present invention may include a hydrazone bonding step of reacting a chiral auxiliary agent having the following chemical formula (CA) with a raw material that is a cyclic compound having a carbonyl bond (C=O) at the second position to form a hydrazone bond (C=NNR2) at the second position; a silylation step of performing silylation at the third position to bond -SiR3; a hydrazone decomposition step of decomposing the hydrazone bond at the second position to form a ketone group at the second position; and a leaving group conversion step of converting the functional group bonded at the second position to a leaving group Z.

[0134] (CA)

[0135] Here, the above R 1 and the above R 2can each independently be alkyl or aryl.

[0136] Here, the above R 1 or the above R 2 can have chirality.

[0137] Here, the -SiR3 may be one selected from the group including -Si(alkyl)3, -Si(alkyl)2(aryl), -Si(alkyl)(aryl)2, -Si(aryl)3, -Si(H)2(alkyl), -Si(H)(alkyl)2, -Si(H)2(aryl), -Si(H)(aryl)2, -Si(H)(alkyl)(aryl).

[0138] Here, the leaving group -Z is -F, -Cl, -Br, -I, -N2+, -OSO2(alkyl), -OSO2(aryl), -OSO2CF3, -OCO(alkyl), -OCO(aryl), -O(alkyl), -O(aryl), -OH, -SCN, -I + (aryl) X - (X is Cl, Br or I), -Br + (aryl) X - (X may be one selected from the group containing Cl, Br or I).

[0139] In the context of this specification, the term "chiral auxiliary" refers to a molecular unit used to induce a specific stereochemical outcome in an asymmetric synthetic reaction. It facilitates selective coupling and transformation during the reaction, while also being readily removable or recyclable after the reaction.

[0140] The type of the chiral auxiliary agent is not particularly limited. In one embodiment, the chiral auxiliary agent may be one of the substances having the following chemical formula (CA-SAMP) or the following chemical formula (CA-RAMP).

[0141] (CA-SAMP)

[0142] (CA-RAMP)

[0143] In the context of this specification, the term SAMP (S-1-Amino-2-methoxymethylpyrrolidine) or RAMP (R-1-Amino-2-methoxymethylpyrrolidine) refers to specific compounds used as chiral auxiliaries for asymmetric synthesis. SAMP and RAMP have S- and R-form stereochemical structures, respectively, and can induce specific stereoselectivities during the reaction. They can be removed or recycled after the reaction, providing an efficient and economical asymmetric synthesis strategy.

[0144] In the context of this specification, the term "carbonyl bond" (C=O) refers to a structure in which one carbon atom is connected to an oxygen atom by a double bond. In the context of this specification, the term "hydrazone bond" (C=NNR2) refers to a structural unit formed through a condensation reaction between a carbonyl group and a hydrazine derivative.

[0145] The role of the above hydrazone coupling step is to impart specific stereochemical characteristics to the cyclic allene precursor through the reaction between the carbonyl group of the raw material and the chiral auxiliary agent. This step can induce chirality and provide the basis for enhancing reaction selectivity in subsequent reactions.

[0146] In the context of this specification, the term "silylation" refers to a chemical reaction that introduces a silyl group (-SiR3) into a molecule. Silylation can primarily serve to modulate the reactivity of a molecule or protect specific positions in subsequent reactions.

[0147] The role of the above silylation step is to introduce a silyl group at the third position of the cyclic allene precursor. This step can control the selectivity of the subsequent reaction or contribute to increasing the chemical stability of the molecule.

[0148] The role of the above hydrazone decomposition step is to decompose the hydrazone bond and regenerate the carbonyl bond (C=O). The role of the above leaving group conversion step is to convert the oxygen of the carbonyl group bonded to the second position into a leaving group, thereby increasing the reactivity of the cyclic allene precursor and enabling selective bonding and conversion in subsequent reactions.

[0149] In one embodiment, the hydrazonolysis step may be performed by ozonolysis or hydrolysis. In the context of this specification, ozonolysis refers to a chemical reaction that uses ozone (O3) to oxidatively break down a double bond or triple bond. This reaction can be utilized to cleave the bond and create a new functional group containing oxygen (e.g., a carbonyl group). Also, in the context of this specification, hydrolysis refers to a chemical reaction that uses water (H2O) to break down a specific bond in a compound. This reaction can be performed under acidic or basic conditions and is used to break down a bonded functional group or to introduce a new functional group.

