JPH07291904A - Production of natural type sphingosine and analog compound thereof - Google Patents

Abstract

PURPOSE:To provide a production method for asymmetrically synthesizing natural type sphingosine and analog compound thereof preferentially, more simply through fewer reaction steps and in a high diastereoisomerism selectivity. CONSTITUTION:A compound of the formula I (R1 and R2 are each H, an aryl or a lower alkyl; X is a urethane type, an acyl type or an alkyl type N- protecting residue) such as 1,1-dimethylethyl (S)-4-formy1-2,2-dimethyl-3- oxazolidinecarboxylate is reacted with a zinc compound of the formula II (R3 is a lower alkyl; R4 is a 4-21C alkenyl) such as 1-pentadecenylmethyl (or ethyl) zinc in the presence of a catalyst and then hydrolyzed to give a compound of the formula III. A chiral catalyst of (R) or (S)-diphenyl (1-methyl-2- pyrrolidinyl) methanol or an achiral catalyst selected from an amino-alcohol- based catalyst, a diamine-based catalyst and a Lewis acid is used as the catalyst used in the reaction. The amine functional group of the compound of the formula III is acylated to give a natural type ceramide.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing natural sphingosine or its analogs.

[0002]

2. Description of the Related Art The skin is liable to dry and lose its flexibility due to aging, external environmental factors and the like. In order to solve this problem, sphingolipids and the like, which are the main components of keratinocyte lipids, have attracted attention and have come to be incorporated in cosmetics and the like. The currently used sphingolipids include those derived from natural products extracted from pig skin, bovine brain, blood cells, plants and the like, as well as those produced by organic synthesis.

However, synthetically obtained sphingolipids are racemic or similar compounds, and thus have lower physiological activity than natural ones.

However, in recent years, several methods have been proposed for the synthesis of optically active sphingosine. A typical one will be described below. The conventional general manufacturing method is 1,1-dimethylethyl (S) -4-formyl-2,2
1-dimethyl-3-oxazolidinecarboxylate
-After alkynylating with pentadecynyl lithium, etc.,
A natural sphingosine was obtained by reducing the triple bond to a double bond and further hydrolyzing it.

For example, P. Herol represented by the chemical reaction formula
Method proposed by d (P. Herold, Helv. Chim. Acta., 198
8, 71, 354), and the method proposed by S. Nimkar et al. (S. Nimkar et al., Tetrahedron Lett., 198) shown in the chemical reaction formula.
8, 29, 3037), and the method proposed by P. Garner et al. Shown in the chemical reaction formula (P. Garner et al., J. Org. Chem., 1988, 5
3, 4395) and so on. All of the above three methods require a step of reducing a triple bond by alkynylation to a double bond, and there are many reaction steps, requiring three or more steps, and the production is complicated.

[0006]

[Chemical 4]

[0007]

[Chemical 5]

[0008]

[Chemical 6]

Further, as shown in the chemical reaction formula, 1,1-dimethylethyl (S) -4-formyl, -2,
A method for producing 2-dimethyl-3-oxazolidinecarboxylate by reacting diisobutyl (1-pentadecenyl) alane with hydrolysis and producing it was also reported (P. Garner et al.,
J. Org. Chem., 1988, 53, 4395). However, although this method requires a small number of reaction steps, unnatural sphingosine, which has low physiological activity, is mainly obtained, so that the production efficiency remains unsatisfactory.

[0010]

[Chemical 7]

On the other hand, it was reported that when O-acetyl-N-phthaloyl-L-serinal shown in the chemical reaction formula was reacted with diisobutyl (1-pentadecenyl) alane, a natural type was mainly obtained (H. Newman, J. Am. Chem. So
c., 1973, 95, 4098). However, this method requires two steps of ester hydrolysis and subsequent removal of the phthaloyl group with hydrazine as a deprotection operation for the protected amino group and hydroxyl group, and the manufacturing method is also complicated.

[0012]

[Chemical 8]

Therefore, in the present invention, the sphingosine of natural type, that is, (2S, 3R) -D-erythro-sphingosine, which has a high diastereoselectivity and a high diastereoselectivity, can be obtained more easily and with a smaller number of reaction steps. It is an object of the present invention to provide a production method of asymmetric asymmetric synthesis. Moreover, it aims at providing the manufacturing method of a natural type ceramide from this natural type sphingosine and its related compound.

