WO2002064643A1 - Polymer-supported allylsilane compound, process for producing the same, and use thereof - Google Patents

Abstract

A polymer-supported allylsilane compound with high stereoselectivity which comprises a polymer support and an allylsilyl compound fixed thereto and which is represented by the general formula (I) (I) (wherein the part located on the left side of L is a polymer support; L is a linker; R?A and RB¿ each is alkyl or phenyl; and R?1, R3, and R4¿ each is hydrogen or an optionally substituted alkyl, cycloalkyl, aryl, or aromatic heterocyclic group). It is suitable for use in producing optically active compounds through solid-phase reactions with various compounds. The compound can react with aldehydes, ketones, etc. through solid-phase reactions to produce various compounds. It is especially suitable for use in producing optically active compounds. It is useful as a reactive material for medicines, etc.

Description

 Description Polymer-carrying arylsilane compounds, their preparation and their use

 The present invention relates to a polymer-supported arylsilane conjugate useful as various reaction materials, a method for producing the same, and use thereof. More specifically, the present invention provides a polymer-supported arylsilane compound obtained by supporting an arylsilyl group on a polymer carrier via a linker, and a method for producing the same. In addition, high-purity homoallyl alcohols, homoallyl ethers, etc. can be produced by solid-phase reaction with various compounds such as ketones, ketals, acetals, etc. It is useful as an intermediate for manufacturing such as. Thus, the present invention also relates to the industrial use of the polymer-supported arylsilane compounds. Background art

In recent years, attention has been focused on solid-phase synthesis or the development of solid-phase-supported reagents with the aim of rapid synthesis of various compound groups. However, research on solid-phase synthesis of optically active compounds, which are expected to have great demand in the near future, has just begun. If an optically active reagent can be supported on a polymer, it is expected to be a useful solid-phase-supporting reagent that can synthesize optically active organic compounds very simply and quickly. Rylsilane is a stable, but highly reactive, regio- and stereoselective compound that reacts with cationic electrophiles (typically aldehydes activated with Lewis acids) in conventional liquid phase reactions. It is known (I. Fleming et al., Organic Reactions (John Willey & Sons, Inc.), vol. 37, 57, 1989). In particular, when the optically active substance is used, the chirality of arylsilane is very effectively transferred to the product, and an optically active compound is obtained. Such properties are those desirable for polymer-supported by 1 9 9 7 years Amerika Panekku (Panek) et al actually solid phase carrier of the optical active ¹ production Arirushiran implemented, Le, of several The allyl-dani reaction is being studied (Panek, JS et al., J. Am. Chem. Soc. 1997, 119, 12022-12023). However, their method is to add hydroxyl groups to the carbon chain of aryl silane, synthesize it by a liquid phase method, and then attach it to a polymer carrier, and if it is only seriously limited by the possible structure of aryl silane, Also, in the synthesis of arylsilane, there was no merit of the simplification of the synthesis by solid-phase support. Disclosure of the invention

 The present inventors have carried out various studies to directly support arylsilane on a solid phase and obtain solid-phase-supporting reagents used for the synthesis of various optically active compounds by a solid-phase method. It has been found that a specific polymer-carrying arylsilyl conjugate having an arylsilane bonded thereto is suitable for the purpose. That is, an object of the present invention is to provide a novel polymer-supported aryl silane compound applicable to various asymmetric syntheses. Another object of the present invention is to provide a method for producing the polymer-supported aryl silane compound. Still another object of the present invention is to provide use as a reaction material for reacting the polymer-supported arylsilane compound with various aldehydes, ketones and the like by a solid phase method.

 According to the study of the present inventors, the following general formula (I):

式中、 は末端フエ二ル環を有するポリマー担体、

Wherein: is a polymer carrier having a terminal phenyl ring,

 L is the linker,

R ^A and RB are each independently an alkyl group or a phenyl group,

R ¹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted

R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, Represents a substituted or unsubstituted aromatic heterocyclic group)

The present inventors have found that the novel polymer-supported arylsilane compound represented by the formula (1) can be applied to the reaction with various aldehydes and ketones by the solid-phase method and is useful as various reaction materials, and completed the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

で示されるポリマー担体としては、 架橋剤として、 例 えばジビュルベンゼンを用いて重合させたポリスチレン樹脂、 ポリエチレンダリ コールとポリスチレンからなる樹脂、 ポリプロピレンダリコールとポリスチレン 力 らなる榭月旨などが挙げられる。 Each substituent in the polymer-supported arylsilane compound (I) of the present invention specifically means the following. The following formula:

As the polymer carrier represented by, for example, a polystyrene resin polymerized using dibutylbenzene as a cross-linking agent, a resin composed of polyethylene daricol and polystyrene, and a luster composed of polypropylene daricol and polystyrene are exemplified. .

Examples of the linker represented by the symbol L include an alkylene group represented by the formula: _ (CH ₂ ) _n — (n = :! to 10), for example, tetramethylene, pentamethylene, and hexamethylene.

Examples of the alkyl group include a linear or branched alkyl group having 1 to 10 carbon atoms. Specific examples include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, and 2-methyl-1-alkyl. 1-Propyl, 1,1-Dimethynoethyl / yl, Bentyl, 1,1-Dimethylpropynole, 2,2-Dimethylpropyl, 1-Methynolebutyl, 3-Methynolebutyl, Hexyl, 2-Methylpentyl, 3,3-Dimethylbutyi And heptyl, 1-ethylpentyl, 5-methylinohexyl, octyl, 1,5-dimethynolehexyl, 2-ethylhexyl, Noel, decyl and the like. R ^A, R ^B, as the preferred alkyl groups in R \ R ³ and R ^4, include straight-chain or branched alkyl group of from 1 to 6 carbon. Further suitable alkyl groups include straight-chain or branched-chain alkyl groups having 1 to 4 carbon atoms.

Examples of the cycloalkyl group include a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of the aryl group include aryl groups having 6 to 15 carbon atoms, and specific examples thereof include phenyl, 1.1-naphthyl, 2-naphthyl, azulenyl, phenanthryl, and anthryl. Preferably, they are phenyl, 1-naphthyl and 2-naphthyl.

