JPH03112976A - Optically active delta-lactone compound - Google Patents

Abstract

NEW MATERIAL:An optically active delta-lactone compound of formula I (R<3> is lower alkyl, alkenyl or benzyl; X' is H or phenylthio; * 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 a delta-lactone antibiotic such as actinobolin or bactobolin. PREPARATION:For example, a compound of formula III is subjected to an 1,4-addition reaction of a cyanoacetic acid ester anion in an inactive solvent such as tetrahydrofuran and the prepared compound of formula IV is reduced with an aluminum hydride reagent to prepare a compound of formula V. The compound of formula V is reacted with a compound of formula VII and subsequently subjected to a reduction reaction, etc., to provide the compound of formula I.

Description

[Detailed Description of the Invention] (Industrial Application Field) The present invention is directed to formula (9) (in the formula, * represents an asymmetric carbon), which forms the core of δ-lactone antibiotics such as aquinovorin and batatovorin. The present invention relates to an intermediate for producing an 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, Cordova, etc.
rahedron Lett,, 25.2945 (1
984)), HlPietruSie
WiCZ et al. (J, 0r (1, Chem, 53.283
7 (1988)), but the only known optically active substance is IOri et al. (Tetrahcdron, 5295 (1985)).

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 intensive studies to efficiently obtain 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 (I[) (6) (△) (7) The present invention provides an intermediate formed in this reaction route (II).

That is, the present invention provides an optically active δ-lactone represented by the general formula (C) (R3 is a lower alkyl group, an alkenyl group, or a benzyl group, X' is a hydrogen atom or a phenylthio group, and * is an asymmetric carbon). This provides compound (C).

R3 of the compound (C) represented by the general formula (C) is methyl, ethyl, propyl, isopropyl, butyl,
Alkyl groups having 1 to 5 carbon atoms such as t-butyl and pentyl groups, allyl, and 2-methylallyl.

Examples include alkenyl groups having 3 to 5 carbon atoms, such as 2-butenyl, 3-butenyl, and 2-pentenyl groups, or benzyl groups.

Compound (C) of the present invention is obtained by converting compound (6) to compound (B).
Compound (6) is synthesized from glycidyl ether (2) according to reaction route (1).

That is, an optically active α,β-unsaturated δ-lactone compound (
6) can be obtained 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 the reaction route (I>). I can do it.

Reaction route (1) (2) (3) (4) (5) (6) In reaction route (I>), R1 represents an easily removable protecting group, specifically benzyl, p-methoxybenzyl, Aralkyl groups such as 0-chlorobenzyl group, methoxymethyl, t-butoxymethyl.

It represents an alkyloxyalkyl group such as 1-ethoxyethyl or 1-isopropoxyethyl group, an alkenyl group such as allyl or methallyl group, or a cycloalkyl group containing a foreign atom in the ring such as tetrahydrofuranyl or tetrahydropyranyl group. Further, R2 represents a lower alkyl group such as n-butyl, isobutyl, t-butyl, or methyl. * represents an asymmetric carbon.

In the reaction route (n), X represents a hydroxyl group, a phenylthio group or 10R1, and Y represents a hydrogen atom or 1002R3. X', R1 and R3 are the same as above.

The method for synthesizing the compound (C) of the present invention from the compound (B) starting from this compound (6) will be explained in detail below according to detailed reaction routes <IIa) and (I[b).

Detailed reaction route (I[a) fJN1 anti-l15711V route (II b ) (9) a) Synthesis of δ-lactone compound A Optically active α, β-unsaturated δ-lactone compound (6) is mixed with an inert solvent such as tetrahydrofuran, ethylene glycol Cyanoacetate (formula CH2(CN)CO) in a solvent such as dimethyl ether, toluene, dimethylformamide
R3 in 2R3 represents the same thing as above. ) to form a compound (A-1>(X=OR
1, Y-CO2R3) was 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 to a phenylthio group to form a compound (A-4>(X=SCs Hs , Y=l-(
> is synthesized.

1) Hydrolysis and decarboxylation of the ester, 2) Elimination of the protecting group,
3) The order of steps for converting the resulting water Ml into a phenylthio group is 1) → 2) → 3), 2) -> 1) → 3), or 2
) → 3) → 1) is also acceptable.

