JPH1180097A - Production of optically active bicyclo derivative and new bicyclo derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject new derivative useful as a raw material or the like for medicines, agrochemicals, perfumes or liquid crystals by carrying out the asymmetric intermolecular-intramolecular tandem nitroaldol reaction of a specific aldehyde compound with nitromethane in the presence of a metallic complex of optically active binaphthols with a rare earth compound. SOLUTION: This new optically active bicyclo derivative is represented by formula I [R<1> is a 1-3C alkyl; Y is O, S or H2 ; (m) is an integer of 2-4; (n) is an integer of 2-5] [e.g. (3aR,4R,5S,7aS)-3a,5-dihydroxy-7a-methyl-4-nitro-3 a,4,5,6,7,7a-hexahydro-1-indanone] and is useful as a raw material or the like for medicines, agrochemicals, perfumes and liquid crystal intermediates. The bicyclo derivative is obtained by carrying out the asymmetric intermolecular- intramolecular tandem nitroaldol reaction of an aldehyde compound represented by formula II with nitromethane in the presence of a metallic complex prepared by reacting an optically active binaphthol or its derivative with a rare earth compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active bicyclo derivative. More specifically, the present invention relates to a method for producing an optically active bicyclo derivative by an asymmetric intermolecular-intramolecular tandem nitroaldol reaction using an asymmetric synthesis catalyst, and a novel bicyclo derivative obtained thereby.

[0002]

2. Description of the Related Art The present inventors have previously conducted various studies on asymmetric synthesis reactions using rare earth complexes having an optically active ligand, for example, Japanese Patent Application Laid-Open Nos. 6-154618 and 6-25.
6270, JP-A-6-306026, WO-95
/ 0132, J.M. Am. Chem. Soc. , 114,
4418 (1992), Tetrahedron Le
tt. , 34, 851 (1993), Tetrahe.
drone Lett. , 34, 855 (1993),
Tetrahedron Lett. , 34,2657
(1993); Am. Chem. Soc. , 11
5, 10372 (1993); Org. Che
m. , 60, 7388 (1995).
The above references include lanthanum chloride and optically active dilithium 1,
A method in which 1'-bi-2-naphthoxide is mixed in tetrahydrofuran and water and sodium hydroxide are added, or an optically active 1,1'-bi-2-naphthol, water is added to a tetrahydrofuran solution of lanthanum alkoxide containing sodium alkoxide. Using a rare earth metal complex catalyst prepared by a method of sequentially adding lithium chloride, a nitroaldol compound having high optical purity is obtained by a catalytic asymmetric nitroaldol reaction between various aldehydes and a nitroalkane. In addition, they have found that rare earth complexes having an optically active ligand are useful catalysts for asymmetric Michael addition reaction, hydrophosphonylation reaction, and asymmetric synthesis of α-aminophosphonic acid.

On the other hand, the development of a method for producing an optically active substance is important in supplying raw materials for medicines, agricultural chemicals, fragrances, and liquid crystal intermediates. The tandem reaction has attracted attention in organic synthesis due to its effective structure construction. ing. Tandem catalytic asymmetric synthesis is particularly effective because optically active compounds with several chiral centers can be synthesized from simple achiral compounds in one pot using a small amount of asymmetric catalyst (Ohsima, T. et.
al., MJAm. Chem. Soc. 1996, 118, 7108), as a method for efficiently obtaining an optically active substance.

[0004]

Nevertheless, heretofore, neither an intramolecular catalytic asymmetric nitroaldol reaction nor a catalytic asymmetric intermolecular-intramolecular tandem nitroaldol reaction has been performed. The present invention provides a process for producing an optically active bicyclo derivative, which can be an important synthetic intermediate for many natural products and / or bioactive compounds by a catalytic asymmetric intermolecular-intramolecular tandem nitroaldol reaction. Aim.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies on the above-mentioned problems, and as a result, using a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound, a catalytic asymmetric molecule is prepared. A novel reaction system capable of obtaining an optically active bicyclo derivative was established by an inter-intramolecular tandem nitroaldol reaction, and the present invention was completed.

