JPS647973B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for asymmetric reduction of ketones, which is advantageous for producing optically active alcohols, and more specifically relates to a method for asymmetric reduction of ketones, which is advantageous for producing optically active alcohols. , in which an optically active secondary alcohol is produced by reduction using a metal hydride in an inert organic solvent. According to the method of the present invention, optically active 4-hydroxycyclopentenones, which are intermediates for producing prostaglandins, which are known to exhibit various pharmacological effects, can be obtained in high yield. In addition, prostaglandins, thromboxanes,
Optically active alcohol moieties contained in the chain partial structures of icotrienes and their analogous compounds can be easily obtained. In addition, the pesticide pyrethroline,
It also becomes possible to efficiently synthesize intermediates for the synthesis of anthracyclines, which are anticancer drugs. Conventionally, lithium aluminum hydride, lithium tri-t-butoxyaluminum hydride, lithium borohydride, sodium borohydride, etc. have been known as methods for reducing the oxo group of a compound having a ketone structure to a hydroxyl group. With this reagent, the resulting alcohol is obtained as a racemate. However, as mentioned above, when used as a medicine or agrochemical, only one of these configurations is necessary and the other is often unnecessary. For example, when producing prostaglandins, only one configuration is prominent. It is known to exhibit pharmacological effects. On the other hand, various methods for obtaining optically active alcohols have been proposed (“Asymmetric Organic
Reactions”, JDMorrison, H.S.Mosher
Practice-Hall, Englewood-Cliffs, NJ
(1972)). Recently, (1) a method for modifying lithium aluminum hydride (J.Chem.Soc.(c)., 197
(1967), J.Org.Chem., 38 , 1870 (1973),
Tetrahedron, 32 , 939 (1976), Heterocycles,
12, 499 (1979), J.Am.Chem.Soc., 101 , 3129
(1979)), (2) Method for modifying borane (J.Chem.
Soc., Chem.Commun., 42 , 2534, 2996
(1977)), (3) Method using enzymes and microorganisms (J.Am.
Chem.Soc., 97 (1975)), (1) Method for modifying sodium borohydride (J.Chem.Soc., Chem.
Commun., 926 (1978), 438 (1976)), etc. are known. However, these methods have problems in the preparation of modifiers, recovery after use, separation and purification, or low chemical and optical yields, making it difficult to apply them to industrial production. . In view of the above problems, the present inventors have developed an industrially advantageous asymmetric reduction method for ketones that uses readily available compounds, is simple in reaction operation, separation and purification, and has high chemical and optical yields. As a result of extensive research to find out, ketones are selectively reduced asymmetrically by reacting them with metal hydrides in the presence of industrially easily available optically active amino acid derivatives and alcohols, and this The present inventors have discovered that an optically active alcohol can be easily obtained in high yield and with high purity, and that the optically active amino acid derivative used in the reaction can be efficiently recovered, leading to the completion of the present invention. The ketone targeted in the present invention is a chain or cyclic ketone represented by the general formula (). (In the formula, R ¹ and R ² are an alkyl group, an alkenyl group,
It represents an alkynyl group, an aryl group, or an aralkyl group, R ¹ and R ² are different from each other, and may be ring-closed. ) Alkyl, alkenyl, and alkynyl groups are linear or branched saturated or unsaturated hydrocarbon groups having 1 to 50 carbon atoms, and these hydrocarbon groups may further include halogen, amide, amine, ether, nitrile, It may be substituted with urethane, nitro group, etc. Examples of the aryl group include phenyl, biphenyl, and naphthyl groups, and the phenyl group has one or more substituents such as halogen, trifluoromethyl, lower alkyl, nitro, amide, amine, ether, nitrile, and urethane groups. It may have. Moreover, the aralkyl group means a lower alkyl group in which one or more hydrogen atoms are substituted with the above-mentioned aryl group. This ketone () has the general formula () (In the formula, R ³ is a commonly used amino group protecting group, R ⁴ is COOH or CH ₂ OH, and Y is S,
Indicates an O atom or NH. ) is reacted with a metal hydride in the presence of an alcohol in an inert solvent. An asymmetric metal hydride having a stable 6-membered ring structure is produced by the reaction of the active hydrogen of the R ⁴ group and the YH group in formula () with the metal hydride.
The protecting group for the amino group used here may be one commonly used, such as benzoyl, acetyl, tosyl, benzyloxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl, 2-naphthoyl, p-nitrocarbobenzoxy group. etc. Preferred examples of these optically active amino acid derivatives include serine, cysteine, and cystine in which the amino group is protected with benzoyl, which is a common protecting group, or derivatives in which the carboxyl group thereof is converted into an alcohol. These optically active amino acid derivatives are easily available industrially and are soluble in alkaline aqueous solutions, so they can be easily recovered by washing after the reaction is completed. Further, cystine, which is an oxidized form of cysteine, is reduced within the reaction system to give cysteine, and therefore has the same effect as cysteine. Therefore, the number of moles of relatively expensive optically active amino acids can be halved, and the optical yield is also high, which is advantageous. These optically active amino acid derivatives are used in a molar amount of 1 to 5 times, preferably 2 to 3 times, relative to the ketone. The steric configuration (R or S) of the resulting alcohol is reversed between when an L-amino acid is used and when a D-amino acid is used. Therefore, the configuration of the amino acid used can be arbitrarily selected depending on the configuration of the desired product. The straight chain or branched lower aliphatic alcohol used in the present invention includes straight chain or branched lower aliphatic alcohols having 1 to 6 carbon atoms such as methanol, ethanol, isopropanol, and t-butanol. Lower aliphatic alcohols having a branched group such as iso-propyl alcohol and t-butanol are preferred. The amount of alcohol used is 1 to 5 times, preferably 1 to 2 times by mole, relative to the ketone. Further, examples of the reducing agent used in the present invention include metal hydrides such as lithium borohydride, sodium borohydride, and lithium aluminum hydride, but lithium borohydride is preferred. The amount used is 1 to 5 times, preferably 3 to 4 times by mole, relative to the ketone. The solvent may be any inert solvent that does not participate in the reaction, such as hydrocarbon solvents such as hexane, aromatic solvents such as benzene, toluene, and xylene, and ether solvents such as ethyl ether, tetrahydrofuran, dioxane, and diglyme. These can be used alone or in a suitable mixture. Next, the preparation of the optically active alcohol obtained by the method of the present invention will be explained. First, under an inert gas atmosphere such as nitrogen or argon, an optically active amino acid derivative and a linear or branched low aliphatic alcohol are dissolved in an inert solvent, a reducing agent is added, and if necessary, the mixture is heated ( (first reaction), and then reduction proceeds by lowering the reaction temperature and adding a ketone (second reaction). In the first reaction, the reaction temperature was between room temperature and solvent reflux temperature.
Allow the reaction to run for minutes to 5 hours. Then, in the second reaction, the reaction temperature is -150 to 0°C, preferably -100 to -
React at 30°C for 1 to 10 hours. After confirming the disappearance of the ketone, the reaction is stopped by adding a 1N aqueous hydrochloric acid solution, and the desired optically active alcohol is obtained through appropriate post-treatment and purification. As for this post-treatment, for example, an aqueous alkali carbonate solution such as 5% sodium bicarbonate is added to the reaction stop solution to adjust the pH to around 10, and then the product is extracted with ether and dried. The crude product thus obtained is purified by conventional purification methods such as column chromatography, recrystallization, distillation, etc. The purity of the obtained optically active alcohol is (S)-(-)-α-
Gas chromatography and ¹ H-NMR were performed according to the known method (MTPA method) to convert methoxy-α-trifluoromethylphenylacetic acid into an ester.
It was determined using On the other hand, since the optically active amino acid derivative remains in an unreacted state, it can be efficiently recovered by combining it with the above-mentioned post-treatment and purification means. For example, when optically active N-benzoylcysteine is used, it can be recovered in high yield by acidifying the aqueous layer after ale extraction in the post-treatment step and extracting it with ether. According to the present invention, a ketone is selectively asymmetrically reduced by using an optically active amino acid derivative that is industrially easily available as described above, so that an optically active alcohol can be converted from a corresponding ketone through a simple reaction operation. It can be manufactured efficiently. Hereinafter, the present invention will be specifically explained with reference to Examples. Example 1 (R)-N-benzoylcysteine 540 mg (2.4
mmol) and t-butanol 0.15 ml (1.6 mmol)
mol) was dissolved in 8.5 ml of THF, and 3.37 ml (3.6 mmol) of a THF solution (1.07 M solution) of lithium borohydride was added at room temperature under an argon atmosphere. The mixture was heated to reflux for 30 minutes, then cooled to -78°C.
A solution of 134 mg (1 mmol) of propiophenone in 2 ml of THF was added. The reaction solution was stirred for 4.5 hours while gradually increasing the reaction temperature from -78°C to -40°C.
The reaction was stopped by adding 3 ml of 1N hydrochloric acid, and the pH of the liquid was adjusted to 10 by adding 5% aqueous sodium hydrogen carbonate. The product was extracted with ether and the organic layer was
After washing with % sodium bicarbonate water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel TLC to obtain 96 mg of (R)-(+)-1-phenylpropanol as a colorless oil.
was gotten. Yield 71%, b.p107℃/15mmHg, [α] ²⁰ _D = +
41.45゜(c=5.09, chloroform), optical purity 91%
(calculated from the standard optical rotation). On the other hand, the aqueous layer after ether extraction was acidified, followed by ether extraction, drying, and solvent distillation to recover 459 mg of the raw material (R)-N-benzoylcysteine (recovery rate 85%). Example 2 In Example 1, 120 mg of acetophenone was used instead of propiophenone, and the reaction temperature was changed to -100
All the same operations and treatments were performed except that the temperature was changed from ℃ to -78℃, and (R)-(+)-1-phenylethanol
Got 80mg. Yield 66%, optical purity 87%. Example 3 In Example 1, 548 mg (1.2 mmol) of (R,R')-N,N'-dibenzoylcystine was used instead of (R)-N-benzoylcysteine, and methyl β- The same operations and treatments were carried out except that 148 mg (1.1 mmol) of phenyl vinyl ketone was used to obtain 67 mg of (R)-(+)-4-phenyl-3-buten-2-ol. yield
44%, optical purity 76%. Example 4 In Example 1, 96 mg of 2-cyclohexen-1-one (1 m
29 mg of 2-cyclohexen-1-ol was obtained by performing all the same operations and treatments except that 2-cyclohexen-1-ol was used. Yield 40%, optical purity 73%. Examples 5 to 14 In Example 1, 548 mg (1.2 mmol) of (R,R')-N,N'dibenzoylcystine was used instead of (R)-N-benzoylcysteine, and the compounds shown in Table 1 were used instead of propiophenone. The same operations and treatments were performed except that the α- or β-haloketone (1.0 mmol) shown in . α used as each raw material
Optically active halohydrins corresponding to - or β-haloketones were obtained in the yields shown in Table 1. Example 15 The same operations and treatments as in Example 6 were carried out using (S,S')-N,N'dibenzoylcystine instead of (R,R')-N,N'dibenzoylcystine. Ivy. The optical antipode (R)-2-bromo-1-phenylethanol of Example 6 was obtained. Yield 80%, optical purity 82%, optical _rotation [α] ^20D : -40.1° (C8.12,
_CHCl3 ). [Table] [Table] Example 16 The same operations and treatments as in Example 3 were performed except that metal (1.6 mmol) was used instead of t-butanol, and (R)-(+)-4-phenyl 111 mg of -3-buten-2-ol was obtained. Yield 75
%, optical purity 21%. Example 17 The same operations and treatments as in Example 3 were performed except that ethanol (1.6 mmol) was used instead of t-butanol, and (R)-(+)-4-phenyl-3-butene-2 -105 mg of ol was obtained. yield
71%, optical purity 49%.

Claims (1)

[Claims] 1. In a method for reducing a ketone by reacting with a metal hydride, the following general formula () (In the formula, R ³ is a protecting group for an amino group, R ⁴ is a COOH group or a CH ₂ OH group, and Y is an S, O atom, or NH.) A method for asymmetric reduction of ketones, characterized by carrying out the reaction in the presence of a branched lower aliphatic alcohol. 2 Ketone has the general formula () (In the formula, R ¹ and R ² are an alkyl group, an alkenyl group,
It represents an alkynyl group, an aryl group, or an aralkyl group, and R ¹ and R ² are different from each other and may be closed. ) The method for asymmetric reduction of a ketone according to claim 1, wherein the ketone is a chain or cyclic ketone represented by: