JPH03112974A - Optically active hemiacetal compound - Google Patents

Abstract

NEW MATERIAL:An optically active hemiacetal compound of formula I (X' is H or phenylthio; * is asymmetrical carbon). USE:Useful as an intermediate for synthesizing an optically active delta-lactone compound of formula II which is a mother nucleus of delta-lactone antibiotics such as actinobolin and bactobolin. PREPARATION:An optically active delta-lactone 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. The prepared compound of formula IV is reduced with an aluminium hydride reagent such as diisopropyl aluminum halide to provide the compound of formula I. The compound of formula IV 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, Cordova, etc. (Tetr
ahedron Lett, 25.2945 (198
4) ) , 0M.

PietrUSieWiCZ et al. (J, Org, Chem
9, 53. 2837 (1988)), but regarding optically active substances, Hori et al. (Tetrahe et al.
The only known example is Dron, 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 (It) (6) (A) (7) The present invention provides an intermediate obtained in this reaction route (n).

That is, the present invention provides an optically active hemiacetal compound (7) represented by the general formula (7) (X' represents a hydrogen atom or a phenylthio group, and * represents an asymmetric carbon).

Examples of X' in compound (7) represented by general formula (7) include a hydrogen atom or a phenylthio group.

Compound (7) of the present invention can be obtained from compound (6) to compound (A>
Compound (6) is synthesized from glycidyl ether (2) according to reaction route (I>).

That is, an optically active α,β-unsaturated δ-lactone compound (
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 (1) (2) (3) <4) (5) (6
) In reaction route (I>), R1 represents an easily removable protecting group, specifically an aralkyl group such as benzyl, p-methoxybenzyl, p-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 lightly treated alkyl group such as lobutyl, isobutyl, t-butyl, and methyl. * represents an asymmetric carbon.

In the reaction route (n), X is a hydroxyl group, a phenylthio group, or -R1, and Y is a hydrogen atom or -CO
Represents 2R3. X' and R1 are the same as above, and R3 is an alkyl group having 1 to 5 carbon atoms such as methyl, ethyl, propyl, inpropyl, butyl, t-butyl, pentyl group, allyl, 2-methylallyl, 2 -butenyl,
It represents an alkenyl group having 3 to 5 carbon atoms such as 3-butenyl or 2-pentenyl group, or a benzyl group.

A method for synthesizing compound (7) of the present invention from compound (A>) starting from compound (6) will be described in detail below according to detailed reaction routes (IIa) and (IIb).

In the detailed reaction route (I[a>, (IIb)), R1,
R2 and R3 each represent the same thing as above.

-Sph represents a phenylthio group, and * represents an asymmetric carbon.

Detailed reaction route (I[a) Detailed reaction route (I[t)) (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. Cyanoacetate (formula CH2(CN)CO) in solvents such as glycol dimethyl ether, toluene; dimethylformamide;
R3 in 2R3 represents the same thing as above. ) to form a compound (A-1>(X=OR
1, Y=CO2R') 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 to a phenylthio group to synthesize a compound (A-4>(X=SCa Hs , Y=H).

1) Hydrolysis and decarboxylation of the ester, 2) Elimination of the protecting group,
3> The order of steps for converting the resulting hydroxyl group into a phenylthio group is either 1) → 2) → 3), 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 the R1 selected. For example, when R1 is a benzyl or allyl group, hydrogenolysis or isomerization using a palladium catalyst may be used.
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 is i~riphenylphosphine, trilobylphosphine, 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>(
It is also possible to lead to the compound (A-4>(X=SC8R5, Y=H) via X=SC6t-1s, Y=CO2R3).

Compound (A-1>(X=OR', Y=CO2R3) to compound (Δ-4>(X=SCs Hs).

Examples of variants for conversion to YH) are shown below, but the production method is not limited to these specific examples.

