KR100379300B1 - Sequential catalytic asymmetric allyl transfer reactions for the enantioselective synthesis of new pyran derivatives - Google Patents

Abstract

The present invention is made by reacting an allylorganosilicon compound of formula (III) with an aldehyde compound of formula (IV) in the presence of a (R)-or (S) -BINOL-Ti [OCH (CF ₃ ) ₂ ] complex An optically active hydroxysilane derivative of formula (II) is prepared, which is reacted with trimethylsilyl chloride to protect the hydroxy group, and reacted with an aldehyde derivative of formula (Va) or (Vb), followed by a Lewis acid such as TMSNTf ₂ Process for preparing optically active 2,6-disubstituted 4-methylenetetrahydropyran derivatives of formula (I) characterized by treatment with a catalyst and novel optically active 2,6-disubstituted compounds of formula (I) thus prepared 4-methylenetetrahydropyran derivatives are provided. The present invention also provides novel optically active compounds of formula (II) and novel allyltransfer reagents of formula (III) and methods for their preparation.

or (I)

(II)

(III)

R ¹ CHO (IV)

(Va) or (Vb)

In the above formula, R ¹ is an alkyl group having 1 to 10 carbon atoms; (Ii) an alkenyl group or an allenyl group having 1 to 10 carbon atoms including one or more double bonds; (Iii) substituted or unsubstituted aliphatic compounds; (Iii) a group derived from the compound of formula (VI):

(Ⅵ)

(In formula VI, R is lower alkyl, lower alkoxy, substituted or unsubstituted phenyl group, n is selected from 0 or an integer from 2 to 10.); Or (iii) a primary alcohol in which a hydroxy group having 1 to 10 carbon atoms is protected (a protecting group is selected from benzyl group, trialkylsilyl group and tetrahydrofuran),

R ² is (i) an alkyl group having 1 to 10 carbon atoms; (Ii) an alkoxy group having 1 to 10 carbon atoms; (Iii) a substituted or unsubstituted benzyl group,

R ₃ represents H, or R ² and R ³ together with the carbon atom to which they are attached In which n is 1 or 2, in which case the oxa (—O—) group is in antiposition with R ¹ ; R ⁴ represents a lower alkyl group having 1 to 6 carbon atoms; R ⁵ represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group; X and Y each independently represent a halogen or alkoxy group.)

Description

Novel optically active pyran derivatives by catalytic asymmetric double allyl transition and preparation method thereof

The present invention relates to novel 2,6 -disubstituted 4-methylenetetrahydropyran derivatives that can be used as chiral building blocks for the production of natural products and bioactive substances, and to methods for their preparation using novel allyl transfer reagents and chiral catalysts.

More specifically, the present invention provides an optically active hydroxide of aldehyde to aldehyde using an allyl transition system comprising a novel allylorganosilicon compound of formula (III) and a chiral catalyst according to Scheme 1 below. A oxysilane compound is prepared and reacted with another carbonyl compound (e.g., aldehyde acetal derivative, ortho formate, ortho ester) to be useful as a chiral building block and in various drugs and bioactive compounds. The present invention relates to an optically active 1,2-disubstituted-4-methylenetetrahydropyran derivative of formula (I) which is a structural core and a method for preparing the same.

In the above formula, R ¹ is an alkyl group having 1 to 10 carbon atoms; (Ii) an alkenyl group or an allenyl group having 1 to 10 carbon atoms including one or more double bonds; (Iii) substituted or unsubstituted aliphatic compounds; (Iii) a group derived from the compound of formula (VI):

(Ⅵ)

(In formula VI, R is lower alkyl, lower alkoxy, substituted or unsubstituted phenyl group, n is selected from 0 or an integer from 2 to 10.); Or (iii) a primary alcohol in which a hydroxy group having 1 to 10 carbon atoms is protected (a protecting group is selected from benzyl group, trialkylsilyl group and tetrahydrofuran),

R ² is (i) an alkyl group having 1 to 10 carbon atoms; (Ii) an alkoxy group having 1 to 10 carbon atoms; (Iii) a substituted or unsubstituted benzyl group,

R ₃ represents H, or R ² and R ³ together with the carbon atom to which they are attached In which n is 1 or 2, in which case the oxa (—O—) group is in antiposition with R ¹ ;

R ⁴ represents a lower alkyl group having 1 to 6 carbon atoms; R ⁵ represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group.)

Until now, many chiral compounds, ie, chiral building blocks, which are useful as raw materials for drugs or bioactive substances have been studied. However, adequate economic chiral building blocks have not yet been developed from an economic and industrial standpoint.

Tetrahydropyran derivatives are frequently found in natural and biologically active substances and are known to have various physiological activities such as antibiotics, anticancer, antifungal and antidiabetic. Related compounds comprising such optically active tetrahydropyran units have been or are being developed as new drugs or drug candidates. For example, Acarbose (USP4,062,950), which is developed as a diabetes treatment agent, shows excellent efficacy as a typical pyranic compound, and OGT-719 is being developed as a new drug for anticancer and antiviral drugs. In addition, the compound of SPA-S-753 [USP 5,298,495] has been characterized by pharmacological activity as an antifungal agent (Antifungal) and is being conducted in preclinical studies. In addition, as compounds present in nature, Acutiphycin [JACS, 1984, 106, 8193], Phorboxazole [JACS, 1995, 117, 8126], Apoptolidin [JACS, 1998, 120, 3524] and the like are known as possible anticancer agents.

Methods of synthesizing these Te trad tetrahydropyran compounds are mostly reported a method of introducing a three-dimensional optionally tetrahydropyran ring (tetrahydropyran ring) with the formation of CO combined with an electrophilic cyclization (electrophilic cyclization) (Tetrahedron , 1987, 43, 3309). [Reference: Scheme 2]

Overman reported the efficient synthesis of tetrahydropyran derivatives (Scheme 3) using the oxocarbenium intermediate, a strong electrophilic carbocation.

As another method, an allylsilicone compound and an aldehyde, which is an equivalent of 2 equivalents of carbonyl compound, are prepared through a Lewis acid catalyst and an allyl addition reaction. (See Tetrahedron Lett., 1987, 28, 3441-3444; Tetrahedron Lett., 1987, 28, 973-976; JOC, 1987, 52, 4128-4130; JOC, 1988, 53, 911-913]

Recently reported method has been reported to produce a pyran compound using an indium catalyst with 2 equivalents of aldehyde using an organotin compound having two functional groups (bifunctional) [Org. Lett., 1999, 1, 993-995].

