JP3471067B2 - Method for producing optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to an optically active 6- (4-substituted inden-1-yl) -useful as an intermediate for pharmaceuticals.
The present invention relates to a method for producing 2-methyl-4-hepten-3-ols. More specifically, 4- (4-substituted inden-1-yl) -2-pentenal and diisopropylzinc are reacted with each other in the presence of an optically active N , N -dialkylaminoalcohol to give a highly optically active 6- (4-
The present invention relates to a method for producing a substituted inden-1-yl) -2-methyl-4-hepten-3-ols in good yield.

[0002]

2. Description of the Related Art Conventionally, the problems to be solved by the invention
As a method for producing an optically active secondary alcohol by asymmetrically adding a dialkylzinc to an aldehyde using an optically active N , N -dialkylaminoalcohol as an asymmetric catalyst, the following method is available. Are known. In that case, Japanese Patent Laid-Open No. 64-68. Oguni et al., JP-A-1-313445. (2) Japanese Unexamined Patent Publication No. 2-142742. (2) Japanese Patent Application Laid-Open No. 2-212452. And Noyori et al., Angew. Chem. Int. Ed. Engl., 30, 49 (199
1) and references cited therein. So, J. Org. Chem., 56, 4264 (1991) and references cited therein.

Among these prior arts, in the patents (~), examples of the alkyl group of dialkylzinc include methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group and hexyl group. Although a saturated hydrocarbon group having 1 to 6 carbon atoms is mentioned, what is actually described in the examples is a methyl group, an ethyl group and a butyl group, which are limited to primary alkyl groups and No examples are given using secondary alkyl groups. Also in the prior art, the research subjects are mainly methyl group, ethyl group, propyl group, butyl group, pentyl group and vinyl group, and there is only one example of isopropyl group. According to the experimental example, when the isopropyl group is used, the yield may be due to the instability of the intermediate active species.
Both the chiral induction rates tend to decrease.

As the inventors of the present invention have proposed separately, saturated aldehydes and diisopropylzinc are used as optically active N , N--
It was shown that when the reaction was carried out in the presence of dialkylamino alcohols, the corresponding isopropylated product was obtained in the form of an optically active substance. At this time, the present inventors usually have the optical activity
When the asymmetric isopropylation reaction was carried out under the conditions of using N , N -dialkylamino alcohols in an amount of 5 to 10 mol% with respect to saturated aldehydes, the desired isopropylation product was obtained only in a low yield. , Optically active N , N-
As a result of various studies on the addition amount of dialkylamino alcohols, it was found that there is an optimum region around 20 mol% with respect to saturated aldehydes. However, even under this optimum condition, the reaction yield was never satisfactory.

When the present inventors carry out an asymmetric isopropylation reaction using diisopropylzinc in the presence of optically active N , N -dialkylaminoalcohols, the further reaction is performed while maintaining a high asymmetric induction rate. As a result of extensive studies aimed at improving the yield, α, instead of saturated aldehydes,
The inventors have found that if β-unsaturated aldehydes are selected as a substrate, asymmetric isopropylation proceeds in high yield while maintaining a high asymmetric induction rate, and thus the present invention has been accomplished.

[0006]

That is, the present invention provides the following formula (I):

[0007]

[Chemical 8]

[In the formula, X represents a case where an oxygen atom, a (E) -bromomethylene group, or a hydrogen atom at the α-position and an -OR group at the β-position are substituted (wherein R is 2 to 2 carbon atoms). 8 represents an acyl group, tri (hydrocarbon group having 1 to 6 carbon atoms) substituted silyl group, or 1- (alkoxy group having 1 to 4 carbon atoms) substituted alkyl group having 1 to 6 carbon atoms), wavy line Represents either one of the E and Z isomers of the double bond, or a mixture thereof. ] 4- (4-substituted inden-1-yl) -2-pentenals represented by the following formula (II)

[0009]

[Chemical 9]

The compound represented by the following formula (III) is characterized in that it is reacted with diisopropylzinc represented by the formula (1) in the presence of optically active N , N -dialkylamino alcohols.

[0011]

[Chemical 10]

[In the formula, X and the wavy line are the same as defined in the above formula (I), and * indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] The optically active 6- (4-substituted inden-1-yl) represented by
-Method for producing 2-methyl-4-hepten-3-ols,
And an optically active 6- (4-substituted inden-1-yl) -2-methyl-4-heptene-represented by the above formula (III)
3-all.