[0150] Figure 1 illustrates an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0151] Referring to FIG. 1, a method for producing a cyclic allene precursor according to an embodiment of the present invention may begin with a step of reacting a cyclic compound having a carbonyl bond (C=O) as a raw material with a chiral auxiliary agent (SAMP or RAMP) to form a hydrazone bond (C=NNR2). In this process, stereochemical properties of the molecule are imparted, and although FIG. 1 only illustrates the formation of an S-type compound using SAMP, the scope of the present invention clearly includes the opposite case. Next, a silyl group (-SiEt3) can be bonded to the third position through silylation. Thereafter, the hydrazone bond is decomposed through ozonolysis or hydrolysis to regenerate a carbonyl bond, and finally, the oxygen of the carbonyl bond can be converted into a leaving group (-OSO2CF3) to complete the cyclic allene precursor.

[0152] When performing the above hydrazone coupling step, the reaction environment in which the chiral auxiliary agent is applied is not particularly limited. In one embodiment, DCM may be used when performing the above hydrazone coupling step. In the context of this specification, DCM refers to dichloromethane. DCM is widely used as an organic solvent and, due to its low boiling point and excellent solubility, can play a role in assisting the dissolution and reactivity of reactants in various reaction environments.

[0153] In performing the above silylation step, the silylation reaction environment is not particularly limited. In one embodiment, in performing the silylation step, LDA may be used first, and then TESCl and THF may be used. In the context of this specification, LDA refers to lithium diisopropylamide. LDA is a strong non-nucleophilic base that can be used to remove a proton of a reactant to generate a carbanion or to induce a specific reaction pathway. In the context of this specification, TESCl refers to triethylsilyl chloride. TESCl is a reagent used in a silylation reaction and can introduce a silyl group (-SiEt3) into a molecule. In the context of this specification, THF refers to tetrahydrofuran. THF is a polar organic solvent that provides strong solubility, allowing it to dissolve various reactants and reagents and promote reactions.

[0154] In performing the above hydrazone decomposition step, the decomposition reaction environment is not particularly limited. In one embodiment, DCM may be used in performing the above hydrazone decomposition step.

[0155] In the above leaving group conversion step, the reaction environment for conversion to a leaving group is not particularly limited. In one embodiment, in performing the leaving group conversion step, LDA may be used first, and then PhNTf2 under THF may be used. In the context of the present specification, the meaning of PhNTf2 refers to nitrophenyl triflate (Phenyl Trifluoromethanesulfonimide). PhNTf2 is a reagent that introduces a triflate group (-OSO2CF3) and can be used to convert the oxygen of a carbonyl bond into a triflate leaving group in the leaving group conversion step.

[0156] In one embodiment, in the hydrazone decomposition step, a carbonyl bond (C=O) may be formed at the second position. In one embodiment, the leaving group conversion step may convert the oxygen of the carbonyl bond (C=O) into a leaving group Z. In one embodiment, in the leaving group conversion step, the bond between the first position and the second position may be converted into a double bond.

[0157] FIG. 2 illustrates another example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0158] Referring to FIG. 2, a method for preparing a cyclic allene precursor according to an embodiment of the present invention may begin with a step of reacting a raw material having a carbonyl bond (C=O) with a chiral auxiliary agent (SAMP or RAMP) to form a hydrazone bond (C=NNR2). In this process, stereochemical properties of the molecule are imparted, and although FIG. 2 only illustrates the formation of an S-type compound using SAMP, the scope of the present invention clearly includes the opposite case. Subsequently, a silyl group (-SiEt3) can be introduced at the third position through silylation, and thereafter, the hydrazone bond can be decomposed through ozonolysis or hydrolysis to regenerate the carbonyl bond. Furthermore, an ester group (-CO2CH3) can be additionally introduced here to change the electronic and stereochemical properties of the molecule. Finally, the process may include converting the oxygen of the carbonyl group to a triflate leaving group (-OSO2CF3) to complete the cyclic allene precursor.

[0159] In performing the above hydrazone coupling step, the reaction environment in which the chiral auxiliary agent is applied is not particularly limited. In one embodiment, DCM may be used in performing the above hydrazone coupling step.

[0160] In performing the above silylation step, the silylation reaction environment is not particularly limited. In one embodiment, in performing the above silylation step, LDA may be used first, and then TESCl and THF may be used.

[0161] In performing the above hydrazone decomposition step, the decomposition reaction environment is not particularly limited. In one embodiment, DCM may be used in performing the above hydrazone decomposition step.

[0162] In one embodiment, in the hydrazone decomposition step, a carbonyl bond (C=O) may be formed at the second position.

[0163] In one embodiment, the method for preparing the cyclic allene precursor may further include, prior to the leaving group conversion step, an acylation step of bonding an ester to the first position, converting the oxygen of the carbonyl bond (C=O) at the second position into a hydroxyl group (-OH), and converting the bond between the first position and the second position into a double bond.

