JP2002234911A - Polymer-carried allylsilane compound and its production method and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a highly stereoselective polymer-carried allylsilane compound which is suitable for the solid phase reaction with various compounds to produce an optically active compound, and its production method and use. SOLUTION: This allylsilane compound is represented by formula (1) (wherein the group at the left side of L is a polymer carrier; L is a linker; RA and RB are each an alkyl or phenyl group; and R1, R3 and R4 are each H or an optionally substituted alkyl, cycloalkyl, aryl, or aromatic heterocyclic group) and is prepared by causing a polymer carrier to carry an allylsilyl. This compound can produce various compounds by the solid phase reaction with aldehydes, ketones, etc., is suitable especially for producing an optically active compound, and is useful as a reaction material for medicines, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a polymer-supported allylsilane compound useful as various reaction materials, a method for producing the same, and use thereof. More specifically, the present invention provides a polymer-supported allylsilane compound in which an allylsilyl group is supported on a polymer carrier via a linker, and a method for producing the polymer.The polymer-supported allylsilane compound includes, in addition to various aldehydes, High optical purity homoallyl alcohols, homoallyl ethers, etc. can be produced by a solid phase reaction with various compounds such as ketones, ketals, acetals, etc. Useful as an intermediate for Thus, the invention also relates to the industrial use of the polymer-supported allylsilane compounds.

[0002]

2. Description of the Related Art In recent years, attention has been focused on solid-phase synthesis or the development of solid-phase-supported reagents for the purpose of rapid synthesis of various compound groups. However, research on solid-phase synthesis of optically active compounds, for which great demand is expected in the near future, has just begun. If an optically active reactant can be supported on a polymer, it is expected to be a useful solid-phase-supported reagent that can synthesize an optically active organic compound very simply and quickly.

It is known in conventional liquid phase reactions that allylsilanes are stable but react with cationic electrophiles (typically aldehydes activated with Lewis acids) with high regio- and stereoselectivity. (I. Fleming et
al., Organic Reactions (John Willey & Sons, In
c.), vol. 37, 57, 1989). In particular, when the optically active substance is used, the asymmetry of the allylsilane is very effectively transferred to the product to give an optically active compound. Such a property is
It is desirable to carry a polymer,
In 997, a solid support of optically active allylsilane was realized by Panek et al. Of the United States, and several allylation reactions have been studied (Panek, JS et al., J. Am.
Chem. Soc. 1997, 119, 12022-12023). However, their method is to add a hydroxyl group to the carbon chain of allylsilane, synthesize it by a liquid phase method, and then attach it to a polymer carrier, which not only imposes serious restrictions on the possible structure of allylsilane. Also, in the synthesis of allylsilane, there was no merit of simplification of the synthesis by solid-phase support.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have carried out various studies to directly support allylsilane on a solid phase and to obtain a solid phase-supporting reagent used for the synthesis of various optically active compounds by a solid phase method. As a result, they have found that a specific polymer-supported allylsilane compound in which allylsilane is bonded to a polymer carrier is suitable for the purpose. That is, an object of the present invention is to provide a novel polymer-supported allylsilane compound applicable to various asymmetric syntheses. Another object of the present invention is to provide a method for producing the polymer-supported allylsilane compound. Still another object of the present invention is to provide
An object of the present invention is to provide a use as a reaction material for reacting the polymer-supported allylsilane compound with various aldehydes and ketones by a solid phase method.

[0005]

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

Embedded image (Where

Embedded image Is a polymer carrier having a terminal phenyl ring, L is a linker, R ^A and R ^B are each independently an alkyl group or a phenyl group, R ¹ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted A cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aromatic heterocyclic group, R ³ and R ⁴ independently represent a hydrogen atom, an optionally substituted alkyl group, A cycloalkyl group which may be substituted, an aryl group which may be substituted, or an aromatic heterocyclic group which may be substituted)). The present invention has been found to be applicable to reactions with ketones and the like and is useful as various reaction materials, and has completed the present invention.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Each substituent in the polymer-supported allylsilane compound (I) of the present invention has the following meaning. The following formula:

Embedded image Examples of the polymer carrier represented by are polystyrene resins polymerized using divinylbenzene, resins composed of polyethylene glycol and polystyrene, and resins composed of polypropylene glycol and polystyrene as crosslinking agents.

The linker represented by the symbol L is represented by the formula:
An alkylene group represented by — (CH ₂ ) _n — (n = 1 to 10), such as tetramethylene, pentamethylene, and hexamethylene.

The alkyl group is, for example, one having 1 to 1 carbon atoms.
0 straight-chain or branched-chain alkyl groups.
Is methyl, ethyl, propyl, 1-methylethyl,
Chill, 1-methylpropyl, 2-methyl-1-prop
1,1-dimethylethyl, pentyl, 1,1-dimethyl
Propyl, 2,2-dimethylpropyl, 1-methylbut
Chill, 3-methylbutyl, hexyl, 2-methylpent
3,3-dimethylbutyl, heptyl, 1-ethylpe
Methyl, 5-methylhexyl, octyl, 1,5-dimethyl
Tylhexyl, 2-ethylhexyl, nonyl, decyl, etc.
Is mentioned. R ^A, R^B, R¹, R³And R⁴In
The preferred alkyl group is a linear alkyl group having 1 to 6 carbon atoms.
Or a branched alkyl group. More suitable a
As the alkyl group, a straight or branched chain alkyl group having 1 to 4 carbon atoms can be used.
Alkyl group.

