JPH03261759A - Nanaomycin a intermediate and synthesis thereof - Google Patents

Abstract

NEW MATERIAL:A 3-protected hydroxy-4-(6,6a,7,7a,8,8a-hexahydro-1-hydroxy-4- alkoxy-5-oxo-2-naphthyl)-4-alkylthiobutyric ester derivative shown by formula I (R<1> is 1-4C alkyl; R<2> is 1-4C straight-chain, branched alkyl; R<3> is hydroxyl- protecting group eliminable under a mild condition; R<4> is carboxyl-protecting group). EXAMPLE:3-Acetoxy-4-(6,6a,7,7a,8,8a-hexahydro-1-hydroxy-4-methoxy-5-ox o-2- naphthyl)-4-isopropylthiobutyric acid methyl ester. USE:A synthetic intermediate for nanaomycin of antifungal agent. PREPARATION:A compound shown by formula II and a compound shown by formula III are reacted with sulfuryl chloride in the presence of pyridine and then with triethylamine to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Use Nanaomycin A is a microbial product that has antisodium activity against bacteria and antisodium sulfate activity against pathogenic sodium sulfate, and is used in livestock as an antisodium sulfate agent. It is.

The present invention provides 3-protected hydroxy-4 (6,6a) useful as an intermediate in the synthesis of nanaomycin A.

7.7a, 8.8a-hexahyto o-1-hydroxy-
The present invention relates to a 4-alkoxy-5-oxo-2-naphthyl)-4-alkylthiobutyric acid ester derivative and an industrial method for producing the same.

4 Zhu Standing Cover 1 Until now, the total synthesis of antibiotics having a pyranonaphthoquinone skeleton, represented by nanaomycin A, has been carried out by T, Li, etc. (J, A+++, Chem, Soc, 100626
3 (1978)), G. A. Kraus et al. (J. Or.
g-CheII+, 434923 (1978)),
Ichihara et al. (Tetrahedron Letters,
2L4469 (1980)), Yoshii et al. (J. Chem.
Soc, Perkin I.

1191 (1981), 1bid, 1197 (198
1), J,Org,Chem,, 482630(1
983), Chem, Phar+++, Bull,...
324779 (1984)).

Narita et al. (Chem, Letters, 609 (198
2), J. Org, Chem-+Inhibition, 350 (1986
), Journal of the Society of Organic Synthetic Chemistry, Yu, 415 (1984))
, M.F., Semmelhack et al. (J.Org.C.
hem,, 47°4382 (1982), 1 bid
,, 50.5566 (1985), J, Am, Ch.
em.

Soc, 104.5850 (1982), 1bi
d, 105.2034 (1983).

Tetrahedron, 41.5803 (1985
)), L, S, Liebskind et al. (J, Am, C
he+a, Soc, 106.4181 (1984)
, Tetrahedron, 41.5839 (19
85)), Tonta et al. (Bull, Chea+, Soc.

Japan, 58.1699 (1985)).

However, these synthetic methods require more steps than the starting materials, or in some cases include steps that cannot be carried out on an industrial scale because they use special reaction reagents.

Furthermore, with the exception of the method of Tonta et al., it is not possible to synthesize only optically active substances having the natural configuration using other methods.

Problems to be Solved by the Invention The present invention has developed a novel synthesis method for nanaomycin A that can be efficiently carried out on an industrial scale and a method for synthesizing an optically active substance having a natural configuration. The purpose of this invention is to provide a useful intermediate for A.

SUMMARY OF THE INVENTION The present invention is based on the general formula [wherein R1 is a lower alkyl group having 1 to 4 carbon atoms, R
2 is a linear or branched lower alkyl group having 1 to 4 carbon atoms, R3 is a hydroxy protecting group that can be removed under mild conditions, and R4 is a carboxyl group protecting group. Protected hydroxy-4-(6,6a,
7,7a,8゜8a-hexahydro-1-hydroxy-
The present invention relates to a 4-alkoxy-5-oxo-2-naphthyl)-4-alkylthiobutyric acid ester derivative and a method for producing the same.