Compound (A-1>(X=OBn, Bn represents a benzyl group. Y=CO2C21-1s) was heated in magnesium chloride and dimethylacetamide, hydrolyzed and decarboxylated, and separated and purified by silica gel column chromatography. Then, the trans and cis forms of compound (A-2>(X=OBn, Y=H) can be obtained respectively. This is hydrogenolyzed using a palladium catalyst to obtain compound (A-3) ( X
=OH.

Y=H) and reacted with tri-n-butylphosphine and diphenyl sulfide in pyridine to form the compound (A-4
) (X=SCe Hs , Y-t1) is obtained.

b) Synthetic compound of hemiacetal compound (7) (A-4
) (X=SCe Hs , Y=H) is reduced with an aluminum hydride reagent such as diisobutylaluminum hydride to obtain hemiacetal (7-1>.The reaction is performed with tetrahydrofuran, ① tyrene glycol dimethyl ether.

It is carried out in an inert solvent such as dioxane at a low temperature of O to -80'. Compound (7-2) (X' = H) is compound (7-
1) Obtained by reducing (X' = -3Cs Hs) using Raney nickel.

Compound (7) of the present invention can be prepared according to the reaction route (n),
It can be an optically active δ-lactone compound (9).

They will be explained in order below.

C) Synthetic compound of carboxylic acid ester compound B (7-1
) is a p-ylide represented by the general formula R30COCH-PZR4 (8) (in formula (8), 7 is oxygen, (OR3)2 or (Cs R5)2, and R4 is OR3 or C6Hs
, R3 represents the same thing as above. ) to form a compound (B-1>(D-E:CH=CH,X'=SC
eHs). From compound (B-1) to compound (C-2
>(X'=H> Step 4) Reduction of double bond.

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 double bonds can be achieved by catalytic hydrogenation with zinc-acetic acid, palladium, platinum, Raney nickel, etc., and step 5) reduction of phenylthio groups 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'-3Cs Hs) is reduced with zinc-acetic acid, compound (B-2) (D-E: CH2CH2, X'
=SCe Hs ) was obtained, and the compound (B-1>(DE
:CH=CH,
CH2CH2, X' = l-1) 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 the compound (C-2) (X' = H) is obtained by reacting with a low-handling alcohol in the presence of an acid catalyst or by reacting with diazomethane for esterification.

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 by the method of previous step (e) to form compound (C-1). >(X'-3Ce Hs
) was hydrogenated with Raney nickel to give the compound (
After setting C-2>(X'=t1), the final intramolecular ring condensation reaction is performed.

The δ lactone compound (A), 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 compound (C-2) (X' = H) is carried out using an inert solvent, such as tetrahydrofuran, ethylene glycol dimedyl ether, t-butanol, dimethylformamide. By reacting with a base such as t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, etc., the known target substance, optically active δ-lactone compound (9), can be obtained with good optical purity and high yield.

(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, Et represents an ethyl group.

same as below. ) Under argon flow, cyanacetic acid ethyl ester 1.24g
(l1m)! > was added under water cooling to 440 mCI (11 mM) of 60 W/W% sodium hydride suspended in mineral oil in 15 ml of tetrahydrofuran.
Stir for minutes at room temperature. Next, 57! of a tetrahydrofuran solution containing 2.09 (9.17mM) of 8 α,β-unsaturated δ-lactones (6) was slowly added under ice cooling and stirred at the same temperature for 1 hour.The reaction solution was diluted with diethyl ether 5 ( The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the 1.4-adduct (A -1> was obtained as a yellow oily substance in an amount of 3.5 g.

'HNMR (CDCb) δ: 1.32 (3H, t, J=7.1Hz >
2.0 (2H, m) 2.60 (2H, m> 2.90 (11-1, m) 3.60 (, ]7 m) 4.30 (2H, Q, J=7.111z >4 .56
(2H, S) 4.60 (IH, m) 7°33 (5H, 5) IR (mouth eat) 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>3.5 g
10 drops of water, 1 part of chloride magnezi "Tam 6 water salt, 86 g (
9,17mM) and dimethylacetamide 30rd! The mixture was heated under reflux at 170'C for 12 hours, returned to room temperature, extracted and separated by adding water and diethyl ether, and the aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was briefly dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 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.
1. Hexane (100:1v/v) flows out and the δ-lactone compound (8-2) of 3R, 53 is converted into a colorless oil.
47 (7 (62% from (6)) was obtained. Further elution with ether yielded 33.53 δ lactone compound (A-2) 1
85 mq ((6) YoV) 7.8%) was obtained. 3R,
The data for the 5S δ-lactone compound (8-2) are as follows.

