JPH05986A - Production of optically active alkoxy alcohol - Google Patents

Abstract

PURPOSE:To simply and efficiently produce the subject compound by asymmetrically alkylating an aldehyde compound having an alkoxy group at the beta position with a dialkyl zinc in the presence of an optically active amino alcohol compound as a catalyst. CONSTITUTION:An aldehyde compound having an alkoxy group at the beta position is dissolved in a solvent such as hexane or THF, mixed with an optically active compound of formula II (R, R' are H, aliphatic hydrocarbon, aromatic hydrocarbon, etc.; * exhibits an optically active carbon) (e.g. dibutyl norephedrine) and further with a dialkyl zinc (e.g. diethyl zinc), stirred at room temperature for 10-20hrs and subsequently mixed with 1N hydrochloric acid to stop the reaction, followed by extracting the reaction solution and drying the extract to provide the objective compound of formula III [R<1> is hydrocarbon, trialkyl silyl of formula: R<3>R<4>R<5>Si (R<3>-R<5> are alkyl); R<2> is aliphatic hydrocarbon, cyclic aliphatic hydrocarbon, etc.] such as 5-benzyloxy-3-hexanol.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION Optically active 1,3-diol units are an important raw material when synthesizing them because they are present in many bioactive substances such as macrolide antibiotics.

The present invention relates to a method for producing an optically active 3-alkoxy-1-alcohol by asymmetrically alkylating an aldehyde having a β-alkoxy group. The alkoxy group of 3-alkoxy-1-alcohol can be easily converted to alcohol by an appropriate reaction such as hydrogenation, hydrolysis under acidic or basic conditions, or cleavage reaction with a fluorine anion. Are known, and 3-alkoxy-1-alcohols give 1,3-diols.

[0003]

2. Description of the Related Art Optically active 1,3-diol or 3
As a method for obtaining -alkoxy-1-alcohol, a method utilizing cleavage of an acetal and a method for asymmetrically reducing a diketone or an alkoxyketone have been conventionally known.

For example, the following methods can be mentioned. T. Oishi et al., Tetrahedron Letters, 24, 3873 (19
83), ibd, 26, 75 (1985) and the like, a method of synthesizing an acetal from a raw material of a natural product and then cleaving it.

R. Noyori et al., J. Am. Chem. Soc., 110,
629 (1988), a method for hydrogenating a β-diketone by using binap as an asymmetric ligand.

[0006] M. Suzuki et al., Tetrahedron Letters, 29,
5432 (1988), ibd, 30, 4383 (1989) and the like, a method of reducing a β-alkoxyketone derived from a natural product with a hydride.

[0007]

However, in the above-mentioned method, a natural optically active compound must be used as a starting material, and many steps such as condensation reaction for carbon chain extension, acetalization, reduction and cleavage are required. In addition, there is a drawback that the final reduction reaction must be performed after synthesizing a diketone or β-alkoxyketone having a required carbon skeleton in advance.

Basically, when constructing an organic compound,
The most important and difficult task is to generate the necessary carbon-carbon bonds.

The present method using asymmetric alkylation provides a method for efficiently achieving the purpose by forming a carbon-carbon bond and simultaneously forming a necessary asymmetric moiety.

[0010]

The present inventors achieved the present invention by asymmetrically alkylating an aldehyde with a dialkylzinc using an optically active amino alcohol as a catalyst.

That is, according to the present invention, an optically active compound represented by the following general formula (I) is obtained by asymmetrically alkylating an unsaturated compound having an aldehyde group with dialkylzinc.
In the method for synthesizing alkoxy-1-alcohol,

[0012]

[Chemical 4]

(However, R ¹ and R ² represent a hydrocarbon group, and are selected from aliphatic, cycloaliphatic, or aromatic hydrocarbon groups. R ¹ may be a silyl group, and a silyl group is generally used. A trialkylsilyl group represented by the formula R ³ R ⁴ R ⁵ Si is used, and R ³ , R ⁴ and R ⁵ are typically alkyl groups having 1 to 6 carbon atoms, but are not limited thereto. is not.
Further, these alkyl groups may be the same or different. * Indicates an optically active carbon atom. ) The following general formula (II) dialkylnorephedrine, (III) dialkyl (1-methylpyrrolidin-2-yl) methanol

[0014]

[Chemical 5]

[0015]

[Chemical 6]

(Provided that R and R'represent a hydrogen atom or a hydrocarbon group, and the hydrocarbon group is an aliphatic, cycloaliphatic,
Alternatively, it is selected from aromatic compounds. * Indicates an optically active carbon atom. ) Is used as a catalyst, the method for producing an optically active 3-alkoxy-1-alcohol.

