JPS6078585A - Optically active cyclopentenone and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R' is H or acyl; R is alkyl, alkenyl or alkynyl). EXAMPLE:l-3-Hydroxy-2-n-pentyl-4-cyclopentenone. USE:An intermediate for agricultural chemicals, perfumes and medicines. PREPARATION:Esterase produced by a microorganism, e.g. lipase of the genus Aspergillus, or esterase derived from animals or plants is added to and mixed with a dl-4-cyclopentenone ester of formula II (R'' is acyl), e.g. dl-3-acetoxy- 2-n-pentyl-4-cyclopentenone, and the resultant mixture is then stirred vigorously in a buffer solution of 5-11pH usually in 0.05-0.5M concentration at 10-16 deg.C for 10-70hr and subjected to asymmetric hydrolysis.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound represented by the general formula (I) (wherein R' represents a hydrogen atom or an acyl group, and ■ represents an alkyl group, an alkenyl group, or an alkynyl group). The present invention relates to optically active 4-cyclobentenones and a method for producing the same.

The optically active 4-cyclobentenones of general formula (I) above are novel compounds synthesized for the first time by the present inventors, and the compounds themselves are useful as intermediates for agricultural chemicals, fragrances, or pharmaceuticals. . For example, in the above formula, R' is a hydrogen atom.For example, if t-2-substituted 18-hydroxy-4-cyclobentenone is rearranged while maintaining its steric configuration, it will have the R(+) coordination. -Substituted-4-hydroxy-2-cyclobentenone, which can be used as a key intermediate for prostaglandin derivatives.

Furthermore, the optically active substance obtained by the above rearrangement may be converted into a sulfonic acid ester using, for example, para-toluenesulfonic acid or methanesulfonic acid, and then reacted with a base, or may be reacted with a base such as sodium acetate, sodium dichloroacetate, or trichloroacetic acid. By reacting with soda etc. to form the corresponding ester and then hydrolyzing it, it is converted into 2-substituted 4-hydroxy-2-cyclobentenone, which has the opposite steric configuration to the original one, and is used. You can also do that.

Such optically active 4-cyclobentenones represented by the above general formula (I) have the general formula (n) (wherein R1' represents an acyl t〆f/tiger group, and R has the same meaning as above). have

) By asymmetric hydrolysis of dl-4-cyclobentenone esters by the action of esterases produced by microorganisms or esterases derived from animals and plants,
It can be obtained as a mixture of optically active 4-cyclobentenones whose substituent R' in the general formula (I) is a hydrogen atom and optically active 4-cyclobentenones whose substituent R' is an acyloxyl group. reactor.

Here, the dl-4-cyclobentenone ester represented by the general formula (II) used as a raw material is the general formula (
+n) (In the formula, ■ has the same meaning as above.) d
It can be easily synthesized by reacting l-2-substituted-3-hydroxy-4-cyclobentenones with organic carboxylic acids.

The tie-2-substituted-8-hydroxy-4-cyclobentenones can be easily obtained, for example, by rearranging furancarbinols, and specific examples thereof include the following compounds.

8-hydroxy-2-methyl-4-cyclobentenone,
2-ethyl-8-hydroxy-4-cyclobentenone,
8-hydroxy-2-n-propyl-4-cyclobentenone, 2-isopropyl-8-hydroxy-4-cyclobentenone, 3-hydroxy-2-n-butyl-4-cyclo-kuntenone, 2-isobutyl -8-hydroxy-
4-cyclobentenone, 3-hydroxy-2-n-pentyl-4-cyclobentenone, 2-isopentyl 71/
-3-hydroxy-4-cyclobentenone, 3-hydroxy-2-n-hexyl-4-cyclobentenone, 3-
Hydroxy-2-n-heptyl-4-cyclobentenone, 2-allyl-3-hydroxy-4-cyclobentenone, 2-(2-cis-butenyl)-8-hydroxy-4-
Cyclobentenone, 2-(ω-butenyl)-8-hydroxy-4-cyclobentenone, 2-(2-cis-pentenyl)-3-hydroxy-4-cyclopentenone, 8-
Hydroxy-2-(2-trans-pentenyl)-4-
Cyclobentenone, 2-(8-cis-hexenyl)-8
-Hydroxy-4-cyclobentenone, 3-hydroxy-2-prohalkyl-4-cyclobentenone, 8-hydroxy-2-(2-pentynyl)-4-cyclobentenone, 8-hydroxy-2-(α- methylallyl)-4-
Cyclobentenone.