 Examples of the aromatic heterocyclic group include, for example, 1 to 3 nitrogen atoms, 0 to 1 oxygen atom,

0 to: A 5- to 14-membered monocyclic, bicyclic or tricyclic aromatic heterocyclic group consisting of one sulfur atom and carbon atom is exemplified. Specifically, frill, chenyl, benzo-cenole, isobenzofuranoe, pyrrolinole, benzofurinole, imidazolinole, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzopyrazol, benzpyrazol, benzpyrazol Pyrimidinyl, pyridazinyl, triazinyl, quinoliel, isoquinolinyl, quinazolyl, quinoxalinyl, carbazolyl and the like.

 The heterocyclic group in the heterocyclic group which may be substituted for the R group described below includes the following aliphatic heterocyclic group in addition to the above aromatic heterocyclic ring.

 Examples of the aliphatic heterocyclic group include a 5- to 7-membered monocyclic aliphatic heterocyclic group consisting of 1 to 3 nitrogen atoms, 0 to 1 oxygen atom, 0 to 1 sulfur atom and carbon atom. For example, pyrrolidinyl, piperazur, piberidyl, morpholinyl, thiomolholiel, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, piperazur, imidazolidinyl, 4,5 -Dihydro-1H-imidazolyl, thiazolidinyl, hexahydropyrimidinyl, 1,4,5,6-tetrahydropyrimidiel, 3,6-dihydro_2H—1,3,5-oxadiazinyl, 4,5,6 , 7-tetrahydro-1H-dazebul, tetrahydrofuryl and the like.

Examples of the substituent for the `` optionally substituted alkynole group '' in RR ³ , R ⁴ and the R group described below include, for example, any group included in each of the following groups a) to c), and these are optional. May be replaced by one or more.

a): a halogen atom, a cyano group, a hydroxyl group, a carboxy group, an optionally substituted diamino group, an optionally substituted rubamoyl group, an optionally substituted sulfamoinole group, and an optionally substituted Aryl group, an optionally substituted aromatic heterocyclic group, or an optionally substituted aliphatic heterocyclic group, b): a cycloalkyl group, a cycloalkyloxy group, or a cycloalkyloxycanolevounole group,

 [Each group in this group is substituted with one to three groups selected from a halogen atom, a hydroxyl group, a carboxy group, an alkyl group, a haloalkyl group, an anoreoxy group, a haloalkoxy group, and an alkoxycarbonyl group. Good

 c): an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an alkylthio group, an alkylcarbonyl group, an alkylcarbonyloxy group, or an alkyl snolephoninole group,

 [Each group in this group may be substituted with a halogen atom, a hydroxyl group, a carboxy group, an alkoxy group, a haloalkoxy group, or an alkoxycarbonyl group. Further, the active group may be protected with a protecting group. For example, the hydroxyl group may be protected with a usual protecting group such as a tetrahydrovinyl group or a trialkylsilyl group. Such protecting groups can be introduced and removed according to known methods (see, for example, Theodora W. Green, rotative Groups in Organic synthesis, John Wiley & Sons (issued in 1981))].

 Examples of the substituent of the “optionally substituted cycloalkyl group” include the substituents in the group (b) in the substituents of the above alkyl group, that is, a halogen atom, a hydroxyl group, a carboxy group, an alkyl group, Examples thereof include a haloalkyl group, an alkoxy group, a non-alkoxy group, and an alkoxycarbonyl group, which can be substituted with 1 to 3 of these.

 Examples of the substituent in the aryl group, the aromatic heterocyclic group, and the aliphatic heterocyclic group include, for example, any group included in each of the following groups a) to c). May be replaced.

 a): halogen atom, cyano group, nitro group, hydroxyl group, carboxy group, optionally substituted amino group, optionally substituted rubamoyl group, or substituted b): cycloalkyl group, cycloalkyloxy Group, or cycloalkyloxycanoleboninole group,

[Each group in this group includes a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, May be substituted with one to three groups selected from an alkyl group, an alkoxy group, a haloalkoxy group, and an alkoxycarbonyl group]

 c): an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an alkylthio group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkylsulfinyl group, or an alkylsulfonyl group,

 [Each group in this group may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group, or an alkoxycarbonyl group.] The above alkyl group, cycloalkyl group, aryl group, and aromatic group Among the substituents of the heterocyclic group and the aliphatic heterocyclic group, the substituents other than those described above respectively mean the following.

 The halogen atom is fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

 The optionally substituted amino group is an amino group, for example, an amino group in which a plurality of the same or different substituents described in a) or b) below are independently substituted.

 a) an alkyl group, an alkylcarbonyl group, an alkylsulfonyl group, or an alkoxycarbonyl group;

 [Each group in this group is selected from a halogen atom, a cyano group, a hydroxyl group, a formyl group, an amino group, an alkylamino group, an alkoxy group, a noloalkoxy group, a cycloalkyl group, an aliphatic heterocyclic group, and the like. May be substituted with

 b) amidino group.

 Specific substituted amino groups include acetoamide, propionamide, butylamide, 2-butylamide, methylamino, 2-methyl-1-propylamino, 2-hydroxyxethylamino, 2-aminoethylamino, dimethylamino , Methylamino, methyl carbamate, ureido, methanesulfonylamino, guanidino and the like.

Examples of the substituent in the optionally substituted sulfamoyl group or the optionally substituted sulfamoyl group include an unsubstituted alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, a haloalkoxy group, a carboxyl group, and an alkoxycarbonyl group. And an alkyl group substituted with a group selected from the group consisting of the same or different groups, and the same or different plural groups may be independently substituted.

 Specific examples of the substituting rubamoyl group include ethylcarbamoyl, dimethylcarbamoyl and the like. Specific examples of the substituted sulfamoyl group include ethylsulfamoyl and dimethylsulfamoyl.

