Method for producing polycyclic compounds containing a spiro skeleton and polycyclic compounds

Abstract

Provided is a method for producing a polycyclic compound containing a spiro skeleton with a small number of steps, and also provided is a polycyclic compound in which the number of atoms constituting the ring (the number of membered rings) is adjusted. [Solution] A ketone having two ketone groups and a leaving group is treated under an environment that causes S N N2 reaction and intramolecular aldol reaction, thereby producing the polycyclic compound containing a spiro skeleton represented by formula (2). TIFF2026143570000022.tif49144 R 1 , R 2 and R 3 each represent a hydrogen atom, a halogen atom, an alkyl group, a hydroxy group or an alkoxy group, and R 1 and R 2 may be bonded to form a ring. n2 is an integer of 1 or more.

Description

[Technical Field]

[0001] The present invention relates to a method for producing polycyclic compounds containing a spiro skeleton, which are useful as intermediates for medical devices, liquid crystal materials, and the like, and to polycyclic compounds produced by this method. [Background technology]

[0002] Polycyclic compounds are abundant in nature, and many of them possess biological activity. For this reason, they are widely used as pharmaceuticals or their raw materials, playing a significant role in life processes. Furthermore, it is well known that polycyclic compounds, such as steroids, are used not only as pharmaceuticals but also as liquid crystal materials. However, while polycyclic compounds with a spiro skeleton are useful for facilitating the production of pharmaceuticals and other products due to the ability to immobilize various substituents, the synthesis methods for polycyclic compounds have traditionally involved numerous steps (see Non-Patent Documents 1 and 2). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] SASnyder, et al. Nature, 569, 703(2019) [Non-Patent Document 2] SASnyder, et al. Angew. Chem. Int. Ed. 59, 13521(2020) [Non-Patent Document 3] K. Shibatomi, et al. Nature Commun. 8, 15600(2017) [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] The technologies disclosed in the aforementioned Non-Patent Documents 1 and 2 have multiple steps as described above, and also have the problem that the number of atoms constituting a ring (number of ring members) cannot be controlled. And a synthetic method for solving these problems has not yet been reported.

[0005] The present invention has been made in view of the above points, and an object thereof is to provide a method for producing a polycyclic compound containing a spiro skeleton with a small number of steps, and to provide a polycyclic compound in which the number of atoms constituting a ring (number of ring members) is adjusted. [Means for Solving the Problem]

[0006] The inventors of the present application have found a method capable of asymmetrically synthesizing α-chloroketones by decarboxylative chlorination of carboxylic acids (see Non-Patent Document 3). Furthermore, as a result of intensive research, they have found that based on this method, a polycyclic compound containing a spiro skeleton can be easily synthesized from synthesized ketones.

[0007] Therefore, the present invention, which relates to a method for producing a polycyclic compound containing a spiro skeleton, is characterized in that a ketone represented by the following formula (1) is treated in an environment where S N 2 reaction and intramolecular aldol reaction are caused to occur, thereby producing a polycyclic compound containing a spiro skeleton represented by the following formula (2).

[0008] [Chemical Formula]

[0009] In the above formulas (1) and (2), R 1 , R 2 and R 3 each represent a hydrogen atom, a halogen atom, a methyl group, an alkyl group, a hydroxy group, an alkoxy group or a benzyl group, R 1 and R 2 may be bonded to form a ring. X represents a leaving group. n1 and n2 are integers of 1 or more.

[0010] In the above invention, the S N 2 reaction and intramolecular aldol reaction may be carried out in a basic solution obtained by dissolving a base in one or more reaction solvents selected from aromatic hydrocarbons, ethers or aliphatic hydrocarbons.

[0011] In each of the above inventions, the ketone represented by formula (1) may be produced by asymmetric synthesis of a carboxylic acid represented by the following formula (3) via decarbonative chlorination reaction.

[0012]

Chemical Formula

[0013] In the above formula (3), R 1 , R 2 and R 3 each represent a hydrogen atom, a halogen atom, a methyl group, an alkyl group, a hydroxy group, an alkoxy group or a benzyl group, and R 1 and R 2 may be bonded to each other to form a cyclic structure.

[0014] On the other hand, the present invention relating to a polycyclic compound is characterized in that at least two cyclic compounds form a spiro structure with each other and the polycyclic compound is represented by the following formula (2).