The cycloalkyl group includes, for example, a cycloalkyl group having 3 to 6 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The aryl group includes, for example, those having 6 to 1 carbon atoms.
5 aryl groups, specifically, phenyl, 1-
Examples include naphthyl, 2-naphthyl, azulenyl, phenanthryl, anthryl and the like. Preferably, they are phenyl, 1-naphthyl, and 2-naphthyl.

Examples of the aromatic heterocyclic group include a 5- to 14-membered monocyclic group consisting of 1 to 3 nitrogen atoms, 0 to 1 oxygen atom, 0 to 1 sulfur atom and carbon atom; Examples include a bicyclic or tricyclic aromatic heterocyclic group. Specifically, furyl, thienyl, benzothienyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl , Triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,
Carbazolyl and the like.

The heterocyclic group in the optionally substituted heterocyclic group of the R group includes the following aliphatic heterocyclic groups in addition to the above aromatic heterocyclic rings. As the aliphatic heterocyclic group, 1 to 3 nitrogen atoms, 0 to 1 oxygen atom, 0 to 1
And a 5- to 7-membered monocyclic aliphatic heterocyclic group consisting of sulfur and carbon atoms, for example, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-di Oxothiomorpholinyl, piperazinyl, imidazolidinyl,
4,5-dihydro-1H-imidazolyl, thiazolidinyl, hexahydropyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, 3,6-dihydro-2H-1,3,
5-oxadiazinyl, 4,5,6,7-tetrahydro-
1H-diazepinyl, tetrahydrofuryl and the like.

Examples of the substituent of the "optionally substituted alkyl group" in the R ¹ , R ³ , R ⁴ and R groups include, for example, any group contained in the following groups a) to c). May optionally be replaced by one or more. a): a halogen atom, a cyano group, a hydroxyl group, a carboxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted aryl group, An aromatic heterocyclic group which may be substituted, or an aliphatic heterocyclic group which may be substituted; b): a cycloalkyl group, a cycloalkyloxy group, or a cycloalkyloxycarbonyl group, wherein each group in this group is 1-3 selected from a halogen atom, a hydroxyl group, a carboxy group, an alkyl group, a haloalkyl 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 or an alkylsulfonyl 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; Also,
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 tetrahydropyranyl group or a trialkylsilyl group. The method for introducing and removing such a protecting group is performed according to a known method (for example, "The Protective Group," by Theodora W. Green.
s in Organic Synthesis ", John Wiley & Sons (1981), etc.)].

The substituent of the "optionally substituted cycloalkyl group" includes, for example, the substituent in the group (b) in the above-mentioned substituents of the alkyl group, that is, a halogen atom, a hydroxyl group, a carboxy group, an alkyl group , A haloalkyl group, an alkoxy group, a haloalkoxy group or an alkoxycarbonyl group, which may be substituted by 1 to 3 of them.

Examples of the substituent in the aryl group, the aromatic heterocyclic group and the aliphatic heterocyclic group include the following a)
Any groups included in each group from (c) to (c) may be mentioned, and these may be optionally substituted by one or more groups. a): a halogen atom, a cyano group, a nitro group, a hydroxyl group, a carboxy group, an optionally substituted amino group, an optionally substituted carbamoyl group, or an optionally substituted sulfamoyl group, b): cycloalkyl Group, cycloalkyloxy group, or cycloalkyloxycarbonyl group, wherein each group in this group is selected from a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and an alkoxycarbonyl group 1-3
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 is
May be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group, or an alkoxycarbonyl group]

Among the substituents of the above-mentioned alkyl group, cycloalkyl group, aryl group, aromatic heterocyclic group and aliphatic heterocyclic group, the substituents other than those mentioned above respectively mean the following.

Halogen atoms include fluorine, chlorine, bromine,
Iodine, preferably fluorine or chlorine.

The amino group which may be substituted is an amino group and an amino group in which a plurality of the same or different ones of the following substituents a) or b) are independently substituted. a) an alkyl group, an alkylcarbonyl group, an alkylsulfonyl group, or an alkoxycarbonyl group, wherein each group in this group is a halogen atom, a cyano group, a hydroxyl group, a formyl group, an amino group, an alkylamino group, an alkoxy group, a haloalkoxy group , A cycloalkyl group, an aliphatic heterocyclic group or the like, and may be substituted with 1 to 3 groups.] B) an amidino group. Specific substituted amino groups include acetamido, propionamido, butylamido, 2-butylamido, methylamino, 2-methyl-1-propylamino, 2-hydroxyethylamino, 2-aminoethylamino, dimethylamino, diethylamino, methyl Carbamate, ureido, methanesulfonylamino, guanidino and the like.

Examples of the substituent in the optionally substituted carbamoyl 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 following, and a plurality of the same or different groups may be independently substituted. Specific examples of the substituted carbamoyl group include ethylcarbamoyl, dimethylcarbamoyl and the like. Specific examples of the substituted sulfamoyl group include ethylsulfamoyl and dimethylsulfamoyl.

The cycloalkyloxy group represents an oxy group having the cycloalkyl group bonded thereto, and the cycloalkyloxycarbonyl group represents a carbonyl group having a cycloalkyloxy group bonded thereto.

The haloalkyl group represents an alkyl group substituted with 1 to 5 halogen atoms. Preferably, 1-3
Represents an alkyl group substituted with halogen atoms. Specifically, trifluoromethyl, 2-trifluoroethyl, 2-chloroethyl and the like can be mentioned.

The alkoxy group represents an oxy group to which the above-mentioned alkyl group is bonded. Specifically, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 2-butoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 2-pentoxy, 3-pentoxy,
-Methylbutoxy, 1,1-dimethylpropoxy, 1,2
-Dimethylpropoxy, 3-methylbutoxy, hexoxy, 2-hexoxy, 3-hexoxy, 2-methylpentoxy, 3,3-dimethylbutoxy and the like.

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

The alkoxycarbonyl group represents a carbonyl group to which the above-mentioned alkoxy group is bonded. Specifically, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, butoxycarbonyl, 2-butoxycarbonyl, 1,1-dimethylethoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, 3,3-dimethylbutoxy Carbonyl and the like.

An alkylthio group, an alkylcarbonyl group,
Alkylcarbonyloxy group, alkylsulfonyl group,
And an alkylsulfinyl group means a thio group, a carbonyl group, a carbonyloxy group, a sulfonyl group and a sulfinyl group to which the above-mentioned alkyl groups are respectively bonded, and specific examples of the alkylcarbonyl group include
Acetyl, propanoyl, 2-propanoyl, butanoyl, 2-butanoyl, pentanoyl, pivaloyl, hexanoyl and the like are mentioned. Specific examples of the alkylsulfonyl group include methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, 2-propanesulfonyl and the like. No.

The polymer-supported allylsilane compound of the present invention
(I) is produced by a method represented by the following reaction formula-1.

Embedded image (Wherein each symbol is the same as above)

That is, the disilanyl ether (II) is
First, heating is performed for 1 to 15 hours in a nonpolar organic solvent such as benzene, toluene and xylene in the presence of a palladium catalyst. 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 disilanyl ether. This results in an intramolecular bissilylation. The intramolecular bissilylated product generated by the above reaction is converted into a desired allylsilane compound by continuing heating. Instead of continuing the heating, as a method of deriving the allylsilane compound in a higher yield under milder conditions, the polymer supporting the generated intramolecular bissilylated form is filtered, and then THF, diethyl ether, Organic lithium or an alkali metal alkoxide is added in an organic solvent such as dioxane, 2-methyltetrahydrofuran, diethylene glycol dimethyl ether, or dimethoxyethane, and the mixture is reacted at -78 ° C to room temperature for 30 minutes to 5 hours. In this reaction, a fluorine anion can be used instead of the organic lithium or the alkali metal alkoxide. In this case, acetonitrile and DMF can be used as the solvent in addition to the above. The reaction temperature is from −78 ° C. to the boiling point of the solvent, preferably from 0 ° C. to 50 ° C.
It is. Thus, the desired polymer-supported allylsilane compound (I) is obtained.

Palladium (Pd) used in the above method
The catalyst is an isocyanide-palladium complex prepared by mixing a zero- or divalent palladium compound with a tertiary alkyl isocyanide or an aromatic isocyanide. Examples of the tertiary alkyl isocyanide include tert-butyl isocyanide, 1,1,3,3-tetramethylbutyl isocyanide, 1-adamantyl isocyanide and the like. As aromatic isocyanides, 2,
6-xylyl isocyanide can be mentioned. Examples of the palladium compound include palladium acetate and palladium acetoacetate (Pd (acac) ₂ ), which may have acetonitrile, benzonitrile or the like as a ligand as appropriate. Further, palladium chloride, PdCl ₂ (C ₆ H ₅ CN) ₂ , PdCl ₂ (H
₂ NCH ₂ CH ₂ NH ₂ ), Pd ₂ (C ₆ H ₅ CH = CH
_{-C (O) -CH = CHC 6} H 5) can be other palladium compounds such as _3.

As the organic lithium, methyl lithium,
1-6 carbon atoms such as ethyllithium and n-butyllithium
And a lithium compound of straight or branched chain alkyl, phenyllithium. In place of the organic lithium, an alkali metal alkoxide such as sodium t-butoxide and potassium t-butoxide can be used.

The 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 and the like. Is done. These organic lithium, alkali metal alkoxide and fluorine anion are used in an amount of 1.0 to 1.0 mol per mol of the disilanyl ether compound (II).
2.0 moles are used.

The starting material disilanyl ether compound (II) used in the above reaction formula-1 is produced by the method shown in the following reaction formula-2. In the following formulas, for convenience, the linker (L) is ^{_{- (CH 2) 4 -,}} R A, R B is ethyl ^(Et), shown when R X, ^{R Y} is a phenyl (Ph).

