JPH0366664A - Production of optically active beta-hydroxy thioester - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a synthetic intermediate for various natural products, medicines, etc., in high optical purity and yield by reacting an aldehyde with a silyl enol ether in the presence of an optically active diamine and a tin reagent. CONSTITUTION:An aldehyde expressed by the formula R<1>CHO (R<1> is alkyl, cycloalkyl, aralkyl or aryl) is reacted with a silyl enol ether expressed by formula I (R<2> and R<4> are alkyl; R<3> is H or alkyl) in the presence of an optically active diamine and a tin reagent in a solvent, such as dichloromethane, at -100 to -30 deg.C to afford a compound expressed by formula II (* indicates asymmetric carbon). 1-Methyl-2-(1-piperidinylmethyl)pyrrolidine is preferably used as the diamine and a combination of tin (II) triflate with tributyltin fluoride is preferably used as the tin reagent.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention is directed to optically active β-hydroxythioester! 2
Regarding the manufacturing method.

The β-hydroxythioester produced by the present invention is useful as a synthetic intermediate for various natural products, pharmaceuticals, and other physiologically active compounds.

[Prior art] β-hydroxythioester is used as a chain such as β-hydroxyester, and the α-methyl-β-hydroxycarbonyl moiety of α-methyl-β-hydroxythioester is used as an intermediate in the synthesis of macrolide antibiotics. [Journal of the American Journal]
Chemical Society ((Journal of t
he American Chemical Society
ety), Volume 108 (26), Page 8279 (198
6) Reference L A method for producing β-hydroxythioester is a method of reducing a sulfonium ylide [Pretan op the
Chemical Society op Java: /
(Bulletan of the Chessl
cal 5oc1ety of Japan), 5th
0(6), p. 1645 (1977) 1, Method for aldol reaction of an optically active boron compound having a carbon-carbon double bond with an aldehyde [Journal of the American Chemical Society, Vol. 108
(26), p. 8279 (1988)] have been reported.

[Problem M to be solved by the invention] β-Hydroxythioester is useful as a synthetic intermediate for various natural products and physiologically active substances such as medical straw, and there is a strong need to develop a method for synthesizing it with high optical purity and high yield. desired.

However, conventionally known methods for producing β-hydroxythioesters have problems such as the optical yield not necessarily being high and the synthesis of optically active raw materials being complicated.

Therefore, an object of the present invention is to provide a method for producing optically active β-hydroxythioester with high optical purity and high yield.

[Means for Solving the Problem] According to the present invention, the above object can be achieved by formula (1) (1) (wherein R+ represents an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group). An aldehyde represented by the general formula (II) R2O)(=C3R"08i(R')z (■)
The general formula (m
) (wherein ll, ll and ni are as defined above, and 'C represents an asymmetric carbon atom). .

In the above general formula, the alkyl groups represented by ll, R2, R1 and R' are preferably lower alkyl groups having 1 to 7 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, t- butyl group,
Examples include pentyl group, hexyl group, and heptyl group. Further, examples of the cycloalkyl group represented by ljl include a cyclopentyl group and a cyclohexyl group, examples of the aralkyl group include a benzyl group and a phenethyl group, and examples of the aryl group include a phenyl group which may have a substituent, Examples include naphthyl group. Here, the W substituent that the phenyl group or naphthyl group may have is a lower alkyl group such as a methyl group or an ethyl group, a halogen atom such as a chlorine atom or a bromine atom, or a lower alkoxy group such as a methoxy group or an ethoxy group. Examples include.

Examples of optically active diamines used in the present invention include l-methyl-2-(1-piperidinylmethyl>pyrrolidine, l-methyl-2-(1-naphthylaminomethyl)pyrrolidine, and 2-(2-methoxymethylpyrrolidine). -1-
2-aminoalkylpyrrolidine derivatives such as (methyl)-1-methylpyrrolidine are preferred, and as the tin reagent it is preferred to use a combination of tin(II)) refrad and tributyltin fluoride.

A preferred embodiment of the present invention will be described below, taking as an example a case where a combination of tin (■) triflate and tributyltin fluoride is used as the tin reagent.

Tin (II) triflate and 1.0 to 1.2 molar equivalents of tributyltin fluoride to the tin (■) triflate and 1.0 to 1 molar equivalent to the tin (II) triflate.
．． Dissolve 5 molar equivalents of optically active diamine in an inert solvent such as dichloromethane or chloroform, and add 0.9 to 1.1 molar equivalents of the general formula (11) to the tin(II) triflate to the resulting solution. The silyl enol ether represented by is added at a temperature in the range of -100 to -30°C, preferably -78°C, and then the tin(II) l-
After adding 0.9 to 1.1 molar equivalents of the aldehyde represented by the general formula (1) to the refrad l, the optically active β- represented by the general formula (III) is obtained by stirring for 1 to 15 hours. Hydroxythioesters can be produced.