[0015]

Chemical Formula

[0016] In addition, R 1 , R 2 and R 3 each represent a hydrogen atom, a halogen atom, a methyl group, an alkyl group, a hydroxy group, an alkoxy group or a benzyl group, R 1 and R 2 may be bonded to each other to form a cyclic structure, and n2 is an integer of 1 or more.

[0017] In the above invention, the two ring compounds are each selected from 5 to 7 member rings, and may have different or the same number of member rings. Furthermore, the two ring compounds may also have other ring compounds bonded to them. [Effects of the Invention]

[0018] According to the present invention relating to a method for producing polycyclic compounds containing a spiro skeleton, by using α-chloroketones asymmetrically synthesized by a method already developed by the inventors of this application, ketones can be synthesized from carboxylic acids, and then polycyclic compounds can be synthesized, thus representing a synthesis method with relatively few steps. Furthermore, by changing the length of the side chains of the ketones, the number of atoms constituting the ring (number of member rings) can be easily adjusted, allowing for the production of a wide variety of polycyclic compounds.

[0019] The present invention relating to polycyclic compounds can be used as intermediates for medical products, liquid crystal materials, etc., and therefore can serve as useful polycyclic compound pharmaceuticals or their raw materials. Furthermore, the polycyclic compounds of the present invention have a spiro skeleton and various substituents can be immobilized, making them usable in a wide range of synthesis applications. [Modes for carrying out the invention]

[0020] The present invention provides a method for producing a polycyclic compound containing a spiro skeleton by using the ketones shown in formula (1) above. N The polycyclic compound shown in formula (2) above is produced by processing under conditions that induce two reactions and an intramolecular aldol reaction. Examples of "ketones" include acetone, MEK, MIBK, 2-butanone, and α-haloketones, but a configuration in which a leaving group is present at the α-position of the ketone and another ketone is present in part of the side chain is preferred, and α-haloketones (α-chloroketones or α-bromoketones) are preferred.

[0021] S NThe two reactions and intramolecular aldol reactions are reactions that yield the polycyclic compound of formula (2) by acting in a suitable solvent in the presence of a reaction solvent and a base. The "reaction solvent" may be a single solvent or a mixture of two or more solvents. Specific examples of reaction solvents include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran (THF), and dimethoxyethane; and aliphatic hydrocarbons such as hexane, heptane, cyclohexane, and methylcyclohexane.

[0022] Examples of "bases" include lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium methoxide, sodium ethoxide, potassium hydroxide, potassium carbonate, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, cesium hydroxide, cesium carbonate, thallium hydroxide, and phosphates.

[0023] The reaction temperature is preferably -100°C to room temperature, and particularly preferably -20°C to room temperature. R in equations (1) and (2) above 1 , R 2 and R 3 The group represents a hydrogen atom, halogen atom, methyl group, alkyl group, hydroxy group, alkoxy group, or benzyl group. A "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom. An "alkyl group" refers to an unsubstituted or substituted alkyl group. Substituents for substituted alkyl groups include aryl groups, alkoxy groups, aryloxy groups, siloxy groups, acyloxy groups, alkylthio groups, arylthio groups, alkylamino groups, acylamino groups, halogen atoms, and others.

[0024] "Alkyl groups" can be linear or branched. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups.

[0025] Also, R 1 and R 2 These may be linked together by alkylene groups, ether bonds (-O-), thioether bonds (-S-), or amines (-N(Q)-) to form a ring.

[0026] In formula (1) above, X represents a leaving group. The "leaving group" is not particularly limited as long as it is a known group, but examples include chlorine, bromine, iodine, p-toluenesulfonate, methanesulfonate, chloromethanesulfonate, and trifluoromethanesulfonate.

[0027] In formulas (1) and (2) above, n1 and n2 are integers greater than or equal to 1. The numbers of n1 and n2 are not particularly limited. This indicates that by changing the length of the side chain (n1) in formula (1), the number of atoms constituting the ring (number of member rings (n2)) in the synthesized polycyclic compound can be adjusted. That is, if we exemplify a polycyclic compound synthesized when the number of n1 is 3, the C ring will be a 5-membered ring as shown in the equation below. In this way, by using ketones with any number of n1, the number of member rings in the C ring can be freely changed. The number of member rings in the A ring can be appropriately changed by using ketones with various numbers of member rings depending on the starting material used.