[0164] The role of the above acylation step is to adjust the properties of the molecule by introducing an ester group at position 1, and to convert the carbonyl bond (C=O) at position 2 into a hydroxyl group (-OH), thereby providing a functional group necessary for subsequent reactions. This step can ultimately contribute to increasing the stereochemical completeness and reactivity of the cyclic allene precursor.

[0165] In the above acylation step, the reaction environment for bonding an ester to the first position, converting the oxygen of the carbonyl bond (C=O) at the second position into a hydroxyl group (-OH), and converting the bond between the first position and the second position into a double bond is not particularly limited. In one embodiment, in performing the acylation step, LDA and THF may be used first, and then HMPA and Mander's reagent may be used. In the context of the present specification, HMPA refers to hexamethylphosphoramide. HMPA is an organic solvent with strong polarity, and is mainly used to help stabilize anions or adjust the steric or electronic environment in specific reactions. In the context of the present specification, Mander's reagent refers to methyl cyanoacetate or a similar compound. This is a reagent used to introduce an ester group including a carbonyl group in an acylation reaction, and can be utilized to selectively bind an ester group to the first position of a cyclic allene precursor.

[0166] In one embodiment, in the leaving group conversion step, the oxygen of the hydroxyl group (-OH) can be converted into a leaving group Z.

[0167] In the above leaving group conversion step, the reaction environment for conversion into a leaving group is not particularly limited. In one embodiment, NaH and PhNTf2 can be used in performing the leaving group conversion step. In the context of the present specification, NaH refers to sodium hydride. NaH is a strong base, and can be used primarily to remove protons to generate carbanions or to form activated intermediates in certain reactions.

[0168] FIG. 3 illustrates another example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0169] Referring to FIG. 3, a method for preparing a cyclic allene precursor according to an embodiment of the present invention may further include a step of introducing a double bond between the first and sixth positions through debromination after forming a bromo compound from a raw material. Subsequently, a chiral auxiliary agent (SAMP or RAMP) may be reacted with this compound having a carbonyl bond (C=O) to form a hydrazone bond (C=NNR2), and then a silyl group (-SiEt3) may be introduced at the third position through silylation. Although FIG. 3 only illustrates the formation of an S-type compound using SAMP, the scope of the present invention clearly includes the opposite case. The hydrazone bond may be decomposed through ozonolysis or hydrolysis to regenerate a carbonyl group, and finally, the oxygen of the carbonyl group may be converted into a triflate leaving group (-OSO2CF3) to complete the cyclic allene precursor.

[0170] In one embodiment, the raw material may have a hexagonal ring. In addition, in one embodiment, the method for producing the cyclic allene precursor may further include, prior to the hydrazone bonding step, an enone forming step of bonding a halogen to the first position of the raw material and then converting the bond between the first position and the sixth position into a double bond through removal.

[0171] In the context of this specification, the term "enone" refers to a compound in which an alkene bond (C=C) and a carbonyl bond (C=O) exist within the same molecule. Enones are generally considered alpha-beta unsaturated carbonyl compounds, characterized by the structural features of adjacent double bonds and carbonyl groups. This structure induces electronic interactions and reactivity, which can play an important role in electrophilic and nucleophilic reactions. Enones can be found in both cyclic and linear structures, offering the potential to be used as intermediates or reactants in a variety of organic synthesis reactions.

[0172] In one embodiment, the halogen may be bromine (Br). The reaction environment for combining the halogen is not particularly limited. In one embodiment, the reaction for combining the halogen may be performed under NBS and DCM. In the context of this specification, NBS refers to N-bromosuccinimide. NBS is a reagent used in a bromination reaction, and can be utilized to induce selective bromination of an allyl group or a benzyl group, or to perform the halogenation of a specific compound.

[0173] In carrying out the reaction of removing the halogen and introducing a double bond between the first and sixth positions, the reaction environment is not particularly limited. In one embodiment, Li2CO3, LiBr, and DMF can be used to carry out the reaction of removing the halogen and introducing a double bond between the first and sixth positions. In the context of the present specification, DMF refers to dimethylformamide. DMF is a polar amide-based organic solvent that can be used to effectively dissolve reactants to increase reactivity and, in particular, to provide a basic and nucleophilic reaction environment. Here, the role of Li2CO3 is to act as a weak base to adjust the pH of the reaction mixture and to promote the formation and dissociation of bonds in a specific reaction. Here, the role of LiBr is to provide bromine ions to maintain the equilibrium of the halogenation reaction or to assist the progress of the reaction during the halogen removal process.