'HNMR (CDCb) δ: 1.7-2.9 (7H, m) 3.65 (2H, d, J=4.4
tlz >4.58 (2H,S) 4.6 (IH,m>7.33 (5H,5) IR(neat) 2940, 2250.7740. 742.7 (10
MS m/e 259 (M+), 91 (100%) 3) Synthesis of compound (A-3> m-1 (A-2>(A-3> 3R, 53 δ-lactone compound (A-2) >1.38
(1 (5,33 mt) was dissolved in 40 ml of ethyl acetate, 180 mg of palladium hydroxide and 1 drop of concentrated hydrochloric acid were added, and the mixture was stirred at the lowest temperature in a hydrogen gas atmosphere for 3 hours. The reaction solution was filtered through Celite, and then poured under reduced pressure. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and the compound (A-3> was converted into a colorless oily substance from the ethyl acetate fraction, 866,7rUJ).
,9. Yield 96% IHNMR (CDα3) δ: 1.65-3.1 (81-1, m>3.78
(2H, m> 4゜57 (1H,5extet, J=4
．． 4HzIR(neat) 333(), 2250.1735 cm-1MS
m/e 170 (M+'l), 138 (100%) 4) Synthesis of compound (A-4)) (A-3) (A-
4>(ph represents a phenyl group, Bu represents a butyl group.

same as below. ) Under an argon stream, the above compound (Δ-3) somg(0
, 296mM>, diphenyl disulfide 193mg
0.22d (0.888mM) of tri-butylphosphine was added to pyridine 2
ml and stirred at room temperature for 12 hours. Pour the reaction solution into 30mf of ethyl acetate! The solution was diluted with water, washed with 10% hydrochloric acid, then washed with saturated copper sulfate aqueous solution, saturated water, and saturated saline in that order, dried over anhydrous magnesium 5A acid, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. Phenyl sulfide (A-4>
71 mg (92%) was obtained.

'HNMR (CDC13) δ: 1.85-2.75 (7H, m>2.94
(IH, dcf, J=14.5.9.011z
)3.30 (IH, dd, J=14.5.5
．． 8tlZ ) 4.45 (IH, tt, J=
9.0.5.8tlz)7.30
(5H, m>IR(neat) 2930, 2250.1740. 740. 695
cm-1MS m/e 261 (M”), 123 (100%)5)
Synthesis of compound (7-1) (A-4) (7-1
> Under argon flow, the above phenyl sulfide (A-4)
To 25 ml of a solution of 984 mg (3,77 mM) in tetrahydrofuran was slowly added 2 ml (4 mM) of a 2M toluene solution of diimbutylaluminum hydride under stirring at -30°C, and the mixture was stirred at -30'C for 10 minutes. A 10% NaOH aqueous solution was added to the reaction solution. A small amount of the mixture was added, stirred at room temperature for 2 hours, filtered through Celite, and the solvent was removed under reduced pressure to obtain 986+ ng of hemiacetal (7-'l).