However, most of these methods are techniques for producing racemate compounds, and other studies have been reported. However, in the case of preparing chiral compounds, expensive chiral reagents are consumed in an equivalent amount. [Note: Tetrahedron Lett., 2000, 41, 4717-4721; Tetrahedren Lett., 2000, 41, 4383-4387; Org. Lett., 2000, 2, 1217-1219]

The present inventors have developed a novel allylorganotin reagent and chiral to ameliorate these disadvantages in the preparation of optically active tetrahydropyran derivatives and to synthesize new structurally more useful tetrahydropyran derivatives into optically active compounds rather than racemic compounds. The synthesis of Lewis catalysts was studied, and new pyran derivatives were developed using one equivalent of aldehyde and several other aldehyde analogs instead of two equivalents of carbonylaldehyde.

Furthermore, the present inventors have developed a new allyl organosilicon compound having two functional groups using a known allyl transition reaction and further conducted a reactivity study using a chiral Lewis acid catalyst. A chiral alcohol derivative that can be converted easily could be prepared using the chiral Lewis acid catalyst. Based on these results, sub-emitter in a variety of carbonyl or aldehyde compound by preparing the optically active tetrahydropyran derivatives having various structures, thereby completing the present invention.

It is an object of the present invention to provide an optically active 2,6-disubstituted-4-methylenetetrahydropyran derivative of formula (I) and a method for preparing the same, wherein the compound of formula (I) is a starting material of a drug or bioactive substance It is particularly useful as a chiral building block into which optically active tetrahydropyran units can be introduced.

Another object of the present invention is to provide an optically active hydroxyalkylsilane derivative of formula (II) and a method for preparing the same, wherein the compound of formula (II) is also useful as a chiral building block, in particular the optical activity of formula (I) It can be readily converted to 2,6-disubstituted-4-methylenetetrahydropyran derivatives.

Another object of the present invention is to provide an allyl organosilicon compound of formula (III) and a method for preparing the compound, wherein the compound of formula (III) is useful as an allyl transition material for asymmetric synthesis of a compound of formula (II).

[Formula I]

or

[Formula II]

[Formula III]

[Formula IV]

R ¹ CHO

[Formula V]

(Va) or (Vb)

(Wherein R ¹ is (i) an alkyl group having 1 to 10 carbon atoms; (ii) an alkenyl group having 1 to 10 carbon atoms or an allenyl group containing one or more double bonds; (iii) a substituted or unsubstituted aliphatic group; (V) a group derived from a compound of formula (VI):

[Formula VI]

(In formula VI, R is lower alkyl, lower alkoxy, substituted or unsubstituted phenyl group, n is selected from 0 or an integer from 2 to 10.); Or (iii) a primary alcohol in which a hydroxy group having 1 to 10 carbon atoms is protected (a protecting group is selected from benzyl group, trialkylsilyl group and tetrahydrofuran),

R ² is (i) an alkyl group having 1 to 10 carbon atoms; (Ii) an alkoxy group having 1 to 10 carbon atoms; (Iii) a substituted or unsubstituted benzyl group,

R ₃ represents H, or R ² and R ³ together with the carbon atom to which they are attached In which n is 1 or 2, in which case the oxa (—O—) group is in antiposition with R ¹ ;

R ⁴ represents a lower alkyl group having 1 to 6 carbon atoms; R ⁵ represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group; X and Y each independently represent a halogen or an alkoxy group.)

Preferably, R ¹ is alkyl, aryl or aralkyl, more preferably Ph-, PhCH ₂ CH _2- , C ₆ H _13- , PhCH = CH-, EtO ₂ CCH ₂ CH ₂ CH _2- , BnOCH ₂ -Represents; R ² represents alkyl, aryl, aralkyl, or alkoxy, more preferably PhCH ₂ CH ₂ , C ₆ H ₁₄ or MeO.

The present invention is explained in more detail below.

The present inventors have studied a lot of allyl organic tin reagents for allyl transition reactions with various aldehyde compounds using BINOL-Ti (IV) complexes and iPrS B Et ₂ and iPrSSiMe ₃ as reaction promoters. (J. Chem. Comm. 1997, 761, TL., 1996. 37.7095, Chem. Comm. 1997.763, Angew. Chem. Int. Ed. 1998, 37, 2392)

Based on this study, the present inventors attempted to synthesize chiral pyran compounds using organotin reagent (1) having two functional groups (tributyltin functional groups) as shown in Scheme 4 below.

[Scheme 6]

To this end, the present inventors present a BINOL-Ti (IV) complex [BINOL: Ti (O ⁱ Pr) ₄ = 2: 1] using tributylstannyl-2-propenyltributylstannane (1), an allyl organic tin reagent having two functional groups. The reaction was carried out with benzaldehyde under THF solvent at -78 ° C. However, the reaction hardly proceeded, which was thought to be due to the weak reactivity of the reactants.

As shown in the following Scheme 7, the present inventors, as the reaction accelerator, the inventors have already reacted to this type of reaction . Note do not know whether by reference) using a 10% ㏖ catalyst in CH ₂ Cl ₂ solvent PrSBEt ⁱ ₂ in the proposed bar at -20 ℃ as was reacted with benzaldehyde. However, ¹ HNMR analysis showed that unwanted compounds 3 and 2 were obtained in a ratio of 2: 1 and 58% yield.

As shown in Scheme 8, the present inventors have appropriately sized a tin group of one of the two tin groups in the reagent (1) to compensate for the problem of the organic tin reagent (1). The introduction of a smaller, more stable silyl substituent resulted in the design of a new allyl organosilicon compound (VI), which plays an important role in the present invention, and the reaction was carried out under the same conditions.

Although compound (5) was obtained in low yield, the present inventors have developed the efficient chiral catalyst based on the above research using a new concept of reaction and introducing various carbonyl analogs to the obtained compound (5) gives us the desired chiral. I thought pyran could be synthesized.

The novel optically active pyran derivatives by the catalytic asymmetric double allyl transition according to the present invention and a method of preparing the same can be illustrated by the following scheme (9). It is naturally understood that the final tetrahydropyrans prepared according to Scheme 9 below are merely examples of compounds that can be prepared according to the present invention.

(In the above formula, R ₁ and R ₂ are the same as R ¹ and R ² as defined above, respectively.)

Allyl Transfer and Chiral Catalysts

Trimethyl- (2-tributhylstannylmethyl-allyl) -silane of formula (III) can be prepared by various methods. The preparation methods illustrated in the examples of the present invention are given by way of example only, and derivatives thereof are also included in the scope of the present invention. For example, in the trimethylsilyl group, there may be exemplified a compound in which one or more of the methyl groups are substituted with another alkyl group or allyl group.

The (R / S) -BINOL-Ti [OCH (CF ₃ )] ₂ complex used as a chiral catalyst in the allyl transfer reaction according to the present invention is composed of (R / S) -BINOL and Ti [OCH (CF). ₃ )] ₄ or by reacting (R / S) -BINOL with Ti [OCH (CH ₃ )] ₄ first at a stoichiometric amount, then (R / S) -BINOL-Ti [OCH (CH ₃ )] ₂ may be prepared by adding di (trifluoromethyl) methanol [HOCH (CF ₃ ) ₂ ] to substitute the -OCH (CH ₃ ) ₂ group bonded to the Ti atom of the complex. (R)-or (S) -BINOL (1,1'-binaphtol) used as chiral ligand is commercially available.