[0174] When performing the above hydrazone coupling step, the reaction environment for applying the chiral auxiliary agent is not particularly limited. In one embodiment, toluene may be used in performing the above hydrazone coupling step. Toluene is an aromatic organic solvent with a methyl group bonded to a benzene ring, and has nonpolar and stable chemical properties. Toluene maintains stability even at high temperatures and can provide the ability to effectively dissolve the reactant.

[0175] In performing the above silylation step, the silylation reaction environment is not particularly limited. In one embodiment, in performing the above silylation step, LDA and THF may be used first, and then TESCl may be used.

[0176] When performing the above hydrazonolysis step, the decomposition reaction environment is not particularly limited. In one embodiment, EtOH may be used when performing the above hydrazonolysis step. EtOH refers to ethanol. Ethanol is a polar organic solvent that can act as a solvent in the reaction mixture or, depending on the reaction conditions, play an auxiliary role in the decomposition reaction.

[0177] In the above leaving group conversion step, the reaction environment for conversion to a leaving group is not particularly limited. In one embodiment, in performing the leaving group conversion step, L-selectride and THF may be used first, and then PhNTf2 under THF may be used. In the context of the present specification, the meaning of L-selectride refers to lithium tri-sec-butylborohydride. L-selectride is used as a selective reducing agent and is useful for selectively reducing a functional group of a specific compound.

[0178] Hereinafter, embodiments of the present invention will be described. However, the embodiments described below are merely some embodiments of the present invention, and the scope of the present invention is not limited to the embodiments described below.

[0179] Method A

[0180] FIG. 4a is an overall schematic diagram of an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0181] Referring to Fig. 4a, the process began with the step of forming a hydrazone bond by reacting a cyclic compound having a carbonyl bond as a starting material with a chiral auxiliary agent (SAMP or RAMP) in DCM solvent at 23°C for 16 hours. Subsequently, a silylation reaction was performed using LDA and TESCl at -78°C for 16 hours to introduce a silyl group (SiEt3) at the third position. Next, the hydrazone bond was decomposed through ozonolysis or acidic hydrolysis to regenerate the carbonyl bond, which was performed at -78°C for 2 hours in 0.5 M DCM. Finally, LDA was first used at -78°C for 0.5 hours, and then PhNTf2 was reacted in 0.215 M THF solvent to convert the oxygen of the carbonyl group into a leaving group (OSO2CF3) to complete the cyclic allene precursor.

[0182] Method B

[0183] FIG. 4b is an overall schematic diagram of an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0184] Referring to Fig. 4b, the reaction started with a step of forming a hydrazone bond by reacting a cyclic compound having a carbonyl bond as a raw material with a chiral auxiliary agent (SAMP or RAMP) in a DCM solvent at 23°C for 16 hours. Subsequently, LDA was used at -78°C for 0.5 hours, and then a silylation reaction was performed using TESCl and THF for 16 hours to introduce a silyl group (SiEt3) at the 3-position. Next, the hydrazone bond was decomposed through ozonolysis or acidic hydrolysis to regenerate the carbonyl bond, and this was performed at -78°C for 2 hours in 0.5 M DCM. Subsequently, the reaction was performed using LDA and HMPA at -78°C, and Mander's reagent was added to form a structure in which an ester group was bonded at the 1-position. Finally, NaH and PhNTf2 were reacted in a 0.15 M THF solvent at a temperature of -78°C to convert the oxygen of the carbonyl group into a leaving group (OSO2CF3), thereby completing the cyclic allene precursor.

[0185] Method C

[0186] FIG. 4c is an overall schematic diagram of an example of a method for producing a cyclic allene precursor according to an embodiment of the present invention.

[0187] Referring to Figure 4c, a bromo compound was formed by reacting a cyclic compound having a carbonyl bond as a raw material using NBS and DCM. Subsequently, Li2CO3 and LiBr were reacted in a DMF solvent at 100°C for 1.5 hours to introduce a double bond between the 1st and 6th positions. This formed an enone. Next, a hydrazone bond was formed by reacting in a toluene solvent for 3 days using SAMP or RAMP. Subsequently, a silylation reaction was performed using LDA and THF for 1 hour at -78°C, and TESCl for 1 hour to introduce a silyl group (SiEt3) at the 3rd position. Thereafter, the hydrazone bond was decomposed through ozonolysis or acidic hydrolysis to regenerate the carbonyl bond, and this was carried out under the condition of -78°C in an EtOH solvent. Finally, the reaction was performed at -78°C for 1 hour using L-selectride and THF, and then PhNTf2 was added under THF solvent and the reaction was performed for 2 hours to convert the oxygen of the carbonyl group into a leaving group (OSO2CF3), thereby completing the cyclic allene precursor.