'HNMR (CDC13) δ: 1.5 ~ 1.9 (4, H, m > 2.2 ~
2.5 (2H, m> 2.7 (11-(, m) 2.9 to 3.6 (2H, m) 3.7 to 4.4 (IH, m> 5.0 to 5.4 ( IH, m> 7.2 ~ 7.45 (51-1, m) IR (neat) 3400, 2910.2250. 745. 695
cm-IMS m/e 263 (M+), 124 (100%) Synthesis of synthesis example compound (B-1><7-1) (
B-1) Under an argon stream, the above hemiacetal (7-1
>986 m (1 (3,75 m) methylene chloride solution 2
07! Add 3,9q (11,25mM) of triphenylphosphine ethoxycarbonylmethyl ylide to
Stir at room temperature for 15 hours. The solvent was distilled off from the reaction solution under reduced pressure,
The residue was subjected to silica gel column chromatography, and from the ether:hexane (3:IV/V) fraction, 5-cyanmethyl-7-hydroxy-8-phenylthiooct-
2-enoic acid ethyl ester (8-1)
．． 03(] (882% obtained as a colorless oil.

'HNMR (CDCb) δ: 1.29 (3H, t, J=
7.1Hz >1.80 (2H, m
)2.0~2.7 (51-1, m) 2.68 (IH, dd, J=13.9.8.
atlZ ) 3.15 (IH, dd, J=1
3.9.3.7Hz >3.70 (IH,
m> 4.90 (2H, (1, J= 7.1
Hz>5.90 (IH, d, J=15.6H
z) 6.80 (IH, dt, J=15.6.
7.1H2) 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.) Add 0.6 ml of an ethanol solution of 0.6 mM Raney nickel to a 1 ml ethanol solution of the above compound (B-1> 87 mg (0.26 mM), and heat at 90°C. After heating under reflux for 20 minutes,
The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and the compound (3-
3) Obtained 37.2 mg (63%) as a colorless oil.

'HNMR (CDC1:+) δ:1.23 (3H, d, J=6.3tlz
>1.26 (31-1,t, J=7.1[
IZ)t4~1.8 (7H,m>1.95 (IH,m>2.33 (2H,t, J=6.6Hz>2
．． 48 (2H, d, J=5.4Hz)3.
90 (IH, m> 4.14 (2f-1, q, J=7.1tlz
)IR(neat) 3400, 2250.1725 cm-1MS m
/e 228 (M+1>, 164 (ioo%) Synthesis of compound (C-2>) (B-3> (C
-21 Under an argon stream, the above compound (B-3>25
0mg (1,1m)f) was dissolved in 1m of 30% aqueous potassium hydroxide solution and 8d of ethanol, and heated under reflux for 12 hours. Add 30 ml of ether to the reaction solution. 20 ml of water was added, extracted and separated, and the aqueous layer was made acidic by adding concentrated hydrochloric acid, and 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, and the residue was subjected to silica gel column chromatography to obtain an ether:hexane (1:IV/V) fraction J=S(C-2>192.
1 mg (82%) was obtained as colorless crystals.

mp 72.5-73°C 1-(NMR (CQCJ13) (3H, d, J=6.3Hz) (11H, m) (3H, S) (1H, m> 2900, 1720 cm-1 δ: 1. 38 1.1-2.9 3.68 4.4 IR (CHα3) MS m/e 215 (M+1 Synthesis of compound (9)), 74 (100%) (C-2) (
9) Under argon flow, compound (C-2> 178 mg
2 ml of tetrahydrofuran solution of (0.83 ml)
Potassium-t-butoxide 289.5 mg (2,6
The mixture was added to 8 ml of a suspension of 8n+H) in tetrahydrofuran at very room temperature, and further stirred at the same temperature for 10 minutes. 20 d of water and 30 mff of ether were added to the reaction solution, and the mixture was extracted and separated.

The aqueous layer was made acidic with concentrated hydrochloric acid, extracted with methylene chloride, and
After the layers were combined and 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) 1061106l11%)
was obtained as colorless needles.

m0121~122°C (lit, mp 120~121°C, F, tl, 5
todola, et al.

Biochem, J., 93.92 (1964)) [α
] da+18.1° (cm1°03.ethanol) (l
it, [α] D+18.2° (cm1.15. Ethanol.

Claims (1)

[Claims] General formula (7) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(7) (X' represents a hydrogen atom or a phenylthio group, and * represents an asymmetric carbon.) Acetal compound.