JPH0662506B2 - Method for synthesizing optically active β-hydroxy ester and optically active β-hydroxy thioester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for synthesizing an optically active β-hydroxy ester and an optically active β-hydroxy thioester, and more specifically, as shown in the following formula 1, α-position and β-position , Or α
The present invention relates to a method for synthesizing an optically active β-hydroxy ester and an optically active β-hydroxy thioester having an asymmetry on either carbon position or β position.

(In the formula, X ¹ represents O or S, and the * mark represents an asymmetric carbon. Further, the definitions of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ will be described later.) [Prior Art And Problem] The optically active β-hydroxy ester and the optically active β-hydroxy thioester shown in Formula 1 have been conventionally synthesized by a multi-step reaction process. Generally, a method of inducing asymmetry at the α-position and β-position of β-hydroxyester or β-hydroxythioester from a compound having a functional group convertible to ester or thioester, and then converting to ester or thioester is used. There is. Representative asymmetric induction methods are shown in the following and Equations 2 to 7.

Example MHPalmer, J.Chem.Soc., 1960 , 931 Example CHHeathcock, J.Am.Chem.Soc., 101, 7077 (1979) Example S. Masamune, J. Am. Chem. Soc., 103, 1566 (1981) Example DAEvans, J. Am. Chem. Soc., 103, 2127 (1981) Example DAEvans, J. Am. Chem. Soc., 103, 2876 (1981) Example C. Gennari, Tetrahedron Lett., 26 , 797 (1985) In all of the above examples, a reaction substrate containing an asymmetric source in the molecule is used, and it is necessary to bind an expensive asymmetric source to the starting material in advance during the reaction.

Furthermore, in order to convert the product obtained here into β-hydroxy ester or β-hydroxy thioester, the asymmetric source must be removed (eg ,,) or the asymmetric source must be decomposed (eg,). . For this reason, there are problems that the operation is complicated and that an expensive asymmetric source is consumed.

Recently, Mukaiyama et al. (Chem.
Lett., 1983 , 297), that an optically active β-hydroxyacyl thiazolidinethione can be synthesized by adding an optically active diamine obtained from s-proline to a reaction system without attaching an asymmetric source to a starting material. Is reported.

However, in any case, in order to synthesize an optically active β-hydroxy ester or β-hydroxy thioester, one or more reaction steps are required after asymmetric induction by the above-mentioned method.

[Means for solving problems]

As a result of intensive studies to solve the above-mentioned problems, the present inventors have developed a method capable of synthesizing an optically active β-hydroxy ester or β-hydroxythioester by a one-step reaction without using an optically active starting material. They have found the present invention.

That is, the present invention is characterized by reacting a ketene with a ketone or an aldehyde in the presence of an optically active diamine derived from prolines, a Lewis acid, and a divalent tin alcoholate or a divalent tin thiolate. The present invention relates to a method for synthesizing active β-hydroxy ester and optically active β-hydroxy thioester.

The reaction formula of the synthesis method of the present invention is shown by the following formula 8.

Although the compounds (a) and (b) have a relative configuration, one of the enantiomers of (a) and (b) can be preferentially synthesized according to the present invention.

Examples of the ketones used in the present invention include those represented by the following general formula.

{In the formula, R ¹ and R ² may be the same or different and each represents hydrogen, halogen, an alkyl group (preferably an alkyl group having 1 to 6 carbon atoms), an aryl group (preferably a phenyl group, or (Wherein R ¹⁴ , R ¹⁵ , and R ¹⁶ may be the same or different and represent the same alkyl group or aryl group as R ¹ or R ² ) and may have a functional group. Specific examples thereof include ketene, alkylketene, arylketene, dialkylketene, alkylarylketene, haloketene, dihaloketene, trialkylsilylketene, dialkylarylsilylketene, diarylalkylsilylketene, triarylsilylketene and dicyanoketene. .

Examples of the aldehyde and ketone used in the present invention include those represented by the general formula R ⁴ COR ⁵ . Where R ⁴ and R ⁵
May be the same or different and each represents H, an alkyl group, an aryl group, a furyl group or the like, which may have a functional group or a hetero atom other than carbon. However, R ⁴ and R ⁵ are
It never becomes H. Further, the aldehyde and ketone may be optically active or inactive. Specific examples include 3-phenylpropionaldehyde, benzaldehyde, cinnamaldehyde, pivalaldehyde, phenylmethylketone and dimethylketone. Also, ester in the molecule,
Aldehydes and ketones having functional groups such as halogen and alkoxy groups, or aldehydes and ketones in which various functional groups in the molecule are protected by protective groups can also be used.

