JPH10175926A - Optically active alcohol and carboxylic acid ester thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an α-H and useful for the synthesis of an optically active anti-aldol by enolizing in the presence of boron triflate and an amine, and then reacting with an aldehyde. SOLUTION: This optically active alcohol is a new compound expressed by formula I (R<1> to R<6> are each H, an alkyl, etc.), e.g. 2-(N-methylenesulfonyl) amino-1-phenyl-1-propanol. The method for producing the compound of formula I is constituted by e.g. using norephedrine as a raw material, performing an N-sulfonylation reaction of the raw material by mesitylene sulfonylchloride and (C2 H5 )3 N in CH2 Cl2 to form a compound of formula II, then performing an N-benzylation reaction of the above compound with benzyl bromide and K2 CO3 in CH3 CN to form an optically active alcohol of formula III, and esterifying the alcohol with propionyl chloride and pyridine in CH2 Cl2 to form a carboxylic acid ester expressed by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active compound having at least one α-hydrogen which is useful for enolizing in the presence of boronantriflate and an amine and reacting with an aldehyde to synthesize an optically active antialdol. It relates to alcohols and carboxylic esters thereof.

[0002]

BACKGROUND OF THE INVENTION 3-Hydroxy-2-methyl-1 represented by the following general formula (2):
-Carbonyl or 2-methyl- represented by the general formula (3)
The structure of 1,3-diol is a basic structure commonly found in physiologically active substances such as polyketide-derived macrolide antibiotics, and a diastereo- and enantioselective synthesis method thereof is required.

[0003]

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[0004]

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Heretofore, the above syn-type structure has been conveniently and selectively synthesized by an asymmetric aldol reaction using an asymmetric auxiliary group, but a corresponding anti-synthesis method has not been established. . Anti (2,
Although several methods have been reported for the synthesis method 3), there are drawbacks in that it is difficult to obtain an asymmetric reagent and the reaction conditions and reaction substrates are not general. Therefore, there has been a demand for a method for synthesizing anti-aldol in a highly selective manner, and for obtaining a compound usable in the method from a material available at a low cost.

[0006]

In view of such circumstances,
The present inventors have conducted intensive studies and have found that a novel optical compound having at least one α-hydrogen useful for enolizing in the presence of boron triflate and an amine and reacting with an aldehyde to synthesize an optically active anti-aldol. Active alcohols and their carboxylic esters have been found, and the present invention has been completed.

That is, the present invention is useful for enolizing in the presence of boron triflate and an amine and reacting with an aldehyde to synthesize an optically active anti-aldol.
An object of the present invention is to provide a novel optically active alcohol having at least one α-hydrogen and a carboxylic acid ester thereof.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the novel optically active alcohol having at least one α-hydrogen of the present invention include, for example, the following general formula (1)

[0009]

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[In the formula, R ¹ and R ^{2 each} represent a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, an acyl group or a substituent. An aryl group, a 4- to 7-membered cyclic hydrocarbon group or an R ⁵ -substituted sulfonyl group; R ³ and R ^{4 each} represent a hydrogen atom, an alkyl group which may have a substituent, Represents an optionally substituted aryl group or a 3- to 8-membered cyclic hydrocarbon group; R ⁵ represents an alkyl group or an aryl group; R ⁶ and R ⁷ represent a hydrogen atom or an optionally substituted alkyl group; groups, represents an optionally substituted aryl group; R ¹
Or R ² and R ³ or R ⁴ may form a ^3- to 7-membered ring; R ³ or R ⁴ and R ⁶ or R ⁷ may form a 4- to 7-membered ring] Optically active alcohols are exemplified.

Specific examples of R ¹ and R ² in the general formula (1) include a hydrogen atom; a (substituted) alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a neopentyl group and a methoxymethyl group; Benzyl group, 2,5-dimethylbenzyl group, 3,5-dimethylbenzyl group, 2,6-
(Substituted) aralkyl groups such as dichlorobenzyl group, 1-naphthylmethyl group and 2-naphthylmethyl group; acyl groups such as benzoyl group; phenyl group, trichlorophenyl group,
A (substituted) aryl group such as a naphthyl group; a 4- to 7-membered cyclic hydrocarbon group such as a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group; a paratoluenesulfonyl group, 2,4,6-trimethylbenzenesulfonyl Group, 2,4,6-trichlorobenzenesulfonyl group, 2,4,6-triisopropylbenzenesulfonyl group, 2- (1,2,3,4,6,7,8,9-octahydroanthracene) sulfonyl Alkyl or aryl-substituted sulfonyl group such as a group; t-butoxycarbonyl group;

Specific examples of R ³ and R ⁴ include a hydrogen atom; a methyl group, an ethyl group, a propyl group, a butyl group,
(Substituted) alkyl groups such as neopentyl group, methoxymethyl group, t-butyldiphenylsilyloxymethyl group; (substituted) aryl groups such as phenyl group, trichlorophenyl group, 1-naphthyl group; cyclopropyl group, cyclobutyl group, cyclopentyl And a 3- to 8-membered cyclic hydrocarbon group such as a cyclohexyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.