1) An aldehyde compound represented by the following general formula (1) and nitromethane are reacted with an asymmetric intermolecular-intramolecular tandem nitroaldol in the presence of a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound. The following general formula characterized by reacting
(3) A method for producing an optically active bicyclo derivative represented by (3).

[0007]

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[0008]

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(In the formula (1) or the formula (3), R ₁ has 1 to ₁ carbon atoms.
3 represents an alkyl group, Y represents O, S or H ₂ ;
Represents an integer of 2 to 4, and n represents an integer of 2 to 5. )

2) The metal complex reacts a rare earth metal compound with an optically active 1,1'-bi-2-naphthol represented by the following general formula (4) or (5) and an alkali metal compound. The method for producing an optically active bicyclo derivative according to the above 1), which is a metal complex obtained by the above method.

[0011]

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(In the formula (4) or (5), R ₃ and R ₄ may be the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a halogen atom, a trialkylsilylethynyl group or a cyano group. 3) The asymmetric intermolecular-intramolecular tandem nitroaldol reaction is carried out in a temperature range of -50 ° C to 0 ° C,
The above 1) characterized in that the step is performed in a temperature range of 0 to 40 ° C.
Or 2) the method for producing an optically active bicyclo derivative according to the above. 4) An optically active bicyclo derivative represented by the general formula (3).

The optically active bicyclo derivative represented by the general formula (3) obtained according to the present invention is a novel compound, and was first found by the production method of the present invention. The compound is
It is effective as a medicine, pesticide, flavor, liquid crystal intermediate raw material, etc., for example, (3aR, 4R, 5S, 7aS) -3a,
5-dihydroxy-7a-methyl-4-nitro-3a,
4,5,6,7,7a-Hexahydro-1-indanone is vitamin D ₃ , digitoxigenin, wortmannin, norcholestan
ne) It is useful as an intermediate such as a derivative. In addition, the amine diol obtained by the reduction can generate an optically active chiral ligand compound for catalytic asymmetric synthesis.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The metal complex used in the present invention is obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound.

As the optically active binaphthol or binaphthol derivative, any one can be used, but only one of the R-form or the S-form is used. The optically active binaphthol or binaphthol derivative is preferably an optically active 1,1'-bi-2-naphthol represented by the general formula (4) or (5). R ₃ is in 3rd position, 4
R ₅ may be any of the 3 ′, 4 ′, 5 ′, 6 ′ and 7 ′ positions.

R ₃ and R ₄ each represent a hydrogen atom or an alkyl group (methyl, ethyl, propyl, isopropyl, n
-Butyl, s-butyl or t-butyl, etc.), a phenyl group, an alkenyl group (including ethenyl, 1-propenyl, 3-butenyl and the like), a trialkylsilylethynyl group (where alkyl is methyl, Ethyl, propyl, isopropyl, n-butyl, s-butyl or t-butyl), a cyano group or a halogen atom. R ₃ and R ₄ are preferably a hydrogen atom and 6,6′-substituted trialkylsilyl ether.

The rare earth metals of the rare earth compounds include Y, La, Nd, Sm, Eu, Gd, Tb, Dy,
Examples thereof include Pr and Yb, and any of them may be used, but La, Sm, Pr, Gd, Dy, and Yb are preferable. Examples of rare earth compounds include alkoxides (including methoxide, ethoxide, propoxide, isopropoxide, n-butoxide, s-butoxide and t-butoxide), and chlorides (any of anhydrides and hydrates). No) or nitrate. As the rare earth compound, preferably, La (O
R) ₃ (where R represents an isopropyl group or a t-butyl group), LaCl ₃ (which may be either anhydride or hydrate), Yb (OR) ₃ (where R is as defined above) .), YbCl ₃ (which may be either anhydride or hydrate), Sm (OR) _{3 and the} like.