[0032]

Embedded image (Wherein each symbol is the same as above)

That is, a commercially available polymer-supported hydrosilane (1) was prepared by a method known in the literature (Y. Hu et al., J. Org. Chem.,
1998, 63, 4518-4521)
Convert to (2). For example, polymer-supported hydrosilane
(1) 1,3-Dichloro-5,5 in an organic solvent such as 1,2-dichloroethane, dichloromethane, diethyl ether, etc.
-Dimethylhydantoin is added, and the mixture is reacted for several hours at room temperature to under heating to lead to the chlorosilane compound (2).

The chlorosilane compound (2) is reacted with a substituted silyllithium (3) such as (diethylamino) diphenylsilyllithium in an organic solvent such as tetrahydrofuran (THF), diethylether, dimethoxyethane, or hexane, and is heated to room temperature to room temperature. The reaction is carried out at a temperature for several to several tens of hours to lead to a disilyl compound (4), which is then treated with acetyl chloride in the same reaction vessel and filtered to obtain a polymer-supported chlorodisilane compound (5).

The above polymer-supported chlorodisilane compound
(5) Allyl alcohol (6) in an organic solvent such as dichloromethane, 1,2-dichloroethane, THF, acetonitrile, and DMF in the presence of an amine such as imidazole, triethylamine and 4-dimethylaminopyridine.
And by reacting for several hours several to tens under room temperature to heating, in dicyanamide Rani ether (II-1) (the formula (II), L = - ( CH 2) 4 -, R A = R B = Et, R ^X =
R ^Y = Ph).

As the polymer-supported hydrosilane (1) as a starting material in the above reaction formula-2, a commercially available product (for example, polystyrene-bonded silane manufactured by Argonaut Technology Co., Ltd.) may be used as it is, or a corresponding polymer-supported hydrosilane may be used. Is easily produced, for example, by a method represented by the following reaction formula-3.

[0037]

Embedded image (Where M is Li or MgX (X = Cl, Br or I), m = n−4, and other symbols are the same as described above)

That is, a polymer carrier obtained by chloromethylation (8) (Experimental Chemistry Lecture (Maruzen) 3rd edition, volume 19-1;
257, p. 331) as a starting material, which is reacted with ω-unsaturated alkyllithium or ω-unsaturated alkylmagnesium halide (1) (J. Org. Chem., 1998, Vo
l. 63, 4518-4521), a polymer compound (10) having an ω-unsaturated alkyl chain. By further reacting with the silane compound (11) in the presence of a rhodium catalyst, a polymer-supported hydrosilane (12) can be obtained (J. Org. C).
hem., 1998, Vol. 63, 4518-4521). As the chloromethylated polymer carrier (8), a commercially available Merrifield's resin may be used as it is. The rhodium (Rh) catalyst used in the above method includes R
hCl (PPh ₃ ) _{3 and the} like.

When an optically active allyl alcohol is used as the reactant allyl alcohol (6) in the method shown in the above reaction formula-2, a polymer-supported optically active allyl 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 allylsilane with various aldehydes, ketones, acetals, ketals, etc., the corresponding homoallyl alcohols, homoallyl ethers, etc. can be obtained in a highly stereoselective manner. The polymer-supported allylsilane of the present invention is also very useful as an optically inactive reagent,
In addition to the above-mentioned reaction substrates, it reacts with α, β-unsaturated aldehydes, α, β-unsaturated ketones and the like to obtain δ, ε-unsaturated carbonyl compounds. Therefore, the polymer-supported allylsilane compound (I) of the present invention is useful as a solid-supported reagent for producing various compounds useful as various pharmaceuticals and the like.

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

[0041]

Embedded image (Wherein each symbol is the same as above)

The reaction of the above reaction formula-4 can be carried out in an aprotic solvent, for example, methylene chloride, 1,2-dichloroethane, carbon tetrachloride, toluene and chlorobenzene. When using a fluorine anion instead of a Lewis acid, tetrahydrofuran, diethyl ether,
Dioxane and acetonitrile may be used as the solvent. In the reaction, the polymer-supported allylsilane (I) and the aldehyde are mixed in these solvents, and the reaction temperature is -100 ° C.
The reaction can be carried out by adding a Lewis acid or a fluorine anion at a temperature up to the boiling point of the solvent, preferably at -78 ° C to room temperature. After completion of the reaction, a usual post-treatment method, for example, removing insoluble polymer by filtration, removing the Lewis acid or fluorine anion by washing the organic layer with water, and removing the organic solvent, the intended 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, Trimethylsilyl triflate, boron trifluoride ether complex and the like. Examples of the fluorine anion used in place of the Lewis acid include potassium fluoride, cesium fluoride, and tetrabutylammonium fluoride.

The polymer-supported allyl silane of the present invention can be applied not only to the reaction with the above aldehyde but also to the reaction with various substrates. For example, homoallyl alcohol reacts with ketone, acetal, homoallyl ether reacts with ketal, and α, β-unsaturated aldehyde (or ketone) reacts with corresponding Michael.
l) Give adduct (Silicon Reagents for Organic Synt
hesis, p. 173-205, author; William P. Weber, publisher; Springer-Verlag, publication year; 1983).

[0045]

The polymer-supported allylsilane compound of the present invention is converted to allylsilane by a reaction on a polymer carrier by using an optically active substance as a raw material.
Since the asymmetric center is transferred to the silicon-bonded carbon, and this 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 allylsilane as shown in the following reaction formula-5.

[0046]

Embedded image (Wherein each symbol is the same as above)

As shown in the above reaction formula-5, optically active
Allyl alcohol (with asymmetric carbon at the base of alcohol)
When (6 ′) is used, the asymmetric center is converted to allylsilane (I-1 ′) by a reaction on the carrier polymer, and is transferred to the asymmetric center of the silicon root. Then
This chiral center is the product of the reaction with the aldehyde.
(IV-1 ′).

Further, in the polymer-supported allyl silane compound of the present invention, depending on the arrangement of the olefin of the optically active allyl alcohol used as a reactant, for example, an allyl alcohol (6 ') in the above reaction formula-5 may be an E-configuration. Depending on whether or not the z-configuration is used, allylsilanes are obtained in which the absolute coordination of the silicon root is reversed. These are shown below as partial structures.

[0049]

Embedded image

[0050]

EXAMPLES General: All reactions were performed under a nitrogen atmosphere with magnetic stirring. Column chromatography is silica gel 6
0 (75-150 mesh, Wako gel). ¹ H and ¹³ C NMR spectra are Varian
Gemini · 2000 (Varian ^{Gemini2000, 1} H 300
MHz, ¹³ C was 75 MHz) and recorded using a residual deuterium peak of the solvent as an internal standard. The high-resolution mass spectrum is JEOL / JMS-HX110A (FA
B) or recorded with a JEOL JMS-SX102A (EI) spectrometer.

Among the various reaction reagents used in the examples,
1,1,3,3-Tetramethylbutyl isocyanide and 1,1-diethoxyheptane were synthesized by methods described in the literature. (Diethylamino) diphenylsilyllithium was also synthesized by the method described in the literature. The optically active (R) -allyl alcohol (compound of the formula (6 ′)) is converted from the corresponding racemate to T
Sharpless kinetic resolution with (L)-(+)-diisopropyltartaric acid at -10 to -20 ° C using i (OPr-i) ₄
(Shapless Kinetic Resolution). These enantiomeric excesses were determined by HPLC after induction to the corresponding N- (3,5-dinitrophenyl) carbamate (Sumichiral OA-4500, hexane / 1,2-dichloroethane / ethanol = 50/1).
5/1 or 15/5/1).

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

Embedded image To a suspension of polystyrene-supported hydrosilane (1) (5.6 g, 8.9 mmol) in methylene chloride (80 ml) was added 1,3-dichloro-5,5-dimethylhydantoin (5.2 g, 26 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. After filtration under a nitrogen atmosphere, the resin was washed with methylene chloride (100
ml × 3) and tetrahydrofuran (100 ml × 4), dried under vacuum and dried with polystyrene-supported chlorosilane (2).
I got The resin was suspended in tetrahydrofuran (80 ml) and chloro (diethylamino) diphenylsilane (7.7
g, 26 mmol) and lithium (0.75 g, 109 mmol) in tetrahydrofuran (70 ml) of (diethylamino) diphenylsilyllithium was added at room temperature. The mixture was stirred at room temperature for 10 hours. After filtration, the resin was washed with tetrahydrofuran (100 ml × 5) and suspended in tetrahydrofuran (70 ml). 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. Then, N, N-dimethylacetamide (983 mg, 8.5 mmol, 96%) generated in the reaction system was added to a GC.
For quantitative analysis, dodecane (840 m
g) was added to the suspension. After filtration under a nitrogen atmosphere, the resin was washed with dimethylformamide (100 ml × 3) and tetrahydrofuran (100 ml × 4), dried in vacuo, and dried with polystyrene-supported chlorodisilane (5) (1.14 mmol / l).
g) was obtained.

(2) Synthesis of polystyrene-supported optically active disilanyl ether (reaction formula-5, compound of formula (II-1'c)) (using optically active (R) -allyl alcohol (6'-c))

Embedded image A mixture of chlorodisilane (5) (1.0 g, 1.14 mmol) and imidazole (283 mg, 4.16 mmol) in methylene chloride (10 ml) was added to an optically active (R) -allyl alcohol (6′-) as shown in Table 1 below. c) (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 ml × 2), tetrahydrofuran
(5 ml × 2), tetrahydrofuran aqueous solution (50%, 5
ml × 2), ethanol (10 ml × 2), and tetrahydrofuran (10 ml × 2), dried in vacuo, and disilenyl allyl ether supported on polystyrene (II-1 ′).
I got The yield of this compound was determined by GC quantitative analysis of the collected filtrate containing allyl alcohol. By GC quantitative analysis using tetradecane as an internal standard, 0.92 mmol of allyl alcohol (6′-c) was bound to the resin and the corresponding disilanyl ether (II-1′c) (1.1
6 g, 0.79 mmol / g).
These results indicate that chlorodisilane on the polymer support
0% indicated that it had reacted with the alcohol compound. The obtained resin is treated with hydrogen fluoride-pyridine to obtain Si-
The starting allyl alcohol (6 ′
The load was double-checked by measuring -c). That is, the disilenyl ether (10
Hydrogen fluoride-pyridine (3M solution in tetrahydrofuran, 0.5 mg) was added to a suspension of 2 mg) in tetrahydrofuran (1 ml).
ml) and treated at room temperature for 7 hours. Methoxytrimethylsilane (1.5 ml) was added to the mixture at room temperature. 1
After stirring for 0 hours, the mixture was filtered, and the filtrate was subjected to GC quantitative analysis to find that 16 mg (0.1%) of the starting material allyl alcohol (6′-c) was obtained.
080 mmol) was found to be released. The loading (0.78 mmol / g) calculated in this way is in good agreement with the yield obtained above (0.79 mmol / g).