Examples of organic carboxylate 9 include saturated or unsaturated organic carboxylic anhydrides and organic carboxylic acid halides, such as acetic anhydride, acetic chloride, or bromide,
Propionic acid chloride or bromide, propionic anhydride, butyryl chloride or bromide, caproyl chloride or bromide, caprylic acid chloride or bromide, stearic acid chloride or bromide caprinoyl chloride or bromide, dodecatuin chloride or bromide, balmitoyl chloride Or bromide, chloroacetyl chloride or bromide, dichloroacetyl chloride or bromide, etc. are exemplified.

For the reaction between tit-2-substituted-8-hydroxy-4-cyclopentenones and organic carboxylic acids, ordinary esterification conditions are not applied, but the reaction is carried out using a catalyst in the presence or absence of a solvent. It will be implemented by making it happen.

In this reaction, when a solvent is used, examples of the solvent include aliphatic or Examples include solvents that are inert to the reaction, such as aromatic hydrocarbons, ethers, and halogenated hydrocarbons, either alone or as a mixture. The amount used can be used without any particular restriction.

The organic carboxylic acids used in the reaction are the raw materials dt-2-
1 equivalent or more is required relative to the N-substituted-8-hydroxy-4-cyclobentenone, and the upper limit is not particularly limited, but is preferably 4 equivalents.

Examples of the catalyst include organic or inorganic basic substances such as triethylamine, tos-n-butylamine, pyridine, picoline, sodium carbonate, sodium methylate, and potassium bicarbonate. The amount used is not particularly limited, but usually dl-2-substituted-3-hydroxy-4
- 1 to 5 equivalents relative to cyclobentenones.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Furthermore, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as catalysts.

The reaction temperature is usually -20°C to 150°C, preferably in the range of -10°C to 120°C.

There is no particular restriction on the reaction time.

Through such a reaction, the general formula (1
The dt-4-cyclobentenone esters shown in 1) can be easily obtained in good yields, and they can be easily isolated from the reaction mixture by conventional separation means such as extraction, separation, concentration, distillation, etc. However, the reaction mixture can be used as is when carrying out the process of the invention.

Kakaro ctt -4->Asymmetric hydrolysis of clobentenone esters is carried out using esterases produced by microorganisms or esterases derived from animals and plants.
This is carried out by hydrolyzing one of the optically active forms of 4-cyclobentenone esters.

The microorganism that produces the esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze di-4-cyclobentenone esters represented by the general formula (old). , but is not particularly limited.

In addition, esterase in the present invention means esterase in a broad sense including lipase.

Specific examples of such microorganisms include Enterobacter genus, Arthrovector genus, Brevibacterium genus, Pseudomonas genus, alkaline earth metals, microorganisms, etc.
Socas spp., Chromobacterium spp., Microbacterium spp., Corynebacterium spp. , Penicillium, Aspergillus, Risophus, Mucor, Aureobasidium, Actinomycosis, Nocardia, Streptomyces, Panzenula, and Achromobacter. hodotorula m1nuta IFO-08
87, IFO-0412, Rhodotorula r
ubra IFO-Q37Q.

Rhodotolura m1nuta var te
xensis IFO-087LTrichoderm
a longibrachiatum IFO-484
7*Candida krusei out -(iQ
Q7. 0andidacylindracea,
C! andida tropicalis PK 2B
B.