The metal complex in the present invention is preferably
A compound obtained by reacting a rare earth metal compound with an optically active 1,1'-bi-2-naphthol represented by the general formula (4) or (5) and an alkali metal compound is preferable. Here, as the alkali metal compound, alkyl alkali metals, alkali metal hydroxide and the like can be used. Here, examples of the alkali metal include lithium, sodium, and potassium. Examples of the alkyl alkali metals include methyl lithium and t-butyl lithium, and examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide.
As the alkali metal compound, alkyl alkali metals are preferable, and n-butyllithium and methyllithium are more preferable. In the production of the metal complex in the present invention, the molar ratio of the above optically active binaphthol or binaphthol derivative, rare earth compound and alkali metal compound in a reaction system is preferably 3: 1: 3 to 3: 5, more preferably 3: 1: 3. 3: 3: 5.

As the solvent that can be used in preparing the metal complex in the present invention, any solvent can be used as long as the structure of the rare earth metal complex is not changed. For example, tetrahydrofuran (THF), ether solvents (diethyl ether, 1,4-dioxane, etc.), halogen solvents (methylene chloride, chloroform, 1,1,1-
Trichloroethane and monochlorobenzene, etc., hydrocarbon solvents (benzene, toluene, n-hexane and n-
Heptane) and fatty acid esters (ethyl acetate, methyl acetate, etc.). In addition, polar solvents such as dimethyl sulfoxide and N, N′-dimethylformamide can be used. These solvents may be used alone or in combination of two or more.

Of these solvents, tetrahydrofuran is particularly preferred. A catalyst solution prepared from a rare earth alkoxide, an alkali metal, and 1,1'-bi-2-naphthol in dry THF, a catalyst solution obtained by adding water to a catalyst prepared by this method, and a rare earth chloride in water-containing THF. , An alkali metal, and a catalyst prepared from 1,1'-bi-2-naphthol. When a rare earth chloride is used as the rare earth compound, a metal complex prepared from aqueous THF can be used.

The metal complexes are disclosed in JP-A-6-154618, JP-A-6-256270 and JP-A-30602.
The compound can be synthesized by the detailed preparation method described in JP-A-6. Here, an example (the following reaction formula) will be briefly described.

[0022]

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Here, a more specific explanation will be given.
The optically active 1,1'-bi-2-naphthol represented by (4) or (5) is dissolved in a solvent such as THF, and lanthanum triisopropoxide [La (O- (i) C ₃ H _{7 3} ) and the like, and after stirring at room temperature, a solution of an alkali metal compound such as butyllithium is added at 0 ° C., and the mixture is stirred at room temperature overnight to give the metal complex of the present invention in the form of a solution. Obtainable. This preparation method is representative, and is not particularly limited as a method for preparing the metal complex used in the present invention.

The metal complex in the present invention is a monomer, a dimer which is a bridging atom such as a halogen atom, a lanthanum atom or an alkali metal atom, or the like, because of various bonding modes characteristic of rare earth elements. It can be a trimer to an oligomer, a polymer or a mixture thereof.

It is assumed that the metal complex in the present invention is represented by the following formula (6) or (7). For example, if Ln is L
In a, when X is Li, it is referred to as a LaLi ₃ tris (R) -binaphthoxide complex (abbreviated as (R) -LLB).

[0026]

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(In the formula (6) or (7), X represents an alkali metal, and Ln represents a lanthanoid metal.)

The metal complex as described above in the present invention is
The aldehyde compound represented by the formula (1), which is a raw material of the reaction, is preferably used in an amount of about 0.005 to 0.3 molar equivalent, but in order to further shorten the reaction time under mild conditions, An amount exceeding 0.3 molar equivalent may be used.

In the catalytic asymmetric intermolecular-intramolecular tandem nitroaldol reaction of the present invention, as shown in the following Scheme 1, an aldehyde compound represented by the general formula (1) is reacted with nitromethane in the presence of the above metal complex. By doing so, it is thought that this is achieved through a compound represented by the following formula (2a) or (2b). That is, first, the compound of the formula (1) reacts with nitromethane in an intermolecular catalytic asymmetric nitroaldol reaction to form an optically active compound of the formula (2), and then the compound of the formula (2) is an intramolecular catalyst. Reaction with an intramolecular ketone by asymmetric nitroaldol reaction
It is considered that the compound of (3) is formed.

[0030]

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In the formulas (1) to (3), R ₁ has 1 to ₁ carbon atoms.
3 represents an alkyl group, preferably a methyl group, Y represents S,
O or H ₂ , preferably an oxygen atom, m represents an integer of 2 to 4, preferably 2, and n represents an integer of 2 to 5, preferably 2 to 4, and particularly preferably 2.