In the present invention, the compound or aldehyde of the general formula (III) as a reactant is used in an amount of 1 to 100 times, preferably 5 to 50, more preferably 10 to 20 times the equivalent of the chiral catalyst. Although reaction temperature is not specifically limited, Generally -78-50 degreeC, Preferably it is -40-40 degreeC, More preferably, it is -20-40 degreeC.

In the allyl transition reaction of the present invention, it is preferable to slowly or dropwise add the compound of formula (III), which is an allyl transition reagent, to a mixture of the chiral catalyst and the aldehyde in the presence or absence of a solvent that does not interfere with the reaction under an inert atmosphere such as nitrogen. Do. Especially when the reaction is carried out in the presence of a solvent, trifluoromethylbenzene is most preferred.

In the allyl transition reaction according to the present invention, a compound having a sulfur atom may be added as a reaction accelerator in some cases. Preferred reaction promoters may include, for example, iPrSSiMe ₃ or ⁱ PrSBEt ₂ , the amount of which is not particularly limited, but is 1 to 20 times based on the chiral catalyst.

Preparation of Tetrahydropyran Derivatives

The hydroxysilane compounds of formula (II) prepared by the allyl transition reaction according to the present invention can themselves be used as starting materials or chiral building blocks for preparing other drugs and bioactive substances.

As an example, in the present invention, formula (I), which can be used as a starting material or chiral building block for imparting structurally important tetrahydropyran units in various drugs or bioactive substances from the hydroxysilane compound of formula (II) A method for preparing the optically active tetrahydropyran derivatives of the present invention is provided [Reference Scheme 9].

The hydroxy group of the hydroxysilane compound of formula (II) is protected with a trimethylsilyl group or the like, and reacted with an aldehyde derivative of formula (V), for example an aldehyde acetal derivative, an orthoformate or an orthoester compound, and TMSN (SO Treatment with ₂ CF ₃ ) ₂ affords compounds of formula (I).

(Va) or (Vb)

(Wherein X and Y each independently represent a halogen, preferably a chloride or alkoxy group, preferably a methoxy group, R ₂ represents PhCH ₂ CH ₂ , C ₆ H ₁₄ or MeO, n is 1 or 2.)

Although the reaction temperature at this time is not specifically limited, Generally -78-0 degreeC is suitable, and especially high temperature shows high optical purity. In addition, dichloromethane, tetrahydrofuran, diethyl ether and the like are used as the solvent in the presence or absence of a solvent that does not interfere with the reaction under an inert atmosphere such as nitrogen.

When using orthoformate as the aldehyde derivative of formula (Va) the substituent R ₂ is MeO- and is introduced at the position of the substituents R ₁ and syn in the tetrahydropyran ring. Likewise, when using orthoesters as aldehyde derivatives of formula (Va), substituent R ₂ is alkyl or arylalkyl and is introduced at the position of substituents R ₁ and syn in the tetrahydropyran ring.

On the other hand, when using a cyclic aldehyde derivative of formula (Vb), a spiropyran compound is produced and the oxa group (-O-) is introduced at the positions of substituents R ₁ and anti in the tetrahydropyran ring.

The amount of the aldehyde derivatives of the formulas (Va) and (Vb) is not strictly limited, but the amount of the chemosugar of the hydroxysilane compound of the formula (II) is preferably 1.0 to 3.0 equivalents.

Optically active 2,6-disubstituted-4-metylene-tetrahydropyran derivatives of formula (I) prepared according to the present invention can introduce various functional groups to substituents R1 and R2 as needed, and 4-methylene substituents As it can be converted into various other functional groups, the use range is very wide. Thus, the compound of formula (I) can be used as a starting material for various drugs and bioactive substances or as a chiral building block for introducing a chiral tetrahydropyran ring.

Best mode for carrying out the invention

The present invention is explained in detail by the following examples, which are merely specific examples of the present invention, and the present invention is not limited to the following examples.

Abbreviations used in the examples have the following meanings, and other symbols have the meanings commonly used in the chemical arts:

Hex: Hexane EA: Ethyl Acetate

TMSiCl: trimethylsilyl chloride THF: tetrahydrofuran

TMSNTf ₂ : trimethylsilylhexafluoromethanesulfonamine

s: singlet d: doublet

t: triplet m: multiplet

dd: double of doublet

Example 1 Preparation of Allyl Transcatalyst

Step 1: Synthesis of 2- (Trimethylsiloxymethyl) allylsilane

The 500 ml round-bottom flask was flame dried and then transferred 24 g (95%; 203 mmol) of t- BuOK in a nitrogen bag. Add 140 ml of THF and stir to dissolve t-BuOK, cool to -78 ℃ using Dry Ice-Acetone Bath and n-BuLi 81 ml (2.5M solution in Hexane, 203 mmol) to flow to the wall. Apply slowly. The resulting orange solution was stirred for 30 minutes, and then 7.8 mL (92.3 mmol) of 2-methyl-2-propen-1-ol was diluted with 15 mL of THF and added through the wall for 40 minutes. The red resultant was stirred with increasing temperature to -20 ° C, and then cooled to -78 ° C.

52 ml (410 mmol) of TMSiCl was added thereto, the bath was removed, and the temperature was raised to room temperature. The reaction solution was placed in a separatory funnel containing ice water, and the layers were separated. The aqueous layer was extracted with Et ₂ O. The combined organic layers were washed with saturated aqueous NaHCO ₃ , water and brine, dried over anhydrous K ₂ CO ₃ and filtered under reduced pressure using a glass filter. The solution was concentrated by evaporation using a rotary evaporator, and distillation under reduced pressure afforded 11.7 g (58.6%, bp: 57-59 ° C./4 mmHg) of 2- (Trimethylsiloxymethyl) -allylsilane.

FT-IR (neat) 2957.5, 2899.4, 1643.2, 1252.5, 1086.2, 843.3 cm ⁻¹ ;

Step 2: Synthesis of 2- (Hydroxymethyl) allyltrimethylsilane

11.7 g (54 mmol) of 2- (Trimethylsiloxymethyl) allylsilane and 80 ml of THF are placed in an oven-dried 250 ml round-bottom flask. Was cooled using ice water Bath container and then _{1N-H 2 SO 4 24 ㎖} (24. 00 m㏖) to be slowly. The temperature was gradually raised to room temperature under stirring, and the resultant was further stirred for 30 minutes at room temperature. The reaction solution was terminated by slowly adding solid K ₂ CO ₃ to the resulting solution until no bubbles formed. After layer separation, the aqueous layer is extracted with Et ₂ O. The resulting solution was dried over K ₂ CO ₃ , filtered under reduced pressure with a glass filter, concentrated using a rotary evaporator, and then distilled under reduced pressure to obtain 5.8 g (74%, bp: 54 to 56 ° C./2 mmHg) of 2- (Hydroxymethyl) -allyltrimethylsilane. Got it.