 The cycloalkyl group represents a oxy group to which the above-mentioned alkyl group is bonded, and the alkyloxycarbonyl group is a carbonyl group to which the alkyloxy group is bonded.

 A haloalkynole group represents an alkyl group substituted with 1 to 5 halogen atoms. Preferably, it represents an alkyl group substituted with 1 to 3 halogen atoms. Specific examples include trifluoromethyl, 2-trifluoroethyl, 2-chloroethyl and the like.

 The alkoxy group represents an oxy group to which the alkyl group is bonded. Specifically, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 2-butoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 2-pentoxy, 3-pentoxy, 2-methylbutoxy, Examples thereof include 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 3-methynolebutoxy, hexoxy, 2-hexoxy, 31-hexoxy, 2-methylpentoxy, 3,3-dimethylbutoxy and the like.

 The haloalkoxy group represents the above-mentioned alkoxy group substituted with 1 to 5 halogen atoms. Preferably, it represents an alkoxy group substituted with 1 to 3 halogen atoms. Specific examples include trifluoromethoxy, 2-trifluoroethoxy, 2-chloroethoxy, and the like.

 The alkoxycarbonyl group represents a carboxy group to which the above-mentioned alkoxy group is bonded. Specifically, methoxycarbonyl, ethoxycanolepo-norre, propoxycanolebonyl,

2-propoxycarbonyl, butoxycarbonyl, 2-butoxycarbonyl, 1,1-dimethylethoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, 3,3-dimethylbutoxycarbonyl and the like.

Alkylthio, alkylcarbinole, alkylcarbonyloxy, al The term “alkylsulfonyl group” refers to a thio group, a carbonyl group, a carboxy group, a sulfol group or a sulfyl group to which the above-mentioned alkyl groups are bonded, respectively. Specific examples of the carbonyl group include acetinol, propanoyl, 2-propanol, butanol, 2-ptanoyl, pentanoyl, bivaloyl, hexanoyl, and the like. Specific examples of the alkylsulfonyl group include methanesulfonolene, ethanesnorehol Ninore, propane snolephoninole, butanesulfonyl, 2-propanesulfonyl and the like.

 The polymer-supported arylsilane compound (e) of the present invention is produced by a method represented by the following reaction formula 11.

Reaction formula 1

P d catalyst

2. Organic lithium, etc.

(II)

(I)

(In the formula, R ^x and RY are each independently an alkyl group or a phenyl group, provided that R ^x and R ^Y are not both alkyl groups. Other symbols are as defined above.)

 That is, disilanyl ether (II) is first heated in a nonpolar organic solvent such as benzene, toluene, or xylene in the presence of a palladium catalyst for 1 to 15 hours. This reaction is preferably performed in an inert atmosphere such as dry nitrogen or argon, and the reaction temperature is between 50 ° C and the boiling point of the solvent. The amount of the palladium catalyst used is desirably 0.5 to 10 mol% based on the disilyl ether. This results in intramolecular bissilylation.

The intramolecular bissilylated product generated by the above reaction is converted to the desired arylsilane compound by continuing the heating. Instead of continuing this heating, As a method for deriving an arylsilane compound at a high yield under mild conditions, a polymer supporting the produced intramolecular bissilyl iridone is collected by filtration, and then THF, ethynoleethenol, dioxane, 2-methynoletetrahydrofuran, diethyleneglycol Add organic lithium or alkali metal alkoxide in an organic solvent such as dimethyl ether or dimethyloxetane, and react at 178 ° C to room temperature for 30 minutes to 5 hours. In this reaction, a fluorine aion can be used in place of the organic lithium or the alkali metal alkoxide. In this case, in addition to the above, aceto nitrile and DMF can also be used as the solvent. The reaction temperature is from about 78 ° C to the boiling point of the solvent, preferably from 0 ° C to 50 ° C. Thus, the desired polymer-supported arylsilane compound (I) is obtained.

The palladium (Pd) catalyst used in the above method is an isocyanide palladium complex prepared by mixing a zero-valent or divalent palladium compound with a tertiary alkyl isocyanide or an aromatic isocyanate. . Examples of the tertiary alkyl isocyanide include tert-butyl isocyanide, 1,1,3,3-tetramethynoleptinole isocyanide, 1-adamantyl isocyanide and the like. Examples of the aromatic isocyanide include 2,6-xylyl isocyanide. Examples of the palladium compound include palladium acetate and palladium acetate acetate (P d (acac) ₂ ), which may optionally have acetonitrile, benzonitrile, or the like as a ligand. Furthermore, Shioi匕_{palladium, P d C 1 2 (C} 6 H 5 CN) 2, P dC 1 2 (H 2 NCH 2 CH 2 NH 2), Pd 2 (C 6 H 5 C

11 = J11-〇 (0) —J ^ 1 = J11. ₆ 11 ₅ ) Other palladium compounds such as ₃ can also be used.

Examples of the organic lithium include a lithium compound of a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, such as methynolelithium, ethynolelithium, and n_butyllithium, and phenyllithium. In addition, alkali metal alkoxides such as sodium t-butoxide and potassium t-butoxide can be used instead of the organic lithium. Fluorine anion means a fluorine compound having an alkali metal or ammonium as a counter cation, for example, potassium fluoride, sodium fluoride, cesium fluoride, ammonium fluoride, tetrabutylammonium fluoride Etc. are examples It is.

 These organolithium, alkali metal alkoxide and fluorine anion are used in an amount of 1.0 to 2.0 mol per 1 mol of the disilenyl ether conjugate (II).

The starting material disilyl ether ether conjugate (II) used in the above reaction formula 11 is produced by the method shown in the following reaction formula 12. In the following formula, for convenience, the linker (L) is-(CH ₂ ) ₄ _, R ^A and R ^B are ethyl (E t), R ^x and R ^Y are feninole (Ph). Show.

