JPH03112975A - Optically active delta-lactone compound - Google Patents

Abstract

NEW MATERIAL:An optically active delta-lactone of formula I (X is hydroxyl group, phenylthio or OR<1>; Y is H, -CO2R<3>; R<1> is a readily releasable protecting group selected from aralkyl, alkyloxyalkyl, alkenyl and cycloalkyl containing a hetero atom in the ring; R<3> is lower alkyl, alkenyl or benzyl; * is asymmetric carbon). USE:Useful as an intermediate for synthesizing an optically active delta-lactone compound of formula II which is the mother nucleus of delta-lactone antibiotics such as actinobolin and bactobolin. PREPARATION:A compound of formula III is subjected to an 1,4-addition reaction of an cyanoacetic acid ester anion in an inactive solvent to provide the compound of formula I. The compound of formula III is synthesized from glycidyl ether.

Description

[Detailed Description of the Invention] (Industrial Application Field) The present invention is based on formula (9) (in the formula, * represents an asymmetric carbon), which forms the core of δ-lactone antibiotics such as actinovorin and bactoporin. The present invention relates to an intermediate for producing the optically active δ-lactone compound.

(Prior art and problems to be solved by the invention) Regarding the production of the δ lactone compound represented by the above formula (9), for the racemate, R, C0rdOVa, etc. (Tetr
ahedron Lett, 25.2945 (198
4) ) , K, )1゜PietruSieWiCZ
et al. (J, Org, Chcm, 53.2837 (198
8)), but regarding the optically active substance, H
oriW (Tetrahedron, , 41.529
5 (1985)) is known.

A method for easily obtaining this compound with high optical purity in good yield is not yet known.

(Means for Solving the Problems) In view of the above points, the inventors of the present invention conducted extensive research with the aim of efficiently obtaining a δ-lactone compound in a high yield through a simple reaction route without causing racemization, and as a result, they found the following: It has been found that optically active δ-lactone compound (9) with high optical purity can be easily obtained from optically active δ-lactone compound (6) according to reaction route (n).

Reaction route (If) (6) (A) (7) The present invention necessarily provides an intermediate obtained in this reaction route (n).

That is, the present invention relates to the general formula (A) (X is a hydroxyl group, a phenylthio group, or 10RI, Y
represents a hydrogen atom or 1002R3. R1 is an easily removable protecting group selected from an aralkyl group, an alkyloxyalkyl group, an alkenyl group, and a cycloalkyl group containing a foreign atom in the ring, and R3 is a lower alkyl group, an alkenyl group, or a benzyl group. represent. * represents an asymmetric carbon. ) An optically active δ-lactone compound (A) represented by the following is provided.

R1 in the compounds represented by formulas (A) and (6) is an easily removable protecting group such as pencil or p-methoxybenzyl.

Aralkyl groups such as p-chlorobenzyl group, methoxymethyl, t-butoxymethyl, 1-ethoxyethyl, 1-
Examples include alkyloxyalkyl groups such as isopropoxyethyl groups, alkenyl groups such as allyl and methallyl groups, and cycloalkyl groups containing heteroatoms in the ring such as tetrahydrofuranyl and tetrahydropyranyl groups. .

Alkyl groups with 1 to 5 carbon atoms such as ethyl, propyl, isopropyl, butyl, 1-butyl, pendel group, allyl, 2
Examples include alkenyl groups having 3 to 5 carbon atoms or benzyl groups such as -methylallyl, 2-butenyl, 3-butenyl, and 2-pentenyl groups.

Compound (A) of the present invention is synthesized from compound (6), and compound (6) is synthesized from glycidyl ether (2) according to reaction route (I>).

In other words, optically active α,β-unsaturated δ-lactone compounds (
6) can be produced from glycidyl ether (2) by the method already disclosed by the present inventors (Journal of the Society of Organic Synthetic Chemistry, Vol. 45, p. 1157 (1987)) as shown in reaction route (I). I can do it.

Reaction route (engineering) (2) (3) (4) (5) <6) In reaction route (I>), R1 represents -b as described above. R2 is n-butyl or isobutyl.

Represents a lower alkyl group such as t-butyl or methyl.

The method for synthesizing the compound (A) of the present invention from this compound'(6) will be explained in detail below according to detailed reaction routes (IIa> and (IIb>).

Detailed reaction route (I[a) Detailed reaction route (nb) (9) a) Synthesis of δ-lactone compound A The optically active α, β-unsaturated δ-lactone compound (6) is treated with an inert solvent such as tetrahydrofuran, ethylene glycol dimethyl ether, Cyanoacetic acid ester with the formula CH2(CN)CO in a solvent such as toluene, dimethylformamide, etc.
R3 in 2R3 represents the same thing as above. ) with the anion of 1,4-added cete compound (A-1>(X=OR
1, Y=CO2R3) is synthesized, and from this Step 1) Hydrolysis and decarboxylation of the ester, Step 2) Elimination of the protecting group.