In the present invention, nitromethane used in the asymmetric intermolecular-intramolecular tandem nitroaldol reaction is preferably used in an amount of 0.8 to 50 equivalents to the aldehyde compound. The optically active target compound can be obtained in a high yield, and the use of 1 to 40 equivalents is preferred.

As the solvent used in the asymmetric intermolecular-intramolecular tandem nitroaldol reaction in the present invention, the solvent used during the preparation of the catalyst, for example, tetrahydrofuran, ether solvents (diethyl ether, 1,4-dioxane, etc.), Halogen solvents (methylene chloride, chloroform, 1,1,1-trichloroethane, monochlorobenzene, etc.), hydrocarbon solvents (benzene, toluene, n
-Hexane and n-heptane, etc.) and fatty acid esters (ethyl acetate, methyl acetate, etc.). In addition, polar solvents such as dimethyl sulfoxide, N, N'-dimethylformamide can be used, and these solvents can be used alone. Alternatively, two or more kinds may be used in combination.

The asymmetric intermolecular-intramolecular tandem nitroaldol reaction in the present invention is carried out at -50 ° C to 0 ° C at the beginning of the reaction.
The reaction is preferably carried out in a temperature range of
It is preferable to carry out the process by raising the temperature to a temperature range of from 40 ° C to 40 ° C, particularly to room temperature. The reaction time of the present invention is not particularly limited, but is preferably 50 to 400 hours. Especially,
The initial temperature of −50 ° C. to 0 ° C. for 50 to 300 hours, and then preferably the disappearance of the starting compound of formula (1) is determined by TL
C, etc., and then raise the temperature to
It is preferable to react for a time.

Further, in the present invention, as the post-processing,
By crystallization from the reaction mixture, it is possible to obtain a nitroaldol compound of the formula (2a) with a higher asymmetric yield as compared with the unpurified nitroaldol compound,
The bicyclo derivative of (3) can be obtained.

In the present invention, the above-mentioned specific asymmetric intermolecular-intramolecular tandem nitroaldol reaction is carried out to convert the readily available aldehyde compound of the formula 1
An optically active bicyclo derivative having a high asymmetric yield can be synthesized in one step. Such novel compounds are useful as intermediates for pharmaceuticals, agricultural chemicals, perfumes, and raw materials for liquid crystal intermediates.

Further, as shown below, by using the following aldehyde compound (11) as a raw material, a novel (3aR, 4R, 5S, 7aS) -3a, 5-dihydroxy-7a-methyl-4-nitro- 3a, 4,5,6
7,7a-Hexahydro-1-indanone (13) can be obtained. The bicyclo compound (13) is particularly useful as a pharmaceutical intermediate as shown below. In addition, the amine diol obtained by the reduction can generate an optically active chiral ligand compound for catalytic asymmetric synthesis.

[0038]

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[0039]

The following examples are representative experimental results and do not limit the content of the present invention. The optical purity was determined by liquid chromatography (HPLC) analysis (CHIRALPAK AD or C
HIRALCEL OD). ¹ H-NM
R was measured at (270 MHz).

Reference Example 1 Preparation of Rare-Earth Metal Complex Solution (A1) 515 mg (1.8 mmol) of (R) -1,1'-dihydroxy-2,2'-binaphthalene was vacuum-dried at 50 ° C. for 2 hours. Under an argon stream, (R) -1,1'-dihydroxy-2,2'-binaphthalene was added to 40 ml of THF.
And tri-i-propoxysilanetan [La at 0 ° C.
(Oi-Pr) ₃ ] A solution of 190 mg (0.6 mmol) of THF (3 ml) is added dropwise. After stirring at room temperature for 30 minutes, 1.8 mmol of n-butyllithium (n
-BuLi) (1.12 ml) hexane solution is added dropwise. Then, the mixture was stirred at room temperature overnight, and water (0.6 mmol) was added.
Is added, and THF is further added to the solution to give 0.03 mmol / dm ³ of the above complex catalyst T.
An HF solution (A1) was prepared. This complex is (LaLi
₃ tris (R) -binaphthoxide) and (R)-
It is abbreviated as LLB.