FT-IR (neat) 3337.0 (br), 2955.7, 1642.0, 1249.7, 841.6 cm ^-1 ;

Step 3: Synthesis of (2-Bromomethyl-allyl) -trimetylsilane

6 g (41.58 mmol) of 2- (Hydroxymethyl) allyltrimethylsilane, 20 mL of CH ₂ Cl ₂ and 11.6 mL (83.16 mmol) of Et ₃ N were added to a flame-dried 250 mL round-bottom flask. Using a dry ice-acetone bath, lower the temperature to -78 ° C and slowly add 4.8 ml (62.37 mmol) of Methanesulfonyl Chloride.

After the temperature was raised to −50 ° C. under stirring, 10.8 g (124.74 mmol) of LiBr was dissolved in 30 ml of THF. The dry ice-acetone bath was removed and stirred at room temperature for 4 hours, after which the reaction was terminated by addition of water and extracted with Pentane. The combined organic layers were washed with water and brine, dried over MgSO ₄ , filtered under a glass filter, concentrated under a rotary evaporator, and distilled under reduced pressure to give 6.5 g (76%, bp: 55-56 ° C / 6 mmHg) of the title compound. )

FT-IR (neat) 2956.1, 1628.7, 1250.2, 847.4 cm ⁻¹ ;

Step 4: Synthesis of Trimethyl- (2-tributhylstannylmethyl-allyl) -silane (III)

Connect the dropping funnel to the flame dried 100 ml two-neck-round bottom flask, add 335 mg (13.78 mmol) of Mg metal, and flame dry again for 30 minutes. 168 mg (0.46 mmol) of PbBr ₂ was added and flushed with nitrogen gas. Then, 10 mL of THF and 2.1 mL (7.74 mmol) of ClSnBu _{3 were} added thereto. Into a dropping funnel, a solution of 1.9 g (9.17 mmol) of (2-Bromomethyl-allyl) -trimetylsilane diluted with 3 ml of THF was added and dropped for 20 minutes, followed by further stirring for 1 hour, followed by addition of a buffer solution (pH 7). Terminate The organic layer extracted with hexane was washed with water and brine and dried over anhydrous Na ₂ SO ₄ . Concentrated by rotary evaporator, Short path column with Alumina and distillation under reduced pressure to obtain 2.26g (70%, bp: 102 ~ 105 ℃ / 0.1 mmHg) of the title compound Trimethyl- (2-tributhylstannylmethylallyl) -silane.

FT-IR (neat) 2957.3, 2924.5, 1615.3, 1460.5, 1250.1, 855.7 cm ⁻¹ ;

¹ H NMR (500 MHz, CDCl ₃ ) δ0.03 (s, 9H), 0.86 (t, J = 7.93, 6H), 0.89 (t, J = 7.33, 9H), 1.72-1.35 (m, 6H), 1.42 (d, J = 0.92, 2H), 1.45-1.52 (m, 6H), 1.72 (d, J = 0.92, 2H), 4.21 (dd, J = 0.91, 2.13, 1H), 4.37 (dd, J = 0.91, 2.14, 1H)

Example 2 Synthesis of 1-Phenyl-3-trimethylsilanylmethyl-but-3-en-1-ol (I)

4Å-Molecular sieve (0.2g) was added to a 15 ml Schlenk flask and flame-dried under reduced pressure (0.4 mmHg), followed by (R)-(-)-BINOL (7 mg, 0.0245 mmol) and CF ₃ in a nitrogen atmosphere. Ph 0.5 mL and Ti (O- i Pr) ₄ (0.13 M in CF ₃ Ph 188 μl, 0.0245 mmol) were added and stirred at 40 ° C. for 2 hours. After cooling to room temperature, HOCH (CF ₃ ) ₂ (0.5 M in CF ₃ Ph 98 μl, 0.049 mmol) was added thereto and stirred at 40 ° C. for 2 hours. Remove the solvent under reduced pressure, add 0.5 ml of toluene and stir for 5 minutes, and then completely evaporate the solvent under reduced pressure.

0.5 ml of CF ₃ Ph was added and stirred for 5 minutes. After cooling to −20 ° C., PhCHO (37.2 mg, 0.3492 mmol) was diluted with 0.1 ml of CF ₃ Ph. Trimethylsilylmethylallyltin (175 mg, 0.4193 mmol) was diluted in 0.3 ml of CF ₃ Ph and slowly poured into the base wall while flowing. The reaction was terminated by adding a buffer solution (pH = 7) to the resultant solution stirred for 20 hours. Extracted with Et ₂ O (× 3), washed with water and brine and dried over anhydrous Na ₂ SO ₄ . Filter through a glass filter, concentrate under reduced pressure, and purified by column chromatography to give the title compound (66.3 mg, 81%).

TLC, Rf = 0.27 (15: 1 Hex: EA);

[α] _D ²⁵ 22.08 (c = 0.23, CHCl ₃ ), 96% ee;

FT-IR (neat) 3404.7 (br), 3069.9, 2953.6, 1631.7, 1250.0, 848.3 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ0.03 (s, 9H), 1.58 (dd, J = 0.92, 13.42, 1H), 1.63 (dd, J = 0.92,13.42,1H), 2.29 (d, J = 2.13,1H), 2.35 (d, J = 9.46, 1H), 2.37 (dd, J = 0.92, 3.94, 1H), 4.74 (d, J = 0.92, 1H), 4.78 (d, J = 0.92, 1H ), 4.80 (d, J = 3.97, 1H), 7.33-7.39 (m, 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ −0.95, 26.93, 49.48, 71.57, 111.49, 126.16, 127.81, 128.80, 144.44, 144.82.

Example 3: 1-Phenyl-5-trimethylsilanylmethyl-hex-5-en-3-ol (II)

Following the same procedure as in Example 2, however, the title compound was obtained in 74% yield using Hydrocinnamaldehyde.

TLC, Rf = 0.6 (3: 1 Hex.:EA); [α] _D ²⁵ -25.23 (c = 0.12, CHCl ₃ ), 82% ee;

FT-IR (neat) 3390.2 (br),, 3027.7, 2951.9, 1630.8, 1249.1, 849.0 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ0.03 (s, 9H), 1.50 (d, J = 3.2, 1H), 1.58 (d, J = 3.2, 1H), 1.77-1.83 (m, 2H), 1.91 (s, 1H), 2.07 (dd, J = 9.38, 13.78, 1H), 2.19 (ddd, J = 1.15,3.52, 13.78, 1H), 2.72 (ddd, J = 7.04, 9.38, 13.78, 1H), 2.85 (ddd, J = 6.46, 9.38, 13.78, 1H), 3.74, (m, 1H), 4.70 (d, J = 1.17, 1H), 4.71 (d, J = 1.17, 1H), 7.20-7.31 (m , 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ-0.68, 27.37, 32.08, 39.40, 47.38, 68.60, 111.19, 126.48, 129.07, 129.15, 142.89, 145.28

Example 4: 2-Trimethylsilanylmethyl-dec-1-en-4-ol (III)

Following the same procedure as in Example 2, the title compound was obtained in 52% yield using Heptnaldehyde.

TLC, Rf = 0.23 (30: 1 Hex.:EA); [α] _D ²⁵ -30.18 (c = 0.0625, CHCl ₃ ), 96% ee FT-IR (neat) 3405.4 (br), 2956.4, 2928.8, 1631.2, 1249.7, 852.2 cm ⁻¹ ;

¹ H NMR (500 MHz, CDCl ₃ ) δ0.03 (s, 9H), 0.89 (t, J = 6.89, 3H), 1.30-1.36 (m, 8H), 1.43-1.49 (m, 2H), 1.52 ( d, J = 3.20, 1H), 1.59 (d, J = 2.90, 1H), 1.84 (d, J = 2.34, 1H), 2.00 (dd, J = 9.68, 13.79, 1H), 2.16 (dd, J = 1.96, 13.79, 1H), 3.69 (s, 1H), 4.69 (d, J = 6.74, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ- 0.68, 14.79, 23.32, 26.46, 27.34, 30.08, 32.55, 37.75, 47.33, 69.24, 111.03, 145.52

Example 5: 1-Phenyl-5-trimethylsilanylmethyl-hexa-1,5-dien-3-ol (IV)

Following the same procedure as in Example 2, the title compound was obtained in 48% yield using Cinnamaldehyde.

TLC, Rf = 0.49 (3: 1 Hex.:EA); [α] _D ²⁵ -11.71 (c = 0.035, CHCl ₃ ), 93% ee;

FT-IR (neat) 3444.9 (br), 3055.7, 2956.0, 1630.5, 1265.3, 853.0 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ0.05 (s, 9H), 1.58 (d, J = 13.43, 1H), 1.63 (d, J = 13.43, 1H), 2.02 (d, J = 2.64, 1H ), 2.24 (dd, J = 9.09, 13.79, 1H), 2.30 (ddd, J = 0.88, 4.40, 13.79, 1H), 4.42 (m, 1H), 4.74 (t, J = 0.88, 1H), 4.77 ( t, J = 0.88, 1H), 6.23 (d, J = 15.84, 1H), 6.64 (d, J = 15.84, 1H), 7.21-7.40 (m, 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ: 0.66, 27.41, 47.52, 70.44, 111.74, 127.16, 128.26, 129.25, 130.69, 132.37, 137.51, 144.62

Example 6 Synthesis of 5-Hydroxy-7-trimethylsilanylmethyl-oct-7-enoic acid ethylester (V)

4Å-Molecular sieve (0.2g) was added to a 15 ml Schlenk flask and flame-dried under reduced pressure (0.4mmHg), followed by (R)-(-)-BINOL (7 mg, 0.0245 mmol) and CF ₃ Ph in a nitrogen atmosphere. 0.5 mL and Ti (O- i Pr) ₄ (0.13 M in CF ₃ Ph 188 μl, 0.0245 mmol) were added and stirred at 40 ° C. for 2 hours. Cool to room temperature and add HOCH (CF ₃ ) ₂ (0.5 μl in CF ₃ Ph 98 μl, 0.049 mmol) and stir at 40 ° C. for 2 hours. Remove the solvent under reduced pressure, add 0.5 ml of toluene and stir for 5 minutes, and then completely evaporate the solvent under reduced pressure.

0.5 ml of CF ₃ Ph was added and stirred for 5 minutes. After lowering the temperature to -20 ° C., Aldehyde (70.5 mg, 0.4889 mmol) was diluted with 0.1 ml of CF ₃ Ph. To this, trimethylsilylmethyl-allyltin (245 mg, 0.5867 mmol) was diluted in 0.3 ml of CF ₃ Ph and slowly poured into the base wall. The reaction was terminated by adding a buffer solution (pH = 7) to the resultant solution stirred for 20 hours. Extracted with Et ₂ O (× 3), washed with water and brine and dried over anhydrous Na ₂ SO ₄ . Filter through a glass filter, concentrate under reduced pressure and purify by column chromatography to give the title compound (61.3 mg, 46%).

TLC, Rf = 0.34 (4: 1 Hex .: EA);

[α] _D ²⁵ -13.97 (c = 0.115, CHCl ₃ ), 91% ee

FT-IR (neat) 3484.0 (br), 3073.6, 2953.7, 1735.1, 1631.3, 1248.6, 851.0 cm ⁻¹ ;

¹ H NMR (500MHz, CDCl ₃ ) δ0.03 (s, 9H), 1.25 (t, J = 7.04, 3H), 1.48 (d, J = 2.05, 2H), 1.51 (d, J = 7.33, 1H ), 1.57 (d, J = 13.49, 1H), 1.67-1.86 (m, 2H), 1.93 (d, J = 2.35, 1H), 2.01 (dd, J = 9.39, 13.49, 1H), 2.12 (dd, J = 3.12, 13.49, 1H), 2.33 (t, J = 7.33, 2H), 3.68-3.73 m, 1H), 4.12 (dd, J = 7.04, 7.34, 1H), 4.13 (dd, J = 7.04, 7.34 , 1H), 4.69 (d, J = 3.52, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ −0.70, 14.95, 21.93, 27.33, 34.91, 37.00, 47.30, 60.45, 68.80, 111.14, 145.25, 174.37.

Example 7: 6-Hydroxy-8-trimethylsilanylmethyl-non-8-en-2-one (VI)

Following the same procedure as in Example 6, using 5-Oxo-hexanal gave the title compound in 84% yield.

TLC, Rf = 0.30 (4: 1 Hex .: EA);

[α] _D ²⁵ -12.78 (c = 0.20, CHCl ₃ ), 94% ee;

FT-IR (neat) 3430.2 (br), 3073.9, 2951.4, 1713.5, 1631.9, 1417.4,1248.8, 854.8 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.03 (s, 9H), 1.42 to 1.48 (m, 2H), 1.52 (s, 1H), 1.56 (s, 1H), 1.65 to 1.72 (m, 2H), 1.95 (d, J = 2.26, 1H), 2.01 (dd, J = 9.42, 13.67), 2.12 (d, J = 3.39, 1H), 2.15 (S, 3H), 2.48 (t, J = 7.16, 2H) , 3.64 to 3.74 (m, 1H), 4.69 (s, 2H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 20.43, 27.03, 30.29, 36.71, 43.98, 47.02, 68.61, 110.83,144.98, 209.46.