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 the R1 selected. For example, when R1 is a benzyl or allyl group, hydrogenolysis or isomerization using a palladium catalyst can be used for methoxymethyl or allyl group.
In the case of -ethoxyethyl, a method of hydrolyzing it in a water-containing solvent using a mineral acid, an organic acid, or a Lewis acid can be used. Step 3) of converting a hydroxyl group into a phenylthio group involves converting diphenyl sulfide and a raw alcohol to pyridine, triethylamine, etc. in the presence of a tertiary phosphine such as triphenylphosphine, trilobylphosphine, or 1,2-bis(diphenylphospho)ethane. This can be achieved by reacting as a solvent.

Also, the compound (A-1>(X=OR1, Y=C02R3)
When reacting through the route of steps 2) → 3) → 1), the compound (
A-5>(X=OH, Y=CO2R3), (A-6>(
X=SCe R5, Y=CO2R3) to form the compound (A
−4>(X=SCs Hs , Y=H).

Compound (A-1) (X=OR', Y=CO2R3) to compound (A-4>(X=SCet-Is).

A specific example of 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) is heated in magnesium chloride and dimethylacetamide, hydrolyzed and decarboxylated, separated and purified by silica gel column chromatography, The trans and cis forms of the compound (A-2>( X
=OH,'Y=t1) and reacted with trilobyl phosphine and diphenyl sulfide in pyridine to obtain compound (A-4) (X=SCs Hs , Y=H>.

b) Synthetic compound of hemiacetal compound (7) (A-4
) (X=SCs Hs , Y=t1) is reduced with an aluminum hydride reagent such as diisobutylaluminum hydride to obtain hemiacetal (7-1>. The reaction is performed with 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>)
1>(X' = -3Cs Hs ) 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 (06H5)2, R4 is OR3 or Cs Hs, R3 is the same as above) ) to form a compound (B-1> (D-E: CH=CH,
We obtain X'=SC6Hs>. Reduction of double bond from compound (B-1> to compound (C-2>(X'=H) in step 4).

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, the 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 double bonds can be achieved by catalytic hydrogenation with zinc-acetic acid or palladium, platinum, Raney nickel, etc., and step 5) reduction of phenylthio groups can be achieved by catalytic reduction with Raney nickel. can. 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, compound (B-1) (D-E: CH=CH.

When X'-3Cs Hs) is reduced with zinc-acetic acid, compound (B2) (D-E:CH2CH2,X'-3
Cs Hs ) was obtained, and the compound (B-1>(DE:
When CH=CH,
2C1-12, 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'=H, R3=H), and is reacted with a lower alcohol in the presence of an acid catalyst or esterified by reaction with diazomethane to form a compound (C-2>(X'=H).

In step 5), the phenylthio group is reduced from compound (B) to (
Instead of carrying out during the conversion 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) are carried out as described above to form compound (C-1>( X'-3Ce H5)
This was hydrogenated with Raney nickel to give the compound (C-
2) After setting (X' = t1), the final intramolecular ring condensation reaction is performed.

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

Compound C of the present invention can be converted into an optically active δ-lactone compound (9) according to the reaction route (I [>). This will be explained below.

Synthesis of e>δ-lactone compound (9) The intramolecular ring condensation reaction of the compound (C-2>(X'=H) is carried out using an inert solvent such as tetrahydrofuran, ethylene glycol dimedyl ether, t-butanol, dimethylformamide, etc. The known target substance, an optically active δ-lactone compound (9), can be obtained in high yield with good optical purity by reacting it with a base such as potassium t-butoxide, sodium hydride, sodium hydroxide, or potassium hydroxide. can.

(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 1) Synthesis of compound (A-1) (6) (A-1)
(Bn represents a benzyl group, and 2t represents an ethyl group.

same as below. ) Under a stream of argon, cyanacetic acid ethyl ester 1.24 (
J (limb) was added under water cooling to 440 mq (15 ml) of 60 W/W% sodium hydride (11 mM) suspended in mineral oil and stirred at room temperature for 10 minutes. A solution of 2.0 g (9,17n+H) of saturated δ-lactone (6) in 5 ml of tetrahydrofuran was slowly added under water cooling and stirred at the same temperature for 1 hour.The reaction solution was diluted with 50 ml of diethyl ether, and neutralized by adding 10% hydrochloric acid. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.5 g of the 1.4-adduct (A-1> as a yellow oily substance. Ta.