Reference Examples 2 to 6 Preparation of Rare Earth Metal Complex Solutions A2 to 5 In the same manner as in Reference Example 1, (R) -1,1'-dihydroxy-2,2'-binaphthalene and the following compound [ Ln (Oi-Pr) ₃ ], complex catalyst THF solutions (A2) to (A6) were prepared, respectively. (Reference Example 2) Tri-i-propoxypraseodymium [P
r (Oi-Pr) ₃ ] (PrLi ₃ tris (R) -binaphthoxide), abbreviation PrLB = complex catalyst THF solution (A2) (Reference Example 3) tri-i-propoxy samarium [Sm
(Oi-Pr) ₃ ] (SMLi ₃ Tris (R) -binaphthoxide), abbreviation SMLB = complex catalyst THF solution (A
3) (Reference Example 4) Tri-i-propoxy gadolinium [Gd
(Oi-Pr) ₃ ] (GdLi ₃ Tris (R) -binaphthoxide), abbreviation GdLB = complex catalyst THF solution (A
4) (Reference Example 5) Tri-i-propoxy dysprosium [D
y (Oi-Pr) ₃ ] (DyLi ₃ tris (R) -binaphthoxide), abbreviation DyLB = complex catalyst THF solution (A5) (Reference Example 6) tri-i-propoxy ytterbium [Y
b (Oi-Pr) ₃ ] (YbLi ₃ tris (R) -binaphthoxide), abbreviation YbLB = complex catalyst THF solution (A6)

Example 1 Synthesis of Aldehyde Compound (11) From commercially available 2-methyl-1,3-cyclopentanedione and acrolein, Schick, H .; Roatsch, B. et al, S. Li
According to the method of ebigs Ann. Chem. 1992, 419, the following aldehyde compound (11) was synthesized in one step (89% yield).

(3aR, 4R, 5S, 7aS) -3
a, 5-dihydroxy-7a-methyl-4-nitro-3
Synthesis of a, 4,5,6,7,7a-Hexahydro-1-indanone (13) 0.517 mmol of the aldehyde compound (11) was dissolved in 0.86 ml of tetrahydrofuran (THF), cooled to -20 ° C, Stir for 30 minutes. Nitromethane (10 molar equivalents)
After stirring for 30 minutes, a solution of 0.03 mmol / dm ³ of the THF solution of LnLB prepared in Reference Examples 1 to 6 above was added and reacted. The following compounds (12a), (12b) and (13a) were obtained.
I got Further, the mixture was stirred until the aldehyde compound (11) disappeared, and then stirred at room temperature for 24 hours.
a) was completely converted to the other diastereomer (13b). The optical purity of the compound (13b) was 39% ee (enantiomeric excess; hereinafter also referred to as asymmetric yield). Purification by silica gel column chromatography was difficult,
1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was crystallized from methylene chloride. The compound (13b) has a white powder of 41% e
e, obtained in 59% yield. Compound (13a), in the above reaction, the reaction was stopped without performing the reaction at room temperature, and extracted and crystallized in the same manner as above,
17% yield was obtained as white crystals.

[0044]

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The structure of the relative configuration of the compound (13b) is X
It was determined by line structure analysis as shown below. The absolute configuration was determined by the CD spectrum of the following compound (14) obtained by subjecting compound (13b) to p-nitrobenzoylation after catalytic reduction.

[0046]

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Compound (13a) ¹ H-NMR (acetone-d ₆ ): δ 1.02 (s, 3
H), 1.10-1.26 (m, 1H), 1.51 (d
t, j = 13.86 Hz, 3.96 Hz), 1.78-
2.02 (m, 2H), 2.39-2.70 (m, 4
H), 4.23 (d, j = 10.23, 1H), 4.2
8-4.42 (m, 1H), 4.45 (d, j = 5.6
1 Hz), 4.83 (s, 1H) ¹³ C-NMR (acetone-d ₆ ): δ 216.3.
95.7, 80.6, 67.0, 55.3, 3
4.4, 30.2, 29.8, 27.2, 19.
8 IR (KBr): 3588, 3381, 1727, 15
50 LRMS (m / z): 229 (M ⁺ ), 212 (M ⁺ -O
H) [α] _D ²⁵ = -0.286 (c = 0.56, acetone)
(0.2% ee) Determination of ee (crystal ee): HPLC, DAICEL:
CHIRALPAK AS Hexane / 2-propanol (4/1), 1.0 ml / min, 230 nm (12 min, 1
5 minutes)