Specific examples of R ⁶ and R ⁷ include a hydrogen atom; a (substituted) alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a neopentyl group and a methoxymethyl group; a phenyl group, a trichlorophenyl group; (Substituted) aryl groups such as 1-naphthyl group and the like can be mentioned. And R
¹ or R ² and R ³ or R ⁴ may form a ^3- to 7-membered ring, or R ³ or R ⁴ and R ⁶ or R ⁷ may form a 4- to 7-membered ring.

In the compound represented by the above general formula (1), R ¹ is paratoluenesulfonyl, 2,4,6-trimethylbenzenesulfonyl, 2,4,6-trichlorobenzenesulfonyl, 4,6-triisopropylbenzenesulfonyl group, 2- (1,2,3,4,6,
An alkyl or aryl-substituted sulfonyl group such as 7,8,9-octahydroanthracene) sulfonyl group; R ² is an alkyl group or an aralkyl group; R ³ and R ⁴ are a hydrogen atom;
An alkyl group, an aryl group; an optically active alcohol wherein R ⁶ or R ⁷ is a phenyl group, and a fatty acid ester thereof,
It is particularly suitable for reacting with an aldehyde in the presence of boron triflate and an amine to synthesize a highly selective optically active antialdol.

The optically active alcohol having at least one α-hydrogen and the carboxylic acid ester thereof of the present invention can be produced by various known methods. For example, the following formula (C)
The carboxylic acid ester represented by the formula (1) can be obtained by starting from inexpensively available norephedrine as a starting material, as shown in the following reaction formula (a), i) mesitylenesulfonyl chloride (MesSO ₂ Cl), triethylamine (methylene chloride) in methylene chloride. N-sulfonylation with Et ₃ N), ii) N-benzylation with benzyl bromide (BnBr), potassium carbonate in acetonitrile to give optically active alcohol (B), which is iii) propionyl chloride in methylene chloride (EtCOCl), synthesized by esterification with pyridine (Py).

[0016]

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Similarly, various optically active alcohols and carboxylic acid esters thereof can be obtained by using compounds having various substituents as starting materials instead of norephedrine and selecting reagents to be reacted in each step. .

Using the obtained carboxylic acid ester of an optically active alcohol, a boron aldol reaction is carried out as represented by the following reaction formula (b), whereby an optically active anti-aldol can be highly selectively converted from an aldehyde. Can be synthesized.

[0019]

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In the above-mentioned aldol reaction, enolate was formed by dicyclohexylboron triflate (cHex ₂ BOTf) and triethylamine, and reacted smoothly with various aldehydes (RCHO). The anti: syn selectivity of the reaction was> 98: 2 and the face selectivity of the anti-isomer was> 95: 5 for various aldehydes.

Thus, by using the optically active ester of the present invention as an asymmetric auxiliary group and performing a boron aldol reaction on a wide range of substrates (aldehydes), an optically active antidol can be synthesized with high selectivity. Can be. The aldol product thus obtained has the reactivity of a normal ester and can be easily converted into various functional groups. At that time, the optically active ester of the present invention used as an asymmetric auxiliary group can be recovered quantitatively and can be reused, so that it is highly practical.

[0022]

Hereinafter, embodiments of the present invention will be described.
These examples do not limit the invention. Example 1 2- (N-mesitylenesulfonyl) amino-1-phenyl-1-propanol (A) (1R, 2S) or (1S, 2R) norephedrine (7.56 g, 0.05 mol) and triethylamine ( A methylene chloride solution (8.4 ml, 0.06 mol) (200 ml) was ice-cooled, and mesitylenesulfonyl chloride (11.0 g, 0.05 mol) was added. The reaction is 0
Stir at room temperature for 2 hours, mix with ether (200 ml), wash with water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated saline.
Dry and evaporate the solvent. The residue was recrystallized from methylene chloride-hexane to obtain 16.7 g (100%) of (A). (1R, 2S) (A) Melting point: 121-122 ° C., specific rotation -12.4 (c2.12, CHCl ₃ ) (1S, 2R) (A) Melting point: 120.5-121.5
° C, specific rotation 12.8 (c2.12, CHCl ₃ )