Examples of the divalent tin alcoholate and divalent tin thiolate used in the present invention include those represented by the general formula Sn (X ¹ R ³ ) ₂ . Here, R ³ represents an alkyl group (preferably an alkyl group having 1 to 4 carbon atoms), an allyl group, an aryl group (preferably a phenyl group) or a pyridyl group, and these have a functional group or a hetero atom other than carbon. May be.
X ¹ is as described above.

The method for synthesizing divalent tin alcoholate and divalent tin thiolate is to react bismethylcyclopentadienyltin (II) with alcohol or thiol, and to react tin (II) chloride with alcohol in the presence of triethylamine. (JS Morrison, J. Inorg. Nucl. Chem., 2
7 , 393 (1967)] and the like, but are not particularly limited.

Examples of the Lewis acid used in the present invention include those represented by the general formula MX ² . Here, M may be a metal or a non-metal, and X ² represents a conjugate base of a strong acid. Specifically, Sn
(OTf) ₂ (Tf indicates -SO ₂ CF ₃ ), Cu (OTf), Cu (OTf) ₂ , Sn
(OSO ₂ C _n F _{2n + 1} ) ₂ (preferably n = 1 to 4), SnClO ₄ , TrO
Examples thereof include Tf (Tr is a triphenylmethyl group) and the like.

The prolines used in the present invention include proline, hydroxyproline, and the like. Examples of the optically active diamine derived from them include those represented by the following formula 9.

R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ may be the same or different, and hydrogen,
It represents an alkyl group, an aryl group or an allyl group, and may have a functional group or a hetero atom other than carbonic acid. Also, R ¹⁹ and R
²⁰ may form a ring with N 2. Specific examples include the following compounds (A) to (U). In the following compounds, Me represents a methyl group, Et represents an ethyl group, iPr represents an isopropyl group, and Ph represents a phenyl group.

In the above formula, n represents 4 to 9 (preferably 4 to 7). The compounds (A) to (U) have an absolute configuration.

Two kinds of optically active diamines having different absolute configurations with respect to the carbon represented by * in the above formula 9 give β-hydroxy (thio) esters having the opposite configurations. For example, the configurations of β-hydroxy (thio) esters obtained by using (A) derived from S-proline in this reaction and by using (B) derived from L-proline are reversed. Therefore, by selecting and using (A) and (B), it is possible to preferentially synthesize any enantiomer of (a) and (b).

In the present invention, as a reaction solvent, tetrahydrofuran, methylene chloride, diethyl ether, toluene,
Either polar or nonpolar solvent such as hexane, acetonitrile, dimethylformamide, dimethylsulfoxide may be used, but methylene chloride is preferably used.

The reaction temperature is -100 ° C to 0 ° C, preferably -100 ° C to
The temperature is −45 ° C., and the molar ratio of ketene (I), divalent tin alcoholate or divalent tin thiolate (II), Lewis acid (III), optically active diamine (IV), ketone or aldehyde (V) used is I / II / III / IV / V = 2.0
To 1.0 / 1.0 / 1.0 to 3.0 / 2.0 to 4.0 / 2.0 to 0.5, preferably I / II / III / IV / V = 1.2 / 1.0 / 2.0 / 3.0
/0.75.

The reaction solvent, reaction temperature, molar ratio and the like are appropriately selected depending on the compound to be used and the desired β-hydroxy (thio) ester.

〔The invention's effect〕

The present invention has the following effects as compared with the above-mentioned prior art.

1) An optically active β-hydroxy (thio) ester can be synthesized by a one-step reaction process.

2) Since the asymmetric source (diamine) is not chemically bonded to the starting material, the expensive asymmetric source can be easily recovered and reused.

〔Example〕

Next, the present invention will be described more specifically by way of examples.
In the examples, tBu is a tertiary butyl group, Me, Ph,
Tf represents the same group as described above.

Example 1 (Production of optically active β-hydroxy-α-methylthioester) The reaction of this example is represented by the following formula.

(a ') and (b') show relative configurations.

According to the method of HGParrison et al., 2-methyl-2-propanethiol was added to a solution of bismethylcyclopentadienyltin (II) 150 mg (0.54 mmol) in methylene chloride (2 ml) at room temperature.
Add 122 μ (1.08 mmol) and stir for 30 minutes, then divalent tin t-
Butyl thiolate was adjusted. In this solution, CCMcCarn
1.2 ml of a tetrahydrofuran solution of methyl ketene obtained by the method of ey et al. (J. Chem. Soc., Parkin I, 1975, 1600).
(0.65 mmol) was added at -78 ° C and stirred for 20 minutes. Further −78
450mg of divalent tin trifluoromethanesulfonate at 1.
08 mmol) as a solid, followed by an optically active diamine.
(A-2) Add 295 mg (1.62 mmol) of methylene chloride (1.5 ml) and benzaldehyde 43 mg (0.41 mmol) of methylene chloride (1 ml), stir for 20 minutes, add 10% aqueous citric acid, and react. After stopping, the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. By separating and purifying this by preparative thin-layer chromatography, the corresponding β-hydroxythioesters (a ′) and (b ′) were 85% {(a ′) :( b ′) = 88 /
12}. The production ratio of diastereomers (a ') :( b') was determined from the integral ratio of benzylic methine proton in ¹ H-NMR.

The optical rotation of the mixture (a ') and (b') obtained here is [α] _D
^{It was 26} 46 (4.33, CH ₂ Cl ₂ ). Furthermore, the mixture of (a ') and (b') was reacted with methoxytrifluoromethylphenylacetic acid chloride in pyridine to give the corresponding methoxytrifluoromethylphenylacetic acid ester, and ¹⁹ F-NMR analysis showed that The asymmetric yield of (a ') was 60% e
It was e.

Examples 2 to 5 The same experiment as in Example 1 was performed except that the optically active diamine was changed.

The results are shown in Table 1.

Examples 6 to 8, except that the aldehyde and divalent tin thiolate were changed,
The same experiment as in Example 1 was performed.

The results are shown in Table 2.

Example 9 (Production of Optically Active β-Hydroxythioester) The reaction of this Example is shown by the following formula.

Bismethylcyclopentadienyltin (II) 150mg (0.54
2-methyl-2-propanethiol 122 μ (1.08 mmol) was added to a methylene chloride (2 ml) solution of
After stirring for 2 minutes, divalent tin t-butyl thiolate was prepared.
0.3 ml (0.65 mmol) of methylene chloride solution of ketene prepared in advance was added to this solution at -78 ° C, and the mixture was stirred for 20 minutes, and then 450 mg (1.08 mmol) of divalent tin trifluoromethanesulfonate was kept as a solid at -78 ° C. In addition, 295 mg (1.62 mmol) of the optically active diamine (A-2) was added to methylene chloride.
(1.5 ml) solution was added. Further, a solution of benzaldehyde 43 mg (0.41 mmol) in methylene chloride (1 ml) was added at −100 ° C., and the mixture was stirred for 20 minutes. After 10% citric acid aqueous solution was added to stop the reaction, the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. By separating and purifying this by preparative thin-layer chromatography, the corresponding β-hydroxythioester was obtained in a yield of 70%. In addition, 14% of benzaldehyde was recovered. β
-Hydroxythioester (c) was methoxytrifluoromethylacetic acid ester, and ¹⁹ F-NMR analysis showed that the asymmetric yield was 76% ee. Also, the absolute configuration which has priority is [S]. The absolute configuration was determined by converting (c) to β-hydroxycarboxylic acid with lithium hydroxide and determining from the degree of its optical rotation [DA Evans, J. Am. Chem. So.
c.].

Examples 10 to 17 The same experiment as in Example 9 was performed except that the aldehyde and the optically active diamine were changed.

The results are shown in Table 3.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07C 69/732 Z 9279-4H 327/06 7106-4H 327/08 7106-4H // C07B 61 / 00 300

Claims (1)

[Claims] 1. The following formula (In the formula, R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ^{20, which} may be the same or different, represent hydrogen, an alkyl group, an aryl group, an allyl group,
It may have a functional group or a heteroatom other than carbon.
R ¹⁹ and R ²⁰ may form a ring with N. ) An optically active diamine derived from a proline represented by, a Lewis acid, and a divalent tin alcoholate or 2
Optically active β characterized by reacting ketene with ketone or aldehyde in the presence of divalent tin thiolate
-A method for synthesizing a hydroxy ester and an optically active β-hydroxy thioester.