[0188] Specific reaction examples

[0189] Hydrazone coupling step - for methods A and B

[0190] Figure 5a illustrates the hydrazone coupling step. In this process, cyclohexanone, SAMP (1.2 equivalents), and benzene (0.5 M) were added to a 50 mL round-bottom flask, and a Dean-Stark trap was installed to configure the reaction system. The reaction mixture was heated at 150°C under countercurrent conditions for 1 day. After the reaction was completed, the mixture was extracted with DCM and water and washed with brine to remove impurities. The solution was then dried over Na2SO4, and the solvent was removed using a rotary evaporator.

[0191] Silylation step - for methods A and B

[0192] Figure 5b shows the silylation step. In this step, LDA was synthesized by reacting diisopropylamine (1.25 equiv) and n-BuLi (1.2 equiv) in THF at -78°C. LDA was stabilized by stirring for 10 minutes. Then, a hydrazone compound dissolved in THF was added dropwise to the resulting LDA, and the mixture was stirred at -78°C for 1 hour. Next, TESCl (1.2 equiv) was added, and the reaction was allowed to proceed overnight at -78°C. After the reaction was completed, water was added to stop the reaction, and the product was extracted with diethyl ether. The extracted organic layer was washed with brine and dried over Na2SO4. The solvent was then removed using a rotary evaporator, and the silylated product was purified using column chromatography (FCC) at a ratio of EA:Hx = 1:8.

[0193] Ozone decomposition reaction - Methods A and B

[0194] Figure 5c shows the ozone decomposition reaction. In this step, first, the hydrazone silylated compound was dissolved in DCM in a vial and then the temperature was lowered to -78°C. This process was performed without using a stirring bar. After that, the ozone generator was operated and stabilized for 5 minutes before the reaction was initiated. The flow was checked using a latex glove to ensure that ozone was sufficiently supplied. The reaction was performed by bubbling ozone into the solution using a long needle, and the reaction progress was monitored using TLC (TLC conditions: EA:Hx = 1:4). After the reaction was completed, nitrogen (N2) was bubbled into the solution to remove the residual ozone. Column chromatography (FCC) was performed directly without removing the reaction solvent using a rotary evaporator, and the FCC conditions were EA:Hx = 1:40.

[0195] Triflation step - for method A

[0196] Figure 5d shows the leaving group conversion step (Triflation). In this step, LDA was synthesized by reacting diisopropylamine (1.25 equiv) and n-BuLi (1.2 equiv) in THF at -78°C. LDA was stabilized by stirring for 10 minutes. Then, the compound dissolved in THF was added dropwise to the resulting LDA, and the mixture was stirred at -78°C for 1 hour. Comins' reagent (1.2 equiv, dissolved in THF) was then added, and the reaction was allowed to proceed overnight at -78°C. After completion of the reaction, the reaction was stopped by adding water, and the product was extracted with diethyl ether. The extracted organic layer was washed with brine and dried with Na2SO4. After the solvent was removed using a rotary evaporator, the product was purified by column chromatography (FCC, Hx 100%).

[0197] Acylation step

[0198] Figure 5e shows the acylation step. In this step, LDA was synthesized by reacting diisopropylamine (1.25 equiv) and n-BuLi (1.2 equiv) in THF at -78°C. The synthesized LDA was stabilized by stirring for 10 minutes. Then, compound 6 dissolved in THF was added dropwise to the resulting LDA, and the mixture was stirred at -78°C for 2 hours. Then, HMPA and Mander's reagent were added dropwise at -78°C, and the reaction was carried out for 1 hour. After completion of the reaction, the temperature was increased to 0°C, and the reaction was stopped by adding water. The product was extracted with diethyl ether, and the extracted organic layer was washed with brine and dried over Na2SO4. The solvent was then removed using a rotary evaporator, and column chromatography (FCC, EA:Hx = 1:40) was performed.

[0199] Triflation step - for method B

[0200] Figure 5f shows the acylation step. In this step, the mineral oil of NaH was first removed using hexane. Then, NaH (2.1 equivalents) was added to THF, and the temperature of the reaction solution was lowered to 0°C. The starting material dissolved in THF was added dropwise to the NaH, and the reaction temperature was raised to room temperature and stirred for 1 hour. Next, the reaction temperature was lowered again to -78°C, PhNTf2 was added, and the mixture was stirred for 15 minutes. The reaction temperature was then raised to room temperature and stirred for an additional 2 hours. Upon completion of the reaction, water was added at 0°C to stop the reaction. The product was extracted using DCM, and the organic layer was washed with brine and dried using Na2SO4. Finally, the solvent was removed using a rotary evaporator, and the product was purified by column chromatography (FCC, EA:Hx = 1:40).