The 4- (4-substituted inden-1-yl) -2-pentenals used as a raw material in the method of the present invention are selected from olefins using, for example, vitamin D ₂ potassium permanganate and sodium metaperiodate. 4- (4-substituted inden-1-yl), which is a common intermediate, is obtained by the following process using a selective oxidative cleavage reaction as a key reaction.
It can be obtained by being induced by an individual reaction route via a 2-pentenoic acid ester and a difference in the substitution pattern of X in the formula below. 4- (4-Substituted inden-1-yl) -2-pentenoic acid
Ester synthesis

[0014]

[Chemical 11]

In the above reaction formula, —OR represents a protected hydroxyl group, and R as a protecting group has, for example, 2 to 2 carbon atoms.
As a protective group for a hydroxyl group, such as an acyl group having 8 carbon atoms, a silyl group substituted with tri (hydrocarbon group having 1 to 6 carbon atoms), or an alkyl group having 1- (alkoxy group having 1 to 4 carbon atoms) substitution Conventionally known ones can be cited. Also, -CO
OR ⁰ represents a carboxylic acid ester group, and examples of R ⁰ of the alkoxy group (OR ⁰ ) include an alkyl group having 1 to 8 carbon atoms.

For example, 4- represented by the above formula (I)
In the case of (4-substituted inden-1-yl) -2-pentenal, when the substituent X is an oxo group,

[0017]

[Chemical 12]

When the substituent X is an (E) -bromomethylene group,

[0019]

[Chemical 13]

When the substituent X is a hydrogen atom at the α-position and a hydroxyl group (--OR) protected at the β-position,

[0021]

[Chemical 14]

The 4- (4-substituted indene represented by the above formula I (including (Ia), (Ib), and (Ic)), which is a starting material of the present invention, through the synthetic route of -1-Iyl) -2-pentenal compound is obtained.

In the above formula (I) in the method of the present invention, X represents a case where an oxygen atom, (E) -bromomethylene group, or a hydrogen atom at the α-position and an —OR group at the β-position are substituted (provided that , R is an acyl group having 2 to 8 carbon atoms, a tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group, or 1
-(C1-4 alkoxy group) substituted C1-6
Represents an alkyl group. ), The wavy line represents either one of the E and Z isomers of the double bond, or a mixture thereof.

When X is an oxygen atom, the above formula (I) has the form of the above formula (Ia), and when X is an (E) -bromomethylene group, the above formula (I) is The above formula (I-
In the form of b), where X is a hydrogen atom at the α-position and a hydroxyl group protected at the β-position, the above formula (I) is represented by the above formula (Ic).

Examples of the acyl group having 2 to 8 carbon atoms for R include acetyl group, propionyl group, butyryl group, pivaloyl group, hexanoyl group, cyclohexanoyl group, benzoyl group, ethoxycarbonyl group, and the like. Are acetyl group, pivaloyl group, benzoyl group and ethoxycarbonyl group.

Examples of the tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group of R include a triethylsilyl group, a triisopropylsilyl group, a t-butyldimethylsilyl group, and a t-butyldiphenylsilyl group. However, a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group are preferable.

1-of R (alkoxy group having 1 to 4 carbon atoms)
A substituted alkyl group having 1 to 6 carbon atoms is understood to be a group that forms an acetal bond with the oxygen atom to which it is bound, and examples of such groups include a methoxymethyl group, a 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy) methyl group, benzyloxymethyl group, 2-
Examples thereof include a tetrahydropyranyl group, and preferably
Examples thereof include methoxymethyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy) methyl group and 2-tetrahydropyranyl group.

R shown here is a group which functions as a protective group for a hydroxyl group, and (1) 4- (4-
When synthesizing a substituted inden-1-yl) -2-pentenal compound, (2) diisopropyl zinc is used as an optically active N , N-
In order to exert the effect of the optically active N , N -dialkylaminoalcohol when it is reacted with an aldehyde in the presence of the dialkylaminoalcohol, (3) the 6- (4-substituted indene-1 obtained by the present production method is used. -Ill-
It is understood that it functions to distinguish the two hydroxyl groups of 2-methyl-4-hepten-3-ols. Therefore, a group satisfying such three functions can be a substitute for R.

The diisopropylzinc represented by the above formula (II) is a known compound, and can be prepared by a known method (for example, CR
Noller, “Organic Syntheses”, Coll. Vol.II, p18
4, John Wiley & Sons (1943)), easily obtained and used.

The method of the present invention is carried out in the presence of optically active N , N -dialkylaminoalcohols capable of coordinating to diisopropylzinc to promote the isopropylation reaction and give a field of asymmetric reaction. It has the desired effect. Optical activity that exerts this effect
As N , N -dialkylamino alcohols, optically active β- ( N , N -dialkylamino) alcohols and optically active γ- ( N , N -dialkylamino) alcohols have been studied, and particularly, optically active β- ( N ,
Numerous studies on N -dialkylamino) alcohols have been reported (see, for example, the above-mentioned prior art documents).
Among the optically active β- ( N , N -dialkylamino) alcohols, 1-alkylpyrrolidin-2-ylmethanol derivatives (prior literature, and) and 2-dialkylamino-1-phenyl-1-propanol derivatives (prior art) It has been well studied in the literature and, in particular). In the method of the present invention, the optically active β- or γ- which is known to exert such an asymmetric induction effect
Essentially any ( N , N -dialkylamino) alcohol can be used. Among them, (1 S , 2 R ) — (−) — or (1 R , 2 S ) as studied in detail in the prior art documents and
-(+)-2- ( N , N -dibutylamino) -1-phenyl-1-propanol or (-)-or (+)
—3-Exo- (dimethylamino) isoborneol is particularly preferable because it can exhibit a high asymmetric induction effect.