[0028] [ka] [Examples]

[0029] Next, we conducted specific experiments, which are described below. First, as a preliminary step, we performed the following experiment. Using α-chloroketones obtained by asymmetric synthesis of carboxylic acids as starting materials, we synthesized the target polycyclic compound in the presence of a reaction solvent and a base. The yield was at best 92%, but by-products were obtained depending on the conditions. The outlines of these products are as follows.

[0030] [ka]

[0031] The experimental conditions, the types of bases and solvents used, and the proportion of the products are summarized in the table below. [Table 1]

[0032] As is clear from the preliminary experiments described above, in addition to the target substance (substance 1), substances that appear to be substrates (substance 2) or by-products (substance 3) were sometimes produced. Therefore, it is desirable to appropriately change the reaction conditions depending on the structure of the ketones used as starting materials. Furthermore, considering the nuclear material produced, S N It is assumed that the preceding substance (substance 4) is produced by two reactions, and then the target substance (substance 1) is produced by an intramolecular aldol reaction.

[0033] Next, based on the preliminary experiments described above, toluene or tetrahydrofuran was used as the reaction catalyst, and potassium tert-butoxide was used as the base to produce a polycyclic compound under suitable conditions. The structure of the compound was determined by nuclear magnetic resonance spectroscopy. It should be noted that the specific manufacturing methods and results exemplified below are not intended to limit the present invention to these examples.

[0034] <Example 1> [Synthesis of 2a,3,4,5,6,7-hexahydro-2H-pentaleno[1,6a-a]naphthalen-2-one] [ka]

[0035] A reaction vessel containing α-chloroketone (55.7 mg, 0.20 mmol) was purged with argon, and toluene (1.0 mL) was added as the reaction solvent. Potassium tert-butoxide (56.1 mg, 0.50 mmol) was then added to this solution, and the reaction was carried out at room temperature for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 5:1) to obtain the tetracyclic compound (shown above) in 97% yield.

[0036] 1 H NMR (400 MHz, CDCl3): δ 7.62 (dd, J = 7.6, 1.5 Hz, 1H), 7.36 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H), 7.27 (dd, J = 7.6, 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.33 (s, 1H), 3.11 (ddd, J = 17.6, 10.7, 7.0 Hz, 1H), 2.94 (ddd, J = 17.6, 4.9, 2.8 Hz, 1H), 2.49 (d, J = 8.5 Hz, 1H), 2.13-2.05 (m, 3H), 1.82-1.72 (m, 2H), 1.70-1.63 (m, 1H), 1.57 (ddd, J = 12.2, 12.2, 6.1 Hz, 1H), 1.43-1.31 (m, 1H); 13 C NMR (100 MHz, CDCl3): δ 211.3, 177.4, 138.6, 130.9, 129.6, 129.5, 127.6, 126.4, 123.8, 58.3, 52.9, 34.9, 34.6, 29.2, 26.8, 24.2

[0037] <Reactions using optically active substances> [ka] When the reaction was carried out using the optically active α-chloroketone (S-isomer, 97%ee) according to the synthesis method described above, the optical purity was 97%ee. The optical purity was determined by HPLC analysis using a chiral column.

[0038] DAICEL CHIRALCEL IE-3 (0.46 cmΦ × 25 cm), hexane : 2-propanol = 10 : 1, flow rate = 1.0 mL / min, retention time; 50.7 min (minor) and 54.2 min (major)).[α] D 24 +224.1 (c = 1.135, CHCl3).

[0039] <Example 2> [Synthesis of 3,4,5,6,7,8-hexahydroindeno[1,7a-a]naphthalen-2(2aH)-one] [ka]

[0040] A reaction vessel containing α-chloroketone (51.1 mg, 0.18 mmol) was purged with argon, and toluene (0.9 mL) was added as the reaction solvent. Potassium tert-butoxide (48.5 mg, 0.43 mmol) was then added to this solution, and the reaction was carried out at room temperature for 4 hours. The crude was purified by flash column chromatography (hexane:ethyl acetate = 8:1) to obtain the tetracyclic compound (shown above) in a yield of 7%.

