JPH0517469A - Synthetic intermediate for macrolide - Google Patents

Abstract

PURPOSE:To obtain as a synthetic intermediate for macrolides useful as antiulcer agents, antimicrobial agents, etc. CONSTITUTION:A compound expressed by formula I (R<1> is tert. butyldiphenylsilyl, tert. butyldimethylsilyl, methoxymethyl, acetyl or benzoyl). The compound is obtained by reacting a compound expressed by formula II (Me is methyl) with tert. BuPh2SiCl and imidazole used as reagents in a solvent of DMF at 0 deg.C to ambient temperature for 1-5hr. Lactol expressed by formula II is obtained by reacting a lactone expressed by formula III with a diisobutylalminamhydride reagent in a solvent such as toluene. By using this intermediate, macrolides can be stereoselectively produced in high yield and purity.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to synthetic intermediates for macrolides, and more particularly to synthetic intermediates such as Swinholide A, bisteonellide A and C.

[0002]

2. Description of the Related Art Swinholide A ( 1 ) was isolated from the Okinawan sponge Theonella Swinhoei , and its absolute structure was recently determined by Kitagawa et al. . Kitagawa, et al., J. Am. Ch
em. Soc., 112, 3710 (1990)). This compound is known to have antitumor activity and antibacterial activity (S.
Carmely, Y. Kashman, Tetrahedron Lett., 26 , 511 (19
85) and M. Kobayashi, et. Al., Tetrahedron Lett.,
30, 2963 (1989)).

[0003]

[Chemical 4]

Further, as structural analogs of Swinholide A, bistionellide A ( 2 ) and B ( 3 )
It has been known. These compounds are also known to have antitumor activity (R. Sakai, T.
Higa, Y. Kashman, Chem. Lett., 1499 (1986), N. Fuse
tani, T.Higa, Y.Kashman, et al., Tetrahedron Let
t., 28 , 6225 (1987), and I. Kitagawa, et al., 32nd.
Symposium on the Chemistry of Natural Products, Ch
iba, Oct. 1990, Symposium Papers, P. 127).

[0005]

[Chemical 5]

However, a method for chemically synthesizing these macrolides has not been known.

[0007]

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide a synthetic intermediate of the above macrolide. Another object of the present invention is to provide a synthetic intermediate for stereoselectively synthesizing the above-mentioned macrolide synthetic intermediate in high yield and high purity.

[0008]

As a result of diligent efforts, the inventors of the present invention corresponded to the side-chain tetrahydrofuran ring of Swinholide A ( 1 ), Bistionellide A ( 2 ) and C ( 3 ). The present invention has been completed by synthesizing a compound having a structure. That is, the present invention provides (1) a macrolide synthetic intermediate represented by the formula I.

[0009]

[Chemical 6]

(2) A macrolide synthetic intermediate represented by the formula II.

[0011]

[Chemical 7]

(3) A macrolide synthetic intermediate represented by the formula III.

[0013]

[Chemical 8]

Examples of R ^{1 in} the formula I include tert-butyldiphenylsilyl group, tert-butyldimethylsilyl group, methoxymethyl group, acetyl group and benzoyl group. Of these, the tertiary butyldiphenylsilyl group is preferable. Examples of R ² in Formula II include a tert-butyldiphenylsilyl group, a tert-butyldimethylsilyl group, a methoxymethyl group, an acetyl group, a benzoyl group and the like. Of these, the tertiary butyldiphenylsilyl group is preferable.

Examples of R ^{3 in} the formula II include oxygen atom, hydroxyl group, methoxy group and the like. Of these, oxygen atom, hydroxyl group and methoxy group are preferable. Examples of R ⁴ in Formula III include an allyl group, an acetaldehyde group, a 3-hydroxypropyl group, a cyano group, and an acetic acid ester group. Of these, an allyl group, an acetaldehyde group, and a 3-hydroxypropyl group are preferable.

The compounds represented by the formulas 4 and 5 have a tetrahydropyran ring segment common to the macrolides represented by the formulas 1 and 2 , and are important intermediates in the synthesis of the above macrolides. Hereinafter, one example of the synthetic intermediate of the macrolide of the present invention and a method for producing the same will be shown in a scheme, but the present invention is not limited to the following reaction scheme.

In the scheme, Me is a methyl group and TBDP
S represents a tertiary butyldiphenylsilyl group, and Et represents an ethyl group. Further, in the scheme, DIBAH represents diisobutylaluminum hydride, DMF represents dimethylformamide, and NBS represents N-bromosuccinimide.