Step 3) The resulting hydroxyl group is converted into a phenylthio group to synthesize a compound (A-4>(X=SCa Hs, Y=T1).

1) Hydrolysis and decarboxylation of the ester, 2) Elimination of the protecting group,
3) The order of the steps for converting the resulting hydroxyl group into a phenylthio group is either 1) → 2) → 3) or 2) → 1) → 3), or 2)
→3) →1) is also fine.

Steps 1), 2>, and 3) can each be performed by methods known per se.

Step 1) is carried out using an alkali or acid catalyst and heating under reflux in a water-containing solvent. As the alkali, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. can be used.

As the acid, mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, and phosphoric acid, or Lewis acids such as magnesium chloride, zinc chloride, and copper sulfate can be used. As a solvent, a polar solvent,
For example, methanol, ethanol, isopropyl alcohol, acetonitrile.

Acetone, dimethylformamide, dimethylacetamide, etc. can be used.

For removing the protecting group in step 2), various methods can be used as appropriate depending on R1 selected. For example, when R1 is a benzyl or allyl group, hydrogenolysis or isomerization using a para-Kum catalyst is used, but when R1 is methoxymethyl or 1-ethoxyethyl, it is hydrolyzed using a mineral acid, an organic acid, or a Lewis acid. A method of hydrolysis in a solvent can be used.Step 3) of converting water 11 into a phenylthio group is performed using triphenylphosphine, tri-butylphosphine, 1,2-
This can be achieved by reacting diphenyl sulfide with a raw material alcohol in the presence of a tertiary phosphine such as bis(diphenylphospho)ethane using pyridine, triethylamine, or the like as a solvent.

Also, compound (A-1) (X=OR1, Y=CO2R3)
When reacting through the route of steps 2) → 3) → 1), the compound (
A-5>(X=OH, Y-CO2R3), (A-6)(
X=SCa Hs, Y=CO2R3) to form the compound (A
−4>(X=SCs Hs , Y=H).

Compound (A-1>(X=OR1, Y=CO2R3) to compound (A-4>(X=SCe Hs).

A specific example of the conversion to Y=H> is shown below, but the manufacturing method is not limited to this specific example.

Compound (A-1) (X = OBn, Bn represents a benzyl group. Y = CO2C2Hs) was heated in magnesium chloride and dimethylacetamide, hydrolyzed and decarboxylated, separated and purified by silica gel column chromatography, The 1 to lance isomer and the cis isomer of compound (A-2) (X=OBn, Y=H) can be obtained, respectively. This product was hydrogenolyzed using a palladium catalyst to form a compound (A-3>(X=
Oh.

Y=H) and reacted with tri-butylphosphine and diphenyl sulfide in pyridine to form the compound (A-4
) (X=SCe Hs , Y=H) is obtained.

Compound A of the present invention can be converted into an optically active δ-lactone compound (9) according to the reaction route (n). They will be explained in order below.

b) Synthetic compound (A-4) of hemiacetal compound (7)
) (X=SCe Hs , Y=H) with an aluminum hydride reagent such as diisobutylaluminum hydride provides the hemiacetal (7-1). The reaction involves tetrahydrofuran and ethylene glycol dimethyl ether.

It is carried out in an inert solvent such as dioxane at a low temperature of 0 to -80°. Compound (7-2>(X' -H) is compound (7-2>(X' -H)
1>(X' = -8Cs R5) using Raney nickel.

C) Synthetic compound of carboxylic acid ester compound B (7-1
) - p-ylide represented by the formula R30COCH-PZR4 (8) (in formula (8), 7 is oxygen, (OR3)2 or (C6H5)2, R4 is OR3 or CaHs,
R3 represents the same thing as above. ) to form a compound (B-1>(D-E :CH-CH,X'-3Cs
Hs) is obtained. Compound (B-1> to compound (C-2)
Step 4) Reduction of double bond to (X' = R1).

This can be achieved by performing four steps: step 5) reduction of the phenylthio group, step 6) hydrolysis of the nitrile, and step 7) ring closure to a δ-lactone ring. In addition, compound (7-2) (X
'-H) is used as a raw material, step 5) is not necessary.