[0041] 1¹H NMR (500 MHz, CDCl₃): δ 7.67 (dd, J = 7.6, 1.2 Hz, 1H), 7.35 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.27 (dd, J = 7.6, 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.38 (s, 1H), 3.11 (ddd, J = 18.0, 13.0, 5.7 Hz, 1H), 2.93 (dd, J = 18.0, 5.7 Hz, 1H), 2.31 (ddd, J = 13.0, 5.7, 1.5 Hz, 1H), 2.28-2.24 (m, 2H), 1.98-1.93 (m, 1H), 1.75 (ddd, J = 13.0, 13.0, 5.7 Hz, 1H), 1.64-1.54 (m, 2H), 1.49-1.42 (m, 1H), 1.38-1.21 (m, 2H), 1.06 (ddd, J = 14.1, 11.5, 3.8 Hz, 1H); 13 ¹³C NMR (126 MHz, CDCl₃): δ 209.0, 177.5, 137.9, 130.8, 129.7, 129.1, 127.2, 126.5, 121.0, 55.9, 43.6, 32.1, 30.4, 26.0, 22.3, 20.7, 20.0

[0042] <Example 3> [Synthesis of 1-methyl-2a,3,4,5,6,7-hexahydro-2H-pentaleno[1,6a-a]naphthalen-2-one]

Chemical Formula

[0043] A reaction vessel containing α-chloroketone (64.1 mg, 0.22 mmol) was purged with argon, and toluene (1.1 mL) was added as the reaction solvent. Potassium tert-butoxide (61.4 mg, 0.55 mmol) was then added to this solution, and the mixture was reacted at room temperature for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 5:1) to obtain the tetracyclic compound (shown above) in 80% yield.

[0044] 1 H NMR (500 MHz, CDCl3): δ 7.67 (dd, J = 7.6, 1.5 Hz, 1H), 7.34 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H), 7.29 (dd, 7.6, 7.6 Hz, 1H), 7.26 (d, 7.6 Hz, 1H), 3.11 (ddd, J = 17.6, 12.6, 5.7 Hz, 1H), 2.98 (dd, J = 17.6, 5.7 Hz, 1H), 2.40 (d, 9.6 Hz, 1H), 2.10 (ddd, J = 12.6, 5.7, 1.5 Hz, 1H), 2.07-2.01 (m, 1H), 2.04 (s, 3H), 2.00 (ddd, J = 12.6, 12.6, 5.7 Hz, 1H), 1.81 (dddd, J = 13.0, 13.0, 9.6, 6.1 Hz, 1H), 1.73-1.70 (m, 1H), 1.62 (dd, J = 12.6, 5.7 Hz, 1H), 1.50 (ddd, J = 12.6, 12.6, 6.1 Hz, 1H), 1.33-1.23 (m, 1H); 13 C NMR (126 MHz, CDCl3): δ 211.9, 168.4, 138.8, 132.9, 131.1, 129.6, 129.4, 129.1, 125.9, 56.3, 52.0, 34.9, 34.6, 29.5, 27.2, 24.2, 10.1

[0045] <Example 4> [Synthesis of 1-benzyl-2a,3,4,5,6,7-hexahydro-2H-pentaleno[1,6a-a]naphthalen-2-one] [ka]

[0046] A reaction vessel containing α-chloroketone (55.0 mg, 0.15 mmol) was purged with argon, and toluene (0.7 mL) was added as the reaction solvent. Potassium tert-butoxide (41.8 mg, 0.37 mmol) was then added to this solution, and the mixture was reacted at room temperature for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 4:1) to obtain the tetracyclic compound (shown above) in 86% yield.

[0047] 1 H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 1H), 7.32-7.24 (m, 4H), 7.20-7.13 (m, 4H), 4.05 (d, 15.7 Hz, 1H), 3.66 (d, 15.7 Hz, 1H), 3.13 (ddd, J = 17.6, 12.2, 5.7 Hz, 1H), 3.00 (dd, 17.6 Hz, 5.7 Hz, 1H), 2.48 (d, J = 9.6 Hz, 1H), 2.15 (ddd, J = 13.0, 5.7, 1.5 Hz, 1H), 2.12-2.04 (m, 2H), 1.87 (dddd, J = 13.0, 13.0, 9.6, 6.1 Hz, 1H), 1.80 (dd, 12.6 Hz, 6.1 Hz, 1H), 1.69 (ddd, J = 13.0, 5.7, 5.7 Hz, 1H), 1.56 (ddd, J = 12.6, 12.6, 6.1 Hz, 1H), 1.43-1.33 (m, 1H); 13C NMR (126 MHz, CDCl3): δ 211.5, 170.6, 139.1, 138.8, 135.4, 130.5, 130.1, 129.4, 129.1, 128.6, 127.9, 126.0, 126.0, 56.3, 52.4, 35.0, 34.7, 29.8, 29.7, 27.1, 24.6