[0201] Bromination reaction - performed prior to enone formation in Method C

[0202] Figure 5g shows the bromination reaction. In this step, 2-methylcyclohexan-1-one and NBS (1.0 equivalent) were first added to DCM (0.4 M) solvent, and the reaction was carried out under countercurrent conditions at 60°C for 4 h. After completion of the reaction, the product was extracted using DCM and water, and washed with brine to remove residual impurities. After drying over Na2SO4, the solvent was removed using a rotary evaporator. Finally, the brominated product was purified by column chromatography (FCC, EA:Hx = 1:60). This reaction was performed as a step to introduce bromine prior to enone formation.

[0203] Enone formation stage

[0204] Figure 5h shows the enone formation step. In this step, 2-bromo-2-methylcyclohexanone, Li2CO3 (2.5 equiv), LiBr (1.7 equiv), and DMF (0.6 M) were added to the reaction flask, and the reaction was carried out at 100°C for 1.5 h. After completion of the reaction, the product was extracted with ethyl acetate (EA) and water, and washed with brine to remove residual impurities. The organic layer was dried over Na2SO4, and the solvent was removed using a rotary evaporator. Finally, column chromatography (FCC, EA:Hx = 1:18) was performed to purify the product with the enone structure.

[0205] Hydrazone coupling step - for method C

[0206] Figure 5i illustrates the hydrazone coupling step. In this step, cyclohexanone, SAMP (1.2 equivalents), and benzene (0.5 M) were added to a 50 mL round-bottom flask, and a Dean-Stark trap was installed to configure the reaction system. The mixture was heated at 180°C under countercurrent conditions for 3 days. After the reaction was completed, the reaction solution was extracted with DCM and water and washed with brine to remove impurities. The organic layer was dried over Na2SO4, and the solvent was removed using a rotary evaporator.

[0207] Silylation step - for method C

[0208] Figure 5j shows the silylation step. In this step, LDA was synthesized by reacting diisopropylamine (2.1 equiv) and n-BuLi (2.0 equiv) in THF at -78°C. The synthesized LDA was stabilized by stirring for 10 minutes. Then, the reactant dissolved in THF was added dropwise to the resulting LDA, and the mixture was stirred at -78°C for 1 hour. After adding TESCl (1.2 equiv), the reaction was allowed to proceed overnight at -78°C. Upon completion of the reaction, water was added to stop the reaction, and the product was extracted with diethyl ether. The extracted organic layer was washed with brine and dried with Na2SO4. After removing the solvent using a rotary evaporator, the silylated product was purified by column chromatography (FCC, EA:Hx = 1:40).

[0209] Ozone decomposition reaction - Method C

[0210] Figure 5k shows the ozone decomposition reaction. In this step, the reactant was dissolved in ethanol (EtOH), placed in a vial, and cooled to -78°C. A stirring bar was not used during this process. The ozone generator was turned on and stabilized for 5 minutes before starting the reaction. The flow was checked using a latex glove to ensure that ozone was supplied properly. The reaction proceeded by bubbling ozone into the solution using a long needle. Because the reaction status could not be monitored by TLC, a portion of the reactant was removed, the ethanol was removed, and the reaction progress was monitored by NMR analysis. The reaction time was adjusted to prevent overreaction. After the reaction was completed, nitrogen (N2) was bubbled into the solution to remove any residual ozone. The solvent was then removed using a rotary evaporator, and column chromatography (FCC, EA:Hx = 1:40) was performed to obtain the purified product.

[0211] Triflation step - for method C

[0212] Figure 5l illustrates the leaving group conversion step. In this step, the starting material was dissolved in THF, placed in a vial, and cooled to -78°C. L-selectride (3.0 eq) was then added at -78°C and stirred for 1 hour. Comins' reagent was prepared by dissolving it in THF in a separate vial, and this was added dropwise to the vial containing the starting material at -78°C. After the complete addition of Comins' reagent, the reaction mixture was warmed to room temperature and reacted overnight. After completion of the reaction, water was added to stop the reaction, and the product was extracted with diethyl ether. The organic layer was washed with brine and dried with Na2SO4. The solvent was then removed using a rotary evaporator, and column chromatography (FCC, Hx 100%) was performed to obtain the purified product with complete leaving group conversion.