These four steps are independent, except that step 6) is performed before step 7), and may be performed in any order. Further, steps 4) and 5), and steps 6) and 7) can be performed simultaneously. Each step can be performed by a method known per se. That is, step 4) reduction of the double bond can be achieved by catalytic hydrogenation with zinc-acetic acid or palladium, platinum, Raney nickel, etc., and step 5) reduction of the phenylthio group can be achieved by catalytic reduction with Raney nickel. Hydrolysis of nitrile in step 6) is carried out using hydrochloric acid,
This can be achieved by heating in a water-containing solvent using a mineral acid such as sulfuric acid or hydrobromic acid or a base such as sodium hydroxide or potassium hydroxide.

Further, the ring closure to the δ-lactone ring in step 7) can be achieved by acid-treating the carboxylic acid produced by hydrolysis of the nitrile. By appropriately selecting each of these steps, desired products can be selectively obtained.

For example, the compound (B-1>(D-E:CH=CH.

When X' = SCs Hs ) is reduced with zinc-acetic acid, a compound (B-2> (DE: CH2CH2, X'
=SCc+Hs> was obtained, and compound (B-1) (D
-E: CH=CH,
: CH2CH2, X' = H> is obtained.

d) Synthesis of δ-lactone compound C The nitrile group of the above compound (B-3) is hydrolyzed by heating under reflux in ethanol in the presence of sodium hydroxide, and the resulting carboxylic acid is treated with hydrochloric acid to produce δ-lactone compound (C). -2
>(X' = 1-1. R3 = H), and react with a lower alcohol in the presence of an acid catalyst or react with diazomethane to esterify the compound (C-2
). The reduction of the phenylthio group in step 5) results in the compound (
Instead of carrying out during the conversion from B) to (C), it may be carried out during the conversion from compound (C) to (9). In this case, step 4) from compound (B) to (C) is carried out by hydrogenation with zinc-acetic acid or palladium or platinum, and steps 6) and 7)
by the method described above (E compound (C-1) (X' = S
Cs Hs ) is obtained, hydrogenated with Raney nickel to give compound (C-2) (X'-to 1), and then subjected to the final intramolecular ring condensation reaction.

The δ-lactone compound (△), hemiacetal compound (7), carboxylic acid ester compound (B), and δ-lactone compound (C) obtained here are all new compounds that have not been described in literature, and have the optical purity described below. It is an important intermediate in producing the high δ-lactone compound (9).

e) Synthesis of δ-lactone compound (9) The intramolecular ring condensation reaction of the compound ((, -2) (X' = H) is carried out using an inert solvent, such as tetrahydrofuran, ethylene glycol dimethyl ether, t-butano-/dimethylformamide, etc. By reacting with a base such as mu-t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, etc., 1q of optically active δ-lactone compound (9), a known target substance, can be produced in high yield with good optical purity. .

(Effects of the Invention) The optically active compound of the present invention is an important compound as an intermediate in the production of compounds that form the core of δ-lactone antibiotics, and by using this compound, δ-lactone with high optical purity can be produced. Compound (9) can be efficiently produced.

(Example) Specific examples will be described below based on Examples.

Example 1 Synthesis of compound (A-1>) (6) (A-1>
(Bn represents benzyl 1, and Et represents ethyl group.

same as below. ) Ethyl cyanacetate Nisder 1, 240 under argon stream
(11 mM) was added under water cooling to 440 m (1111111 M) of 60 w/w% sodium hydride suspended in mineral oil under water cooling.
The mixture was stirred at maximum temperature for 0 minutes. Next, a solution of 2.0 (1 (9.17 ml)) of 8 α,β unsaturated δ lactones (6) in tetrahydrofuran was slowly added under water cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with 50 d of diethyl ether, neutralized with 10% hydrochloric acid, separated into layers, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.4 -3.5 g of the adduct (A-1>) was obtained as a yellow oily substance.

'HNMR (CDCb) δ: 1.32 (3!-1,t, J=7.
1112 ) 2.0 (2H,m> 2.60 (2H,m) 2.90 (IH,m> 3.60 3H,m) 4゜30 2H,q, J=7.1H2) 4.56 2
H, S) 4.60 1H, m> 7.33 5H, s> JR (neat) 2940, 2250.1740. 740. 700M
5 m/e 332 (M+1), 91 (100%>m-1 Example 2 Synthesis of compound (A-2>) (A1) (A-2) Under an argon atmosphere, the above 1,4-adduct (A-2) -1>3.5
g, 10 drops of water, 1.86q (9
, 17mM) and 170 d in dimethylacetamide 30d.
After heating under reflux for 12 hours and returning to the lowest temperature, water and diethyl ether were added and extracted and separated. The aqueous layer was made acidic with hydrochloric acid and then extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was dissolved in 50 ml of benzene and heated under reflux for 12 hours. Next, the solvent was distilled off from the reaction solution under reduced pressure, and the residue was subjected to silica gel column chromatography, and ether:hexane (100:1v/v) was eluted to obtain a colorless 3R, 5S δ-lactone compound (A-2). 1.47 as an oily substance!
IJ (62% from (6)) was obtained. Further elution with ether yielded 3S, 53 δ-lactone compound (A-2>185
7.8%) was obtained from m1(6). The data of the 3R, 5S δ-lactone compound (A-2) are as follows.