0andida utilus IFO-1086, P
quedomonas fragj IFO-8458,
P! Ieudomonas pntid FIIFO
-12996, Pseudomona8fluores
cens IFO-3g6B, Psp+tdomo
nas aeruginoqa IFO-8080+B
acillus cerenq IFO-8466, B
ar+1lluqqubtilis ATOO-668
8, Bacillus pulmiluIIIFO-1
2092, BfLCilln! l5ul〕tiliq
var niger IFO-3108, Nocardi
a uniformis 5ubtsuya-nar
enuq ATCC-21806, Nocardia
uniformisIFO-18072, Cbromo
bacterium chocolatum IFO-8
758, Chromobact, eri+tm iod
inumIFO-3553, Flavnbacteri
nm arbonesCensIFO-8750, Fl
avobacterium heparinumUFO
-12017* R, iy, opuRchinenqi
p IFO-4768゜Mucor, 1avanic
us IFO-4572, Aspergillusn!
ger ATOO-9642, Alcaligenes
faecalis UFO-12669, Tornlo
pIIis cnndida IFO-0768゜0o
rynebacterium gepedonicum
IFO-137 (iJ3.

Saccharomyces roux IFO-050
5.

Arthrobacter simlcx IFO-
8580+Streptomyces griserr
! IIFO-313513.

Brevibacterium ammonium
es IFO-12072.

Brevibacterium divaricaru
m ATOO-14020+Micrococous
varianl IFO-8765+Microco
ccus 1uteus IFO-3Q(i(i.

Enterobaoter cloacae IFO-
8820+Corynebaotherium equi
ATCC-76gg.

Lacto bacillus casei IFO-
8822+0ryptococcus albidus
IFO-0878+Pihia polimorph
a IFO-1166+Penicillium fr
equontans IFO-5692+Aureob
asidium pullulans IFO-446
4+Actinomuor elegans IFO
-4022.

Hansenula anomala var oif
errii out 6095 +Hansenula
anomala IFO-0118+Achromo
bacterium parvui-us IFO-1818
1g Achromobacter 5inplex I
For culturing the above-mentioned microorganisms such as FO-12069, a culture solution is usually obtained by performing liquid culture according to a conventional method.

For example, a sterilized liquid medium [malt extract for mold and yeast, yeast extract medium (dissolve peptone sy, 10 g of glucose, 8 f of malt extract, and 8 f of yeast extract in 1 t of water, and adjust the pH to 6.5); For bacteria, a sweetened bouillon medium (glucose 10f1 Pefton 5f, meat extract 5f Nac18f is dissolved in 1 t of water, pH is adjusted, and solid culture may be carried out if necessary.

Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following IJ.

Lipase of the genus Pseudomonas (manufactured by Ohno Pharmaceutical), lipase of the genus Aspergillus [Lipase AP (manufactured by Amano Pharmaceutical)], lipase of the genus Mucor (manufactured by Amano Pharmaceutical), lipase of Candida and Cylindrace [Lipase MY (manufactured by Polysaccharide Sangyo)], Lipase of alkaline earth layer [Lipase PL (
Polysaccharide Sangyo)], Achromobacter lipase [Lipase A, 1. (Meito Sangyo IV)'), Arthrobacter
Genus lipase [Lipase Joint BSL (Joint Sake Refining)],
Chromobacterium lipase (manufactured by Toyo Jozo), Rhizopus. Deremer's lipase [Talipase (Tanabe Seiyaku Axis)]
], Rhizopus lipase [Lipase Saiken (Osaka Bacteria Research Institute)].

Furthermore, animal and plant esterases can also be used, and specific examples of these esterases include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Gevm-c:X, +5 (+
'.