Example 8 10-hydroxy-12-trimethylsilanylmethyl-trides-12-en-5-one (VII)

Following the same procedure as in Example 6, 6-Oxo-decanal was used to obtain the title compound in a yield of 87%.

TLC, Rf = 0.40 (4: 1 Hex .: EA);

^{_{[α] D 25- -13.59 (c}} = 0.0325, CHCl 3), 88% ee;

FT-IR (neat) 3488.4, 2995.0, 1713.8, 1630.9, 1249.0, 850.6 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.07 (s, 9H), 0.90 (t, J = 7.33, 3H), 1.31 (ddd, J = 7.63, 7.63, 7.33, 2H), 1.43 to 1.50 (m, 4H), 1.54-1.59 (m, 6H), 1.86 (d, J = 2.34,1H), 2.00 (dd, J = 9.39, 13.50, 1H), 2.14 (dd, J = 3.23, 13.79, 1H), 2.39 (t, J = 7.33, 1H), 2.42 (t, J = 7.33, 1H), 3.68-3.70 (m, 1H), 4.69 (d, J = 2.64, 2H)

Example 9 Synthesis of 4-methylene-2-phenethyl-6-phenyl-tetrahydropyran (VIII)

[Step 1]

In a flame-dried 10 ml round-bottom flask, Acetal (90.1 mg 0.4999 mmol) and 0.5 ml CH ₂ Cl ₂ were added and cooled to 0 ° C., followed by BCl ₃ (167 l, 1M-Solution in Hexane, 0.167 mmol) Apply slowly After stirring for 2 hours while raising the temperature to room temperature, the resulting solution was concentrated under reduced pressure carefully [flask (1)].

Into a flame-dried 10 ml round-bottom flask, alcohol (58.6 mg, 0.2499 mmol), 0.6 ml CH ₂ Cl ₂ and i Pr ₂ NEt (87.1 µl, 0.4999 mmol) were cooled to 0 ° C. The contents of the flask (1) obtained above were dissolved in 0.5 ml of CH ₂ Cl ₂ . The mixture was stirred for 20 hours while gradually increasing the temperature. The resulting solution was terminated with water, extracted with Et ₂ O, washed with NaHCO ₃ , water, brine and dried over MgSO ₄ . After filtration under reduced pressure with a glass filter, the resultant was concentrated under reduced pressure with a rotary evaporator. The resulting solution was subjected to column chromatography to obtain a product (82 mg, 86%).

[Step 2]

1.2 ml of CH ₂ Cl ₂ and 50 µl of 0.1 M-TMSNTf ₂ were added to a flame-dried 5 ml round-bottom flask, and the temperature was lowered to -78 ° C. To this was added a compound prepared from Phenethyl allylsilane prepared in step 1 (19 mg, 0.0497 mmol) in 0.3 ml of CH ₂ Cl ₂ , using a Syring pump for 1 hour. After 30 minutes more stirring, water was added to the resultant solution to terminate the reaction. Extracted with Et ₂ O (× 3), washed with water and brine, dried over anhydrous Na ₂ SO ₄ , filtered with a glass filter, concentrated under reduced pressure, and the resulting oil was subjected to column chromatography to give the title compound (13.3 mg). , 96%).

TLC, Rf = 0.28 (50: 1 Hex .: EA);

FT-IR (neat) 3028.4 (br), 2941.9, 2855.7, 1653.0, 1451.9, 1094.7, 1060.6, 891.6 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.85 (ddd, J = 4.27, 7.02, 9.46, 13.73 1H), 1.99 (dddd, J = 5.49, 7.93, 9.46, 13.73, 1H), 2.09 (ddd, J = 1.52, 12.21, 12.21, 1H), 2.24 (dd, J = 1.83, 2.14, 1H), 2.29 (dd, J = 1.83, 2.14, 1H), 2.48 (ddd, J = 1.83, 2.14, 13.44, 1H) , 2.75 (ddd, J = 7.02, 9.15, 13.73, 1H), 2.84 (ddd, J = 5.49,9.46, 13.73, 1H), 3.44 (dddd, J = 2.44, 4.27, 7.94, 11.29, 1H), 4.32 ( dd, J = 2.44, 11.59, 1H), 4.79 (dd, J = 1.83, 3.97, 1H), 7.17-7.42 (m, 10H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 32.39, 38.60, 41.29, 43.43, 78.35, 80.60, 109.52, 126.41, 126.48, 128.06, 129.02, 129.21, 142.95, 143.38, 145.41.

Example 10 2-Benzyl-4-methylene-6-phenyl-tetrahydro-pyran (IX)

According to the same procedure as in Example 9, the title compound was obtained.

TLC, Rf = 0.21 (50: 1 Hex .: EA);

FT-IR (neat) 3031.2 (br), 2946.3, 2855.3, 1653.2, 1452.5, 1246.8, 1083.9, 844.2 cm ⁻¹ ;

¹ H NMR (500 MHz, CDCl ₃ ) δ2.06 (ddd, J = 1.53, 11.29, 11.29, 1H), 2.20 (dddd, J = 1.53, 11.91, 11.91, 1H), 2.24 (ddd, J = 1.83, 13.13, 13.13, 1H), 2.45 (ddd, J = 2.14, 13.44, 13.44, 1H), 2.82 (dd, J = 6.41, 13.74, 1H), 3.08 (dd, J = 5.81, 13.44, 1H), 3.68 ( dddd, J = 2.44, 6.41, 6.41, 11.29, 1H), 3.34 (dd, 1H), 4.74 (t, J = 1.83, 1H), 4.77 (t, J = 1.83, 1H), 7.20-7.39 (m, 10H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 40.57, 43.51, 43.54, 80.12, 80.83, 109.68, 126.44, 126.89, 128.03, 128.90, 128.99, 130.31, 145.17.

Example 11 2-Hexyl-4-methylene-6-phenyl-tetrahydro-pyran (X)

The title compound was obtained following the same procedure as in Example 9.

TLC, Rf = 0.26 (50: 1 Hex .: EA);

FT-IR (neat) 3031.0 (br), 2927.9, 2857.1 1653.6, 1458.0, 1125.0 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.99 (t, J = 7.03, 3H), 1.25 to 1.56 (m, 11H), 1.66 (ddd, J = 4.88, 6.72, 13.13, 1H), 2.03 (ddd , J = 1.53, 1.83, 13.13, 1H), 2.22 (dddd, J = 0.31, 1.53, 13.13, 1H), 2.29 (ddd, J = 2.14, 2.14, 13.43, 1H), 2.47 (ddd, J = 1.83, 2.14, 13.13, 1H), 3.43 (dddd, J = 2.45, 5.20, 6.71, 11.29, 1H), 4.32 (dd, J = 2.45, 11.29, 1H), 4.79 (t, J = 1.84, 2H), 7.25- 7.40 (m, 5 H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.81, 23.38, 26.13, 30.41, 32.58, 37.07, 41.27, 43.55, 79.57, 80.73, 109.25, 126.51, 128.01, 143.45, 145.78

Example 12 2-Hexyl-4-methylene-6-phenethyl-tetrahydro-pyran (XI)

The title compound was obtained following the same procedure as in Example 9.