Anti Formula 1 2

R ³ R '

 I I

 Et Ph HO-C-CH = CH (6)

 AcCI I

R CH ₂ ) ₄ -Port-CI

 Et Ph

 (Five)

Et Ph R ^d R ¹

Et Ph R '

 (11-1)

 (Wherein each symbol is the same as above)

That is, a commercially available polymer-supported hydrosilane (1) is converted to a chlorosilane compound (2) according to a method known in the literature (Y. Hu et al., J. Org. Chem., 1998, 63, 4518-4521). For example, 1,3-dichloro-5,5-dimethylhydantoin is added to a polymer-supported hydrosilane (1) in an organic solvent such as 1,2-dichloroethane, dichloromethane, and dimethyl ether, and the mixture is allowed to react at room temperature to heating for several hours. To the silane compound (2). The chlorosilane compound (2) is reacted with a substituted silyllithium (3) such as (getylamino) diphenylsilyllithium in an organic solvent such as tetrahydrofuran (THF), getyl ether, dimethyloxetane, hexane, etc. The reaction was conducted at a temperature for several to several tens of hours to lead to a disilyl compound (4). Then, the mixture was treated with acetyl chloride in the same reaction vessel and filtered to obtain a polymer-supported disilane compound (5). Can be

The polymer-supported chlorodisilane compound (5) is added to an organic solvent such as dichloromethane, 1,2-dichloroethane, THF, acetonitrile, DMF or the like in the presence of an amine such as imidazole, triethylamine, or 4-dimethylaminopyridine. By reacting the lilcohol (6) with the mixture for several hours at room temperature to under heating for several hours, L = — (CH 2 ₂ ) ′ 4 R A-

R ^B = E t, R ^x = R ^Y = Ph).

 As the polymer-supported hydrosilane (1) as a starting material in the above reaction formula 12, a commercially available product (for example, a polystyrene-bonded silane manufactured by Anorrego Note Technology Co., Ltd.) may be used as it is, and other corresponding polymer-supported hydrosilanes include, for example, It is easily manufactured by the method shown in Reaction Formula-3 below.

Reaction Scheme 1 3 Chloromethylation

 (7) (8)

R ^A R ^B SiH (11)

(式中、 Mは L iまたは Mg X(X = C 1、 B rまたは I )、 m=n— 4、 他の記 号は前記に同じ） Rh catalyst

(Where M is Li or Mg X (X = C1, Br or I), m = n—4, and other symbols are the same as above)

 That is, a polymer carrier obtained by chloromethylation (8) (Experimental Chemistry Lecture (Maruzen), 3rd edition, 19-1 vol., 257, 331) is used as a starting material, and ω-unsaturated alkyllithium or ω- The unsaturated alkyl magnesium halide (1) is reacted (J. Org. Chem., 1998, Vol. 63, 4518-4521) to obtain a polymer compound (10) having an ω-unsaturated alkyl chain. Further reaction with a silane compound (11) in the presence of a rhodium catalyst gives a polymer-supported hydrosilane (12) (J. Org. Chem., 1998, Vol. 63, 4518—4521).

 As the chloromethylated polymer carrier (8), a commercially available Merrifield's resin may be used as it is.

Examples of the rhodium (Rh) catalyst used in the above method include RhC 1 (PPh ₃ ) ₃ .

 When an optically active aryl alcohol is used as the reactant aryl alcohol (6) in the method shown in the above reaction formula 12, a polymer-supported optically active aryl silane compound (I) is obtained, which is a polymer having a high optical purity. It is held on a carrier. By reacting the polymer-supported optically active arylsilane with various aldehydes, ketones, acetals, ketanoles, etc., the corresponding homoallyl alcohols, homoallyl ethers, etc. can be obtained in a highly stereoselective manner. The polymer-supported arylsilane of the present invention is also very useful as an optically inactive reagent. In addition to the above reaction substrates, α, jS-unsaturated aldehydes, α,] 3-unsaturated ketones, etc. To give a δ, ε-unsaturated carbonyl derivative. Therefore, the polymer-supported arylsilane compound (I) of the present invention is useful as a solid phase-supporting reagent for producing various compounds useful as various pharmaceuticals and the like.

The case where the polymer-supported arylsilane compound (I) of the present invention is subjected to a reaction with an aldehyde is shown below as an example. Reaction formula 1 4

 (I)

R 1 R ³ OH

 HC = CH-C— CH-R

R ⁴

 (IV)

 (In the formula, R is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocycle, Other symbols are the same as above.)

 The reaction of the above reaction formula _4 is performed in a non-protonic solvent, for example, methylene chloride, 1,

It can be performed in 2-dichloroethane, carbon tetrachloride, toluene and chlorobenzene. When a fluorine anion is used instead of a Lewis acid, tetrahydrofuran, methyl alcohol, dioxane, or acetonitrile may be used as a solvent. In the reaction, the polymer-supported arylsilane (I) and the aldehyde are mixed in these solvents, and the reaction temperature is from 100 to the boiling point of the solvent, preferably from 178 ° C to room temperature. It can be carried out by adding a Lewis acid or fluorine anion. After completion of the reaction, a usual post-treatment method, for example, filtration of the insoluble polymer, removal of the Lewis acid perfluoroanion by washing the organic layer with water, and removal of the organic solvent yields the desired homoaryl. Alcohol (IV) can be obtained.

 Examples of the Lewis acid used in the above method include aluminum chloride, titanium tetrachloride, tin tetrachloride, or those obtained by substituting part or all of the halogen with a lower alkoxide, magnesium bromide, antimony pentachloride, and trimethylsilyl. Triflate, boron trifluoride atheno-isomer, and the like. Examples of the fluorine anion used in place of the Lewis acid include lithium fluoride, cesium fluoride, and tetrabutylammonium fluoride.

The polymer-supported arylsilane of the present invention is not limited to the reaction with the aldehyde, It can adapt to reactions with various substrates. For example, the reaction with ketone reacts with homoaryl alcohol, reacts with acetal or ketal, reacts with homoallyl ether, or reacts with a, j8-unsaturated aldehyde (or ketone) to form the corresponding Michael adduct. (Silicon Reagents for Organic Synthesis, p. 173-205, author; William P. Weber, publisher; Springer-Verlag, publication year; 1983). In the polymer-supported aryl silane compound of the present invention, by using an optically active substance as a raw material, it is converted into aryl silane by a reaction on the polymer carrier, and the asymmetric center is transferred to the silicon-directed carbon. Since the asymmetric center is transferred to the product of the reaction with the aldehyde, it is advantageously used for producing an optically active compound having high optical purity.