As the esterase used in this reaction, enzymes obtained from animals, plants, and microorganisms are used, and their usage forms include purified enzymes, crude enzymes, enzyme-containing materials, microbial culture fluids, cultures, bacterial cells, and culture samples. They can be used as needed in various forms such as and processed products, and enzymes and microorganisms can also be used in combination. Or again,
It can also be used as an immobilized enzyme immobilized on a resin or the like, or as an immobilized bacterial cell.

The asymmetric hydrolysis reaction of the present invention is carried out by vigorously stirring a mixture of the raw material dt-4-cyclopentenone ester and the above-mentioned enzyme or microorganism in a normal buffer solution.
It will be done.

As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc., are used, and the pH thereof is adjusted to suit the desired pH. The preferred concentration is usually 0.05-2, with a pH of 3 to 11 for culture solutions of alkaline bacteria and alkaline esterases, and a pH of 5 to 8 for culture solutions of microorganisms that are not alkalophilic and esterases that do not have alkali resistance.
M, preferably in the range of 0.05-0.5M.

The reaction temperature is usually 10 to 60°C, and the reaction time is generally 10 to 70 hours, but is not limited thereto.

Through this reaction, either one of the optically active forms of the raw material tu-4-cyclobentenone esters is hydrolyzed to form an optically active 2-substituted - in which the substituent R' is a hydrogen atom in the general formula (■). 8-Hydroxy-4-cyclobentenone is produced, and on the other hand, the optically active 2-f substitution in which the substituent ■′ is an acyloxyl group in the general formula (1), which is the other optically active form of the starting compound, -8-acyloxyl-4-cyclobentenone remains as it is as a hydrolysis residue, and as a result, in the method of the present invention, the above two optically active compounds are simultaneously produced as a hydrolysis product and a hydrolysis residue. You will get it.

After completion of such hydrolysis reaction, in order to separate the hydrolysis product and hydrolysis residue from the reaction solution, the hydrolysis reaction solution must be treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction treatment is performed with a solvent such as ethyl ether, the solvent is distilled off from the organic layer, and the concentrated residue is further distilled or treated with column chromatography.
Thereby, optically active 2-substituted-8-hydroxy-4-cyclobentenone represented by general formula (I) and optically active 2W-substituted 8-acyloxyl-4-cyclobentenone can be separated.

The optically active 2-substituted-8-acyloxyl-4-cyclobentenone obtained here can be further hydrolyzed and used as a raw material for producing a symmetrical object.

Incidentally, the optically active 4-cyclobentenones represented by the general formula (1) of the present invention have not been known at all,
d of 2-[converted-8-hydroxy-4-cyclobentenone
Tctrahedron Le
tter, A89 + 8555-8558 (19
76) states that it is a pair of (1).

(1) However, there is no specific description or separation of the pair of optically active forms mentioned in (1), nor is there even a mention of the possibility. Possibility of dislocation while retaining
Nothing is known about the steric configuration of 2-substituted-4-hydroxy-2-en clopentenone obtained by rearrangement while maintaining the steric structure.

The present invention will be explained below with reference to Examples.

Example 1 dl-3-hydroxy-2-n-pentele-4-cyclobentenone 16 was placed in a flask equipped with a stirrer and a thermometer.
．． 8g of p-toluenesulfonic acid, 0.1g of p-toluenesulfonic acid, and 88.6F of acetic anhydride were charged, and stirring was continued at 100°C for 2 hours.

After the reaction is completed, acetic anhydride is distilled off under reduced pressure, and the residue is extracted with toluene. The toluene layer was washed with 1% sodium bicarbonate solution,
Wash further with water.

Toluene was distilled off from the organic layer to give 19.5 ttt-B-acetoxy-2-n-pentyl-4-cyclobentenone.
& (yield 98%) was obtained.

(b, p, 105-110℃/0.2-0.5 ya
nHf) dl-8-acetoxy-2-n-pentyl-
4-cyclopentenone 5fI and lipase P-30A
(manufactured by Ohno Pharmaceutical) 100 "F't O, I M')
Stir vigorously at 25-35°C for 20 hours in 200 ml of phosphoric acid bar 7 (pH 7,0).