[0018]

[Chemical 9]

[0019]

[Chemical 10]

[0020]

[Chemical 11]

[0021]

[Chemical 12]

[0022]

[Chemical 13]

[0023]

[Chemical 14]

[0024]

[Chemical 15]

In the above reaction scheme, reagents and reaction conditions which can be preferably used are described below. 1 6 → 7 solvent toluene, methylene chloride, tetrahydrofuran Temperature -78 to-30 ° C. Time 0.5-5 hours reagent DIBAH 2 7 → 8 solvent DMF Temperature 0 ° C. ~ rt time 1-5 hours Reagent t-BuPh ₂ SiCl, Imidazole 3 8 → 9 solvent CH ₃ CN-H ₂ O temperature 0 ° C ~ room temperature time 10 minutes ~ 3 hours Reagent NBS 4 9 → 10 (1) solvent Et ₂ O, THF temperature 0 ° C ~ room temperature time 0.5 minutes ~ 5 hours Reagent LiAlH _4, LiBH ₄ , Zn (BH ₄ ) ₂ (2) Solvent MeOH, EtOH Temperature 0 ° C to room temperature Time 0.5 to 5 hours Reagent NaBH ₄ 5 10 → 11 solvent THF, DMF Temperature 0 ° C to room temperature time 0.5 minutes to 5 hours reagent MeI, KH or NaH 6 11 → 12 solvent CH ₂ Cl _2, CH ₃ CN temperature -30 ° C. ~ room temperature for 10 minutes to 5 hours reagent allyltrimethylsilane, BF ₃ · Et ₂ O , trimethylsilyl triflate 7 12 → 4 solvent MeOH, EtOH, EtOAc temperature -78 to-40 ° C. for 10 minutes to 5 During reagents O _3, Me ₂ S or Ph ₃ P 8 12 → 5 solvent MeOH, EtOH, EtOAc temperature -78 ° C. ~ room temperature for 10 minutes to 5 hours Reagent O _3, NaBH ₄

[0026]

The following example illustrates in detail one preferred embodiment of the present invention. The scope of the invention is not limited to this example. The numbers of the compounds in this example are the same as the numbers of the compounds in the scheme. [Example 1] Synthesis of compound 6 Using 25 g of S-(+)-tert-butyl-3-hydroxybutanoate (> 99% ee, manufactured by Chisso Corporation),
Nakata et al. (T. Nakata, et al, Tetrahedron Lett., 26 , 73
(1985)), 20.9 g of Compound 6 was synthesized (yield 65%). Example 2 Lactone 6 (2.048 g, 10.0 mmole) was dissolved in toluene (60 ml) under 6 → 7 → 8 Ar and DIBAH (1.7
6M n-hexane solution, 22.78 ml, 40.1 mmole,
(4 equivalents) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After the reaction, -7
I-Propanol (4 ml) and H ₂ O (4 ml) were added dropwise at 8 ° C., and the mixture was stirred at room temperature for 20 minutes and then diluted with ethyl acetate,
It was dried with MgSO ₄ and the solvent was distilled off to obtain 1.97 g of a pale yellow oil. This was purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 5: 1 → 3: 1) to obtain 7 (colorless oil, 1.825 g, 88%).

Lactol 7 (200 mg, 0.97 mmole) was dissolved in DMF (1 ml) and imidazole (198) was added under ice cooling.
mg, 2.9 mmole, 3 equivalents), ^t BuPh ₂ SiCl (378 μl,
(1.45 mmole, 1.5 eq) were added successively and the mixture was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated NaCl, dried over MgSO ₄ , and evaporated to give 444 mg of colorless oil. This was purified by column chromatography (silica gel 12 g, hexane: ethyl acetate = 7: 1) to obtain 8 (colorless oil, 309 mg, 99%).