Compound (13b) C ₁₀ H ₁₅ NO ₅ : F. W. 229.23, orthorhombic, P2
₁ 2 ₁ 2 ₁ , a = 10.81 (16), b = 16.76 (7), c
= 6.05 (10), volume = 1096.8Å ^3, Z = 4, the absorption coefficient = 0.949 / mm, F (000 ) = 488

¹ H-NMR (acetone-d ₆ ): δ1.
13 (s, 3H), 1.18-1.38 (m, 1H),
1.53-1.78 (m, 2H), 1.90-2.08
(M, 2H), 2.22-2.62 (m, 3H), 4.
21-4.46 (m, 1H), 4.62 (d, j = 1
0.2 Hz, 1H), 4.63 (s, 1H), 4.69
(D, j = 6.27 Hz, 1H) ¹³ C-NMR (acetone-d ₆ ): δ 217.6.
98.2, 81.4, 70.3, 55.8, 3
4.4, 29.9, 29.4, 29.2, 13.
2 IR (KBr): 3379,1745,1548 HRMS (m / z): calcd _{(C 10 H 15 NO 5)} 22
9.1225. 229.0940 found. LRMS (m / z): 230 (M ⁺ ), 212 (M ⁺ -O
H) [α] _D ²⁵ = + 14.606 (c = 0.50, methanol) (57% ee) Method for determining ee (crystal ee): HPLC, DAICEL:
CHIRALPAK AS, (reaction mixture ee) hexane / 2-propanol (12 /
1), 1.0 ml / min, 230 nm (62 min, 84 min) (crystal ee) hexane / 2-propanol (9/1),
1.0 ml / min, 230 nm (36 min, 51 min)

Examples 2 to 10 In the same manner as in Example 1, as shown in Table 1 below, the compounds (13a) and (1a)
3b) was synthesized.

[0051]

[Table 1]

As can be seen from Table 1, when the reaction temperature is raised to 50 ° C., the enantiomeric excess (ee) of compound (13b) decreases (Example 2). It was also found that the selection of the lanthanum-based metal complex was effective in improving the asymmetric yield of compound (13b) (Examples 3 to 7). When PrLi ₃ tris ((R) binaphthoxide) (PrLB) is used as a catalyst, the crude product (13b)
Increased in optical purity to 48% ee. Also, the initial temperature seems to affect the asymmetric yield. That is, the initial temperature is -4.
At 0 ° C., the optical purity of compound (13b) increased to 58% ee (Example 8). Further, the amount of (R) -PrLB may be reduced, and when 5 mol% of PrLB is used, the optical purity of the compound (13b) is 53% ee (Example 9). It was surprisingly found that increasing the amount of nitromethane increased the asymmetric yield of compound (13b). That is, in the presence of 5 mol% of (R) -PrLB, compound (11) and 30 molar equivalents of nitromethane were converted to -40.
C. for 112 hours at room temperature and then for 24 hours at room temperature
Compound (13b) with 5% ee was obtained and after further crystallization, 79%
Compound (13b) of ee was isolated in 41% yield (Example 1)
0). The optical purity (69% ee) of compound (13b) increased to 95% ee after recrystallization from ethyl acetate-hexane (3/1) containing a small amount of methanol (57% recovery).

Incidentally, many other heterobimetallic asymmetric catalysts other than the present invention, such as LSB [LaNa ₃ tris (binaphthoxide)], LPB [LaK ₃ tris (binaphthoxide)], ALB [AlLi bis (binaphthoxide)] and GaLB [GdLi bis (naphthoxide)]
The same experiment as in this example was carried out under various reaction conditions using, but the desired product of the present invention could not be obtained as expected.