[0213] NMR

[0214] Figure 6f shows the 13C NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-(triethylsilyl)cyclohexylidene)pyrrolidin-1-amine.

[0215] Figure 6g shows the 1H NMR spectrum of (R)-2-(triethylsilyl)cyclohexanone.

[0216] Figure 6h shows the 13C NMR spectrum of (R)-2-(triethylsilyl)cyclohexanone.

[0217] Figure 6i shows the 1H NMR spectrum of (R)-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0218] Figure 6j shows the 13C NMR spectrum of (R)-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0219] Figure 6k shows the 1H NMR spectrum of (R)-methyl 2-hydroxy-3-(triethylsilyl)cyclohex-1-enecarboxylate.

[0220] Figure 6l shows the 13C NMR spectrum of (R)-methyl 2-hydroxy-3-(triethylsilyl)cyclohex-1-enecarboxylate.

[0221] Figure 6m shows the 1H NMR spectrum of (R)-methyl 3-(triethylsilyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-enecarboxylate.

[0222] Figure 6n shows the 13C NMR spectrum of (R)-methyl 3-(triethylsilyl)-2-(((trifluoromethyl)sulfonyl)oxy)cyclohex-1-enecarboxylate.

[0223] Figure 6o shows the 1H NMR spectrum of 2-methylcyclohexanone.

[0224] Figure 6p shows the 13C NMR spectrum of 2-methylcyclohexanone.

[0225] Figure 7a shows the 1H NMR spectrum of 2-bromo-2-methylcyclohexanone.

[0226] Figure 7b shows the 13C NMR spectrum of 2-bromo-2-methylcyclohexanone.

[0227] Figure 7c shows the 1H NMR spectrum of 2-methylcyclohex-2-enone.

[0228] Figure 7d shows the 13C NMR spectrum of 2-methylcyclohex-2-enone.

[0229] Figure 7e shows the 1H NMR spectrum of (S,E)-2-(methoxymethyl)-N-(2-methylcyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0230] Figure 7f shows the 13C NMR spectrum of (S,E)-2-(methoxymethyl)-N-(2-methylcyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0231] Figure 7g shows the 1H NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-methyl-6-(triethylsilyl)cyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0232] Figure 7h shows the 13C NMR spectrum of (S,Z)-2-(methoxymethyl)-N-((R)-2-methyl-6-(triethylsilyl)cyclohex-2-en-1-ylidene)pyrrolidin-1-amine.

[0233] Figure 7i shows the 1H NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-2-enone.

[0234] Figure 7j shows the 13C NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-2-enone.

[0235] Figure 7k shows the 1H NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0236] Figure 7l shows the 13C NMR spectrum of (R)-2-methyl-6-(triethylsilyl)cyclohex-1-en-1-yl trifluoromethanesulfonate.

[0237] Although the present invention has been described above with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various modifications and changes may be made to the present invention without departing from the spirit and scope of the present invention as set forth in the claims below.

Claims

1. In the cyclic allene precursor, Positions 1 and 2 have double bonds, The leaving group -Z is combined in the second position, The third position is where -SiR3 is combined. Cyclic allene precursors: Here, The above leaving group -Z is -F, -Cl, -Br, -I, -N2 + , -OSO2(alkyl), -OSO2(aryl), -OSO2CF3, -OCO(alkyl), -OCO(aryl), -O(alkyl), -O(aryl), -OH, -SCN, -I + (aryl) X - (X is Cl, Br or I), -Br + (aryl) X - (X is one selected from the group containing Cl, Br or I), The above -SiR3 is one selected from the group containing -Si(alkyl)3, -Si(alkyl)2(aryl), -Si(alkyl)(aryl)2, -Si(aryl)3, -Si(H)2(alkyl), -Si(H)(alkyl)2, -Si(H)2(aryl), -Si(H)(aryl)2, -Si(H)(alkyl)(aryl).

2. In paragraph 1, The third position above is a chiral position, The above cyclic allene precursor has an enantiomeric excess other than 0%. Cyclic allene precursor.

3. In paragraph 1, The above cyclic allene precursor has a hexagonal ring, Cyclic allene precursor.

4. In paragraph 4, The 4th or 5th position of the above cyclic allene precursor is one selected from the group consisting of CH2, N, O, and SO2 bonded to a protecting group, Cyclic allene precursors: Here, The protecting group is one selected from the group comprising -(alkyl), -(aryl), -CO(alkyl), -CO(aryl), -COO(alkyl), -COO(aryl), -SO2(alkyl), and -SO2(aryl).