Further, optically active N used in the method of the present invention, N - optical purity of dialkylamino alcohol are not necessarily close to 100% ee (enantiomeric excess), optical purity is low N, N - dialkylamino Even if alcohols are used, the main product with high optical purity can be obtained. This phenomenon, in which the optical purity of the obtained product is higher than the optical purity of the asymmetric source used, has been studied in detail as an asymmetric amplification phenomenon (see, for example, prior art documents).

In the production method of the present invention, the above formula (I) is used.
4- (4-Substituted inden-1-yl) -2 represented by
-Pentenals and diisopropylzinc represented by the above formula (II) are reacted in an organic solvent in the presence of optically active N , N -dialkylaminoalcohols,
Optically active 6- (4-substituted inden-1-yl) -2-methyl-4-heptene-3-represented by the above formula (III)
The manufacture of all kinds can be achieved.

In the production method of the present invention, diisopropylzinc represented by the above formula (II) has a stoichiometric amount with respect to 4- (4-substituted inden-1-yl) -2-pentenal represented by the above formula (I). Theoretically, an equimolar reaction is carried out, but since it is used to form a complex active species by reacting with partially added optically active N , N -dialkylaminoalcohol, it is usually 1 to 3.5 equivalents. Range, particularly preferably 2
It is performed in the range of 2.5 equivalents. Use of 3.5 equivalents or more is not preferable because it tends to accelerate the reduction reaction of 4- (4-substituted inden-1-yl) -2-pentenals represented by the above formula (I).

On the other hand, the optically active N , N -dialkylaminoalcohols have a slightly different optimum use amount depending on their isopropylation reaction accelerating effect, but the 4- (4-substituted indene represented by the above formula (I) is used. -1-yl) -2-Pentenal, usually 2 to 100
Mol%, preferably 2 to 30 mol%, particularly preferably 5
It is used in the range of ~ 25 mol%.

Examples of the organic solvent used in the production method of the present invention include hydrocarbon solvents such as hexane, heptane and cyclohexane, aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as diethyl ether and tetrahydrofuran, or Examples thereof include mixed solvents thereof. Among these, hydrocarbon solvents and aromatic hydrocarbon solvents are preferable, and toluene and hexane are particularly preferable. The amount of the organic solvent used is not particularly limited as long as the desired reaction proceeds smoothly, but usually m
1 to 100 in terms of reaction scale expressed in mol
An amount of solvent of about ml, particularly preferably about 10 ml, is selected.

The reaction temperature is −78 ° C. to 50 ° C., preferably −30 ° C. to 30 ° C., particularly preferably 0 ° C. to room temperature. The reaction time varies depending on the type and amount of the asymmetric ligand catalyst used and the reaction temperature, and is usually carried out by tracing the disappearance of the starting materials using an analytical means such as thin layer chromatography. Several hours at room temperature
After reacting for several tens of hours, it ends.

After completion of the reaction, the desired compound of the above formula (III)
The optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols are isolated by treating with an acidic substance such as hydrochloric acid, and then using a usual post-treatment means. For example, a crude product obtained by a method such as extraction, washing, drying, and concentration is separated and purified by a method such as chromatography and recrystallization. The asymmetric induction rate (% d) of the isopropylated product obtained by the production method of the present invention
e) is determined by an analytical method such as liquid chromatography after introducing the product itself or an appropriate derivative.

Thus, according to the present invention, the following formula (III)

[0039]

[Chemical 15]

[In the formula, X and the wavy line have the same definition as those in the above formula (I), and * indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] The optically active 6- (4-substituted inden-1-yl) represented by
-2-Methyl-4-hepten-3-ols are produced. X and the wavy line in the formula (III) are as defined above, * mark indicates that the isomers derived from the asymmetric carbon is biased to one of the isomers, the optically active N using, Either one of the N -dialkylaminoalcohols is abundantly produced due to the asymmetry, and the enantiomers of the optically active N , N -dialkylaminoalcohols having the opposite configurations are used. Optically active 6- (4-
Only the 3-position of the substituted inden-1-yl) -2-methyl-4-hepten-3-ols gives abundant reversed diastereoisomers. Specific examples of the optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ol represented by the above formula (III) are preferable as R in the above formula (I). Derivatives substituted with the listed groups can be given as they are, and R- and S- stereomers at the 3-position can be manufactured and divided, but since the 3 S- form is a more useful compound from the standpoint of drug development, the 3 S- form. The optically active N , N -dialkylamino alcohols that give the