Example 2 2- (N-benzyl-N-)
Mesitylenesulfonyl) amino-1-phenyl-1-
Propanol (B) (A) obtained in Example 1 above (3.3 g, 10 mmol)
l), benzyl bromide (1.43 ml, 13 mmol) and potassium carbonate (2.09 g, 15 mmol) were heated under reflux in acetonitrile (40 ml) for 7 hours. After cooling, the salt was filtered off, the solvent was distilled off, and the residue was recrystallized from hexane-ethyl acetate to obtain 13.3 g (95%) of (B). (1R, 2S) (B) Melting point: 123-124 ° C., specific rotation -6.31 (c2.06, CHCl ₃ ) (1S, 2R) (B) Melting point: 123-124 ° C., specific rotation 6. 43 (c2.05, CHCl ₃ )

Example 3 2- (N-benzyl-N-)
Mesitylenesulfonyl) amino-1-phenyl-1-
Propyl propionate (C) (B) obtained in Example 2 above (15.0 g, 35.4)
(mmol) Propionyl chloride (3.8 ml, 42.5 mmol) was added dropwise to a methylene chloride solution (200 ml) of pyridine (3.7 ml, 46 mmol) under ice cooling. The reaction was stirred at 0 ° C. to room temperature for 12 hours, and ether (300 m
The mixture was diluted with 1), washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated saline, dried, and evaporated. The residue was recrystallized from ethyl acetate-hexane to obtain 16.8 g (100%) of (C). (1R, 2S) (C) Melting point: 124,147-148
° C, specific rotation 11.1 (c 2.24, CHCl ₃ ) (1S, 2R) (C) melting point: 124, 147 to 148
° C, specific rotation -11.2 (c 2.38, CHCl ₃ )

(Synthesis example) Synthesis of optically active anti-aldol (1R, 2S) (C) (480) obtained in Example 3 above
mg, 1 mmol), triethylamine (0.34 m
1, 2.4 mmol) in methylene chloride (10 ml)
At −78 ° C. for dicyclohexyl boron triflate (2
mmol) in hexane (2 ml) was added dropwise. -7
The mixture was stirred at 8 ° C. for 2 hours, and each aldehyde (1.
2 mmol) was added dropwise. 0 ° C at -78 ° C for 1 hour
For 1 hour, and the reaction was stopped by adding a pH 7 buffer solution (4 ml). Methanol (10 ml) and 30% aqueous hydrogen peroxide (1 ml) were added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into saturated saline (20 ml), extracted with ether (20 ml × 3), the organic layer was washed with water and saturated saline, dried and concentrated. The residue was purified by column chromatography to isolate the aldol product. Aldol product was converted into the diol by LiAlH ₄ reduction, were determined absolute conformation. At this time, the chiral auxiliary group (C) could be quantitatively recovered. The aldol reaction shows a high anti: syn selectivity for all aliphatic, aromatic, α, β unsaturated aldehydes (> 98:
The process proceeded in 2), and the face selectivity of the anti form was also> 95: 5, which was a synthetically satisfactory value. Table 1 shows the results.

[0026]

[Table 1]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 311/16 C07C 311/16 // C07B 53/00 C07B 53/00 C C07M 7:00

Claims (3)

[Claims] 1. An optically active alcohol having at least one α-hydrogen and a carboxylic acid ester thereof, which is useful for enolizing with boron triflate or amine and reacting with an aldehyde to synthesize an optically active antialdol. 2. An optically active alcohol having the following general formula (1): ## STR1 ## [In the formula, R ¹ and R ² represent a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, an acyl group, and an aryl which may have a substituent. A 4- to 7-membered cyclic hydrocarbon group or an R ⁵ -substituted sulfonyl group; R ³ and R ⁴ represent a hydrogen atom, an alkyl group which may have a substituent, A good aryl group or a 3- to 8-membered cyclic hydrocarbon group; R ⁵ represents an alkyl group or an aryl group; R ⁶ and R ⁷ represent a hydrogen atom, an alkyl group which may have a substituent, An aryl group which may have a group; R ¹ or R ² and R
³ or R ⁴ may form a 3-7 membered ring; R ^3, or R
⁴ and R ⁶ or R ⁷ may form a 4- to 7-membered ring], the optically active alcohol and the carboxylic acid ester thereof according to claim 1. 3. The method according to claim 1, wherein R ¹ is an R ⁵ -substituted sulfonyl group, R ² is an alkyl group or an aralkyl group, R ³ and R ⁴ are a hydrogen atom, an alkyl group, an aryl group, and R ⁶ or R ⁷ is a phenyl group. The optically active alcohol and the fatty acid ester thereof according to claim 2.