[0014]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in accordance with the above-mentioned object, and as a result, completed the invention of a method for producing natural sphingosine and its related compounds having excellent diastereoselectivity. It was

That is, the present invention is a compound represented by the general formula I

[Chemical 9] (In the formula, R ₁ and R ₂ are a hydrogen atom, an aryl group or a lower alkyl group, and X is a urethane type, an acyl type or an alkyl type N.
(Representing a protected residue) in the presence of a catalyst, a zinc compound represented by the general formula II

[Chemical 10] (In the formula, R ₃ represents a lower alkyl group, and R ₄ represents C _{4 to} C ₂₁
Of the natural type), and then hydrolyzes the natural sphingosine of the general formula III and its analogs.

[Chemical 11] Manufacturing method.

A preferred compound of general formula I is 1,1-dimethylethyl (S) -4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate, which has the general formula
A preferred compound of II is 1-pentadecenylmethyl or 1-pentadecenylethyl.

As the catalyst, it is preferable to use a chiral catalyst, an achiral amino alcohol catalyst, a diamine catalyst or a Lewis acid catalyst.

The present invention also provides a method for producing a ceramide, which comprises acylating the amine functional group of the natural sphingosine or its analogues produced by the above method.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The starting materials for the production method of the present invention include:
The compound of formula I is diastereoselectively alkenylated by using a prochiral aminoaldehyde compound of formula I and an organozinc compound of formula II to react in the presence of a catalyst. The functional group protection is then removed by hydrolysis to produce the natural sphingosine compounds of formula III. As described above, according to the production method of the present invention, it becomes possible to preferentially produce natural sphingosine and its analogs in as few as two steps.

[0020]

[Chemical 12]

The aminoaldehyde compound represented by the general formula I is a compound known as a starting material for producing sphingosine as described above, and is described, for example, in P. Garner et al., J. Org.
Chem, 1987, 52, 2361 or RS Coleman et al., Tetrahedron Le.
tt., 1992, 33, 1697 or P. Garner et al., J. Org. Chem, 1988, 5
It is synthesized as described in 3,2979. Most preferred is
1,1-dimethylethyl (S) -4-formyl-2,2
-Dimethyl-3-oxazolidinecarboxylate.

The organozinc compound represented by the general formula II is
It acts as an effective diastereoselective alkenylating agent in the presence of a catalyst. Preferably W. Oppolzer et al., Helv. C
It is synthesized as described in him. Acta., 1992, 75, 170. In the method for producing natural sphingosine or a related compound thereof according to the present invention, sphingosine is most preferred when R ₄ in the formula II is a 1-pentadecenyl group. For example, 1-pentadecenylmethylzinc, 1-pentadecenylethylzinc, and the like.

A catalyst is required to carry out the reaction between the compound of formula I and the compound of formula II, and it does not matter whether the catalyst is chiral or achiral. Examples of the chiral catalyst include (R) -diphenyl (1-methyl-2-
Pyrrolidinyl) methanol or (S) -diphenyl (1
-Methyl-2-pyrrolidinyl) methanol and the like. In addition, (R) -diphenyl (1-methyl-2-pyrrolidinyl) methanol has a higher diastereoselectivity to the natural form than its S-form.

As the achiral catalyst, for example, 2-
Examples thereof include amino alcohol catalysts such as (N, N-dibutylamino) ethanol, diamine catalysts such as piperazine and tetramethylethylenediamine, and Lewis acid catalysts such as tetraalkoxy titanium and titanium tetrachloride. When 2- (N, N-dibutylamino) ethanol was selected as the catalyst, the natural diastereoselectivity was particularly excellent.

By the way, the racemic isomers have the same physical properties except that the optical activities are different from each other, but the diastereomers have slightly different physical properties from each other. Therefore, sphingosine or its analog obtained by the production method of the present invention is obtained as a diastereomer, and therefore, by purifying by utilizing the difference in the physical properties, only the natural erythro form can be easily obtained. For example, the product is dissolved in a hexane solution and then recrystallized to separate the erythro form and the threo form.

The amine functional group of natural sphingosine is
By acylation by a known method, ceramide having the same optical activity as natural one can be synthesized. For example, it is acylated by reacting with carboxylic acid or carbonyl chloride in the presence of a catalyst. Furthermore, by combining this ceramide with glucose, galactose, choline, etc., it becomes possible to produce various sphingolipids having the same optical activity as that in nature.

[0027]

EXAMPLE A specific production example by the production method of the present invention will be described below. However, the present invention is not limited to these.