In the above method, optically active (R) -allyl alcohol (6'-a) shown in Table 1 below was used in place of optically active (R) -allyl alcohol (6'-c) as a reactant.
By using and (6′-b), polymer-supported optically active disilanyl ethers (II-1′a) and (II-1′b) are obtained, respectively. The loading ratio of allyl alcohol to the resin in the product of the above reaction and the optical purity of the product are as shown in Table 1 below (the optical purity of the product is
It is considered to be the same as the optical purity of the alcohol used).

[0055]

[Table 1]

(3) Polystyrene-supported allylsilane (I-
Synthesis of 1'c)

Embedded image Disilanyl ether (II-1′c) obtained in (2) above
(1.06 g, 084 mmol) in toluene (10 ml) was suspended in Pd (acac) ₂ (15 mg, 0.05 mmol).
And 1,1,3,3-tetramethylbutyl isocyanide (66
mg, 0.38 mmol) of a catalyst in tetrahydrofuran (0.25 ml) was added and the mixture was stirred under reflux for 5 hours. After evaporating the solvent in vacuo, tetrahydrofuran (1
3 ml) was added to the residue. After cooling to 0 ° C., n-butyllithium (1.54 M in hexane, 2.2 ml, 3.4 mmol) was added to the mixture, and the mixture was stirred at 0 ° C. for 1 hour, and ethanol (5 ml) was added at 0 ° C. To stop the reaction.
After filtration, the resin was washed with ethanol (10 ml × 2) and water (10 m
l), an aqueous solution of tetrahydrofuran (50%, 10 ml),
Tetrahydrofuran (10 ml) and ethanol (1
0 ml). Washed resin ethanol (12m
To a suspension of 1) and tetrahydrofuran (6 ml) was added p-toluenesulfonic acid (monohydrate, 60 mg, 0.32 mmol) and the mixture was stirred at 55 ° C. for 5 hours. After filtration, the resin was washed with ethanol (10 ml × 2), tetrahydrofuran (10 ml × 2), and methylene chloride (10 ml × 2).
After washing in 2) and drying under vacuum, allylsilane (I-1′c) supported on polystyrene (0.79 g) was obtained. Assuming that the conversion from disilanyl ether to allylsilane is 100% efficient and the recovery is also 100%, the maximum loading of allylsilane on the resin can be estimated to be 1.05 mmol / g.

Example 2 Polystyrene-supported allylsilane (I-1′a) (in the formula (I),
L =-(CH₂)₄-, R ^A, R^B= Et, R¹= Ph,
R³= Me, R⁴= H) with aldehyde compounds

Embedded image The polystyrene-supported allylsilane (I-1 ′) obtained in the same manner as in Example 1 above (however, a p-toluenesulfonic acid treatment step for deprotection of the tetrahydropyranyl group is unnecessary).
a) (101 mg, <0.097 mmol) of methylene chloride
Acetaldehyde (1.1 × 10 ⁻² m) was added to the suspension (2 ml).
1, 0.20 mmol) and titanium tetrachloride (2.1 × 10 ⁻²⁾
ml, 0.19 mmol) at -78.degree.
The mixture was stirred at 78 ° C for 0.5 hours. After filtering the reaction solution, water was added, the organic matter was extracted with ether, and the filtrate was dried and filtered.
Then it was distilled off in vacuo. The obtained residue is subjected to silica gel column chromatography (hexane / ether = 4/1 to 2).
/ 1) and homoallylic alcohol (in the formula (IV), R
¹ = Ph, R = Me) [9.2 mg, yield: 54% (total from disilanyl ether, the same applies hereinafter)]. Syn / anti ratio = 96: 4, optical purity: 98.6% e
e. ¹ H NMR (CDCl ₃ ) δ: 1.14 (d, J = 6.8 Hz, 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, 1
H), 7.16-7.42 (m, 5H).

Examples 3 and 4 In the same manner as in Example 2 except that heptanal or isobutyraldehyde was used instead of acetaldehyde as the aldehyde compound to be reacted, (E) -3-methyl-1-phenyl was used. -1-decene-
4-ol (in the formula (IV), R ¹ = Ph, R = n-hexyl) or (E) -3,5-dimethyl-1-phenyl-1-
Hexen-4-ol (in the formula (IV), R ¹ = Ph, R =
Isopropyl). The physical properties and the like of these compounds are shown below.