 The conversion of this asymmetric center can be shown by the reaction using a specific arylsilane as shown in the following reaction formula-5.

 (twenty five)

 (11-1 '(1-1')

 (IV-1,)

(Wherein each symbol is the same as above) As shown in Reaction Scheme 15 above, when optically active aryl alcohol (6 ′) (having an asymmetric carbon at the base of the alcohol) is used, the asymmetric center is the aryl silane (I-I) in the reaction on the carrier polymer. It is converted to 1 ') and transferred to the chiral center of the root. In turn, this asymmetric center is converted to the product (I v_) resulting from the reaction with the aldehyde.

 Further, in the polymer-supported aryl silane compound of the present invention, depending on the arrangement of the olefin of the optically active aryl alcohol used as the reactant, for example, the force of using the one in which the aryl alcohol (6 ′) in the above-mentioned reaction formula-5 is in a positive arrangement is used. Depending on whether or not the 配置 -configuration is used, the resulting aryl silane is obtained by inverting the absolute coordination of the silicon root. These are shown below as partial structures.

R ³

 , Si

Ph ₂ R3 SiR ^A R ^B

R ^A R ^B Si ヽ R ³ R ¹

 ヽ Si

Ph ₂ ³ R ¹ SiR ^A R ^B

EXAMPLES All reactions were performed under a nitrogen atmosphere under magnetic stirring. Column chromatography was performed using silica gel 60 (75-150 mesh, Kogel). And ¹³ C NMR spectra were recorded on a Varian Gemini 2000 (Varian Gemini 2000, 300 MHz, ¹³ C, 75 MHz) spectrometer using the residual deuterium peak of the solvent as an internal standard. High-resolution mass spectra were recorded on a J EOL JMS-HX 110 A (FAB) or J EOL JMS-SX 102A (EI) spectrometer.

Among the various reaction reagents used in the examples, 1,1,3,3-tetramethylbutyl isocyanide 1,1-jetoxyheptane was synthesized by a method described in the literature. (Jethylamino) diphenylsilyllithium was also synthesized by the method described in the literature. The optically active (R) -aryl alcohol (compound of formula (6 ')) can be converted from the corresponding racemate using (L)-(+)-diisopropyltartaric acid using Ti (OPr-i) _4. ~ 1 2 Obtained by performing Sharpless Kinetic Resolution at 0 ° C. These enantiomeric excesses were determined by HP LC after induction to the corresponding N_ (3,5-dinitrophenyl) force (Sumichiral / SUMICHIRAL ™ OA — 4500, 1,2 diketone roetane Z ethanol = 50/15/1 or 15/5 no 1).

Example 1

 (1) Synthesis of polysilane-supported disilane (reaction formula 1-2, compound of formula (5))

 A suspension of polystyrene-supported hydrosilane (1) (5.6 g, 8.9 millimono) in methylene chloride (801111) was added to 1,3-dichloromethane_5,5-dimethylhydantoin (5.2 g,

26 mmol) at room temperature and the mixture was stirred at room temperature for 5 hours. After filtration under a nitrogen atmosphere, the resin was washed with methylene chloride (10 Om 1 X 3) and tetrahydrofuran (100 m 1 X 4), and dried under vacuum to obtain chlorosilane (2) supported on polystyrene. The resin was suspended in tetrahydrofuran (80 ml), and (Jetylamino) diphenylsilyl, which had just been synthesized from chloro (diethylamino) diphenylsilane (7.7 g, 26 mmol) and lithium (0.75 g, 109 mmol). A solution of lithium in tetrahydrofuran (70 ml) was prepared at room temperature. The mixture was stirred at room temperature for 10 hours, filtered, washed with tetrahydrofuran (10 Oml X 5), and suspended in tetrahydrofuran (7 Oml). Acetyl chloride (2.5 ml, 35 mmol) was added to the suspension cooled to 0 ° C at 0 ° C, and the mixture was stirred at room temperature for 5 hours. In order to perform quantitative analysis of N, N-dimethylacetamide (983 mg, 8.5 mmol, 96%) generated in the reaction system by GC, dodecane (84 Omg) was suspended as an internal standard. Added to the suspension. After filtration under a nitrogen atmosphere, the resin was washed with dimethylformamide (10 Oml X 3) and tetrahydrofuran (10 Om 1 X 4), dried in vacuo, and polystyrene-supported chlorodisilane (5) (1.14 mmol Zg) I got

(2) Polystyrene-supported optically active disilyl ether (reaction formula 15, formula (I 1 -1 ′) Synthesis of compound c)) (using optically active (R) coal (6,1c))

 (11-1, C)

A mixture of chlorodisilane (5) (1.0 g, 1.14 mmol) and imidazole (283 mg, 4.16 mmol) in methylene chloride (10 m 1) was mixed with an optically active (R) -arinole alcohol (Table 1) shown in Table 1 below. 6,1c) (1.18 mmol) was added at room temperature and the mixture was stirred at room temperature for 10 hours. Then, methanol (2 ml) was added to the mixture. After stirring for 1 hour, the mixture was filtered, and ether (5 m 1 X 2), tetrahydrofuran (5 m 1 X 2), tetrahydrofuran aqueous solution (50%, 5 m 1 X 2), ethanol (10 m 1 X 2), The residue was washed with tetrahydrofuran (1 Oml X 2), and dried in vacuo to obtain polystyrene-supported disilanylyl ether (I1-1 '). The yield of this compound was quantified by GC quantitative analysis of the filtrate containing the collected aryl alcohol. By GC quantitative analysis using tetradecane as an internal standard, 0.92 mmol of allylic alcohol (6 ′-() was bound to the resin and the corresponding disilanyl ether (II-I'c) (1.16 g, 0.79 mmol / g) These results indicated that 80% of the chlorodisilane on the polymer support had reacted with the alcoholic compound. The load was double-checked by treating with pyridine and measuring the starting aryl alcohol (6'-c) produced by the cleavage of the 31-0 bond. To a suspension of 10 2 mg) in tetrahydrofuran (1 ml) was added hydrogen pyridine-monopyridine (3 M solution in tetrahydrofuran, 0.5 ml), and the mixture was treated at room temperature for 7 hours. Add silane (1.5 m 1) at room temperature . After stirring for 10 hours, the mixture was filtered, the filtrate was GC quantitative analysis, 1 of the material of § Lil alcohol (6 '_c) It was found that 6 mg (0.080 mmol) had been released. The load calculated by this method (0.78 mmol Zg) is in good agreement with the yield obtained above (0.79 mmol Zg).