[0041]

INDUSTRIAL APPLICABILITY As described above in detail with respect to the production method of the present invention, 4- (4-substituted inden-1-yl) -2-pentenal represented by the above formula (I) is added to the above formula (II )
Optically active N with diisopropyl zinc represented in, N
—Optically active 6- (4-substituted inden-1-yl) -2-represented by the above formula (III) through an asymmetric isopropylation reaction carried out in the presence of dialkylamino alcohols
Unlike the asymmetric isopropylation reaction of saturated aldehydes using diisopropylzinc, the method for producing methyl-4-hepten-3-ols has a high asymmetric induction rate and a high yield of the desired asymmetric isopropylation. It is possible to obtain things, and such facts have not been reported to date in such combinations.

6- (4-
Substituted inden-1-yl) -2-methyl-4-hepten-3-ols, in which X is an oxygen atom, represented by the following formula (III
-A)

[0043]

[Chemical 16]

[In the formula, * indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] And X is a (E) -bromomethylene group, the following formula (II
I-b)

[0045]

[Chemical 17]

[In the formula, the definition of * indicates the above formula (III-a)
Is the same as the definition in. ] 6- (4-
Substituted inden-1-yl) -2-methyl-4-heptene
All the 3-ols are at the 4-position of the indene skeleton.
An oxo group, which is a substituent, or (E) -bromomethyle
Vitamin D as a clue₃The A ring part of the skeleton
When combined by a reaction known per se, 24 (R) -hydroxide
Roxy vitamin D ₃Useful new that can lead to derivatives
It is the starting material for the rule, and has been 24 until now.RBody and 24SBlack body
It has been separated using a separation operation such as matography.
Considering that, the production method of the present invention has high stereoselectivity and high yield.
Rate, short process,RSEfficiency in terms of avoiding separation operation
To provide a practical and industrially superior manufacturing method
It is a thing.

Further, the following formula (III-c) wherein X is a hydrogen atom at the α-position and a hydroxyl group protected at the β-position

[0048]

[Chemical 18]

[In the formula, R is the same as the definition in the formula (I), and the * mark is the same as the definition in the formula (III-a). ] 6- (4-substituted indene-1-
Yl) -2-methyl-4-hepten-3-ols are
It is a novel compound useful as a precursor derivable to the above formulas (III-a) and (III-b).

[0050]

The present invention will be described in more detail with reference to the following examples.

[0051]

[Example 1]

[0052]

[Chemical 19]

(4R) -4-[(4S, 7aS) -4-
Benzoyloxy-7a-methylinden-1-yl]
-2-Pentenal (1) (85mg, 0.25mmo
l) and (1S, 2R)-(-)-2- (N, N-dibutylamino) -1-phenyl-1-propanol ((-)
-DBNE; 13 mg, 0.05 mmol; 20 mol%) in toluene (2 ml) solution of diisopropyl zinc in toluene (0.87M; 0.63 ml, 0.55 m)
(mol) was added dropwise at 0 ° C, and the mixture was stirred at 0-5 ° C for 24 hours. After completion of the reaction, 0.5N hydrochloric acid (25 m
l) was added for post-treatment, and the mixture was extracted with ethyl acetate (25 ml). The separated organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, dried and filtered over anhydrous magnesium sulfate, and concentrated to obtain a crude product. This was subjected to column chromatography using silica gel (15 g) (eluent: hexane: ethyl acetate = 40: 1 → 1: 1).
Purified by and is the isopropylated product (6R)
-6-[(4S, 7aS) -4-benzoyloxy-7
a-Methylinden-1-yl] -2-methyl-4-hepten-3-ol (2) (85 mg, 0.22 mmo
1, 89%). NMR (CDCl ₃ , ppm) δ; 0.85-1.0
(19H, m), 1.05 (3H, s), 1.1 to 2.
4 (16H, m), 3.80 (1H, t, J = 6H
z), 5.43 (1H, br, s), 5.4 to 5.65.
(2H, m), 7.4 to 7.6 (3H, m), 8.0
8.1 (2H, m). IR (neat) cm ^-1 ; 3500, 2953, 287
0, 1717, 1410, 1314, 1113. To obtain the stereoselectivity in the isopropylation reaction, the isopropylation product (14 mg, 0.04 mmo
l) in ethanol (1 ml) in a catalytic amount of 5% platinum /
Activated carbon was added and catalytic reduction was carried out for 2 hours at room temperature in a hydrogen atmosphere. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain a crude product, which was subjected to silica gel (10 g) column chromatography (eluent; hexane: ethyl acetate = 30 :).
1 → 15: 1) and purified (6R) -6-[(4S,
7aS) -4-Benzoyloxy-7a-methylinden-1-yl] -2-methyl-3-heptanol (11
mg, 0.042 mmol, 85%) was obtained. This product was analyzed by HPLC, and the production ratio of the 3R form and the 3S form (the 3R form and the 3S form are described as the 24R form and the 24S form in the following examples) was compared with that of a standard sample having an absolute structure. Since it was calculated to be 24R: 24S = 95: 5, the stereoselectivity of the isopropylated product in Example 1 was calculated to be 24S: 24R = 95: 5. HPLC conditions were performed using a Zorbax SIL column, and the composition of the eluent was hexane: methylene chloride: ethanol = 9.
Using 0: 10: 0.3 (flow rate 2.0 ml / min), 2
It was detected and quantified at a UV wavelength of 54 nm. NMR (CDCl ₃ , ppm) δ; 0.85-1.0
(9H, m), 1.05 (3H, s), 1.1 to 2.1
5 (18H, m), 3.25 to 3.4 (1H, m),
5.42 (1H, br, s), 7.4 to 7.6 (3H,
m), 8.0 to 8.15 (2H, m). IR (neat) cm ^-1 ; 3500, 2870, 171
0, 1440, 1265, 1110.