From the above, a generation mechanism as shown in the following scheme 2 is considered. PrLB is a multifunctional heterobimetallic asymmetric catalyst exhibiting both Lewis acidity and Bronsted basicity. The Pr atom acts as a Lewis acid and the Li-naphthoxide moiety acts as a Bronsted base. Then, the starting compound (11) is activated by the Pr atom, and nitromethane is deprotonated by the Li-naphthoxide portion to form the structural formula I. Next, the compound (11) and nitromethane react with each other between the molecules to give the structural formula II. Furthermore, the structural formula again
Lithium nitronate formed from II reacts kinetically with an intramolecular ketone (-40 ° C or -20 ° C) to form structural formula III, followed by formation of compound (13a) and PrLB
Regeneration takes place. However, at room temperature, structural formula III
It appears that there is an equilibrium between Structural Formula II and Structural Formula IV, and the reaction is likely to be towards the formation of a more thermodynamically stable compound (13b).

[0055]

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Actually, when 42% ee of the compound (13b) and 30 equivalents of nitromethane were reacted at room temperature for 7 days in the presence of 10 mol% of PrLB, trace amounts of the compounds (12a) and (1a) were obtained.
2b) is formed, 42% ee of compound (13b) is recovered and compound (13a) is a kinetic product and at room temperature has the structure II
It was confirmed that there was an equilibrium between I-II-IV. PrLB
A mixture of compounds (12a) and (12b) separated when reacting compound (11) with nitromethane at -40 ° C in the presence of nitromethane and nitromethane in the presence of PrLB at -40 ° C for 59 hours and then at room temperature For 28 hours to obtain a compound (13b) with 65% ee. On the other hand, a mixture of the compounds (12a) and (12b) obtained under the same conditions was used instead of PrLB in NaO-t-Bu
To give a compound (13b) with 66% ee. These results indicate that the optical purity of compound (13b) depends only on the enantioselection of the intermolecular nitroaldol reaction, and in the intramolecular reaction, there is no kinetic control of compound (12) and the compound from compound (12) It is suggested that the cyclization to (13b) is controlled by the absolute configuration of the hydroxy group of compound (12a).

[0057]

According to the present invention, an asymmetric intermolecular-intramolecular tandem nitroaldol reaction using an asymmetric synthesis catalyst using a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound is provided. In a single step, an optically active bicyclo derivative of the formula (3), which is important for supplying a drug, a pesticide, a fragrance, and a liquid crystal intermediate material, can be obtained from the aldehyde compound of the formula (1) and nitromethane. Further, a novel optically active bicyclo derivative of the formula (3) useful as a pharmaceutical intermediate can be obtained by the production method of the present invention.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07M 7:00

Claims (4)

[Claims] 1. An asymmetric intermolecular-intramolecular tandem nitro aldol, comprising an aldehyde compound represented by the following general formula (1) and nitromethane in the presence of a metal complex obtained by reacting an optically active binaphthol or a binaphthol derivative with a rare earth compound. Characterized by reacting, the following general formula (3)
A method for producing an optically active bicyclo derivative represented by the formula: Embedded image Embedded image (In the formula (1) or the formula (3), R ₁ represents an alkyl group having 1 to 3 carbon atoms, Y represents O, S or H ₂ , m represents an integer of 2 to 4, and n represents 2 Represents an integer of 5 to 5) 2. The method according to claim 1, wherein the metal complex comprises a rare earth metal compound,
Optical activity 1, represented by the following general formula (4) or general formula (5)
2. The method for producing an optically active bicyclo derivative according to claim 1, wherein the metal complex is a metal complex obtained by reacting 1'-bi-2-naphthols with an alkali metal compound. Embedded image (In the formula (4) or the formula (5), R ₃ and R ₄ may be the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, a halogen atom, a trialkylsilylethynyl group or a cyano group. Represents.) 3. The asymmetric intermolecular-intramolecular tandem nitroaldol reaction is performed in a temperature range of -50 ° C to 0 ° C.
3. The method for producing an optically active bicyclo derivative according to claim 1, wherein the method is carried out in a temperature range of 10 to 40 ° C. 4. An optically active bicyclo derivative represented by the general formula (3) according to claim 1.