Among the optically active amino alcohols used as a catalyst in the present invention, dialkyl norephedrine has a structure represented by the general formula (II), and R and R'are hydrocarbon groups and are aliphatic or cyclic fatty acids. It is selected from the group consisting of aromatic hydrocarbon groups.

The aliphatic group is typically one having about 1 to 12 carbon atoms, but is not limited to this. The cycloaliphatic or aromatic hydrocarbon group includes unsubstituted ones and those substituted with 1 to 5 halogen or nitro groups. R and R'may be the same or different.

The following are typical examples.

(+)-N, N-Dibutylnorephedrine (-)-N, N-dibutylnorephedrine These can be easily derived by the reaction of generally commercially available norephedrine and alkyl halides.

Dialkyl (1-methylpyrrolidine-2-
Iyl) methanol has a structure represented by the general formula (III), and R and R ′ are selected from hydrogen, or an aliphatic, cycloaliphatic, or aromatic hydrocarbon group.

Typical examples of the aliphatic group are those having 1 to 12 carbon atoms, but the aliphatic group is not limited thereto. The cycloaliphatic or aromatic hydrocarbon group includes an unsubstituted one and one having 1 to 5 halogen or nitro groups substituted. R and R'may be the same or different.

The following are typical examples. (S)-(+)-Diphenyl (1-methylpyrrolidin-2-yl) methanol These can be easily derived from commercially available proline by alkylation by the Grignard method and reduction by lithium aluminum hydride.

Dialkyl zinc used as a raw material is
R having the structure represented by the general formula (IV):² Is aliphatic, cyclic
Indicates an aliphatic or aromatic hydrocarbon group, which are the same
It may be one or different.

Examples of the R ^{₂ 2} Zn ··· (IV) aliphatic group is a representative is of the order of 1 to 12 carbon atoms, but is not limited to this. The cycloaliphatic or aromatic hydrocarbon group includes unsubstituted ones and those substituted with 1 to 5 halogen or nitro groups.

Dialkyl zincs can be easily synthesized from the corresponding alkyl aluminum and zinc chloride.

The aldehyde as the other raw material has a structure represented by the general formula (V), and R ¹ is an aliphatic, cycloaliphatic, aromatic hydrocarbon group, or silyl group, or a substituent to these groups. The added one is typically one having a total carbon number of 1 to 20, but is not limited to these.

As the silyl group, a trialkylsilyl group represented by the general formula R ³ R ⁴ R ⁵ Si is used, and R ³ , R ⁴ and R
⁵ is typically an alkyl group having 1 to 6 carbon atoms, but is not limited thereto.

Further, these alkyl groups may be the same or different.

[0030]

[Chemical 7]

The reaction of the present invention proceeds as follows.

[0032]

[Chemical 8]

[0033] _{^{R 1 = -Ch 2 Ph (a}} ), - CPh 3 (b), - Si t BuMe 2 (c) Catalyst: (1S, 2R) - ( -) Djibouti Runoru ephedrine (2a) (S) - (+)-Diphenyl (1-methylpyrrolidine-
2-yl) methanol (2b)

In the example of the production method of the present invention, a catalyst, for example, dibutylnorephedrine, is added to a solution of the β-alkoxyaldehyde, which is the starting material, of the cerami body, and a dialkylzinc, for example, diethylzinc is added thereto at room temperature. Stir for 10-20 hours.

After the reaction is completed, 1N-HCl is added to stop the reaction, and the product is obtained through post-treatments such as extraction and drying.

The molar ratio of aldehyde to dialkylzinc used is in the range of 1: 1 to 3, preferably around 1: 1 to 2. The amount of catalyst is 0.05-
0.5 is preferably 0.1 to 0.2.

[0037]

EXAMPLES Examples will be described below.

[0038]

Example 1 0.8 ml of a solution of 1 mmol of 3-benzyloxybutanal (1a) in n-hexane was used as a catalyst (1S, 2R)-
0.6 ml of an n-hexane solution of (-) N, N-dibutylnorephedrine (2a) (0.2 mmol) was added, and the mixture was stirred at room temperature for 30 minutes.