'HN-MR (CDC13) δ: 1.32 (3H, t, J=7.1Hz >2
．． 0 (2H, m) 2.60 (2f-1, m> 2.90 (IH, m) 3.60 (3H, m> 4.30 (2H, q, J=7.1H2) 4.5
6 (2H, S > 4.60 (IH, m) 7.33 (5H, 5) IR (neat) 2940, 2250.1740. 740. 700M
5 m/e 332 (M+1), 91 (100%) 2) Synthesis of compound (A-2) m-1 (A-1) (A-2> Under an argon atmosphere, the above 1,4-adduct (A -1>3.50
10 drops of water, 1.86 (] (9
9,17 mf) and 1 in 30 ml of dimethylacetamide.
The mixture was heated under reflux at 70°C for 12 hours, returned to air temperature, water and diethyl ether were added, extracted and separated, and 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, the solvent was distilled off under reduced pressure, and the residue was dissolved in benzene 5 (7) and heated under reflux for 12 hours.Then, the reaction solution was distilled off under reduced pressure to remove the solvent. It was subjected to silica gel column chromatography, and ether:hexane (ioo:iv/v) was flowed out, yielding 1.4 yg of 3R, 5S δ-lactone compound (8-2) as a colorless oil.
(62% from (6)). Further elute with ether and
S, 5S δ-lactone compound (A-2>185m
c+ (7.8% from (6)) was obtained. The data for the 3R,58 δ-lactone compound (A-2) are as follows.

'HNMR (CDC13) δ: 1.7-2.9 (7H, m) 3.65
(2H, d, J=4.4Hz) 4.58
(2H,S) 4.6 (,IH,m> 7.33 (5H,5) lR(neat) 2940, 2250.1740. 742. 700M
5 m/e 259 (M+), 91 (100%) 3) Synthesis of compound (A-3> m-1 (A-2) (A-3
) The above 3R,53 δ-lactone compound (A-2>1.
38g (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 at air temperature under a hydrogen gas atmosphere for 3 hours. The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 866.7 mg of compound (A-3> as a colorless oily substance from the ethyl acetate fraction. Yield: 96) % 'HNMR (CDCU: +) δ: 1.65-3.1 (8tl, m) 3.78
(21-(,m) 4.57 (JR(neat) 3330, 2250.1735 M5 m/e 170 (M+1), 138 (100%)
4) Synthesis of compound (A-4> J=4.4l-12 sextet.

m-1 11-1゜) (A-3) (A-4
) (ph represents a phenyl group, [3u represents a butyl group.

same as below. ) Under an argon stream, the above compound (A-3 > 50 mg (0,
296mM), diphenyl disulfide 193mg (
Add 0,888 m)l) and 0.22rnll of triherb tylphosphine (0,888 m)f) to 2d of pyridine and stir at air temperature for 12 hours. The reaction solution was diluted with 30 d of ethyl acetate, washed with 10% hydrochloric acid, then sequentially washed with saturated 6A copper acid aqueous solution, saturated sodium chloride solution, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and phenyl sulfide (A-4') was extracted from the ether fraction.
71 mg (92%) was obtained.

'HNMR (CDCJ2:+) δ: 1.85-2.75 (7H, m>2.94
(1H, dd, J=14.5.9.
011z ) 3.30 (IH, dd
, J=14.5. 5.8H2) 4.45
(IH, u, J= 9.0.5.8117)7.3
0 (5H, m)IR(neat) 2930, 2250.1740. 740. 695
cnrIMS m/e 261 (M+”), 123 (100%)5
) Synthesis of compound (7-1) (A-4> (7
-1) Under an argon stream, the above phenyl sulfide (A4
) To 25 d of a solution of 984 mCl (3,77 ml) in tetrahydrofuran, add 2 ml of a 2 M toluene solution of diimbutylaluminum hydride (4 mM) under stirring at 306 C.
) was added slowly and stirred at -30°C for 10 minutes. A small amount of 10% NaOH aqueous solution was added to the reaction solution, the mixture was stirred at air temperature for 2 hours, filtered through Celite, and the solvent was distilled off under reduced pressure to obtain hemiacetal (7-1>986m(I).