Conversion of intermediate (I) related to the present invention to nanaomycin A can be carried out as follows.

That is, in the compound represented by the formula (I), R12 and R are methyl groups, R is isopropyl group, and R3 is 2.2.
2-trichloroethoxycarbonyl group.

3-(2,2,2-1lichloroethoxylponyloxy)-4(6,6a, 7.7a.

8.8a-Hexahydro-1-hydroxy-4-methoxy-5-oxo-2-su7thyl)-4-ingrovir thiobutyrate in methanol solvent in the presence of methyl orthoformate, DDQ (2,3 -dichloro-5,6-dicya2-P-benzoquinone), aromatization and quinonation reactions occur simultaneously, and 3-(2,2,2-1-lichloroethoxylponyloxy)-4-isopropylthio- This yields methyl (IV) 4-(1-methoxy-5,8-dioxo-6-su7tyl)butyrate.

When (IV) was treated with zinc and acetic acid, the 2,2,2-trichloroethoxycarbonyl group was eliminated and the quinone was reduced to 3-hydroxy-4-isopropylthio-4-(1
, 4-dihydroxy-5-methoxy-6-naphthyl)butyrate (V) can be obtained. (V) by subjecting it to a standard desulfurization reaction using Raney nickel.
This can lead to methyl hydroxy-4-(1,4-dihydroxy-5-methoxy-〇-naphthyl)butyrate (VI).

By oxidizing (Vl), it can be led to a known quinone compound which has already been synthesized with T, Li, etc.

(Vl) contains a portion of quinone that has undergone air oxidation, so when it was treated with zinc and acetic acid, reacted with acetaldehyde, and then oxidized with DDQ, a pyran ring was formed (9-methoxy- l-methyl-5,10-dioxo-3
,4,5,to-tetrahuman CI-IH-naphtho(2,
3-c) pyran-3-yl) methyl acetate (■).

The thus obtained (■) was treated with aluminum chloride, and the methyl group of the 9-position methoxy group was eliminated (9-
Hydroxy-1-methyl-5,10-dioxo-3,4
,5,10-tetrahydro-1H-naphtho(2,3-c
) pyran-3-yl) methyl acetate (■), and then treated with concentrated sulfuric acid to isomerize the 1-position methyl group and lead to nanaomycin A methyl ester (II).

Nanaomycin A methyl ester can be converted to nanaomycin A by alkaline hydrolysis.

In this way, the intermediate (I) of nanaomycin A related to the present invention is an important intermediate for synthesizing nanaomycin A, and the development of this efficient and industrial synthesis method is is important.

The details will be described below.

For some time now, the present inventors have been able to selectively react the general formula phenols with sulfides in the presence of sul7lyl chloride, as shown in the following reaction formula, to selectively form alkyl compounds at the ortho position of phenols. (Sahara et al., Bull, Chem, Soc, Japan, 60°4
184 (1987)).

This reaction can be carried out using 5-hydroxy-
This research was completed based on the belief that if this method could be applied to 1-tetralone, intermediate (I) of nanaomycin A could be easily obtained.

5-hydroxy-8-alkoxy-1-tetralone (II) represented by the formula (wherein R1 has the above meaning) and 3 represented by the general formula (wherein R, R and R4 have the above meanings) -Protected hydroxy-4-alkylthiobutyric acid ester (I[I) is reacted with sulfuryl chloride in the presence of pyridine in an inert solvent, and then with tidoethylamine to form a 3-protected hydroxy-4
-(6,6a.

7.7a, 8.8a-hexahyto o-1-hydroxy-
4-Alkoxy-5-oxo-2-su7tyl)-4-alkylthiobutyric acid ester (I) can be obtained in high yield.

R1 in compound (II). For R3 and R4 in compound (III), J, F, W, McOmie
.