Example 1 Synthesis of (2S, 3R) -D-erythro-sphingosine 1,1-Dimethylethyl (S) -4-formyl-2,2
-Dimethyl-3-oxazolidinecarboxylate as (R) -diphenyl (1-methyl-2-pyrrolidinyl)
0 in toluene in the presence of methanol (10 mol%) catalyst
C, 1.5 hours, literature (W. Oppolzer et al., Helv. Chim.
Acta., 1992, 75, 170) and reacted with 1-pentadecenylethylzinc to give a protected sphingosine in a yield of 52%, erythro: threo = 4: 1.
Got with.

The structure of the product was confirmed by ¹ H-NMR analysis (500 MHz, C ₆ D ₆ , 60 ° C.) (erythro.
-(anti) ー, δ4.285 (br s); threo- (syn)-, δ4.391 (t, J
7.0)). Then in the literature (J. Org. Chem., 1988, 53, 439
According to 5), the target natural sphingosine was obtained by deprotection with 1M hydrochloric acid.

[0030]

[Chemical 13]

<Example 2> Sphingosine was synthesized in the same manner as in Example 1 except that (S) -diphenyl (1-methyl-2-pyrrolidinyl) methanol was used as the catalyst. The diastereoselectivity of the functional group-protected sphingosine produced was erythro: threo = 2: 1.
Met.

<Example 3> As a catalyst, an achiral 2-
Sphingosine was synthesized in the same manner as in Example 1 except that (N, N-dibutylamino) ethanol was used. The diastereoselectivity of the prepared protected sphingosine was erythro: threo = 7.3: 1.

<Example 4> 1-pentadecenylmethylzinc was used in place of 1-pentadecenylethylzinc as a zinc compound, and 2- (N, N-dibutylamino) was used as a catalyst.
When the reaction was performed under the same conditions as in Example 1 except that ethanol was used, the yield of protected sphingosine was 51%,
Obtained at erythro: threo = 7.2: 1.

[0034]

In the production method of the present invention, the number of reaction steps is small, and sphingosine or its analogs are obtained as diastereomers rather than racemates, so that subsequent natural separation and purification are easy. Is. Further, it is also excellent in active natural diastereoselectivity. Therefore, according to the production method of the present invention, natural sphingosine and its related compounds can be produced easily and efficiently and industrially stably, and the production cost can be suppressed to a low price.

By the method for producing a natural ceramide of the present invention, it is possible to easily and stably provide a ceramide having the same optical activity as that of naturally occurring ceramide and high physiological activity.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // C07B 53/00 B 7419-4H 61/00 300

Claims (12)

[Claims] 1. A compound represented by the general formula I: (In the formula, R ₁ and R ₂ are a hydrogen atom, an aryl group or a lower alkyl group, and X is a urethane type, an acyl type or an alkyl type N.
(Representing a protected residue) is a zinc compound represented by the general formula II in the presence of a catalyst: (In the formula, R ₃ represents a lower alkyl group, and R ₄ represents C _{4 to} C ₂₁
Of alkenyl group), and then hydrolyzes the natural sphingosine of the general formula III and related compounds thereof. Manufacturing method. 2. The process according to claim 1, wherein the compound of the general formula I is 1,1-dimethylethyl (S) -4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate. . 3. A compound of the general formula II, characterized in that it is selected from 1-pentadecenylmethylzinc or 1-pentadecenylethylzinc.
The manufacturing method described in the item. 4. The method according to claim 1, wherein the catalyst is a chiral catalyst. 5. The catalyst is (R) -diphenyl (1-methyl-
The process according to claim 4, characterized in that it is selected from 2-pyrrolidinyl) methanol or (S) -diphenyl (1-methyl-2-pyrrolidinyl) methanol. 6. The method according to claim 1, wherein the catalyst is an amino alcohol catalyst. 7. The method according to claim 6, wherein the catalyst is 2- (N, N-dibutylamino) ethanol. 8. The method according to claim 1, wherein the catalyst is a diamine-based catalyst. 9. Process according to claim 8, characterized in that the catalyst is selected from piperazine or tetramethylethylenediamine. 10. The method according to claim 1, wherein the catalyst is a Lewis acid. 11. Process according to claim 10, characterized in that the catalyst is selected from tetraalkoxy titanium or titanium tetrachloride. 12. A method for producing a natural ceramide, which comprises acylating an amine functional group of a natural sphingosine or an analogue thereof produced by the method according to any one of claims 1 to 11.