 In the above method, the optically active (R) -aryl alcohol (6, 1a) and the optically active (R) -aryl alcohol (6, 1a) shown in Table 1 below are used instead of the optically active (R) -aryl alcohol (6, 1c) as a reactant. By using (6′-b), a polymer-supported optically active disilanyl ether (I 1-1 ′ &) (11-1 ′ b) is obtained, respectively.

 The loading ratio of aryl alcohol to the resin and the optical purity of the product in the above reaction product are as shown in Table 1 below (the optical purity of the product is considered to be the same as the optical purity of the alcohol used). Is).

 Synthesis of I-1 'c)

Pd (acac) ₂ (15 mg, 0.05 mmol) was added to a suspension of disilyl ether (II-I'c) (1.06 g, 084 mmol) obtained in (2) above in toluene (1 Om1). And a solution of the catalyst obtained from 1,1,3,3-tetramethynolebuty / leisocyanide (66 mg, 0.38 mmol) in tetrahydrofuran (0.25 ml) was added, and the mixture was stirred under reflux for 5 hours. After distilling off the solvent in vacuo, tetrahydrofuran (13 ml) was left. Added to the residue. After cooling to 0 ° C., n-butyllithium (1.54 M hexane solution, 2.2 ml, 3.4 mmol) was added to the mixture, and the mixture was stirred at 0 ° C. for 1 hour and then 0. (The reaction was stopped by adding ethanol (5 ml) at (:). After filtration, the resin was ethanol (10 ml 1 × 2), water (1 Oml), tetrahydrofuran aqueous solution (50%, 10 ml), tetrahydrofuran (10 ml ) And ethanol (1 Om 1) Washed The suspension of ethanol (12 ml) and tetrahydrofuran (6 ml) was washed with p-toluenesulfonic acid (monohydrate, 60 mg, 0.32 ml). Mmol), and the mixture was stirred for 5 hours at 55 ° C. After filtration, the resin was filtered using ethanol (1 Oml × 2), tetrahydrofuran (10 ml × 2), methylene chloride (1 Om 1 × 2). And dried in vacuo to give polystyrene-carrying acrylylsilane (I-l, c) (0.79 g), which converts disilanyl ether to arylsilane with 100% efficiency and 100% recovery. Therefore, it is estimated that the maximum loading of arylsilane on resin is 1.05 mmol Z g. That.

Example 2

Polystyrene-supported arylsilane (I-1, a) (where L = one (CH ₂ ) ₄ —, R ^A , R ^B = Et, R ^ PR ³ = Me, R ⁴ = H) and aldehyde Reaction of compound

(1-1, a)

Polystyrene-supported arylsilane (I-l, a) (101 mg, 0.097 mmol) obtained in the same manner as in Example 1 above (excluding the step of treating with p-toluenesulfonic acid for deprotection of the tetrahydrovinyl group). methylene chloride (2 m 1) suspension § acetaldehyde (1. 1 X 10 one ² m 1, 0.20 mmol) and Yonshioi匕titanium ^{(2. 1 X 10- 2 ml,} 0. 19 mmol) At -78 ° C and the mixture is -78. The mixture was stirred at C for 0.5 hour. After filtering the reaction solution, water was added, the organic matter was extracted with ether, and the filtrate was dried, filtered, and evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane / ether = 4/1 to 2/1) to give homoaryl alcohol. Cole (in formula (IV), I ^ PlR = Me) [9.2 mg, yield: 54% (total from disilenyl ether, the same applies hereinafter)] was obtained.

 Thin Z anti ratio = 96: 4, optical purity: 98.6% e e.

_{NMR (CDC1 3) δ: 1.14} (d, J = 6.8Hz, 3H), 1.20 (d, J = 6.2Hz, 3H), 1.48 (d, J = 6.2Hz, 1H), 2.42 (ddq, J = 8.0 , 6.2, 6.8Hz, 1H), 3.77 (sextet,

J = 6.2Hz, 1H), 6.17 (dd, J = 16.0, 8.0Hz, 1H), 6.46 (d, J = 16.0Hz, 1H), 7.16-7.42 (m, 5H).

Examples 3 and 4

In the above Example 2, except that heptanal or isobutyraldehyde was used instead of acetoaldehyde as the aldehyde compound to be reacted, (E) -3-methyl-11-phenyl-2-decene was used, respectively. _ 4-all (in the formula (IV), R ^X = P h, R = n-hexyl) or (E) _ 3,5-dimethyl-1- 1-pheninole 1-hexene _4-—onole (formula In (IV), Ri Pl R = isopropyl) was obtained. The physical properties and the like of these compounds are shown below.

(E) _ 3—Methinole 1—Phenyl 1 1—Decene _ 4—Onolle:

 Yield: 44%, Syn Z anti ratio = 93: 7, Optical purity: 99.0% e e.