[0048] <Example 5> [Synthesis of 1,2,3,3a-tetrahydropentaleno[1,6a-a]inden-4(10H)-one] [ka]

[0049] A reaction vessel containing α-chloroketone (52.8 mg, 0.20 mmol) was purged with argon, and tetrahydrofuran (1.0 mL) was added as the reaction solvent. Potassium tert-butoxide (55.9 mg, 0.50 mmol) was then added to this solution, and the mixture was reacted at room temperature for 3 hours. The crude was purified by flash column chromatography (hexane:ethyl acetate = 3:1) to obtain the tetracyclic compound (shown above) in 86% yield.

[0050] 1 H NMR (500 MHz, CDCl3): δ 7.62 (d, J = 7.6 Hz, 1H), 7.42 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.32 (dd, J = 7.6, 7.6 Hz, 1H), 6.12 (s, 1H), 3.17 (d, J = 15.3 Hz, 1H), 2.98 (d, J = 15.3 Hz, 1H), 2.80 (d, J = 8.0 Hz, 1H), 2.17-2.13 (m, 1H), 1.87-1.79 (m, 2H), 1.73-1.66 (m, 1H), 1.62 (ddd, J = 12.6, 10.7, 6.1 Hz, 1H), 1.51-1.42 (m, 1H); 13C NMR (126 MHz, CDCl3): δ 213.1, 186.8, 148.6, 135.0, 131.6, 127.3, 126.1, 124.8, 120.2, 63.2, 57.6, 44.1, 39.6, 29.7, 24.8

[0051] <Example 6> [Synthesis of 2a,3,4,5,7,8-hexahydrobenzo[h]cyclopenta[c]azulen-2(6H)-one] [ka]

[0052] A reaction vessel containing α-chloroketone (51.1 mg, 0.17 mmol) was purged with argon, and toluene (0.9 mL) was added as the reaction solvent. Potassium tert-butoxide (48.3 mg, 0.43 mmol) was then added to this solution, and the reaction was carried out at room temperature for 23 hours. The crude was purified by flash column chromatography (hexane:ethyl acetate = 4:1) to obtain the tetracyclic compound (shown above) in 88% yield.

[0053] 1 H NMR (500 MHz, CDCl3): δ 7.28 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H), 7.20 (dd, J = 7.6, 7.6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.16 (dd, J = 7.6, 1.5 Hz, 1H), 6.12 (s, 1H), 2.87 (dd, J = 14.5, 6.9 Hz, 1H), 2.77 (dd, J = 14.5, 11.9 Hz, 1H), 2.44 (dd, J = 9.6, 2.7 Hz, 1H), 2.20-2.15 (m, 1H), 2.01 (dd, J = 13.0, 2.7 Hz, 1H), 2.00-1.95 (m, 1H), 1.90-1.73 (m, 3H), 1.65-1.56 (m, 2H), 1.35-1.25 (m, 2H);13 C NMR (126 MHz, CDCl3): δ 211.4, 185.2, 140.6, 136.2, 131.4, 129.9, 129.7, 129.5, 126.2, 59.8, 58.2, 43.7, 37.6, 34.8, 29.7, 25.3, 24.6

[0054] <Example 7> [Synthesis of 10-bromo-2a,3,4,5,6,7-hexahydro-2H-pentaleno[1,6a-a]naphthalen-2-one] [ka]

[0055] A reaction vessel containing α-chloroketone (45.0 mg, 0.13 mmol) was purged with argon, and toluene (0.7 mL) was added as the reaction solvent. Potassium tert-butoxide (72.9 mg, 0.65 mmol) was then added to this solution, and the mixture was reacted at room temperature for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 4:1) to obtain the tetracyclic compound (shown above) in 87% yield.