[0054]

Example 2

[0055]

[Chemical 20]

(4R) -4-[(7aS) -7a-methyl-4-oxoinden-1-yl] pentanal (1) (59 mg, 0.25 mmol) and (-)-DB
Toluene (2 ml) solution of NE (13 mg, 0.05 mmol; 20 mol%) and diisopropyl zinc toluene solution (0.87 M; 0.63 ml, 0.55 mmol)
Was added dropwise at 0 ° C, and the mixture was stirred at 0-5 ° C for 24 hours. After completion of the reaction, post-treatment and purification by column chromatography were carried out in the same manner as in Example 1 to obtain the isopropylated product (6R) -6-[(7aS) -7a-methyl-4-oxoinden-1-yl. ] -2-Methyl-4-heptene-
3-ol (2) (60 mg, 0.22 mmol, 89
%) Was obtained. NMR (CDCl ₃ , ppm) δ; 0.62 (3H,
s), 0.8 to 0.95 (6H, m), 1.06 (3
H, d, J = 6 Hz), 1.1 to 2.5 (16H,
m), 3.73 (H, t, J = 6 Hz), 5.3-5.
55 (2H, m). IR (neat) cm ^-1 ; 3450, 2957, 278
4,1715,1458,1381,1024. In order to determine the stereoselectivity in the isopropylation reaction, the isopropylation product (13 mg, 0.05 mmo
l) was dissolved in THF (1 ml), and lithium tri-t-butoxyaluminum hydride (100 mg, 0.78 m) was added.
mol) was added and the mixture was stirred at room temperature for 30 minutes. 1N after water injection
The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate (15 ml), and the obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (15 ml) and saturated brine (15 ml). The organic layer separated by filtration after drying over anhydrous magnesium sulfate was concentrated under reduced pressure to give (6R) -6-[(4S, 7aS) -4.
-Hydroxy-7aS-methylinden-1-yl]-
A crude product of 2-methyl-4-hepten-3-ol was obtained. This product was dissolved in ethanol (1 ml), a catalytic amount of 5% platinum / activated carbon was added, and the mixture was subjected to catalytic hydrogenation reaction in a hydrogen atmosphere at room temperature for 1 hour, then the catalyst was filtered off, and the solvent was distilled off under reduced pressure ( 6R) -6-[(4S, 7aS) -4-hydroxy-7aS-methylinden-1-yl] -2-methyl-3-heptanol was obtained as a crude product. This was dissolved in methylene chloride (1.5 ml), 4-dimethylaminopyridine (225 mg, 1.83 mmol) and benzoyl chloride (0.15 ml, 1.55 mmol) were added, and 4
The mixture was stirred at 0 ° C for 1 hour. Then, 1N hydrochloric acid and ethyl acetate (15 ml) were added for extraction, and the separated organic layer was 1N.
It was washed successively with hydrochloric acid (25 ml × 2) and saturated saline (25 ml). The organic layer separated by filtration was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was subjected to silica gel (10 g) column chromatography,
Elute with hexane: ethyl acetate = 60: 1 (6R)-
6-[(4S, 7aS) -4-benzoyloxy-7a
-Methylinden-1-yl] -2-methyl-3-heptylbenzoate (14 mg, 0.029 mmol, 5
9%) was obtained. NMR (CDCl ₃ , ppm) δ; 0.75 to 1.05
(12H, m), 1.05 to 2.15 (18H, m),
4.90 to 5.05 (1H, m), 5.38 (1H,
m), 7.35 to 7.60 (6H, m), 7.91
8.10 (4H, m). IR (neat) cm ^-1 ; 3060, 1720, 171
0,1270,1110,710. This product was analyzed by HPLC and the ratio of the 24R form and the 24S form was determined by comparison with a standard product of known absolute structure. 24R: 2
Since the calculated 4S = 95: 5, the stereoselectivity of the isopropylated product in Example 2 was 24S: 24R = 9.
It was calculated to be 5: 5.