Then, 2.2 ml of n-hexane solution containing 2.2 mmol of diethyl zinc was added, and the mixture was stirred at room temperature for 20 hours. 1N
-After adding 6 ml of HCl to stop the reaction, the purification operations of extraction, drying and concentration were carried out. As a result, 0.120 g of 5-benzyloxy-3-hexanol (3a-6a) was obtained with a yield of 57%. Anti-type products (3a and 4a) and syn-type products (5a
And the production ratio with 6a) was 58:42.

Among them, the anti type product (3a) was 81% ee,
The syn-type product (5a) was obtained with a high asymmetric yield of 85% ee. The purity and asymmetric yield were determined by liquid column chromatography using a dicel chiral column.

[0041]

Example 2 The reaction was carried out under the same conditions as in Example 1, except that only the starting material was changed to 3-triphenylmethoxybutanal (1b).

As a result, 5-triphenylmethoxy-3-
Hexanol (3b to 6b) was obtained with a yield of 58%, and the production ratio of anti-type products (3b and 4b) and syn-type products (5b and 6b) was 55:45. The asymmetric yield of anti-type product (3b) reached 93%.

[0043]

Example 3 In Example 1, only the catalyst (S)-
The reaction was carried out under the same conditions except that (+)-diphenyl (1-methylpyrrolidin-2-yl) methanol (2b) was used.

As a result, 5-benzyloxy-3-hexanol (3a to 6a) was obtained with a yield of 80% (the production ratio of the anti type and the syn type was 55:45), and the chiral anti type (3a) was obtained. Yield 64%,
The asymmetric yield of syn type (5a) was 70%.

[0045]

Example 4 In Example 1, dimethylzinc was used instead of diethylzinc, and the other conditions were the same.

As a result, the yield of 4-benzyloxy-2-pentanol was 34% (the production ratio of anti type and syn type was 67: 3).
Obtained in 3), the anti-type asymmetric yield was 61%, and the syn-type asymmetric yield was 74%.

[0047]

Example 5 The reaction was carried out under the same conditions as in Example 1 except that diethylzinc was replaced with dinormal butylzinc.

As a result, the yield of 2-benzyloxy-4-octanol was 28% (the production ratio of anti type and syn type was 58:42).
The anti-type asymmetric yield was 74%, and the syn-type asymmetric yield was 64%.

[0049]

Example 6 The reaction was carried out under the same conditions as in Example 1, except that only the starting material was changed to 3-tert-butyldimethylsilyloxybutanal.

As a result, the yield of 5-tert-butyldimethylsilyloxy-3-hexanol (3c-6c) was 68% (anti
The asymmetric yield of anti-type (3c) was 73% and that of syn-type (5c) was 73%.

[0051]

EFFECT OF THE INVENTION By the method of the present invention, an optically active 3-alkoxy-1-alcohol can be efficiently produced with a small number of steps. For example, when dibenzylnorephedrine is used as a catalyst and 3-benzyloxybutanal is alkylated with diethylzinc, syn-type 5-benzyloxy-3-hexanol is obtained with an optical purity of 85%.

By using the appropriate enantiomeric aminoalcohol catalyst, the desired type of enantiomeric product can be obtained.

By changing the alkyl group of the dialkylzinc used, 3-alkoxy-1-alcohols having different alkyl groups can be obtained all at once from the same β-alkoxyaldehyde. This has been difficult with conventional techniques.

As described above, according to the method of the present invention, an optically active 3-alkoxy-1-alcohol can be synthesized much more efficiently and in a wider application range than the conventional method.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07F 7/18 F 8018-4H // C07B 61/00 300

Claims (1)

Claims: 1. An aldehyde compound having an alkoxy group at the β-position is asymmetrically alkylated with dialkylzinc to give a compound represented by the following general formula (I): (However, R ¹ represents a hydrocarbon group or a silyl group, R ² represents a hydrocarbon group, and the hydrocarbon group is selected from an aliphatic, cycloaliphatic, or aromatic hydrocarbon group. Is a trialkylsilyl group represented by the general formula R ³ R ⁴ R ⁵ Si, and R ³ , R ⁴ , and R ⁵ are alkyl groups, and these alkyl groups may be the same or different.
* Indicates an optically active carbon atom. ) In the method for producing an optically active 3-alkoxy-1-alcohol represented by the following general formula (II) or formula (III): [Chemical 3] (However, R and R'represent a hydrogen atom or a hydrocarbon group, and the hydrocarbon group is selected from an aliphatic, cycloaliphatic, or aromatic hydrocarbon group. * Represents an optically active carbon atom. ) A method for producing an optically active 3-alkoxy-1-alcohol, which comprises using an optically active amino alcohol represented by the formula (1) as a catalyst.