Optically active β- represented by general formula (111) from the reaction solution
Hydroxythioester can be separated and purified according to conventional methods. For example, the reaction solution is poured into aqueous sodium bicarbonate solution, extracted with dichloromethane, diethyl ether, etc., and then separated and purified using silica gel column chromatography, thin layer chromatography, etc. By adding the general formula (
The optically active β-hydroxythioester represented by III) can be obtained.

Aldehyde represented by general formula (1) and general formula (■1)
The silyl enol ether represented by is a known compound.

[Implementation fRJ] The present invention will be specifically explained below with reference to Examples, but the present invention is not limited thereto.

Tin (■) triflate 0.4ssol and (S)-1
-Methyl-2-(+-piperidinylmethyl)pyrrolidine 0.48 mA was dissolved in 1 ml of dichloromethane, and 0.44 mA of tributyltin fluoride was added to this solution at room temperature.
The reaction solution was stirred for 30 minutes and cooled to 178°C, and then a solution of 1-ethylthio-1-trimethylsiloxy ester 0.4-■O1 dissolved in 0.5 ml of dichloromethane was added to the reaction solution. was added dropwise and stirred for 30 minutes. 0.36-mal of benzaldehyde was added to the resulting reaction solution.
After adding a solution consisting of 1 ml of dichloromethane and 1 ml of dichloromethane and stirring for 12 hours, aqueous sodium bicarbonate was added to the resulting reaction solution, and the mixture was extracted with dichloromethane. The extract was dried and concentrated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography to obtain (S)-5-monoethyl 3-hydroxy-3-phenylpropanethiodine having the following physical properties. Art 59.0Ig was obtained (yield 78χ).

嘗H-NMR spectrum (CC1a) δ: '1.15 (
t, 3H, J=7.0Hz), 2.70(q, 211
．． J=7.0Hz), 2.70(d, 21(, J=6
．． 0I(z).

3.10 (brs, IH), 4.85 (t, 18.J
=6.0Hz), 7.00(m, 5Hz optical purity
822 In Example 1, (S)-1-methyl-2-(1-naphthylaminomethyl) was used instead of (S)-1-methyl-2-(1-piperidinylmethyl)pyrrolidine 0.48 ) Pyrrolidine 0.48■■ol or (S,S)-
(S)-3-ethyl 3-Hydroxy-3-phenylpropanethioate was obtained.The results of each reaction are shown in Table 1.

Table 1 with margin below Optical purity 86χ Yield (χ) Optical purity (χ) Actual alR5~7 2 52 9
27478 Example 4 In the actual m1M1, 0.4-■ol of 1-t-butylthio-1-trimethylsiloxyetheno was substituted for 0.4maol of 1-ethylthio-1-trimethylsiloxyethene.
(S)-i9- having the following physical properties was obtained by performing the reaction, separation and purification in the same manner as in Example 1 except that
62.5-g of butyl 3-hydroxy-3-phenylpropanethioate was obtained (yield: 7 kg).

H-N14R spectrum (CCI,) δ: 1.45 (s
, 9H), 2.65 (d, 2H, J=6.0Hz),
3.05 (brs, LH), 4.85 (t, IH,
J=8.0Hz), ? , CMl (m, 5) 1) Real fi (Ite to Ml, benzaldehyde 0.36ss
ol) instead of β-phenylpropionaldehyde 0.
36-■ol, isobutyraldehyde methylacetaldehyde O. The same as in Example 1 except that Colo-ol was used. S)-
S-ethyl 3-hydroxy-4-methylpentanethioate, (S)-3-ethyl 3-hydroxy-4,4
-Dimethylbencunthioate was obtained. The reaction results for each are shown in Table 2.

l″A bottom margin Table 2 Example 8 Example Vehicle collection optical purity 'H-NMR spectrum (z) <X) (CC1,)δ: 0 7 0 8 5 〉95 1, 25 (t, 3H, J=7.0Hz).

1, 50-1.90 (m, 2H).

2, 60-3.05 (s, 7H).

3, 75-4.10 (m, IH).

7, 10 (m, 5H) 0,90(d,8H,J=7.0Hz).

1, 25 (t, 3H, J=7.0Hz).

1,40-1.80(m,1)1).

2, 50-2.75 (Kaku, 3H).

2, 85 (q, 2H, J=7.OHz).

3,70(s,18) 0, 90 (s, 3H), 1.25 (t.

311, J=7.0Hz), 2.45-2, 75(
■, 31), 2.85 (q.