[0057]

Example 3

[0058]

[Chemical 21]

(4R) -4-[(4S, 7aS) -4-
t-Butyldimethylsilyloxy-7a-methylinden-1-yl] -2-pentenal (1) (88 mg,
0.25 mmol) and (−)-DBNE (13 mg,
0.05 mmol; 20 mol%) of toluene (2 ml)
A solution of diisopropyl zinc in toluene (0.87
M; 0.63 ml, 0.55 mmol) was added dropwise at 0 ° C, and the mixture was stirred at 0-5 ° C for 24 hours. After the reaction, post-treatment and purification by column chromatography were performed in the same manner as in Example 1 to obtain an isopropylated product (6R) -6-
[(4S, 7aS) -4-t-Butyldimethylsilyloxy-7a-methylinden-1-yl] -2-methyl-4-hepten-3-ol (2) (88 mg, 0.2
2 mmol, 89%) was obtained. NMR (CDCl ₃ , ppm) δ; -0.02 (3H,
s), 0.00 (3H, s), 0.8 to 0.95 (9
H, m), 0.87 (9H, s), 1.01 (3H,
d, J = 6 Hz), 1.05 to 2.15 (16H,
m), 3.73 (1H, t, J = 6Hz), 4.0 (1
H, br, s), 5.35 to 5.55 (2H, m). IR (neat) cm ^-1 ; 3380, 2950, 293
0,2859,1472,1374,1252,116
5,1082. To obtain the stereoselectivity in the isopropylation reaction, the isopropylation product (10 mg, 0.03 mmo
1) was dissolved in ethanol (1 ml), a catalytic amount of 5% platinum / activated carbon was added, and a catalytic hydrogenation reaction was carried out at room temperature in a hydrogen atmosphere for 13.5 hours. After the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain (6R) -6-[(4S, 7aS) -4-
A crude product of t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-methyl-3-heptanol was obtained. This whole amount is acetonitrile (0.5 ml)
Pyridinium polyhydrofluoric acid (0.2m
1) was added and the mixture was stirred at room temperature for 1.5 hours to carry out a desilylation reaction. After the reaction, water was added and ethyl acetate (15 m
The organic layer obtained by extraction with l) was washed successively with water (15 ml), saturated aqueous sodium hydrogen carbonate solution (15 ml) and saturated brine (15 ml), dried over anhydrous magnesium sulfate and filtered off. The layer was concentrated under reduced pressure (6R) -6-
A crude product of [(4S, 7aS) -4-hydroxy-7a-methylinden-1-yl] -2-methyl-3-heptanol was obtained. This crude product was dibenzoylated by the same method as the benzoylation method of Example 2 to give (6R) -6.
-[(4S, 7aS) -4-benzoyloxy-7a-
Methylinden-1-yl] -2-methyl-3-heptylbenzoate (7 mg, 0.015 mmol, 50
%) Was obtained.

This product was analyzed by HPLC to give 24R and 2
When the ratio of the 4S form was determined by the same method as in Example 2, it was calculated as 24R: 24S = 96: 4.
The stereoselectivity of the isopropylated product at 24S:
It was calculated that 24R = 96: 4. HPLC conditions are in Example 2
Under the same conditions as above, using a Zorbax SIL column and an eluent composition of hexane: methylene chloride: ethanol = 90: 10: 0.1 (flow rate 2.0 ml / min), and detecting at a UV wavelength of 254 nm. , Quantified.

[0061]

Example 4

[0062]

[Chemical formula 22]

Just as in Example 3, (4R) -4-
[(4S, 7aS) -4-t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-pentenal (88 mg, 0.25 mmol) was used as a starting material. However, the asymmetric ligand is 20 mol% of Example 3.
Decreased to 5 mol% from (-)-DBNE (3.3 m
g, 0.013 mmol; 5 mol%) with 0-5 ° C
And reacted for 24 hours. Isolation of the isopropylated product was carried out as in Example 3, except that (6R) -6-[(4S, 7
aS) -4-t-Butyldimethylsilyloxy-7a-
Methylinden-1-yl] -2-methyl-4-hepten-3-ol (89 mg, 0.23 mmol, 90
%) Was obtained. The determination of the stereoselectivity of isopropylation was carried out in the same manner as in Example 3 by subjecting the isopropylated product to catalytic hydrogenation, desilylation and dibenzoylation to obtain (6R) -6-[(4
S, 7aS) -4-Benzoyl-7a-methylinden-1-yl] -2-methyl-3-heptylbenzoate was derived by HPLC analysis of 24R: 2.
From the calculation of 4S = 96: 4, the stereoselectivity of the isopropylated product itself was calculated to be 24S: 24R = 96: 4.