(E) -3-methyl-1-phenyl-1-decene-4-ol: yield: 44%, syn / anti ratio = 93: 7, optical purity:
99.0% ee. ¹ H NMR (CDCl ₃ ) δ: 0.88 (t, J = 6.9 Hz, 3H), 1.13 (d,
J = 6.9Hz, 3H), 1.18-1.66 (m, 11H), 2.37-2.51 (m, 1
H), 3.50-3.61 (m, 1H), 6.19 (dd, J = 15.9, 7.8 Hz, 1
H), 6.44 (d, J = 15.9 Hz, 1H), 7.18-7.25 (m, 1H), 7.
27-7.41 (m, 4H) ¹³ C NMR (CDCl ₃ ) δ 14.0, 14.9, 22.5, 26.0, 29.3, 3
1.8, 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, C, 82.
87, H, 10.64; found, C, 82.70, H, 1
0.84

(E) -3,5-dimethyl-1-phenyl-
1-hexen-4-ol: yield: 40%, syn / anti ratio = 97: 3, optical purity:
93.0% ee. ¹ H NMR (CDCl ₃ ) δ: 0.95 (d, J = 6.8 Hz, 6H), 1.14 (d,
J = 6.8Hz, 3H), 1.40 (d, J = 5.0Hz, 1H), 1.81 (octet,
J = 6.8Hz, 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 allylsilane (I-1′b) (in the formula (I),
L =-(CH₂)₄-, R ^A, R^B= Et, R¹= N-he
Kishiru, R³= Me, R⁴= H) and isobutyl aldehyde
Reaction with C

Embedded image Polystyrene-supported allylsilane (I-1'b) (100 m
g, <0.10 mmol) in methylene chloride (2 ml) was added to a suspension of isobutyraldehyde (9.5 × 10 ⁻³ ml, 0.1 ml).
1 mmol) and titanium tetrachloride (2.2 × 10 ⁻² ml, ^0.1 ml).
(20 mmol) at -78 ° C and the mixture was stirred at -78 ° C for 2 hours. The mixture was filtered through a pad of Celite (registered trademark) in a 2M aqueous solution of sodium hydroxide, and the organic matter was extracted with ether. The filtrate was dried, filtered and evaporated in vacuo. The obtained residue is purified by silica gel column chromatography (hexane / ether = 8/1) to give (E) -2,4-dimethyl-5-dodecene-3-ol (homoallyl alcohol (in formula (IV)) , R ¹ = n-hexyl, R ³ = Me,
R ⁴ = H, R = isopropyl)) (7.3 mg, yield: 34)
%). Syn / anti ratio = 99: 1, optical purity: 9
5.6% ee. _{^{1 H NMR (CDCl 3) δ}} 0.87 (t, J = 6.9Hz, 3H), 0.907 (d,
J = 6.6Hz, 3H), 0.914 (d, J = 6.6Hz, 3H), 0.99 (d, J = 6.
9Hz, 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, 1
H), 5.47 (dt, J = 15.3, 6.9Hz, 1H) ¹³ C NMR (CDCl ₃ ) δ 14.0, 14.3, 16.9, 19.6, 22.5, 1
8.7, 29.4, 30.3, 31.6, 32.6, 39.6, 79.9, 131.0, 13
3.2 Elemental _analysis: as _C 14 _{H 28} O, theoretical, C, 79.
18, H, 13.29; found, C, 78.88, H, 1
3.07

Example 6 Reaction of polystyrene-supported allylsilane (I-1'c) with aldehyde

Embedded image Polystyrene-supported allylsilane (I-1'c) (100 m
g, <0.105 mmol) in methylene chloride (2 ml) was added at −78 ° C. with n-heptanal (n-Hex-CHO) (1.05 mmol) and trimethylsilyl triflate (2.1 mmol). The mixture was stirred at -78 C for 2 hours. The mixture was filtered and the filtrate was collected directly in 1M aqueous sodium hydroxide. After extraction with ether, the solvent was distilled off to obtain almost pure oxacycloheptene, which was further purified by silica gel column chromatography to obtain the following compound. 2-hexyl-3-methyl-2,3,6,7-tetrahydrooxepin: yield: 64%, trans / cis ratio = 92: 8, optical purity: 97.9% ee. ¹ H NMR (CDCl 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 (m, 1
H), 2.27-2.43 (m, 2H), 3.07 (dt, J = 2.4, 8.4Hz, 1
H), 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
(m, 1H) ¹³ C NMR (CDCl ₃ ) δ 14.8, 18.8, 22.6, 25.5, 29.4, 3
1.6, 31.8, 34.2, 41.5, 69.7, 84.7, 127.7, 137.4 HRMS: as ^{_{C 13 H 24 O (M +}} ), theoretical values, 19
6.1827; found 196.1828.

Example 7 In Example 6, n-heptanal diethyl acetal (n-heptanal) was used in place of n-heptanal as a reactant.
-Hex-CH (OEt) ₂ ) to give the same compound as in Example 6. Yield: 67%, trans / cis ratio = 93: 7, optical purity: 97.9% ee.