'HNMR (CDC13) δ: 1.5 ~ 1.9 (4H, m) 2.2 ~ 2
．． 5 2H, m) 2.7 1H, m> 2.9 to 3.6 2H, m> 3.7 to 4.4 1H, m> 5°0 to 5.4 1. m) 7.2-7.
45 5H, m> IR (neat) 3400, 2910.2250. 745. 695
cm-IMS m/e 263 (M”), 124 (100%)6)
Synthesis (7-1) of compound (B-1>) (B-1) Under an argon atmosphere, the above hemiacetal (7-1>986
Methylene chloride solution of mc+ (3,75+++H) 20
Add 3.9 g (11,25n+H) of ethoxylated triphenylphosphine to m1,
Stir at air temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
Ether: 1.03 g (82%) of 5-cyanmethyl-7-hydroxy-8-phenylthiooct-2-enoic acid ester (B-1) was obtained from the hexane (3:IV/V) fraction. Obtained as a colorless oil.

18NMR (CDα3) δ: 1.29 (3H, t, J=7.1H2)
1.60 (2H, m> 2.0~2.7 (5H, m> 2.68 (IH, dd, J=13.9.8
．． 8Hz >3.15 (IH, dd, J=
13.9.3.7Hz )3.70 (1)-
1, m> 4.90 (2H, q, J= 7
．． 1112>5.90 (1t-1, (1, J
= 15.6117) 6.80 (IH, dt,
J=15.6.7.1112) IR (neat) 3450, 2910.2250.1910.1650°740, 690 cm-1 MS m/e 333 (M”), 124 (100%)7)
Synthesis of compound (B-3><8-1><
8-3> (Me represents a methyl group. The same applies hereinafter) 87 mg (0,26+nH) of the above compound (B-1) in 1 mf of ethanol! After adding 0.6% of Raney nickel 0.6mM ethane solution to the solution and heating and refluxing at 90'C for 20 minutes, the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Compound (B-3> 37.2mc+ (63%)) was obtained as a colorless oil from a needle:hexane (7:1 v/v) fraction.

'HNMR (CDC13) δ: 1.23 3H, d, J=6.3Hz >
1.26 3H,t, J=7. IH7) 1.4
~1.8 7H,m> 1.95 1H,m)2.33
2! -1,t, J=6.6Hz>
2.48 2H, d, J=5.4H2) 3.9
0 1H, m) 4.14 21-1. q, J=7.1tlZ
)IR(neat) 3400, 2250.1725 cm-1MS m
/e 228 (M+1 > , 164 (1oo%)8
) Synthesis of compound (C-2>(B-3> (C
-2> Under an argon stream, the above compound (B-3> 25
0mc+ (1.1 mN) was dissolved in 1 ml of 30% aqueous potassium hydroxide solution and 87 ml of ethanol, and heated under reflux for 12 hours. 30 ml of ether and 20 d of water were added to the reaction solution for extraction and separation, and concentrated hydrochloric acid was added to the bottom of the water to make it acidic, followed by extraction 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 from the ether:hexane (i:iv/v) fraction (C-2) 192.1
mq (82%) is 1q as colorless crystals.

mp72.5~73°C 'HNMR (CDCI23> δ: 1.38 (3H, d.

1.1~2.9 (11H, m> 3.68 (3H, s> 4.4 (IH, m> IR(CHCb) 2900.1720M5
m/e 215 (M+1 > , 74 (100%) J=6
．． 3H7 m-1) Synthesis Example Synthesis of Compound (9) (C-2>(9) Under an argon atmosphere, Compound (C-2> 178m(](
2d of a tetrahydrofuran solution (0.83mM) was mixed with 289.5mg (2.68mM) of potassium t-butoxide.
The mixture was added to 8 d of tetrahydrofuran suspension at room temperature, and further stirred at the same temperature for 10 minutes. Add 20ml of water to the reaction solution. 30 ml of ether was added and extracted and separated. The aqueous layer was acidified with concentrated 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. Compound (9) (1061106l 11%) was obtained as colorless needle crystals from the hexane (1:5 v/v) fraction.

m0121~122°C (m, mp 120~121°C, F, tl, 5to
dola, et al.

Biochem, J., 93.92 (1964)) [α
]'[+18.1° (C=1.03. eta/-/
L,) (lit, [α], +18.2° (cm
1.15. ethanol.

Claims (2)

[Claims] (1) General formula (C) ▲Mathematical formulas, chemical formulas, tables, etc.▼(C) (R^3 is a lower alkyl group, alkenyl group, or benzyl group, X' is a hydrogen atom or a phenylthio group, * is an unsubstituted An optically active δ-lactone compound represented by: (2) In general formula (C), R^3 is a lower alkyl group consisting of methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl group, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, The optically active δ-lactone compound according to claim 1, which is selected from an alkenyl group consisting of a 2-pentenyl group and a benzyl group.