[0064]

Example 5

[0065]

[Chemical formula 23]

Just as in Example 3, (4R) -4-
[(4S, 7aS) -4-t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-pentenal (1) (88 mg, 0.25 mmol) was used as a starting material. However, the asymmetric ligand was changed from (−)-DBNE in Example 3 to (+)-DBNE,
(+)-DBNE (13 mg, 0.05 mmol; 20
Was used for 24 hours at 0 to 5 ° C. Isolation of the isopropylated product was carried out as in Example 3,
(6R) -6-[(4S, 7aS) -4-t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-methyl-4-hepten-3-ol (2)
(89 mg, 0.23 mmol, 90%) was obtained. The stereoselectivity of isopropylation was determined by catalytic hydrogenation, desilylation and dibenzoylation of the isopropylated product in the same manner as in Example 3 to obtain (6R) -6-[(4S, 7aS) -4.
-Benzoyl-7a-methylinden-1-yl] -2
-Since it was derived to -methyl-3-heptylbenzoate and HPLC analysis of this product calculated 24R: 24S = 4: 96, the stereoselectivity of the isopropylated product itself was calculated as 24S: 24R = 4: 96. Was done.

[0067]

Example 6

[0068]

[Chemical formula 24]

Just as in Example 3, (4R) -4-
[(4S, 7aS) -4-t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-pentenal (1) (88 mg, 0.25 mmol) was used as a starting material. However, the optical purity of the asymmetric ligand decreased from 100% ee of Example 3 to 20% ee,
(−)-DBNE of e (66 mg, 0.25 mmol)
Was reacted for 24 hours at 0 to 5 ° C. Isolation of the isopropylated product was carried out as in Example 3, (6R)-
6-[(4S, 7aS) -4-t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-methyl-4-hepten-3-ol (2) (87 mg,
0.22 mmol, 88%) was obtained. The stereoselectivity of isopropylation was determined by catalytic hydrogenation of the isopropylated product, desilylation and dibenzoylation in the same manner as in Example 3 to obtain (6R) -6-[(4S, 7aS) -4-benzoyl- 7a-Methylinden-1-yl] -2-methyl-3
-Induced by heptyl benzoate, HPL of this
The stereoselectivity of the isopropylated product itself was 24, since 24R: 24S = 94: 6 was calculated by C analysis.
It was calculated that S: 24R = 94: 6.

[0070]

Example 7

[0071]

[Chemical 25]

Just as in Example 3, (4R) -4-
[(4S, 7aS) -4-t-butyldimethylsilyloxy-7a-methylinden-1-yl] -2-pentenal (1) (88 mg, 0.25 mmol) was used as a starting material. However, the asymmetric ligand is the same as in Example 3 (-).
-(-)-3-exo-dimethylaminoisoborneol ((-)-DAIB; 10 mg instead of DBNE,
0.05 mmol; 20 mol%) at 0-5 ° C for 2
The reaction was carried out for 4 hours. Isolation of the isopropylated product was carried out as in Example 3, except that (6R) -6-[(4S, 7a
S) -4-t-Butyldimethylsilyloxy-7a-methylinden-1-yl] -2-methyl-4-hepten-3-ol (2) (93 mg, 0.24 mmol, 9
4%). The determination of the stereoselectivity of isopropylation was carried out in the same manner as in Example 3 by catalytic hydrogenation of the isopropylation product,
After desilylation and dibenzoylation (6R) -6-
[(4S, 7aS) -4-benzoyl-7a-methylinden-1-yl] -2-methyl-3-heptylbenzoate was derived by HPLC analysis of this compound.
Since the calculated R: 24S = 97: 3, the stereoselectivity of the isopropylated product itself is 24S: 24R = 9.
It was calculated as 7: 3.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification Code FI C07C 49/743 C07C 49/743 C 67/343 67/343 69/76 69/76 Z C07F 7/18 C07F 7/18 A / / C07C 401/00 C07C 401/00 (56) Reference Patent 2905024 (JP, B2) Tetrahedron Letters, 1992, Vol. 33, No. 44, 6683-6686 (58) Fields investigated (Int.Cl. ⁷ , DB name) C07C 49/743 C07C 45/68 C07C 29/40 C07C 401/00 C07B 53/00 CA (STN) REGISTRY (STN)

Claims (14)