[0056] 1 H NMR (500 MHz, CDCl3): δ 7.73 (d, J = 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 1.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 3.03 (ddd, J = 18.0, 12.2, 5.7 Hz, 1H), 2.90 (ddd, J = 18.0, 5.4, 1.5 Hz, 1H), 2.48 (d, J = 8.8 Hz, 1H), 2.12-2.00 (m, 3H), 1.81-1.72 (m, 2H), 1.67 (ddd, J = 12.6, 6.1, 6.1 Hz, 1H), 1.55 (ddd, J = 12.6, 12.2, 6.1 Hz, 1H), 1.40-1.30 (m, 1H);13 C NMR (126 MHz, CDCl3): δ 210.9, 175.5, 137.3, 133.6, 131.5, 131.1, 130.9, 124.6, 120.0, 58.2, 52.7, 34.8, 34.2, 29.3, 26.4, 24.1

[0057] <Example 8> [Synthesis of 10-chloro-2a,3,4,5-tetrahydro-2H,6H-pentaleno[6a,1-c]chromen-2-one] [ka]

[0058] A reaction vessel containing α-chloroketone (45.2 mg, 0.14 mmol) was purged with argon, and toluene (0.7 mL) was added as the reaction solvent. Potassium tert-butoxide (39.3 mg, 0.35 mmol) was then added to this solution, and the mixture was reacted at -20 °C for 5 hours, at 0 °C for 18 hours, and at room temperature for 5 hours. The crude was purified by flash column chromatography (hexane:ethyl acetate = 4:1) to obtain the tetracyclic compound (shown above) in 54% yield.

[0059] 1 H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 2.7 Hz, 1H), 7.31 (dd, J = 8.8, 2.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.27 (s, 1H), 4.37 (d, J = 10.3 Hz, 1H), 4.20 (d, J = 10.3 Hz, 1H), 2.46 (d, J = 8.0 Hz, 1H), 2.16-2.13 (m, 1H), 1.85-1.73 (m, 4H), 1.54-1.37 (m, 1H); 13C NMR (126 MHz, CDCl3): δ 209.2, 169.6, 154.1, 133.0, 126.9, 126.2, 122.1, 119.3, 118.1, 75.0, 54.1, 50.8, 35.1, 29.2, 24.5

[0060] <Example 9> [Synthesis of 7-methyl-1,2,3,3a,8,9-hexahydro-4H-cyclopenta[c]inden-4-one] [ka]

[0061] A reaction vessel containing α-chloroketone (55.0 mg, 0.20 mmol) was purged with argon, and toluene (1.0 mL) was added as the reaction solvent. Potassium tert-butoxide (56.1 mg, 0.50 mmol) was then added to this solution, and the mixture was reacted at -20 °C for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 5:1) to obtain the tricyclic compound (shown above) in a yield of 22%.

[0062] 1 H NMR (500 MHz, CDCl3): δ 5.81 (d, J = 1.5 Hz, 1H), 2.74-2.71 (m, 1H), 2.35 (dddd, J = 13.8, 13.8, 5.7, 1.5 Hz, 1H), 2.27 (d, J = 9.6 Hz, 1H), 2.04-2.00 (m, 1H), 1.97-1.86 (m, 3H), 1.77-1.69 (m, 2H), 1.67-1.62 (m, 1H), 1.59-1.52 (m, 2H), 1.46-1.36 (m, 2H), 1.32-1.22 (m, 1H); 13 C NMR (126 MHz, CDCl3): δ 211.9, 186.1, 127.3, 58.4, 55.5, 40.1, 35.2, 28.8, 28.6, 27.4, 24.9, 22.9

[0063] <Example 10> [Synthesis of 7-methyl-1,2,3,3a,8,9-hexahydro-4H-cyclopenta[c]inden-4-one] [ka]

[0064] A reaction vessel containing α-chloroketone (48.0 mg, 0.20 mmol) was purged with argon, and toluene (1.0 mL) was added as the reaction solvent. Potassium tert-butoxide (55.6 mg, 0.50 mmol) was then added to this solution, and the mixture was reacted at room temperature for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 4:1) to obtain the tricyclic compound (shown above) in 42% yield.