TLC, Rf = 0.25 (50: 1 Hex .: EA);

FT-IR (neat) 3027.6 (br), 2929.4, 2856.1, 1652.7, 1455.9, 1263.4, 803.3 cm ⁻¹ ;

¹ H NMR (500 MHz, CDCl ₃ ) δ 0.99 (t, J = 7.04, 3H), 1.25-1.36 (m, 6H), 1.43-1.54 (m, 3H), 1.57-1.64 (m, 1H), 1.69-1.76 (m, 2H), 1.86-1.97 m, 3H), 2.18 (ddd, J = 1.76, 2.05, 14.23, 2H), 2.70 (dd, J = 7.62, 8.80, 13.78, 1H), 2.81 (ddd , J = 5.28, 9.39, 13.49, 1H), 3.20 (dddd, J = 2.35, 4.11, 8.80, 12.88, 1H), 4.67 (ddd, J = 1.76, 1.76, 7.04, 2H), 7.17-7.29 (m, 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 14.82, 23.37, 26.39, 30.03, 32.49, 32.58, 37.13, 38.64, 41.76, 41.81, 79.08 ,, 108.78, 126.37, 128.97, 129.23, 142.98, 145.93.

Example 13: 4- (4-methylene-6-phenethyl-tetrahydropyran-2-yl) butyric acid ethyl ester (XII)

The title compound was obtained following the same procedure as in Example 9.

TLC, Rf = 0.29 (15: 1 Hex .: EA);

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.26 (t, J = 7.04, 3H), 1.57 to 1.66 (m, 2H), 1.70 to 1.79 (m, 2H), 1.87 (ddd, J = 3.81, 3.81 , 4.96, 1H), 1.90 (ddd, J = 3.81, 3.81, 4.96, 1H), 1.91-1.97 (m, 2H), 2.16-2.21 (m, 2H), 2.35 (ddd, J = 4.11, 7.04, 8.22 , 2H), 2.69 (ddd, J = 7.60, 9.10, 13.79, 1H), 2.81 (ddd, J = 5.28, 7.04, 9.39, 13.50, 2H), 3.21 (m, 2H), 4.17 (ddd, J = 7.04 , 7.04, 7.33, 2H), 4.68 (ddd, J = 2.05, 2.05, 2.64, 2H), 7.16-7.29 (m, 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 0.66, 14.95, 21.78, 32.47, 34.95, 36.36, 38.60, 41.64, 78.59, 108.98, 126.37, 128.98, 129.18, 142.92, 145.55, 174.32.

Example 14 Synthesis of 4-methylene-2-phenethyl-1,7-dioxa-spiro [5,5] undecane (XIII)

[Step 1]

Into a flame-dried 10 ml round-bottom flask, alcohol (75 mg, 0.2858 mmol), Et ₃ N (80 µl, 0.4286 mmol) and 1 ml CH ₂ Cl ₂ were added and cooled to -10 ° C. TMSCl (54 Μl, 0.4255 mmol) is added slowly. The resultant was stirred while raising the temperature to room temperature. The resulting solution was terminated with water, and the organic layer extracted with Et ₂ O was washed with NaHCO ₃ , water and brine, dried over MgSO _4, and filtered under reduced pressure. The compound concentrated under reduced pressure with a rotary steam machine was used as it is for the next reaction or purified by Flash column chromatography to obtain a product (87.6 mg, 91%).

[Step 2]

Into a flame-dried 5 ml round-bottom flask, 1 ml of O-silyl allylsilan compound (16.5 mg, 0.049 mmol), dimethoxypyran (7.9 mg, 0.054 mmol) and CH ₂ Cl _{2 prepared in step} 1 were added. Lower the temperature to 78 ° C. 49 μl of 0.1M-TMSNTf ₂ is slowly added to the wall. After stirring for 1 hour, water was added to the resultant solution to terminate the reaction. Extract with Et ₂ O, wash the combined organic layers with water and brine, dry the organic layer with anhydrous Na ₂ SO ₄ , filter with a glass filter and concentrate under reduced pressure. The resulting oil was purified by column chromatography to give the title compound (10.2 mg, 75%).

TLC, Rf = 0.41 (15: 1 Hex .: EA);

FT-IR (neat) 3027.1, 2942.2, 2869.9, 1655.6, 1450.6, 997.5 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.49 to 1.52 (m, 2H), 1.55 to 1.61 (m, 2H), 1.78 to 2.00 (m, 5H), 2.16 (dddd, J = 1.17, 1.76, 1.76 , 13.79, 1H), 2.26 (ddd, J = 2.06, 2.06, 13.50, 1H), 2.27 (dd, J = 1.17, 14.08, 1H), 2.67 (ddd, J = 5.87, 10.56, 14.08, 1H), 2.94 (ddd, J = 5.57, 10.85, 13.97, 1H), 3.58 (d, J = 2.05, 1H), 3.60 (d, J = 2.35, 1H), 3.60 (d, J = 2.35, 1H), 3.67 (dddd , J = 2.35, 4.10, 8.51, 9.38, 1H), 4.76 (d, J = 2.05, 1H), 4.80 (d, J = 2.05, 1H), 7.18 to 7.30 (m, 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 19.52, 25.76, 32.91, 3614, 38.52, 40.77, 45.77, 45.78, 61.59, 70.20, 110.70, 126.43, 129.00, 129.02, 142.66, 142.98.

Example 15 Synthesis of 9-methylene-7-phenethyl-1,6-dioxa-spiro [4,5] decane (XIV)

In a flame-dried 5 ml round-bottom flask, the O-silyl allylsilan compound (16.5 mg, 0.049 mmol), dimethoxypyran (7.2 mg, 0.0545 mmol) and CH ₂ Cl ₂ 1 prepared in Step 1 of Example 14 were prepared. Put ㎖ and lower the temperature to -78 ℃. 49 μl of 0.1M-TMSNTf ₂ is slowly added to the wall. After stirring for 1 hour, water was added to the resultant solution to terminate the reaction. The same treatment as in Example 14 gave the title compound (9.9 mg, 78%).