'HNMR (CDCf13) δ: 1.7-2.9 (7 days, m) 3.65
(2H, d, J=4.4Hz) 4.58
(217S) 4.6 (tithe 1.m) 7.33 (5H, 5) IR (neat) 29a0.2250.1740. 742. 700M
5 m/e 259 (M+), 91 (100%) cm- Example 3 Synthesis of compound (A-3> (A-2) (A-3)
The above 3R,53 δ-lactone compound (A-2')1.
38Q (5.33mM) was dissolved in 40ml of ethyl acetate, 180mg of palladium hydroxide and 1 drop of concentrated hydrochloric acid were added, and the mixture was stirred for 3 hours at seedling temperature under a hydrogen gas atmosphere.The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7 mg of compound (A-3) as a colorless oil from the ethyl acetate fraction.

Yield 96% IHNMR (CDα3) δ: 1.65-3.1 (8H, m> 3.78 (2H, m) 4.57 (1f-f, 5extet,
J=4 ■R (neat) 3330, 2250.1735 cm-1MS m
/e 170 (M+1>, 138 (100%) 4+12 ) Example 4 Synthesis of compound (A-4>(A-3> (Δ-4)
(ph represents a phenyl group, and 3u represents a butyl group.

same as below. ) Under an argon stream, the above compound (A-3 > 50 mg (0,
296mM), diphenyl disulfide 193m(1
(0,888 ml), t'-n-butylphosphine (0.22 ml) was added to pyridine 2d and stirred at room temperature for 12 hours. The reaction solution was diluted with 30 ml of ethyl acetate, and diluted with 10% hydrochloric acid. The solution was then washed with a saturated aqueous solution of copper sulfate, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure.
The residue was subjected to silica gel column chromatography, and from the ether fraction, phenyl sulfide (A-4) 71
m0 (92%) was obtained.

'HNMR (CDCb) δ: 1.85-2.75 (11m) 2.94 (IH, dd, J=14.5.9.
0H7) 3.30 (IH, dd, J=14.
5.5.8+1Z)4.45(1N, tt
, J=9.0.5.8tlz)7.30
(5H, m) IR(neat) 2930, 2250.1740. 740. 695
cm-1MS m/e 261 (M0), 123 (100%) Synthesis example Synthesis of compound (7-1) (A-4> (7-1) Under argon stream, the above phenyl sulfide (A-4) 9
To 25 ml of a solution of 84 mg (3.77 ml) in tetrahydrofuran was slowly added 2 ml (4 mH) of a 2M toluene solution of diisobutylaluminum hydride under stirring at -30°C, and the mixture was stirred at -30'C for 10 minutes. 1 in the reaction solution
0% Nao! -(A small amount of aqueous solution was added, stirred at room temperature for 2 hours, filtered through Celite, and then the solvent was removed under reduced pressure to obtain 986 mg of hemiacetal (7-1).

IHNMR (CDα3) δ: 1.5-1.9 (41-1, m>2.2-2.
5 (2H, m> 2.7 (1H, m> 2.9 to 3.6 (2H, m) 3, γ to 4.4 (IH, m) 5.0 to 5.4 (IH, m> 7.2-7.45 (5H, m) IR (neat) 3400, 2910.2250. 745. 695M
5 m/e 263 (M+), 12/l (100%) Synthesis of compound (B-1) m-1 (7-1)
<8-1) Under an argon stream, the above hemiacetal (
7-1> To 20 d of a methylene chloride solution containing 986 mg (3,75 ml), 3.9 g (11,25 ml) of triphenylphosphine ethoxycarbonylmethyl ylide is added, and the mixture is stirred at room temperature for 15 hours. The reaction solution was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and 5% of the ether:hexane (3:1 v/v) fraction was
-cyanmethyl-7-hydroxy-8-phenylthioocta-2-enoic acid ethyl ester (B-1
>1.03 (1 (82%)) of colorless oil was obtained.