5. In paragraph 4, In the above cyclic allene precursor, at least one of the first, fifth, and sixth positions is additionally bonded with a substituent Y. Cyclic allene precursors: Here, The above substituent Y is one selected from the group containing -H, -(alkyl), -(aryl), -F, -Cl, -Br, -I, -CF3, -NO2, -CN, -CO2H, -COO(alkyl), -COO(aryl), -O(alkyl), -O(aryl), -OH, -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2, -N(aryl)2, -SO2(alkyl), -SO2(aryl), -S(alkyl), -S(aryl), and -PO4H2.

6. In paragraph 1, The above cyclic allene precursor has the chemical formula (S1), (S2), (S3), (S4), (S5), (S6), (R1), (R2), (R3), (R4), (R5), or (R6). Cyclic allene precursors: (S1) (S2) (S3) (S4) (S5) (S6) (R1) (R2) (R3) (R4) (R5) (R6) Here, wherein X is one selected from the group consisting of CH2, N, O, and SO2 combined with a protecting group, The protecting group is one selected from the group comprising -(alkyl), -(aryl), -CO(alkyl), -CO(aryl), -COO(alkyl), -COO(aryl), -SO2(alkyl), and -SO2(aryl), The above substituent Y is one selected from the group containing -H, -(alkyl), -(aryl), -F, -Cl, -Br, -I, -CF3, -NO2, -CN, -CO2H, -COO(alkyl), -COO(aryl), -O(alkyl), -O(aryl), -OH, -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2, -N(aryl)2, -SO2(alkyl), -SO2(aryl), -S(alkyl), -S(aryl), and -PO4H2.

7. A method for producing a cyclic allene precursor, A hydrazone bonding step of forming a hydrazone bond (C=NNR2) at the second position by reacting a chiral auxiliary agent having the following chemical formula (CA) with a raw material that is a cyclic compound having a carbonyl bond (C=O) at the second position; A silylation step in which silylation is performed at the third position to bind -SiR3; A hydrazone decomposition step of decomposing the hydrazone bond at the second position to form a ketone group at the second position; and A leaving group conversion step for converting the functional group bonded to the second position into a leaving group Z; Method for preparing cyclic allene precursors: (CA) Here, Above R 1 and the above R 2 are each independently alkyl or aryl, Above R 1 or the above R 2 has chirality, The above -SiR3 is one selected from the group containing -Si(alkyl)3, -Si(alkyl)2(aryl), -Si(alkyl)(aryl)2, -Si(aryl)3, -Si(H)2(alkyl), -Si(H)(alkyl)2, -Si(H)2(aryl), -Si(H)(aryl)2, -Si(H)(alkyl)(aryl), The leaving group -Z is -F, -Cl, -Br, -I, -N2+, -OSO2(alkyl), -OSO2(aryl), -OSO2CF3, -OCO(alkyl), -OCO(aryl), -O(alkyl), -O(aryl), -OH, -SCN, -I + (aryl) X - (X is Cl, Br or I), -Br + (aryl) X - (X is one selected from the group containing Cl, Br or I).

8. In paragraph 7, The above chiral auxiliary agent is one of the substances having the following chemical formula (CA-SAMP) or the following chemical formula (CA-RAMP): Method for preparing cyclic allene precursors: (CA-SAMP) (CA-RAMP).

9. In paragraph 7, The above hydrazone decomposition step is performed by ozonolysis or hydrolysis. A method for preparing a cyclic allene precursor.

10. In paragraph 7, In the above hydrazone decomposition step, a carbonyl bond (C=O) is formed at the second position, The above leaving group conversion step converts the oxygen of the carbonyl bond (C=O) into a leaving group Z, In the above leaving group conversion step, the bond between the first position and the second position is converted into a double bond. A method for preparing a cyclic allene precursor.

11. In paragraph 7, In the above hydrazone decomposition step, a carbonyl bond (C=O) is formed at the second position, The method for producing the above cyclic allene precursor further includes an acylation step of, prior to the leaving group conversion step, bonding an ester to the first position, converting the oxygen of the carbonyl bond (C=O) at the second position into a hydroxyl group (-OH), and converting the bond between the first position and the second position into a double bond. In the above leaving group conversion step, the oxygen of the hydroxyl group (-OH) is converted into a leaving group Z. A method for preparing a cyclic allene precursor.

12. In paragraph 7, The above raw material has a hexagonal ring, The method for producing the above cyclic allene precursor further includes an enone forming step of, prior to the hydrazone bonding step, bonding a halogen to the first position of the raw material and then converting the bond between the first position and the sixth position into a double bond through removal. A method for preparing a cyclic allene precursor.

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