[0065] 1 H NMR (500 MHz, CDCl3): δ 6.34 (s, 1H), 5.71 (s, 1H), 2.46-2.37 (m, 1H), 2.34 (d, J = 8.0 Hz, 1H), 2.21 (dd, J = 18.7, 4.6 Hz, 1H), 2.06-2.02 (m, 1H), 1.92 (s, 3H), 1.93-1.89 (m, 1H), 1.85 (ddd, J = 12.2, 12.2, 5.4 Hz, 1H), 1.79-1.61 (m, 3H), 1.49 (ddd, J = 12.2, 12.2, 6.1 Hz, 1H), 1.39-1.29 (m, 1H); 13 C NMR (126 MHz, CDCl3): δ 211.6, 177.0, 150.7, 123.0, 119.3, 57.5 , 51.5, 35.9, 34.1, 29.6, 28.9, 24.3, 24.1

[0066] <Example 11> [Synthesis of 6-methyl-7-(phenylthio)-1,2,3,3a,8,9-hexahydro-4H-cyclopenta[c]inden-4-one] [ka]

[0067] A reaction vessel containing α-chloroketone (71.1 mg, 0.20 mmol) was purged with argon, and toluene (2.0 mL) was added as the reaction solvent. Potassium tert-butoxide (114.5 mg, 1.02 mmol) was then added to this solution, and the mixture was reacted at room temperature for 1 hour. The crude was purified by flash column chromatography (hexane:ethyl acetate = 3:1) to obtain the tetracyclic compound (shown above) in 81% yield.

[0068] 1 H NMR (500 MHz, CDCl3): δ 7.46-7.42 (m, 2H), 7.39-7.35 (m, 3H), 5.89 (s, 1H), 2.39-2.30 (m, 1H), 2.36 (d, J = 8.0 Hz, 1H), 2.23-2.18 (m, 1H), 2.13 (dd, J = 2.3, 1.2 Hz, 3H), 2.06-2.01 (m, 1H), 1.82-1.77 (m, 3H), 1.70-1.60 (m, 2H), 1.44 (ddd, J = 12.2, 12.2, 6.1 Hz, 1H), 1.42-1.30 (m, 1H); 13 C NMR (126 MHz, CDCl3): δ 211.2, 177.1, 144.0, 134.0, 131.5, 129.2, 128.5, 126.6, 122.4, 57.9, 51.9, 35.8, 34.5, 29.2, 28.9, 24.2, 16.4 [Industrial applicability]

[0069] The polycyclic compounds of the present invention can be used as intermediates in medical applications, liquid crystal materials, and the like. Furthermore, the method for producing polycyclic compounds containing a spiro skeleton allows for the production of various types of polycyclic compounds by changing the type of ketones used as starting materials or by altering the length of the side chains of the ketones. Therefore, useful polycyclic compounds can be easily produced as described above.

Claims

1. The ketones shown in the following formula (1) are S N A method for producing a polycyclic compound containing a spiro skeleton as shown in formula (2) below, characterized by processing under conditions that induce two reactions and an intramolecular aldol reaction. 【Chemistry 1】 R 1 , R 2 and R 3 R represents a hydrogen atom, halogen atom, methyl group, alkyl group, hydroxy group, alkoxy group, or benzyl group. 1 and R 2 The elements may combine to form a ring. X represents a leaving group. n1 and n2 are integers greater than or equal to 1.

2. The aforementioned S N A method for producing a polycyclic compound containing a spiro skeleton according to claim 1, wherein the environment for causing the two reactions and intramolecular aldol reaction is a base solution obtained by dissolving a base in one or more reaction solvents selected from aromatic hydrocarbons, ethers, or aliphatic hydrocarbons.

3. A method for producing a polycyclic compound containing a spiro skeleton according to claim 1 or 2, wherein the ketones shown in formula (1) are produced by asymmetric synthesis of the carboxylic acid shown in formula (3) by a decarbonative chlorination reaction. 【Chemistry 2】 R 1 , R 2 and R 3 each represent a hydrogen atom, a halogen atom, a methyl group, an alkyl group, a hydroxy group, an alkoxy group or a benzyl group, and R 1 and R 2 may be bonded to form a cyclic structure.

4. A polycyclic compound characterized in that at least two ring compounds form a spiro structure relative to each other, as shown in formula (2) below. 【Transformation 3】 R 1 , R 2 and R 3 R1 represents a hydrogen atom, a halogen atom, an alkyl group, a hydroxyl group, or an alkoxy group, and R1 and R2 may be bonded together to form a ring. n2 is an integer of 1 or more.

5. The polycyclic compound according to claim 4, wherein the two ring compounds are each selected from 5 to 7 member rings, and have different or the same number of member rings.

6. The polycyclic compound according to claim 4 or 5, wherein the two ring compounds are further bonded to other ring compounds.

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