“Protective Groups in Org
anic Chemistry”, Premnum Press,
London, New York, 1973, T, W+G
reen, ”Protective Groups
In Organic Synthesis, Wiley, New York 1981, protecting groups are known in the art.

That is, R1 is a normal phenolic hydroxyl protecting group, R
is a normal hydroxyl group-protecting group, and R4 is a normal carboxyl group-protecting group.

In compound (m), R2 is an aryl group such as a phenyl group or a substituted phenyl group, or a methyl group.

Alkyl groups such as ethyl group, propyl group, isopropyl group, butyl group, secondary butyl group, and tertiary butyl group are included, and from the viewpoint of reaction yield and reaction selectivity, isopropyl group is preferred.

In addition, compound (III) has an asymmetric carbon at the 3-position,
Those whose absolute configuration is R, those whose absolute configuration is S, and mixtures of R and S can all be used.

The solvent used in this reaction can be any solvent that does not react with the reagent sul7lyl chloride under the reaction conditions, and includes halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, ethyl acetate, and acetic acid. Examples include acetate esters such as butyl, ethers such as diethyl ether, tetrahydrofuran, and dioxane. Or mixtures thereof can also be used. The reaction starts with the compound (I
I), compound (III) and pyridine at -60°C.
This is carried out by adding sulfuryl chloride at a temperature of -20°C. Preferably, the temperature is around -40°C.

After stirring at this temperature for 10-30 minutes, the reaction solution was
Cool to 5°C to -45°C and add triethylamine. Thereafter, the temperature after the reaction is slowly raised to room temperature to complete the reaction.

Isolation of reaction product (I) is carried out by the following general operation.

Pour the reaction solution into a mineral acid such as diluted hydrochloric acid to neutralize the basic substance used during the reaction, extract with an appropriate solvent, and after removing the solvent, perform purification such as recrystallization or chromatography as necessary. By doing so, a pure product of (I) can be obtained.

In order to specifically explain the present invention, examples related to the present invention will be given using the synthesis method of the raw material compound as a production example, and a reference example of the conversion of the substance obtained by the present invention to nanaomycin A. Described as . The examples are merely for illustrating the invention and are not intended to limit the scope of the invention.

rIRJ and rNM used to characterize the products.
The word RJ is an abbreviation for infrared absorption spectrum and proton nuclear magnetic resonance spectrum, and the solvent used during the measurement is appended.

NMR values are also reported as parts per hundred (ppm).

p-dimethoxybenzene pionate 20 g (0.14 mol)
and 16 g (0.14 mol) of succinic anhydride were dissolved in nitrobenzene 125 and cooled to 5°C. Add 43 g (0.32 mol) of aluminum chloride to this and add 3
The mixture was stirred at 5°C for 3 hours. Then, 3.5N hydrochloric acid 80mf
f and separate the organic layer. The organic layer was washed with water and then extracted with saturated sodium bicarbonate solution. After washing the aqueous layer with a small amount of methylene chloride, concentrated hydrochloric acid was added to precipitate crystals. The crystals were collected by filtration and recrystallized from chloroform to obtain 25.4 g of the title compound.

Yield 74%, m, p, 102-104°C.

g (yield 69%).

m, p-144-5 to 145.5°C (C) γ-(2-hydroxy-5-methoxyphenyl)butyric acid O β-(2,5-dimethoxybenzoyl)propion l1
4.76g (20a+mol) in acetonitrile 50
Dissolved in a+ffi, 5.3 g of aluminum chloride (4
The mixture was stirred at 65°C for 20 hours. After adding water to the reaction solution, it was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain crude product 4.
．． 5g was obtained. Purified by silica gel chromatography (developed with chloroform), crystals of the title compound 3.10
β-(2-hydroxy-5-methoxybenzoyl)propionic acid 10-1 g (45 mmol) and caustic potassium 8
．． 3g (148ma+ol) was dissolved in diethylene glycol 56m12, and hydrazine 5-2a+Q (104
mmol) was added thereto, and the mixture was heated under reflux for 1.5 hours. After removing excess hydrazine and water by distillation, the reaction solution was heated to 200°C.
The mixture was stirred for 4 hours.

After cooling, the mixture was diluted with 56IIIQ of water, poured into 3amQ of 6N hydrochloric acid, and extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated to yield 1068 g of crude product.
I got it.

Silica gel chromatography (developed with chloroform)
8.58 g (yield: 82%) of the title compound was obtained.

IR(KBr) cm' 3350.1700.121
0°NMR (CDCI23) 81.96 (ABq, 2
H, J = 7Hz) 2.42 (t, 2H, J = 7Hz) 2.65 (t, 2H, J = 7Hz) 3.73 (s, 3H) 7.0 (bs, 2H) Laron at 100°C Stir for 30 minutes. The reaction solution was poured into 650ml of ice water and extracted with chloroform. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 6 g of a crude product.

Purified by silica gel column chromatography (developed with chloroform) to obtain 5.59 g of the title compound (yield: 51
%) was obtained.

IR(nujol)am' 3150.1640.15
80.1280,108ONMR(CDC108ON
1.97-2.18 (a+, 2H) 2.53-2.68
(m, 21) 2.82-2.96 (m, 2H) 3.82 (s, 3H) 6.86 (ABq, 2H, J□31.8.9Hz) 75
% sulfuric acid 12g (57m+mol) was dissolved in 12g (57m+mol) of γ-(2-hydroxy-5-methoxyphenyl)butyric acid, Production Example 2.3 Hydroxy-4-inpropyl IR (neat) cll NMR (CCQ4) δ 1740.1700, 1250.10501.20(s
, 3H) 1.33 (s, 3H) 2.7-3.2 (m, 1H) 3.33 (s, 2H) 3.60 (s, 2H) 3-37 (s, 3H) Caustic soda 6- 6 g (0,165 mol) and 15-3 m (! (0-165 mol) of isopropyl mercaptan
) was dissolved in 150 mQ of methanol. Here, 17.3 mff of methyl 4-chloro-acetoacetate (0,15 m
ol) was added over 30 minutes. The reaction solution was heated to 30°C.
After stirring for an hour, the mixture was poured into 300 ml of water and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give the crude product 27.
I got g.

Silica gel column chromatography (ethyl acetate: n
- Hexane=1:4) to obtain the title compound 2.
5.2 g (yield 88%) was obtained.

Methyl butyrate 5.70 g (
30mmo 1 ) was dissolved in 99m methanol (2),
Sodium borohydride 0.57g (15m+aol
) was added over 5 minutes and stirred at room temperature for 3 hours. water 18
011<1 was added and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 5.5 g of a crude product. It was purified by silica gel column chromatography (developed with n-hexane and ethyl acetate 20-hexane-3N) to obtain 5.04 g (yield: 87%) of the title compound.

IR(neat)c113450, 1740, 1250
．． 105ONMR (C105ON 1.23(s, 3H
) 1.33 (s, 3H) 2.5-2.7 (m, 4H) 2.7-3.2 (m, IH) 3.2-3.3 (m, IH) 3.73 (s , 3H) 4.1 (bs, IH) Chil 0.57 g (3 mmol) and acetic anhydride 0.4
g (3,9a+mol) was added and cooled to 0°C, and p-toluenesulfonic acid 0.017g (0-09mmol) was added.
) and then stirred at room temperature for 2 hours. 2m of water in the reaction solution
Q was added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain 0.7 g of crude product. It was purified by silica gel column chromatography (developed with n-hexane and n-hexane:ethyl acetate-9=1) to obtain 0.66 g (yield 94%) of the title compound.

IR(neat)cm' 1740.1240.103
ONMR(103ONδ l-20(s, 3H)1-3
0 (s, 3H) 1-97 (s, 3H) 2.5-2.7 (w+, 4H) 2.7-3.2 (m, IH) 3-60 (s, 3H) 4.8- 5.3(m, IH) 3-hydroxy-4-isopropylthiobutyric acid production example 4
．． Synthetic leather of methyl 3-t-butyldimethylsilyloxy-4-isopropylthiobutyrate 1.0 g (5,2 ma+ol) of methyl 3-hydroxy-4-inpropylthiobutyrate was dissolved in 10 mQ of dimethylformamide, and 0.88 g (13 mmol) of imidazole was dissolved. and 1.18 g (7.8 mmol) of t-butyldimethylsilyl chloride were added thereto, and the mixture was stirred at room temperature for 8 hours. 40 mQ of IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with diethyl ether.

The organic layer was washed with saturated sodium bicarbonate solution and anhydrous F
After drying with magnesium hydroxide, it was concentrated to obtain the crude product 1.
8g was obtained. It was purified by silica gel chromatography (developed with ethyl acetate:n-hexane-1:9) to obtain 1.55 g (yield: 97%) of the title compound.

1R(neat)am-1 NMR (CDC(23)δ 1740.1260,1090,840.7800.0
4 (s, 3H) 0.09 (s, 3H) 0.85 and 0.90 (each s, 9H) 1
．． 22 (s, 3H) 1.29 (s, 3H) 2.2-3.0 (m, 5H) 3.66 (s, 3H) 4.1-4.3 (m, IH) 3-hydroxy- Methyl 4-isopropylthiobutyrate9.
6 g (50 mmol) was dissolved in methylene chloride 15IIIQ, 4.74 g (60 mmol) of pyridine was added, and the mixture was cooled to 0°C. 8.9 mQ (60 mmol) of chlorophyll 1112.2.2-trichloroethyl was added thereto, and the mixture was stirred at room temperature for 1 hour. Insoluble matter was filtered off, and the filtrate was diluted with IN hydrochloric acid 1
00 mm and extracted with ethyl acetate. After washing the organic layer with saturated brine and drying with anhydrous magnesium sulfate,
Concentration yielded 19 g of crude product. Purified by silica gel column chromatography (developed with n-hexane and n-hexane:ethyl acetate-1:9) to obtain 18 g of the title compound.
(yield 98%).

IR(neat)co+-' 1750,1250.
1000.820.74ONMR(CDC123)δ
1.24 and 1.25 (each s, 3H) 1
．． 31 and 1.32 (each s, 3H)2.
7-2.9 (+e, 4H) 2.9-3.2 (m, IH) 3.71 (s, 3H) 4.78 and 4.80 (each s, 2H) 5
．． 1 to 5.3 (m, IH) Example 1 0.29 g of 5-hydroxy-8-methoxytetralone
(1-5 mmol), 0.23 g (1 mmol) of methyl 3-acetoxy-4-isopropylthiobutyrate, and 0.09 g (1.2 mmol) of pyridine were dissolved in 5 ml of methylene chloride and cooled to 40°C. To this, 1 ml (1.2 mmol) of sulfuryl chloride O was added, and -40
Stirred at ℃ for 15 minutes. Next, after cooling the reaction solution to -55°C, 1.5% of triethylamine was added. On+<2 (7mmo
l) After that, the room temperature was slowly raised. The reaction solution was poured into 10 mL of IN hydrochloric acid, extracted with chloroform, and the organic layer was washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated to yield 0.36 g of the above substance as an oil. Obtained. Yield 86% IR (neat) cm-1: 3450.1740,1
670.1240.1090°6O NMR (CDCI23) δ: 1.1=1.2(a+,
6H).

2.05 and 2.07 (3H) 2.0-2. l (m, 2H) 2.5-3.0 (m, 5H) 2.75 (d, 2H, J=6.8Hz) 3.68 a
nd 3.70 (each s, 3H) 3.85 (s,
38) 4.55 (d, IH, J=4.9Hz) 5.3-5.
5 (m, 1H) 6.79 and 6.86 (each s, IH)
7.2 (bs, IH) Example 2 Methyl butyrate Same as Example 1, 1.3 g (6,75a+mol) of 5-hydroxy-8-methoxytetralone and 3-(t-butyldimethylsilyloxy)-4- 70 g (yield 77%) of the title compound L was obtained from 1.38 g (4,5+++ mol) of methyl inpropylthiobutyrate.

IR(neat)c113300.1740.1670
, 1250.1090° NMR (CDCQ3) δ −0.2 to 0.1 (m, 6H).

0.81 and 0.82 (each s, 9H)
1.1=1.3 (m, 6H) 1.9-2.9 (m, 9H) 3.60 and 3.63 (each s, 3H)
3.74 and 3.79 (each s, 3H
) 4.3-4.4 (m, 2H) 6-88 (s, IH) 7-26 (s, 3H) Example 3 - 5-hydroxy-8-methoxytetralone 2 in the same manner as in Example 1 .59g (13-5++v+ol) and 4-
Methyl isopropylthio-3-(2,2,2-trichloroethoxycarbonyloxy)butyrate 3.31g (9mm
3.48 g of the title compound (yield 69%) from
I got it.

IR(neat)ca+-13350,1760,16
60,1240,1090°820.73O NMR (CDCI23) δ: 1.2-1.3 (m, 6
H).

1.9-2.2 (+a, 2H) 2.4-2.9 (m, 7H) 3.67 and 3.68 (each s, 3H) 3
-86 (s, 3H) 4.6-4.8 (m, IH) 4.78 (s, 2H) 5.4-5.6 (m, IH) 6.88 and 6-96 (each s, IH)7
．． 2 (bs, IH) Reference example, (±) Nanaomycin A synthetic leather 3-(2,2,
2-trichloroethoxycarbonyloxy)-4-(6
, 6a, 7.7a, 8.8a-hexahydro-1-hydroxy-4-methoxy-5-oxo-2-su7tyl)-
Methyl 4-inpropylthiobutyrate 3.34g (6mm
ol) and methyl orthoformate 0.64 g (6 mmol
) and dissolved in 15 mQ of methanol and 4.09 g of DDQ.
A methanol 20+o12 solution of (1 g++u++ol) was added, and the mixture was heated under reflux for 1 hour and 30 minutes.

The reaction solution was concentrated, chloroform was added, and insoluble matter was filtered out.
The filtrate was concentrated to obtain the crude product. It was purified by silica gel column chromatography (developed with chloroform) to obtain 2.75 g (yield: 82%) of the title compound.

IR(neat)cm' 1760,1740.16
50.1580.124ONMR (CDCQ3)a 1000.820,770.750 1.27 (dd, 6H, J=6.6.1.5Hz)2.
8-3.1 (m, 3H) 3.69 (s, 3) 1) 4.01 (s, 3H) 4.3-4.6 (m, IH) 4.7-4.8 (m, 2H) 5.5-5.7 (m, LH) 7.7-7.8 (+n, 4H) C-2-su7tyl) methyl butyrate (V) 3- (2,2,2-trichloroethoxycarbonyl oxy)-4-(1-methoxy-5,8-dioxo-6-
2-5 g of methyl (su7tyl)-4-inpropylthiobutyrate
(4.5 mmol) was dissolved in 15Il112 acetic acid,
4 g of zinc powder was added and stirred at room temperature for 3 hours. water 40w
5 (l) was added, the solid matter was filtered, the filtrate was extracted with chloroform, the organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, concentrated, and the crude product 1
．． 7 g were obtained as an oil. This was subjected to silica gel column chromatography (ethyl acetate:n-hexane-1:4
(Development) and purification. 1.42g of the listed compound (
A yield of 83%) was obtained.

IR(neat)c113450.1730.1650
．． 1590,1260°6O NMR (CDCQ3) δ 11-1=1-3(,6H) 2.5-2.9(m, 3H) 3.66(s, 3H) 3.7(bs, 1B) 4 .04 (s, 3H) 4.4-4.7 (m, 2H) 6-6-8.0 (m, 6H) Methyl (Vl) 3-Hydroxy-4-ingropyruthio 4-(1, 4
-42 g (3.7 mmol) of methyl butyrate (dihydroxy-5-methoxy-2-su7tyl) in 40 ml of ethanol
-, add about 15g of Raney nickel (W4),
Stirred at room temperature for 30 minutes. The solid content was filtered off, and the filtrate was concentrated to obtain 1.2 g of a crude product. This was purified by silica gel column chromatography (developed with chloroform) I; the title compound was obtained as an oily substance, 0.925 g (yield: 8
2%) was obtained.

IR(CHC(23)cm-' 3470,1730,
1650.1580.12607O NMR (CDCQ3) δ 2.5-2.7 (m, 4H) 3.4 (bs, 1H)
3.72 (s, 3H) 3.99 (s, 3B) 4.2
~4.4 (m, IH) 6J ~7.7 (m, 6H) yl) Methyl acetate (■) Methyl 3-hydroxy-4-(1,4-dihydroxy-5-methoxy-2-naphthyl)butyrate 91 mg (0.3m
mol) in a mixed solvent of 15 ml of methylene chloride and 5 mff of diethyl ether, and 0.1 g of zinc powder (1,
5 mmol) and 0.6 mm of salt production were added, and the mixture was stirred at room temperature for 10 minutes.

To this, 1.7 mQ of acetaldehyde was added, and the mixture was heated under reflux for 2 hours. The reaction solution was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain a corrugated material.

This oil was dissolved in methanol 3111a and DDQo
, 081 g (0.36 mmol) was added, and 1
Stirred for 0 minutes. After adding 10 ml of water and 5-chloroform to the reaction solution and filtering off insoluble matter, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 0.12 g of a crude product. This was purified by silica gel column chromatography (developed with n-hexane:chloroform ratio 1:3) to obtain 74+ng of the title compound (yield 74%).
) was obtained.

IR (CHCQ3) cm-” NMR (CDC (23) a 1730.1650.1580.12701.53 (d
d, 3H, J=6.7. 3.5Hz) 2.25(dd
d, LH, J=1g, 3.10.3.5Hz) 2.6
7 (dd, 2H, J = 6-6.2.5Hz) 2.85 (
dd, IH, J=15.3.2-7Hz) 3.73(s
, 3H) 4.00 (s, 3H) 4.0-4.4 (+o, 1H) 4.8-5.0 (m, IH) 7.2-7.3 (m, 1) f) 7 .6-7.8 (a+, 2H) monoyl) methyl acetate (■) (9-methoxy-1-methyl-5,lO-dioxo-3
,4,5,10-tetrahydro-IH-nut(2,3
-c) pyran-3-yl) methyl acetate 130 mg (0
, 39 mmol) was dissolved in 5 ml of methylene chloride, 0-27 g (2.0 mmol) of aluminum chloride was added, and the mixture was stirred at room temperature for 2 hours. Add water, separate the organic layer,
Washing with IN hydrochloric acid and then water, drying over anhydrous magnesium sulfate, and concentration gave 130 mg of crude product. Purification by silica gel column chromatography (developed with n-hexane:chloroform-1:1) gave 84 mg (yield 70%) of the title compound.

IR(CHCQ3)Cm-' 3100.1?30,1
660.164ONMR(CDC(23)81.57(
dd, 3H, J=6.7.1.6Hz) 2-32(dd
d, IH, J=19.11.2Hz) 2.68(dd,
2H, J=6.6.2.7Hz) 2.88(dd, IH
,15,9,2,7Hz) 3.74 (s, 3H) 3.8-4.1 (m, IH) 4.8-5.0 (m, IH) 7.2-7.3 (m , IH) 7.5-7.6 (m, 2H) pyran-3-yl) methyl acetate (■) (9-hydroxy-1-methyl-5,10-dioquine-
3,4,5,1O-tetrahydro-LH-naphtho(2,
3-c) pyran-3-yl) methyl acetate 83 mg (0
, 26 mmol) was dissolved in 10- concentrated sulfuric acid, and 30 mmol was dissolved at room temperature.
Stir for a minute. The mixture was poured into saturated brine, extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain 90 mg of a crude product. When purified by silica gel column chromatography (developed with chloroform), a mixture of trans and cis forms was obtained almost quantitatively. This mixture was diluted with n-hexane-methylene chloride (4: l
), the trans isomer 62mg (
A yield of 75%) was obtained.

IR(CHCQ3)cm-' 3100.1730,1
660.164ONMR(CDCQ3)δ 1.57(
d, 3H, J=6.7Hz) 2.32(ddd, LH,
J=19.10.2Hz) 2.65(d, 2H, J□6
．． 6Hz) 2.88 (dd, IH, J=19.3Hz)
3.74 (s, 3H) 4.0-4.3 (m, 1H) 4.8-5.0 (m, 1H) 7.2-7.3 (m, 1H) 7.5-7. 6(m,2H) (G)(±)-Nanaomycin A trans-(9-hydroxy-1-methyl-5°10-
Dioxo-3,4,5,10-tetrahydro-IH-naphtho(2,3-c)pyran-3-yl)methyl acetate 32
mg (0.1 mmol) was dissolved in 10 ml of ethanol, 50 IIIQ of 0.1 M aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain 50 mg of a crude product. Purified by silica gel column chromatography (developed with chloroform), (±)-
29 mg (yield 97%) of Nanaomycin A was obtained.

IR(nujol)am-12800,1710,16
60, 1640, 161ONMR (CDC43-CDC
43-D) 8 1.58 (d, 3H, J =
6-6Hz) 2.31 (ddd, IH, J=19.4.
10.1.2.1Hz) 2.63(d, 2H, J=6.
3Hz) 2.88 (dd, LH, J=19.5. 3.
4) 1z) 4.2-4.5 (m, IH) 4.9-5.1 (m, IH) 7.18-7.34 (m, IH) 7.58-7.64 (m, 2H)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 is a lower alkyl group having 1 to 4 carbon atoms,
R^2 is a linear or branched lower alkyl group having 1 to 4 carbon atoms, R^3 is a hydroxy protecting group that can be removed under mild conditions, and R^4 is a carboxyl protecting group. ] 3-protected hydroxy-4- (6,6a,7,7a,8,8a-hexahydro-1-
Hydroxy-4-alkoxy-5-oxo-2-naphthyl)-4-alkylthiobutyric acid ester derivative. 2,3-acetoxy-4-(6,6a,7,7a,8,
8a-hexahydro-1-hydroxy-4-methoxy-
The compound according to claim 1, which is methyl 5-oxo-2-naphthyl)-4-isopropylthiobutyrate. 3,3-(t-butyldimethylsilyloxy)-4-(
6,6a,7,7a,8,8a-hexahydro-1-hydroxy-4-methoxy-5-oxo-2-naphthyl)
2. The compound according to claim 1, which is methyl -4-isopropylthiobutyrate. 4,3-(2,2,2-trichloroethoxycarbonyloxy)-4-(6,6a,7,7a,8,8a-hexahydro-1-hydroxy-4-
2. The compound according to claim 1, which is methyl methoxy-5-oxo-2-naphthyl)-4-isopropylthiobutyrate. 5. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) 5-hydroxy-8-alkoxy-1-tetralone (in the formula, R^1 represents what is described in claim 1) II) and General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^2, R^3 and R^4 are stated in claim 1 3-protected hydroxy-4 represented by
A claim represented by the general formula ▲ Numerical formula, chemical formula, table, etc.▼ by reacting -alkylthiobutyric acid ester (III) with sulfuryl chloride in an inert solvent in the presence of pyridine, and then reacting with triethylamine. 1. Method for synthesizing the compound described in 1.