(57) [Claims] 1. The following formula (I): [In the formula, X is an oxygen atom, (E) -bromomethylene group,
Alternatively, X represents two groups that are single-bonded to the indene ring, one of which represents a hydrogen atom at the α-position and the other of -OR group at the β-position (wherein R is an acyl group having 2 to 8 carbon atoms). , A tri (hydrocarbon group having 1 to 6 carbon atoms) -substituted silyl group, or a 1- (alkoxy group having 1 to 4 carbon atoms) -substituted alkyl group having 1 to 6 carbon atoms). Represents either one of the E and Z isomers or a mixture thereof. ] 4- (4-Substituted inden-1-yl) -2- represented by
Pentenals and the following formula (II): Represented by the following formula (III): wherein diisopropyl zinc represented by the formula (III) is reacted in the presence of an optically active N, N-dialkylamino alcohol. [In the formula, X and the wavy line are the same as defined in the above formula (I), and the asterisk indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] The manufacturing method of optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols represented by these. 2. An optically active N, N-dialkylaminoalcohol in an amount of 2 to 30 mol% based on 4- (4-substituted inden-1-yl) -2-pentenal represented by the formula (I). The optically active 6- (4 according to claim 1, which is used in a range.
-Process for producing substituted inden-1-yl) -2-methyl-4-hepten-3-ols. 3. Diisopropylzinc represented by the formula (II) is converted into 4- (4-substituted indene-1-) represented by the formula (I).
2. The optically active 6- (4-substituted inden-1-yl) -2-methyl-4-heptene-3 according to claim 1, which is used in a range of 1 to 3.5 equivalents relative to (yl) -2-pentenal.
-A method for producing oats. 4. A 4- (4-substituted inden-1-yl) -2-pentenal compound represented by the formula (I) has the following formula (I-
a) The optically active 6- (4-substituted inden-1-yl) -2-methyl- according to any one of claims 1 to 3, represented by
Process for producing 4-hepten-3-ols. 5. A 4- (4-substituted inden-1-yl) -2-pentenal compound represented by the formula (I) has the following formula (I-
b) The optically active 6- (4-substituted inden-1-yl) -2-methyl- according to any one of claims 1 to 3, represented by
Process for producing 4-hepten-3-ols. 6. A 4- (4-substituted inden-1-yl) -2-pentenal compound represented by the formula (I) has the following formula (I-
c) [In the formula, the definition of R is the same as the definition in the above formula (I). ] The optically active 6- (4-substituted inden-1-yl) -2-methyl- of any one of Claims 1-3 represented by these.
Process for producing 4-hepten-3-ols. 7. The optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols according to claim 6, wherein R is an acyl group having 2 to 8 carbon atoms. Manufacturing method. 8. The method for producing an optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols according to claim 6, wherein R is an acetyl group. 9. The wavy line of 4- (4-substituted inden-1-yl) -2-pentenal represented by formula (I) is an E-form double bond. The method for producing the optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols according to 1. 10. The optically active 6- (4-substituted indene-) according to claim 1 or 2, wherein the optically active N, N-dialkylaminoalcohol is an optically active β- (N, N-dialkylamino) alcohol. 1-yl) -2-methyl-
Process for producing 4-hepten-3-ols. 11. The optically active 6- (4-substituted indene-group according to claim 1 or 2, wherein the optically active N, N-dialkylaminoalcohol is an optically active γ- (N, N-dialkylamino) alcohol. 1-yl) -2-methyl-
Process for producing 4-hepten-3-ols. 12. The optically active N, N-dialkylaminoalcohol is (1S, 2R)-(−)-or (1R,
2S)-(+)-2- (N, N-dibutylamino) -1
-Phenyl-1-propanol-The optically active 6- (4-substituted inden-1-yl)-according to claim 1 or 2.
A process for producing 2-methyl-4-hepten-3-ols. 13. The optically active N, N-dialkylaminoalcohol is (−)-or (+)-3-exo- (dimethylamino) isoborneol.
Optically active 6- (4-substituted inden-1-yl) described in 1.
A method for producing 2-methyl-4-hepten-3-ols. 14. The following formula (III): [In the formula, X represents an oxygen atom, a (E) -bromomethylene group, or X represents two groups that are single-bonded to the indene ring, one of which is a hydrogen atom at the α-position and the other is a hydrogen atom at the β-position. Represents an OR group (wherein R is an acyl group having 2 to 8 carbon atoms, a tri (hydrocarbon group having 1 to 6 carbon atoms) substituted silyl group, or a 1- (alkoxy group having 1 to 4 carbon atoms) substituted carbon; Represents the alkyl group of the formulas 1 to 6), and the wavy line represents either one of the E and Z isomers of the double bond, or a mixture thereof. *
The mark indicates that the isomer derived from the asymmetric carbon is biased to one isomer. ] Optically active 6- (4-substituted inden-1-yl) -2-methyl-4-hepten-3-ols represented by: