JPS6050793B2 - Dioxaspirocyclic compound and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel dioxaspirocyclic compound represented by the structural formula: and a method for producing the same.

The object compound of the present invention is Calcimycin [A23l87] having the following structural formula.
Since it contains all of the asymmetric moieties, it can be an important intermediate in the synthesis of the antibiotic.

Calcimycin The above antibiotic A23l87 is used to treat Streptomyces chartreuscens.
eusensis) and whose structure has already been determined, and contains divalent cations (Mn++, Ca++,
ionophore (10n0p, etc.).
h0re) (R.L. Hamill, M.
Gorman, R. M. Gale, C. E. Higgins, M. M
．． Horn, Abstracts, 12th Edition, Interscience●Conference●On●Anti-Micro Vial●
Agience●and●Chemotherapy, Atlantic City, N. J. , September 26th-29th, 1972
P65;M. O. Sianyi, P.N. Demaro, N. D. Johns, J. L. Okorowitz, Journal of American Chemical Society, ? , 1932 (
1974):D. Rj Pfeiffer, R. W. lJ-do, H. A. Laday, Biochemistry 154007 (
1974) R. L. Hamil, M. GOrrTl
an, R. M. Gale, C. E. Hi 廚1ns, M.
M. H0ehn, Abstracts, 12thInt
ersscienceC0nference0nAntI
micrObialA? NtsandChemOthe
rapy, Atlantic City, N. J. ,Se
pt26-29, 1972p65:M. O. Chane
y, P. V. DemarO,N. D. JOnes, J.
L. OccOlOwitz, J. Am. Chem. S0
c. , 1932. (1974)D. R. Pfeif
fer, P. W. Reed, H. A. Lardy, Bl.
(See Ochemistry, Concave 4007 (1974), etc.).

Considering that the heterocyclic moiety of A23l87 is excluded, the chiral moiety of the molecule can be synthesized by synthesizing the dioxaspiro ring moiety. Therefore, in view of the above-mentioned purpose, the present inventors conducted intensive research on the synthesis of a dioxaspiro ring compound having the configuration A23l87, and as a result, completed the present invention. 5 The present invention will be explained in detail below.

First, the compound (1) and the iodo compound (■), which are the raw material compounds of the present invention, are both derived from methyl α-D-glycoside (N.L. Holder, B.J.
Laser Raid Canadian ● The O'Yarnal Chemistry, Ou 3357 (1973) N. L. Holder,
B. Fraser-Reid Can. J. Chem. ，
3357 (1973)) by the following process (Yoshiaki Nakahara, Kazuo Beppu, Tomoya Ogawa, No. 22
Annual Natural Organic Compounds Symposium (Fukuoka) Lecture Abstracts No. 549
(See page 3).

The compound (1) thus obtained was subjected to the next step by J.
This can lead to the target compound of the present invention.

That is, compound (1) is dissolved in a suitable solvent, and 1,3-propanedithiol and an acid catalyst such as BF3-ether, zinc chloride, hydrochloric acid, or an acidic ion exchange resin are added thereto and stirred. Obtained reaction. The product was extracted, washed, dried, and the solvent was distilled off using a conventional method, and then purified by silica gel chromatography, resulting in a dithioacetal (■).
is obtained. As a solvent, dichloromethane, chloroform. Alternatively, benzene or the like is suitable, and the reaction temperature and reaction time are preferably 0 to 25°C and 11 to 2°C, respectively. The obtained compound (■) is stirred in a suitable solvent with the addition of t-butyldimethylchlorosilane and a base such as imidazole.

The obtained reaction product is extracted by a conventional method, washed, dried, and the solvent is distilled off, and then purified by silica gel chromatography to obtain a silyludithioacetal compound (■). Suitable solvents include dimethylformamide, pyridine, and tetrahydrofuran, and suitable reaction temperatures and reaction times are -10 to 25°C and 1 to 3 hours, respectively. The obtained compound (■) was dissolved in a suitable solvent, and ethyl vinyl ether and a catalytic amount of pyridine● were added to it.
Add p-toluenesulfonate, pyridine*methanesulfonate, and an acid catalyst such as hydrochloric acid or sulfuric acid and stir.

The obtained reaction product is washed, dried, and the solvent is distilled off by a conventional method, and then purified by silica gel chromatography to obtain compound (■).

Dichloromethane, ether, benzene, etc. are suitable as the solvent, and the reaction temperature and reaction time are each 0 to 2.
5℃, 5-24? ! The interval is appropriate. The resulting compound (
(2) is dissolved in a suitable solvent, and to this is added a solution of t-butyllithium dissolved in the same solvent in an inert atmosphere such as Ar. After continuing stirring, compound (■) is added and stirred. The reaction product is left in a cool, dark place, washed, dried, and the solvent is distilled off in a conventional manner, followed by purification by silica gel column chromatography to obtain compound (■).
Suitable solvents include hexane, pentane, tetrahydrofuran, hexane-hexamethylphosphoramide, etc., and the reaction temperature and reaction time are -78 to 0.00%, respectively.
C13 to 24 hours is appropriate.

The obtained compound (■) is added to a solution of n-butylammonium fluoride and stirred. The obtained reaction product is washed, dried, and the solvent is distilled off by a conventional method, and then purified by silica gel chromatography to obtain compound (■). Tetrahydrofuran, ether, dichloromethane, etc. are suitable as the solvent, and the reaction temperature and reaction time are suitably 0 to 25°C and 3 to 7 hours, respectively. The obtained compound (■) is dissolved in a suitable solvent, benzoyl chloride is added thereto, and the mixture is stirred.

The obtained reaction product is extracted, washed, dried, and the solvent is distilled off using a conventional method, and then purified by silica gel chromatography to obtain compound (■). As the solvent, pyridine, ether-pyridine, benzene-pyridine, etc. are suitable, and the reaction temperature and reaction time are 0 to 25°C, respectively.
, 10 to 2 fences is appropriate. The obtained compound (■) was dissolved in a suitable solvent, HgCl2/CaCO3, Hg
Cl2/CdCO3, HgCl2/Hg2O, N-chlorosuccinimide/AgNO3 or N-bromsuccinimide, etc. are added and stirred.

The insoluble portion of the obtained reaction product was filtered through Celite, and the Oki solution was washed in a conventional manner, dried, the solvent was distilled off, and purified by silica gel column chromatography to obtain the compound (
■) Obtain. Suitable solvents include acetonitrile, methanol, acetone, tetrahydrofuran, and water-containing solvents thereof. Suitable reaction temperatures and reaction times are -10 to 80°C and 1 to 24 hours, respectively.

The obtained compound (■) is dissolved in a suitable solvent, phosphoric acid is added thereto, and the mixture is heated under reflux.

The obtained reaction product is extracted by a conventional method, washed, dried, and the solvent is distilled off, then purified by silica gel chromatography, and further recrystallized to obtain the desired dioxaspiro-reduced compound (X). As the solvent, tetrahydrofuran or dioxane is suitable, and the reaction temperature and reaction time are suitably 70 to 100°C and 5 to 2 bridges, respectively.

The above steps are illustrated as follows. In this way, the dioxaspirocyclic compound of the present invention is obtained, and the antibiotic A23l87 can be synthesized, for example, by the following steps. The present invention will be explained below with reference to Examples, and all of the obtained compounds are novel compounds.
Example 1 280 mg of imino ether (14) was mixed with 5 TnL of 80% water-containing methanol containing 5% sulfuric acid at 60°C.
Heat and stir for an hour.

After cooling, the mixture was extracted with ether to obtain 260 m9 of a crude product.
Next, this was dissolved in 20 ml of anhydrous ether, and 15
Heat to reflux with 0 m9 of lithium aluminum hydride for 3 hours. After cooling, add water to decompose excess reducing agent and
Extract with a mixed solvent of tellu-ethyl acetate (approximately 1:1). The extract is washed successively with potassium sodium tartrate water and saturated saline, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the remaining oil is dissolved in 7 ml of dichloromethane and stirred with 0.8 ml of 1,3-propanedithiol and 3α boron trifluoride, ether complex overnight at room temperature. Add Lml of saturated sodium bicarbonate solution to the reaction solution 3
After stirring thoroughly, extract with ethyl acetate. The extract is washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting crude product was purified using a 20 g silica gel column. It was eluted with 1:1 hexane-ethyl acetate to obtain 201 mg of diothiacetal compound (■) (yield: 54 .5%).

[Physical properties of compound (■)] IR. (Neat): 3
350, C! TL-1, NMR. (CDCl3) (10
0MHz): δ0.83 (3H, dj=6Hz), 0.
86 (3FI, d.J=6Hz), 1.07 (3FI,
d. J = 6Hz), 2.83 (4H, m), 4.11 (
1H, d. J=4Hz).

Example 2 Compound (■) 120m9 with 84m9 of t-butyldimethylchlorosilane and 53m9 of imidazole in 27711% of anhydrous dimethylformamide
Stir at C for 2 hours.

The reaction solution was extracted with ether, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crude product is column chromatographed on 20 g of silica gel. Elute with 85:15 ethyl hexane diacetate to obtain the desired product (■) of 150*XTL9 (yield 8
8.6%).

[Physical properties of compound (■)] IR. (Neat): 3
500cm-1 NMF. (CDCl3): δ0.08 (light, s), 0.
88 (911,s), (100MHz)1.
06 (3F[, D.J=7Hz), 2.85 (4H
, m), 4.10 (2H, d.J=4Hz).

Example 3 150 mg of compound (■) was dissolved in 5 mL of anhydrous dichloromethane, 0.2 TL1 of ethyl vinyl ether and a catalytic amount of pyridine/P-toluenesulfonate were added, and the mixture was stirred overnight at room temperature.

The reaction solution was washed with saturated brine and dried over anhydrous potassium carbonate. After distilling off the solvent, the crude product was column chromatographed on 20 g of silica gel and eluted with 95:5:1 to hexane-ethyl acetate-triethylamine to obtain 154 mg of the target product (■). (2) is obtained (yield 88.6%).

[Physical properties of compound (■)] IR. (Neat): 3
500cm-1 NMF. (CDCl3): δ0.08 (light, s), 0.
88 (911,s), (100MHz)1.
06 (3F[, D.J=7Hz), 2.85 (4H
, m), 4.10 (2H, d.J=4Hz).

Example 3 140 mg of (■) are dissolved in 0.2 ml of anhydrous hexane and cooled to -30°C.

To this, 0.6N (specified) t of 0.6m1 under argon flow
- Add butyl lithium hexane solution. As it is -3
After stirring at 0°C for 4 hours, 112 m9 of (■) was mixed in a 1:1
Add as a 1 ml solution of hexane nihexamethylphosphoramide. After stirring at -20°C for 1 hour, the mixture was left in a refrigerator at 5°C overnight. The reaction solution was diluted with ether, washed with water and saturated brine, dried over anhydrous potassium carbonate, and the solvent was distilled off. 30 g of the crude product obtained was purified on silica gel. Elute with 9:7:1 hexane diacetate ethylnitriethylamine, recover 51 m9 of raw material (■), and then obtain 102 m9 of the target product (■) as an oily substance (yield 54.5%, Yield of 85.8% calculated from consumed (■)).

[Physical properties of compound (■)]

IR. (Rleat): 1455, 1370, 1250
,1210,1155,1065,995,835,7
75I:! n-1NMR. (CDCl3): δ0.05
(61(,s), 0.89(9H,s) (1
00MHz) 1.34 (3H, s) 1.40 (311,
s) ~2.80 (4H, m) 4.66 (1H, m
).

Example 5 Compound (■) 200mg was added to 1.5N of 4Tnt.
Stir in the tetra-n-butylammonium fluoride-tetrahydrofuran solution at room temperature for 5 hours.

After diluting with ether, the mixture is washed with water and saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent, the crude product is purified using a 20 g silica gel column. 70:
30:3 hexane diacetate ethyl nitriethylamide 30
: 3 was eluted with hexane diacetate ethyl nitriethylamine to obtain 140 mg of the target product (■) (yield 85.8%)
.

[Physical properties of compound (■)]

IR (Neat): 3450, 1450, 1375, 1
210,1120,1050,985,855,675
3 mt of c1ri-1 Example 6 compound (■) 139m9
of benzoyl chloride in anhydrous pyridine overnight at room temperature.

After adding 0.5 ml of water and stirring three times, the extract was extracted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is column chromatographed on 18 g of silica gel.
*Elute with C9O:10:3 hexane diacetate ethylnitriethylamine 14
5m9 of the target product (■) was obtained as an oily substance (yield: 86
．． 5%). [Physical properties of compound (■)] IR. (Neat): 1720, 1600, 1450,
1380, 1275, 1120, 1070, 715cw
1-1 Example 7 104 mg of compound (■) is stirred with 200 m9 of mercuric chloride and 100 TI, g of calcium carbonate in 5 m1 of 80% aqueous acetonitrile at room temperature overnight.

Dilute with ether and pass the insoluble part through Celite! The solution was washed successively with water, saturated sodium bicarbonate solution, and saturated saline, and dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was chromatographed on 10 g of silica gel, 90:10
Elution was performed with hexane diacetate ethyl nitriethyl amine (3) to obtain 77 mg of the desired product (yield 86.9%).

[Physical properties of compound (■)]

IR. (Neat): 1730, 1600, 1450,
1375, 1270, 1110, 1060, 710cm
-1NMR (CCl4): δ1.27 (3FI, s)1
．． 32(31(, s), (100MHz)7
．． 20-8.20 (5H, m).

Example 8 Compound (■) 94 mg was dissolved in a mixture of 3 ml of 10% phosphoric acid aqueous solution and 3 ml of tetrahydrofuran.
Heat to reflux for 1 hour.

Extraction is performed with ether, and the extract is washed successively with water, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated and the crude product is purified by column chromatography on 10 g of silica gel. Elution with 85:15 ethyl hexane diacetate gave 56 mg of crystals (yield 79%).

Further, it was recrystallized from hexane to obtain needle-shaped crystals with a melting point of 108°C. [Physical properties of compound (X)] Light intensity: [α] 3+84.2 (C=0.55, in chloroform), IR. (KBr):3550,1705
, 1600cm-1NMR. (CCl4): δ0.87
(3H, d.J=7Hz), (100MH
z) 0.95(.31(, D.J=7Hz), 1.
00(3H, d.J=7Hz), 1.0((3H,
d. J=7Hz), 4.46(2H.d.J=4H
z), 7.30-8.20 (5H, m).

Claims (1)

[Claims] 1. A dioxaspirocyclic compound represented by the following structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼. 2 A compound represented by the structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is reacted with 1-propanedithiol in the presence of an acid catalyst to form a compound represented by the structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The compound is reacted with t-butyldimethylchlorosilane to form a structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, t-Bu is a tertiary-butyl group,
Me represents a methyl group. ) is obtained, and this compound is reacted with ethyl vinyl ether in the presence of an acid catalyst to form 3 Structural formula: ▲There are numerical formulas, chemical formulas, tables, etc.▼ (However, in the formula, t-Bu, Me are The same as above) is obtained, and this compound is reacted with a compound represented by the structural formula: ▲ Numerical formula, chemical formula, table, etc.▼ in the presence of t-butyllithium to form the structural formula ▲ , chemical formulas, tables, etc. ▼ (However, in the formula, t-Bu and Me are the same as above.) A compound represented by is obtained, and the compound is treated with tetra-n-butylammonium fluoride to obtain the structure. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Obtain a compound represented by and react the compound with benzoyl chloride to form a structural formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, φ (represents a phenyl group), and hydrolyzes the dithioacetal moiety of the compound to obtain a compound represented by the structural formula: 1. A method for producing a dioxaspirocyclic compound, which comprises obtaining a dioxaspirocyclic compound represented by the structural formula: ▲Numerical formula, chemical formula, table, etc.▼ by treating the compound with phosphoric acid.