After the reaction is complete, add 50 m of methyl isobutyl ketone to the reaction solution.
Extract 4 times at l. The solvent was distilled off from the obtained organic layer, and the concentrated residue was purified by column chromatography using a mixed solution of ethyl acetate:toluene-5=5 to obtain t-8-hydroxy-2.
-n-pentyl-4-cyclobentenone (1.8 g, chloroform), refractive index n 1.46921 and d-73-
Acetoxy-2-n-pentyl-4-cyclobentenone 2.549 (Optical rotation α] 20+112.0° (C=
1, chloroform), and a refractive index n 1.46211 was obtained.

Example 2 ttt-2-allyl-8-hydroxy-4 in a flask
-Cyclobentenone 18.81 Toluenesulfonic acid 0
, 1f and acetic anhydride at 90-10.
Heat at 0°C for 8 hours. Hereinafter, post-treatment and purification were carried out according to Example 1, and de-8-acetoxy-2-allyl-
4-cyclobentenone 16 F (yield 89%) wi%
? ,=.

(b, p, 80-85°C/0.6-1 naxHI
) dl -13-acetoxy-2-allyl-4-cyclobentenone 6.5 g and lipase PL (hexasaccharide industry f
M) 0.2g to 0.1M phosphate bath(I)
H7,0) 24 at 25-85°C in 250 jnt
Time, intense 1. <fi Stir. After the reaction, Example 1
After treatment and purification according to the method, -2-allyl-3-hydroxy-4-cyclopentenone 1. 40% yield at ft81F) (σ]ゎ5 -28.2° (Q z l, chloroform), nDl,
504R1 and d-3-acetoxy-2-a0 true 4-cyclobentenone 2.56y(α]05 -1-68.8° ((+ = 1, riooporm), n
Dl, 48243 was obtained.

Example 3 0.1M of dt-8-ace(-xy-2-n-pentyl-4-diclobentenone 8d) and 150 ml of lipase Godo BSL (Godo Sake Refining Co., Ltd.) (
pH 7.0) Stir vigorously for 20 hours at 80°C under 120 mA. After completion of the reaction, post-treatment and purification were performed according to Example 1 to obtain L-8-hydroxy-2-n-pentyl-
4-cyclopenotenone 1.01 F (yield 42%) (
α) D-51,6° (e=1, chloroform), 5 n Dl, 470') and d-8-acetoxy 2 n
-Pentyl-4-cyclobentenone 1.541 Example 4 dl -3-acetoxy-2-propargyl-4-cyclobentenone 8f and reverse M ~ 2 at 35 °C
Stir vigorously for 0 hours. After the reaction is complete, the reaction solution is extracted 8 times with 50 ml of hexane. The solvent of the hexane layer was distilled off under reduced pressure, and the concentrated residue was mixed with ethyl acetate:toluene=1:
Column chromatography was carried out using a mixed solution of
1,)) o o ho71/A), n251.50
Get 421.

Then extract the remaining water with water (Mi), methyl isobutyl ketone (50 ntL), and trowel 4 times (4TIIL).
l,l. The solvent of the methyl isobutyl ketone layer is removed under reduced pressure.

0.999 of L-8-hydroxy-2-brono/-4-cyclopenotenone is obtained.

Claims (2)

[Claims] (1) In the general formula 1, R' is a hydrogen atom or an optically active 4-cyclobentenone represented by acyl l/γ. (2) Microorganisms are present in the di-4-cyclobentenone esters represented by the general formula (where B, ″ represents an acyl t〆tf group, and R represents an alkyl group, an alkenyl group, or an alkynyl group). A general formula characterized by asymmetric hydrolysis by the action of produced esterases or esterases derived from animals and plants (in the formula, kan is a hydrogen atom or acyl t, f
It represents a pβ group, and 几 has the same meaning as above. ) A method for producing optically active 4-cyclobentenones.