Tin (11) triflate 0.4 liter*ol and (S)-
Dissolve 0.48 ml of 1-methyl-2-41 naphthylaminomethyl)pyrrolidine in 1 liter of dichloromethane,
Add 0.44-1 tributyltin fluoride to this solution at room temperature.
01 was added and stirred for 30 minutes. After cooling the reaction solution to -78°C, (Z)-1-ethylthio-
1-trimethylsiloxy! -Propene 0.4-■Ol
A solution of 0.5 ml of dichloromethane was added dropwise, and the mixture was stirred for 30 minutes. A solution consisting of benzaldehyde 0,36-■al and 1 ml of dichloromethane was added to the obtained reaction solution, and the mixture was stirred for 3 hours. Aqueous sodium bicarbonate was added to the PJ reaction solution, and the mixture was extracted with dichloromethane. The extract was dried and concentrated under reduced pressure, and the resulting residue was soaked in silica gel fl.
By purifying with Ill chromatography, 4 mg of (2S,3S)-3-ethyl 2-methyl-cohydroxy-cophenylpropanethioate 89 having the following physical properties was obtained (86% yield, syntoa%):
The optical purity was determined from the ratio of diastereomers as an ester of (S)-methoxytrifluoromethylphenylrn acid.

H-NMR spectrum (CCh) δ: 1.10 (d, 3
H, J=7.0Hz), 1.15(t, 3H, J=7
．． 0Hz), 2.65 (brs, IH), 2.75
(jIH), 2.80 (q, 2H, J=7.0Hz)
, 5.00 (d, II (, J: 4.OII).

7.20 (m, 5) 1) Optical purity 〉98χ Co5)-5-ethyl 2-methyl-3-hydroxy-cophenylpropanethioate was obtained. The reaction results for each are shown in Table 3.

Third table fruit! 1 Example Yield Bn/anti Optical Purity (X) 1) g3/7 Real rf, Examples 9 and 10 88/12 In Example 8, (S)-1-methyl-2-(1-naphthylaminomethyl)pyrrolidine (S)-1-methyl-2-(l-piperidinylmethyl)pyrrolidine instead of 0.48-■ol or (S, S)
-2-(2-Methoxymethylpyrrolidin-1-ylmethyl)-1-methylpyrrolidine using 0.48■■O1 and adding benzaldehyde f! 201fIIJllll By performing the reaction, separation and purification in the same manner as in Example 8, except for stirring (2S.

Examples 11 to 1B SYn anti In Example 8, benzaldehyde 0.36 mol
p-chlorobenzaldehyde 0.36■■o instead of
l, ρ-methylpenzaldehyde 0.36■■o1
．． p-methoxybenzaldehyde 0.36■■ol,
The corresponding reactions were carried out in the same manner as in Example 8, except that 0.36 ■■ ol of isobutyraldehyde, 0.38 ■■ ol of cyclohexanecarbaldehyde, or 0.36 ■■ ol of octanal were used. (2S,3S)-S-ethyl 2-methyl-cohydroxy-3-(4-chlorophenyl)propanethioate, (2S,3S)-S-ethyl 2-methyl-3-
Hydroxyco(4-methylphenyl)propanethioate, (1,33)-3-ethyl 2-methyl-3-hydroxy-3-(4-methoxyphenyl)propanethioate, (2S,3R)-S- ethyl 2-methyl-3
-Hydroxy-4-methylpentanethioate, (2S
, 3R)-S-ethyl 2-methyl-3-hydroxy-
3-cyclohexylpropanethioate or (2S,coR)-3-ethyl 2-methyl-3-hydroxydecanethioate was obtained. The reaction results for each are shown in Table 4.

Below is the blank space BrLR81: Oite, (Z) -L-x chill'
rt -1-trimethylsiloxy-1-propene 0.4
S-ethyl 2- Methyl-3-hydroxy-
52.4-g of 3-phenylpropanethioate was obtained (
65L syn/anti=70/30).

, Optical purity of syn form 55z C Effect of the invention] According to the present invention, it is possible to produce the optically active β-hydroxythioester represented by the general formula ([11)] with a high optical yield and a high yield vehicle. It is Noh.

Claims (1)

[Claims] An aldehyde represented by the general formula R^1CHO (wherein R^1 represents an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group) and a general formula R^3CH=CSR^2 OSi (R^4)_3 (In the formula, R^2 and R^4 each represent an alkyl group, and R^3 represents a hydrogen atom or an alkyl group ▲ mathematical formula, chemical formula,
There are tables etc. ▼ (In the formula, R^1, R^2 and R^3 are as defined above, and ^*C represents an asymmetric carbon atom.) Production method.