NMR (500 MHz, CDCl ₃ ): δ 4.77 (dd, J = 2.2,
9.2Hz, 1H, Si-O-CH-O), 3.45 (d, d, d, d, J = 16.9, 6.
2, 6.2, 1.8Hz, 1H, CH ₃ -C H -O), 2.21, 1.89 (each d
dd, J = 13.2, 2.2, 2.2Hz, 1H × 2, -CH- (eq)), 2.04 (dd,
J = 13.2, 9.0Hz, 1H, -CH- (ax)), 1.78 (dd, J = 13.2, 1
0.8Hz, 1H, -CH- (ax)), 1.16 (d, J = 6.2Hz, 3H, CH _3- ). Example 3 Under 8 → 9 Ar, a solution of Na ₂ CO ₃ (335 mg, 3.2 mmole) in H ₂ O (2 ml) was added to a solution of AgNO ₃ (1.074 g, 6.3 mmole) in CH ₃ CN (6 ml). Was added and stirred at room temperature for 10 minutes, and then NBS (1.02
3 g, 5.7 mmole) was added under ice cooling, and the mixture was stirred at the same temperature for 5 minutes. Then, thioacetal 8 (426 mg, 0.96 mmol
A CH ₃ CN (3 ml) -H ₂ O (1 ml) solution of e) was added at 0 ° C, and the mixture was stirred at the same temperature for 20 minutes. After the reaction, saturated Na ₂ SO ₃ (4 ml) was added to 0.
The mixture was added at 0 ° C., diluted with CH ₂ Cl ₂ , filtered through Celite, the Celite layer was thoroughly washed with ethyl ether, and the organic layers were combined and washed successively with saturated NaHCO ₃ and saturated NaCl. After drying over MgSO ₄ , the solvent was distilled off to obtain 581 mg of a mixture of pale yellow prism crystals and oil. This was purified by column chromatography (silica gel 8 g, hexane: ethyl acetate = 8: 1) to obtain 9 (pale yellow oil, 333 mg, 94%).

NMR (500 MHz, CDCl ₃ ): δ 4.84 (dd, J = 3.4,
7.9Hz, 1H, Si-O-CH-O), 3.45 (ddd, J = 6.1, 12.2, 15.
0Hz, 1H, CH ₃ -C H -O-), 2.61 (dd, J = 3.2, 14.6Hz, 1H,-
CH- (eq)), 2.56 (dd, J = 7.9, 15.0Hz, 1H, -CH- (ax)),
1.26 (d, J = 6.1Hz, 3H, CH _3- ). Example 4 Ketone 9 (2.435 g, 6.6 mmole) was added anhydrous Et ₂ O under 9 → 10 Ar.
Dissolve in (80 ml) and LiAlH ₄ (752 mg, 19.8 mmole
(3 equivalents) was added under ice cooling, and the mixture was stirred at 0 ° C. for 40 minutes. After the reaction, at 0 ° C., H ₂ O (750 μl), 15% NaOH (7
50 μl) and H ₂ O (2.25 ml) were sequentially added, and the mixture was stirred at room temperature for 10 minutes. Add more MgSO ₄ (excess amount) at room temperature to 30
After stirring for 1 minute, the solid matter was filtered off, the solvent was distilled off, and 2.51
g orange oil was obtained. This was subjected to column chromatography (silica gel 100 g, hexane: ethyl acetate = 1.
Purify with 0: 1 → 3: 1, 10 (yellow oil, 2.1
77 g, 89%).

NMR (500 MHz, CDCl ₃ ): δ 4.57 (dd, J = 2.1,
9.2Hz, 1H, SiO-CH-O), 3.63 (q like, 1H, HO-CH-),
3.22 (m, 1H, CH ₃ -C H -O-), 2.41, 1.81 (each m, 1H ×
2, -CH- (eq)), 1.47 (ddd, J = 9.5, 11.6, 11.6Hz, 1H,-
CH- (ax)), 1.19 (d, J = 6.1Hz, 3H, CH _3- ). Example 5 Alcohol 10 (2.177 g, 5.9 mmole) was dissolved in anhydrous THF (70 ml) under 10 → 11 Ar to prepare CH ₃ l (3.85 ml, 58.8 ml).
mmole, 10 eq) and KH (35 wt%, excess)
Were sequentially added at 0 ° C., and the mixture was stirred at 0 ° C. for 45 minutes. After the reaction
H ₂ O was added at 0 ° C., extracted with ethyl acetate, saturated NH ₄ Cl,
It was washed successively with saturated NaCl, dried over MgSO ₄ , and evaporated to give 3.43 g of orange oil. This was purified by column chromatography (silica gel 100 g, hexane: ethyl acetate = 40: 1 → 10: 1) to obtain 11 (yellow oil, 2.096 g, 93%).