'HNMR(CD(J3) δ: 1.29 (3H,t, J=7.
1) 12 >1.60 (2H, m> 2.0~2.7 (5H, m> 2.88 (IH, dd, J=13.9.8.
8tlz ) 3.15 (IH, dd, J=1
3.9.3.7Hz >3.70 (IH,m>4.90 (2H,Q,, J=7.1H2
)5.90 (IH, d, J=15.61
12) 6.80 (IH, dt, J=15
．． 6.7.1Hz) IR (neat) 3450, 2910.2250.1910.1650°740, 690 cm-1 MS m/e 333 (M”), 124 (100%) Synthesis of compound (B-3> B-1) (B-3> (Me represents a methyl group. The same applies hereinafter.) The above compound (
B-1) Add 0.6 d of Raney nickel 0.6 mM ethanol solution to 1 d ethanol solution of 87n+g (0.26n+H), heat under reflux at 90°C for 20 minutes, filter the reaction solution through Celite, and distill the solvent under reduced pressure. The residue was subjected to silica gel column chromatography and ether:
Compound (B-3>) was extracted from hexane (7:IV/V) fraction.
Obtained 37.2mc+ (63%) as a colorless oil.

'HNMR(CD(1'3) δ:1.23<3H,d, J=6.3Hz
>1.26 (3H,t, J=7.1Hz
)1.4~1.8 (7H, m> 1.95 (IH, m) 2.33 (2H, t, J=6.6Hz)2
．． 48 (2H, d, J=5.4NZ3.9
0 (1H, m> 4.14 (2H, q, J=7.1Hz(
R(neat) 3400, 2250.1725 cm-1MS m
/e 228 (M+1), 164 (100%) Compound (Synthesis of C-2>) ) (B-3>
(C-2> Under an argon stream, the above compound (B-3>
Dissolve 250!111J (1.1mM) in 1ml of 30% potassium hydroxide aqueous solution and 8mf! of ethanol, 12
The mixture was heated to reflux for an hour. Add 30 parts of ether and 20 parts of water to the reaction solution, extract and separate, and add 1 part to the aqueous layer. Add hydrochloric acid to make it acidic,
Extracted with methylene chloride. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved with methylene chloride, and an ether solution of diazomethane was added to give a methyl ester. The solvent was distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography, and (C-2
) 192.1ma (82%) as colorless crystals 1q
Ta.

mp 72.5~73°C 'HNMR (CDC13) δ: 1.38 (31~I, d, J=8゜3
tlz ) 1.1~2.9 (11H, m> 3.68 (3f-1, s) 4.4
(IH,m) I R(CHCb) 2900.1720 c
m-'MS m/e 215 (M+1), 74 (100%) Synthesis of compound (9) (C-2> (9) Under an argon atmosphere, compound (C-2> 178 mg (0
,83m)! 2 d of tetrahydrofuran solution of 289.5 m (J (2,68n+
The mixture was added to 8rI11 of the tetrahydrofuran suspension of H) at room temperature, and further stirred at the same temperature for 10 minutes. Add 2 parts of water to the reaction solution
0d, 30rItl of ether was added, and the mixture was extracted and separated. The aqueous layer was made acidic with g hydrochloric acid, extracted with methylene chloride, and the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Hexane (1:5 V/V)
From the fraction, 106 mg (70%) of compound (9) was obtained as colorless needle crystals.

m0121-122°C (lit, ml) 120-121°C, F, lI. 5
todola, et al.

Biochem, J., 93.92 (1964)
) [α]￥+18,1° (C=1.03.ethanol) (lit, [α]D→-18,2° (cm1.
t5. ethanol.

Claims (2)

[Claims] (1) General formula (A) ▲Mathematical formulas, chemical formulas, tables, etc.▼(A) (X is a hydroxyl group, a phenylthio group, or -OR^1,
Y represents a hydrogen atom or -CO_2R^3. R^
1 is an easily removable protecting group selected from an aralkyl group, an alkyloxyalkyl group, an alkenyl group, and a cycloalkyl group containing a foreign atom in the ring, and R^3 is a lower alkyl group, an alkenyl group, or a benzyl group. represents a group. *
represents an asymmetric carbon. ) An optically active δ-lactone compound represented by: (2) In general formula (A), R^1 is benzyl, p-
Chlorbenzyl, aralkyl group consisting of p-methoxybenzyl group, methoxymethyl, t-butoxymethyl, 1-
Selected from alkyloxyalkyl groups consisting of ethoxyethyl and 1-isopropoxyethyl groups, alkenyl groups consisting of allyl and methallyl groups, and cycloalkyl groups containing a foreign atom in the ring consisting of tetrahydrofuranyl and tetrahydropyranyl groups. The optically active δ-lactone compound according to claim 1, which is an easily removable protecting group.