 ¾ NMR (CDCI3) δ: 0.88 (t, J = 6.9Hz, 3H), 1.13 (d, J = 6.9Hz, 3H), 1.18-1.66 (ra, 11H), 2.37-2.51 (m, 1H), 3.50 -3.61 (m, 1H), 6.1.9 (dd, J = 15.9, 7.8 Hz, 1H), 6.44 (d, J = 15.9 Hz, 1H), 7.18-7.25 (m, 1H), 7.27-7.41 (m , 4H)

¹³ C NMR (CDCI3) δ 14.0, 14.9, 22.5, 26.0, 29.3, 31.8, 34.2, 43.1, 75.3, 126.1, 127.2, 128.6, 130.4, 132.8, 137.5

Elemental analysis: as C ₁₇ H ₂₆ O, theoretical value, C, 82.87, H, 10.64 ; real Hakachi, C, 82. 70, H, 10.84

(E) _ 3, 5—Dimethinole 1—Feninole 1—Hexene — 4—Onole:

 Yield: 40. Thin Z anti ratio = 97: 3, Optical purity: 93.0% e e.

¾ NMR (CDCI3) δ: 0.95 (d, J = 6.8 Hz, 6H), 1.14 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 5.0 Hz, 1H), 1.81 (octet, J = 6.8) Hz, 1H), 2.42-2.62 (m, 1H), 3.21-3.34 (m, 1H), 6.16 (dd, J = 16.0, 7.6Hz, 1H), 6.43 (d, J = 16.0Hz, 1H), 7.15-7.41 (m, 5H)

Example 5

Polystyrene-supported arylsilane (I-1, b) (wherein L = — (CH ₂ ) ₄ —, R ^A , R ^B = Et, R ¹ ^ !! — hexyl, R ³ = Me, R ⁴ = H) with isoptyl aldehyde

(1-1, b) A suspension of polystyrene-supported arylsilane (I, l, b) (100 mg, 0.10 mmol) in methylene chloride (2 ml) was treated with isobutyraldehyde (9.5 x 10-1). ³ m 1, 0. 11 mmol) and Yonshioi匕titanium (2.2X 10 one ² m 1, 0.20 mmol) was added in one 78 ° C, the mixture was stirred for 2 hours at one 78. The mixture was filtered through an aqueous solution of sodium hydroxide with a Celite (registered trademark) pad, the organic matter was extracted with ether, the filtrate was dried, filtered and evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane ether = 8-1) to give (Ε) -2,4-dimethyl-5-dodecene-13-ol (homoallyl alcohol (formula (IV); ¹ ^ !!-hexyl, R ³ = Me, R ⁴ = H, R = isopropyl)) (7.3 mg, yield: 34%). Thin Z anti-ratio = 99: 1, optical purity: 95.6% ee.

_{¾ NMR (CDC1 3) δ 0.87} (ΐ, J = 6.9Ηζ, 3Η), 0.907 (d, J = 6.6Hz, 3Η), 0.914 (d, J = 6.6Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 1.16-1.40 (m, 9H), 1.76 (octet, J = 6.6Hz, 1H), 2.00 (q, J = 6.9Hz, 2H), 230 (sextet, J = 6.9Hz, 2H), 3.07- 3.16 (m, 1H), 5.34 (dd, J = 15.3, 6.9Hz, 1H), 5.47 (dt, J = 15.3, 6.9Hz, 1H)

_{^{13 C NMR (CDC1 3) δ}} 14.0, 14.3, 16.9, 19.6, 22.5, 18.7, 29.4, 30.3, 31.6, 32.6, 39.6, 79.9, 131.0, 133.2

Elemental analysis: as C ₁₄ H ₂₈ O, theoretical, C, 79. 18, H, 13. 29; real Hakachi, C, 78.88, H, 13.07

Example 6 Reaction of polystyrene-supported arylsilane (I-1, c) with phenol

 (1-1 '0

 A suspension of polystyrene-supported arylsilane (I-l'c) (100 mg, 0.15 mmol) in dimethylene chloride (2 ml) was treated with n-heptanal (n-HeHe-CHO) (1.05 Millimono) and trimethinoresili 7-retiflate (2.1 mmol) were heated at 178 ° C, and the mixture was stirred at 178 ° C for 2 hours. The mixture was filtered and the filtrate was collected directly in 1M aqueous sodium hydroxide. The mixture was extracted with ether, and the solvent was distilled off to obtain almost pure oxasik-heptene. This was further purified by silica gel column chromatography to obtain the following compound.

2-hexynole-3-methinole 2,3,6,7-tetrahydroxepin:

 Yield: 64%, trans / cis ratio = 92: 8, optical purity: 97.9% ee.

_{Ή NMR (CDC1 3) δ 0.87} (t, J = 6.9Hz, 3H), 0.98 (d, J = 7.2Hz, 1H), 1.15- 1.61 (m, 10H), 2.12-2.25 (ra, 1H), 2.27 -2.43 (m, 2H), 3.07 (dt, 1 = 2.4, 8.4Hz, 1H), 3.43 (ddd, J = 3.0, 9.3, 11.7Hz, 1H), 4.03 (dt, J = 11.7, 4.5Hz, 1H ), 5.39-5.48 (m, 1H), 5.61—5.74 (ra, 1H)

¹³ C NMR (CDCI3) δ 14.8, 18.8, 22.6, 25.5, 29.4, 31.6, 31.8, 34.2, 41.5, 69.7, 84.7, 127.7, 137.4

HRMS: as _{C 13 H 24 O (M +} ), theoretical, 1 9 6.1 8 2 7; Found, 1 9 6.1 8 2 8.

Example 7

In Example 6 above, n-heptanal getyl acetal (n-Hex-CH (OEt) ₂ ) was used in place of n-heptanal as a reactant, and the reaction was carried out in the same manner. The same compound was obtained.

 Yield: 67%, trans Z cis ratio = 93: 7, optical purity: 97.9% ee.

Example 8 ' The following compounds were obtained by the same reaction as in Example 6 except that acetoaldehyde was used instead of n-heptanal as a reactant.