TLC, Rf = 0.44 (15: 1 Hex: EA);

FT-IR (neat) 3027.2, 2941.3, 2887.3, 1655.2, 1454.1, 1021.0 cm ^-1 ;

¹ H NMR (500 MHz, CDCl ₃ ) δ1.72-1.79 (m, 2H), 1.80-1.85 (m, 1H), 1.88-1.93 (m, 1H), 1.97 (ddd, J = 1.51, 11.38, 12.90 , 1H), 2.03 (dd, J = 3.23, 8.51, 1H), 2.10 (dddd, J = 2.64, 2.93, 5.28, 5.58, 17.02, 1H), 2.24 (ddd, J = 1.76, 1.95, 13.10, 1H) , 2.31 (dd, J = 1.46, 13.49, 1H), 2.50 (ddd, J = 1.46, 1.47, 13.49, 1H), 2.62 (ddd, J = 6.16, 9.68, 14.08, 1H), 2.79 (ddd, J = 5.58, 9.98, 13.78, 1H), 3.74 (dddd, J = 2.35, 4.11, 8.51, 13.20, 1H), 3.85 (ddd, J = 6.16, 8.21, 8.22, 1H), 3.92 (ddd, J = 5.58, 8.21 , 8.22, 1H), 4.78-4.79 (m2H), 7.17-7.27 (m, 5H);

¹³ C NMR (125 MHz, CDCl ₃ ) δ 24.43, 32.60, 38.14, 38.35, 40.72, 42.84, 67.96, 70.85, 107.02, 110.35, 126.40, 129.00, 129.08, 142.96, 143.24.

According to the invention, optically active hydroxysilane derivatives of formula (II) and optical activities of formula (I) which are useful as starting materials of various drugs and bioactive substances or as chiral bildilblocks for introducing chiral tetrahydropyran units , 2-disubstituted 4-methylene-tetrahydropyran derivatives can be readily prepared. According to the present invention there is also provided a compound of formula (III) which is a chiral catalyst and allyl transition reagent which can be used in the preparation of such compounds.

Claims (14)

An optically active pyran compound of formula (I) [Formula I] or (I) In said Formula (I), R <^1> is a (i) alkyl group of 1-10 carbon atoms; (Ii) a C1-C10 alkenyl group or alkynyl group containing one or more double bonds; (Iii) a substituted or unsubstituted aromatic group; (Iii) a group derived from the compound of formula (VI): [Formula VI] (In formula VI, R is lower alkyl, lower alkoxy, substituted or unsubstituted phenyl group, n is selected from 0 or an integer from 2 to 10.); Or (iii) a protected hydroxy group (a hydrocarbon group having 1 to 10 carbon atoms having a protecting group, wherein the protecting group is selected from benzyl, trialkylsilyl and tetrahydrofuran), R ² is (i) an alkyl group having 1 to 10 carbon atoms; (Ii) an alkoxy group having 1 to 10 carbon atoms; (Iii) a substituted or unsubstituted benzyl group, R ³ represents H, or R ² and R ³ together with the carbon atoms to which they are attached In which n is 1 or 2, in which case the oxa (—O—) group is in antiposition with R ¹ ; X and Y each independently represent a halogen or an alkoxy group. The compound of claim 1, wherein R ¹ is selected from methyl, phenyl, phenylethyl, benzyl, and R ² is selected from methyl, ethyl, propyl, hexyl, phenyl, benzyl, phenylethyl. Optically active hydroxyalkylsilane derivatives of formula (II) [Formula II] Wherein R ¹ represents Ph-, PhCH ₂ CH _2- , C ₆ H _13- , PhCH = CH-, EtO ₂ CCH ₂ CH ₂ CH _2- , BnOCH _2- , and R ² represents Ph-, PhCH ₂ CH _2- , C ₆ H ₁₄ -or MeO-. An optically active hydroxysilane derivative of formula (II) characterized by reacting an allylorganosilicon compound of formula (III) with an aldehyde compound of formula (IV) in the presence of a chiral Lewis acid catalyst Manufacturing method. [Formula II] (II) [Formula III] (III) [Formula IV] R ₁ CHO (IV) Wherein R ₁ represents Ph-, PhCH ₂ CH _2- , C ₆ H _13- , PhCH = CH-, EtO ₂ CCH ₂ CH ₂ CH _2- , BnOCH _2- , and R ⁴ represents 1 to 6 carbon atoms R ⁵ represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group.) The method according to claim 4, wherein the chiral Lewis acid catalyst is ( R )-or ( S ) -BINOL-Ti [OCH (CF ₃ )] ₂ . The process according to claim 4 or 5, wherein the reaction is carried out in a solvent, wherein the solvent used is trifluoromethylbenzene. The optically active hydroxysilane derivative of formula (II) is reacted with trimethylsilyl chloride to protect the hydroxy group, reacted with an aldehyde derivative of formula (Va) or (Vb) and then treated with a Lewis acid catalyst such as TMSNTf ₂ A process for preparing an optically active 2,6-disubstituted 4-methylenetetrahydropyran derivative of formula (I) [Formula I] or [Formula II] [Formula V] (Va) or (Vb) Wherein R ₁ is alkyl, aryl or aralkyl, preferably Ph-, PhCH ₂ CH _2- , C ₆ H _13- , PhCH = CH-, EtO ₂ CCH ₂ CH ₂ CH _2- , BnOCH _2- R ₂ represents alkyl, aryl, aralkyl, or alkoxy, preferably PhCH ₂ CH ₂ , C ₆ H ₁₄ or MeO, R ₃ represents H, or R ₂ and R ₃ to which they are attached With carbon atoms In which n is 1 or 2, in which case the oxa (—O—) group is in antiposition with R ₁ ; X and Y each independently represent a halogen or alkoxy group, n is 1 or 2, and R ⁵ represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group.) 8. The method according to claim 7, wherein the optically active pyran compound is prepared by the reaction of the following formula (II) and the following formula (V). [Formula II] [Formula V] Cl (MeO) CHR ² (Wherein R ¹ , R ² and R ⁵ are as defined in claim 7). The compound according to claim 7 or 8, wherein the formula (II) is reacted with triethylamine and trialkylchlorosilane to protect a hydroxy group with a silyl group, and the formula (V) is triisomethyl which is diisopropyl epitamine and a Lewis acid. A process for preparing an optically active pyran compound of formula (I) by reaction with silylhexafluoromethanesulfonamine [TMSN (SO ₂ CF ₃ ) ₂ ]. The process according to claim 7 or 8, which proceeds in a temperature range of -78 ° C to 0 ° C. Process according to claim 10, in particular in a low temperature reaction below -40 ° C. The process according to claim 7 or 8, wherein the reaction is carried out in an organic solvent selected from the group consisting of dichloromethane, tetrahydrofuran and diethyl ether. A compound of formula (III) [Formula (III)] (III) (In the formula, R ⁴ represents a lower alkyl group having 1 to 6 carbon atoms; R ⁵ represents a substituted or unsubstituted lower alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group.) The compound of formula (III) according to claim 13, wherein R ⁴ is a butyl group and R ⁵ is methyl.