Example 8 The same compound as in Example 6 was used except that acetaldehyde was used instead of n-heptanal as a reactant to obtain the following compound. 2,3-Dimethyl-2,3,6,7-tetrahydrooxepin: yield: 70%, trans / cis ratio = 91: 9, optical purity:> 97.2% ee. ¹ H NMR (CDCl 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, 1H), 3.45 (ddd, J = 12.3, 1
0.2, 2.7Hz, 1H), 4.02 (ddt, J = 12.3, 0.9, 4.2Hz, 1
H), 5.43 (dt, J = 11.4, 3.0Hz, 1H), 5.69-5.77 (m, 1
H) ¹³ C NMR (CDCl ₃ ) δ 19.1, 21.0, 31.7, 42.8, 69.8, 8
1.1, 128.5, 137.5 HRMS: C ₈ H ₁₄ O (M ⁺ ), theoretical value, 12
6.1045; found, 126.1041.

Example 9 The same reaction as in Example 6 was carried out except that cyclohexanealdehyde was used instead of n-heptanal as a reactant to obtain the following compound. 2-cyclohexyl-3-methyl-2,3,6,7-tetrahydrooxepin: yield: 59%, trans / cis ratio = 91: 9, optical purity: 98.1% ee. _{^{1 H NMR (CDCl 3) 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), 2.1
1-2.24 (m, 1H), 2.27-2.42 (m, 1H), 2.43-2.60 (m, 1
H), 2.92 (d, J = 9.3Hz, 1H), 3.39 (ddd, J = 3.3, 9.3,
12.0Hz, 1H), 4.02 (dt, J = 12.0, 4.5Hz, 1H), 5.41-5.
51 (m, 1H), 5.59-5.72 (m, 1H) ¹³ C NMR (CDCl 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: C ₁₃ H ₂₂ O (M ⁺ ), theoretical value, 19
4.1671; found, 194.1167.

Example 10 In the same manner as in Example 6, but using benzaldehyde instead of n-heptanal as a reactant, the following reaction was carried out to obtain the following compound. 3-methyl-2-phenyl-2,3,6,7-tetrahydrooxepin: yield: 70%, trans / cis ratio = 92: 8, optical purity: 98.1% ee. ¹ H NMR (CDCl ₃ ) 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), 3.5
7 (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 = 1
2.0, 2.7Hz, 1H), 5.79-5.89 (m, 1H), 7.23-7.38 (m,
5H) ¹³ C NMR (CDCl ₃ ) δ 19.4, 31.9, 42.1, 70.6, 88.8, 12
7.0, 127.5, 128.4, 129.0, 137.3, 142.8 HRMS: C ₁₃ H ₁₆ O (M ⁺ ), theoretical value, 18
8.11201; found 188.1207. Example 11 Disilanyl ether (II-) obtained in Example 1- (2)
1′c) (1.06 g, 0.84 mmol) in toluene (10
To the suspension was added the catalyst tetrahydrofuran (0.25 ml) obtained from Pd (acac) ₂ (15 mg, 0.05 mmol) and 1,1,3,3-tetramethylbutyl isocyanide (66 mg, 0.38 mmol). ) The solution was added and the mixture was stirred under reflux for 5 hours. After filtering the resin, toluene (10 ml
× 3) and tetrahydrofuran (10 ml × 3). The obtained resin (102 mg) was treated with n-heptanal.
(0.011 ml, 0.079 mmol) and trimethylsilyl triflate (0.027 ml, 0.15 mmol) in dichloromethane at −78 ° C. for 2 hours,
The same tetrahydrooxepin derivative as the product of Example 6 was obtained. Yield: 31%, trans / cis ratio = 82:18.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) C07F 7/08 C07F 7/08 F // C07B 61/00 300 C07B 61/00 300 C07D 313/04 C07D 313/04 C07M 7:00 C07M 7:00 F-term (reference) 4C062 JJ02 4H006 AA02 AC41 BA32 BA37 BA67 FC52 FE11 4H039 CA60 CD40 4H049 VN01 VP01 VQ07 VR24 VS07 VS76 VT17 VU32 VU36 VW02 4J100 AB02P BA71H BA72P BC43H BC31 BC

Claims (3)

[Claims] 1. A compound of the general formula (I): (Wherein, Is a polymer carrier having a terminal phenyl ring; L is a linker; R ^A and R ^B are each independently an alkyl group or a phenyl group; R ¹ is a hydrogen atom, an optionally substituted alkyl group; A cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aromatic heterocyclic group, R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group, A cycloalkyl group, an aryl group which may be substituted, or an aromatic heterocyclic group which may be substituted). 2. A compound of the general formula (II):(Wherein,L, R^A, R^B, R¹, R³And R⁴Is described in claim 1.
Same as above, R^XAnd R ^YAre independently an alkyl group
Or an aryl group. Where R^XAnd R^Y
Are not alkyl groups.)
Treatment of nyl ether compounds in the presence of a palladium catalyst
Having the general formula (I):(Wherein each symbol is the same as described in claim 1)
Production method of mer-supported allylsilane compound. 3. A compound of the general formula (I): (Wherein each symbol is the same as described in claim 1), a polymer-supported allylsilane compound represented by the general formula (III): R-CHO (III) R is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group)
Wherein the aldehyde represented by the general formula (IV) is reacted: (Wherein R ¹ , R ³ and R ⁴ are the same as described in claim 1 and R is the same as described above).