2,3-dimethyl-2,3,6,7-tetrahydroxepin:

Yield: 70%, trans Z cis ratio = 91: 9, optical purity:> 97.2% ee. _{¾ NMR (CDC1 3) δ 0.98} (t, J = 7.5Hz, 3H), 1.19 (d, J = 6.3Hz, 3H), 2.08-

2.21 (m, 1H), 2.23-2.47 (m, 2H), 3.22 (dq, J = 8.7, 6.3Hz, IH), 3.45 (ddd, J = 12.3, 10.2, 2.7Hz, 1H), 4.02 (ddt, J = 12.3, 0.9, 4.2Hz, 1H), 5.43 (dt, J = 11.4, 3.0Hz, IH), 5.69-5.77 (m, IH)

¹³ C NMR (CDCI3) δ 19.1, 21.0, 31.7, 42.8, 69.8, 81.1, 128.5, 137.5 HRMS: as C ₈ H ₁₄ O (M ⁺ ), theoretical value, 126.1045;

6. 1041.

Example 9

 In the above Example 6, the same reaction was carried out using cyclohexanealdehyde instead of n-heptanal as a reactant to obtain the following compound.

2-cyclohexyl 3-methyl-1,2,3,6,7-tetrahydroxepin: yield: 59%, trans cis-ratio: 91: 9, optical purity: 98.1% e e.

 NMR (CDCI3) δ 0.97 (t, J = 7.2Hz, 3H), 1.09-1.34 (m, 4H), 1.40-1.53 (m, 3H), 1.56-1.81 (m, 4H), 2.11-2.24 (m, IH), 2.27-2.42 (m, IH), 2.43- 2.60 (m, 1H), 2.92 (d, J = 9.3Hz, IH), 3.39 (ddd, J = 3.3, 9.3, 12.0Hz, IH), 4.02 (dt, J = 12.0, 4.5Hz, 1H), 5.41-5.51 (ra, IH), 5.59-5.72 (m, IH)

_{^{13 C NMR (CDC1 3) δ}} 18.4, 25.2, 26.5, 26.6, 26.7, 30.8, 31.5, 38.1, 40.0, 70.1, 88.8, 127.4, 137.8

HRMS: as _{C 13 H 22 0 (M +} ), theoretical values, 194.1671; Found, 1 94.1671.

Example 10

 The following compound was obtained in the same manner as in Example 6 except that benzaldehyde was used instead of n-heptanal as a reactant.

 3-Methyl-2-phenyl 2,3,6,7-tetrahydroxepin:

Yield: 70%, trans / cis ratio = 92: 8, optical purity: 98.1% ee. ¾ NMR (CDClg) δ 0.71 (t, J = 6.9Hz, 3H), 2.17-2.29 (m, 1H), 2.49-2.64 (m, 1H), 2.73-2.87 (m, 1H), 3.57 (ddd, J = 2.1, 11.1, 12.3Hz, 1H), 4.01 (d, J = 9.6Hz, 1H), 4.15 (dt, J = 12.3, 3.9Hz, 1H), 5.57 (dt, J = 12.0, 2.7Hz, 1H) , 5.79-5.89 (m, 1H), 7.23--7.38 (m, 5H)

_{^{1 3 C NMR (CDC1 3)}} δ 19.4, 31.9, 42.1, 70.6, 88.8, 127.0, 127.5, 128.4,

129.0, 137.3, 142.8

HRMS: as ^{_{C 13 H 16 0 (M +}} ), theoretical values, 188.1201; Found, 1 88.1207.

Example 11

 Example 1—The disilanyl ether (II-c) obtained in (2) (1.06 g, 0.

Pd (acac) ₂ (l 5 mg, 0.05 mmol) and 1,1,3,3-tetramethylbutyl isocyanide (66 mg, 0 mmol) were added to a suspension of toluene (1 Om1) in 84 mmol). (38 mmol) in tetrahydrofuran (0.25 ml) was added and the mixture was stirred under reflux for 5 hours. After the resin was collected by filtration, the resin was washed with toluene (1 Oml X 3) and tetrahydrofuran (1 Om 1 X 3). The obtained resin (102 mg) was reacted at −78 ° C. for 2 hours in dichloromethane in the presence of n-heptanal (0.011 ml, 0.079 mmol) and trimethinolesilyl triflate (0.027 ml, 0.15 mmol). As a result, the same tetrahydroxepin derivative as the product of Example 6 was obtained.

 Yield: 31%, trans cis ratio 82:18. Industrial applicability

 The polymer-supported arylsilane compound of the present invention, in particular, the polymer-supported optically active arylsilane compound, is subjected to a solid-phase reaction with various aldehydes, ketones, ketals, acetals, and other various conjugates to obtain a high optical purity homoallyl. It can produce alcohols, homoaryl ethers and the like in a highly stereoselective manner, and is useful as a solid-phase-supported reagent for producing compounds useful as various pharmaceuticals.

Claims

 General formula (I) (I)

In the formula, is a polymer carrier having a terminal phenyl group,  L is the linker, R ^A and R ^B are independently of each other alkenyl or phenyl, R ¹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted (It means aromatic heterocyclic group) A polymer-supported arylsilane compound represented by the formula: 2, —General formula (II):

(Wherein, i, L, R ^A , R ^B , RR ³ and R ⁴ are the same as described in claim 1, and R ^x and R ^Y independently represent an alkyl group or an aryl group. , R ^x and R ^Y are not both alkyl groups) Wherein the disilenyl ether compound represented by the general formula (I) is treated in the presence of a palladium catalyst: (I)

 (Wherein each symbol is the same as described in claim 1) A method for producing a polymer-supported aryl silane compound represented by the formula:  3. General formula (I): (I)

 (Wherein each symbol is the same as described in claim 1) In the presence of a Lewis acid or a fluorine anion, a polymer-supported arylsilane compound represented by the general formula (II)  R-CHO (I I I)  (In the formula, R represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aldehyde represented by the formula General formula (IV) characterized by R ¹ R ³ OH  (IV)  HC = CH-C— CH-R  Four  R ' (Wherein, R ¹ R ³ and R ⁴ are the same as described in claim 1, and R is the same as described above).