NMR (500MHz, CDCl₃): Δ 4.56 (dd, J = 2.1,
 9.5Hz, 1H, SiO-CH-O), 3.28 (S, 3H, OCH₃), 3.19 (m,
 2H, CH₃-CH-O-, CH₃-CH-), 2.17, 1.86 (each m, 1H
 × 2, -CH- (eq)), 1.43 (ddd, J = 9.5, 11.6, 11.6Hz, 1H,
 -CH- (ax)), 1.19 (d, J = 6.4Hz, 3H, CH₃-). [Example 6]11→12→Four Under Ar, silyl body11CH (75mg, 0.20mmole)₂Cl₂
Dissolve in (1 ml) and add allyltrimethylsilane (9
3μl, 0.6mmole, 3eq) and BF₃・ Et ₂O (74
μl, 0.6mmole, 3eq) were added sequentially, and at 0 ° C for 35 minutes.
It was stirred for a while. After reaction, saturated NaHCO 3 at 0 ° C₃And Et₂At O
After dilution, saturated NaHCO₃, Washed sequentially with saturated NaCl, MgSO
_FourAfter drying and evaporation of the solvent, 82 mg of colorless oil was obtained. this
Column chromatography (silica gel 5 g, hexa
: Ethyl acetate = 15: 1 → 5: 1),12
(Colorless oil, 80 mg,> 100%) was obtained. CH this
₃Dissolve in OH (5 ml) and prepare from ozone generator at -78 ℃
Done O₃Stir for 20 minutes while passing gas through. Ar gas
Then, at -78 ° C (CH₃)₂Add S (2.5 ml) and at room temperature
Stir for 11 hours. After reaction, CH₃OH and (CH₃)₂Evaporate S
82 mg of colorless oil was obtained. Column chromatography
Graphography (5 g silica gel, hexane: ethyl acetate =
6: 1 → 4: 1),Four(Colorless oil, 16 mg,
11Yield (46%) was obtained.

NMR (500 MHz, CDCl ₃ ): δ 9.76 (dd like, 1
H, CHO), 4.69 (ddd like, 1H, OHC-CC H -O), 3.78 (m,
1H, CH ₃ -C H -O-), 3.51 (ddd like, 1H, CH ₃ OC H- ),
3.34 (s, 3H, OCH ₃ ), 2.81, 2.48 (each ddd, 1H × 2,
-OCH-C H _2- ), 1.98, 1.81 (each m, 1H × 2, -CH- (e
q)), 1.72 (ddd, 1H, -CH- (ax)), 1.23 (d, J = 6.4Hz, 3
H, CH _3- ). [Example 7] Under 11 → 12 → 5 Ar, the silyl compound 11 (2.169 g, 5.6 mmole) was converted into CH ₂ C.
Dissolve in l ₂ (30 ml), add allyltrimethylsilane (2.7 ml, 17.0 mmole, 3 equivalents) and BF ₃ · diethyl ether (2.13 ml, 17.0 mmole, 3 equivalents) at 0 ° C., and in the middle Allyltrimethylsilane (0.45 ml, 0.5 eq) and BF ₃ .diethyl ether (0.355 ml, 0.5)
(Equivalent weight) was added and the mixture was stirred at 0 ° C. for 1 hour and 40 minutes.
After the reaction, saturated NaHCO ₃ was added at 0 ° C., diluted with diethyl ether, and washed successively with saturated NaHCO ₃ and saturated NaCl.
SO _{4 was} dried and the solvent was distilled off to obtain 2.54 g of a yellow oil.
Column chromatography (silica gel 100
g, hexane: ethyl acetate = 10: 1 → 5: 1), 12 (pale yellow oil, 1.570 mg,> 100%)
Got Dissolve this in CH ₃ OH (20 ml) and -78 ℃
Then, the mixture was stirred for 30 minutes while passing O ₃ gas prepared from the ozone generator. Further cooled to 0 ° C NaBH ₄ (1.687 g, 4
A solution of 5.1 mmole) in MeOH (10 ml) was added while raising the temperature from -78 ° C to 0 ° C, and the mixture was stirred at 0 ° C for 15 minutes and at room temperature for 15 minutes. After the reaction, add saturated NH ₄ Cl and add 1 with ethyl acetate.
After being extracted 0 times, it is washed successively with H ₂ O and saturated NaCl, then MgSO ₄
After drying and evaporation of the solvent, 1.44 g of a pale yellow oil was obtained. This was purified by column chromatography (silica gel 50 g, hexane: ethyl acetate = 2: 1 → ethyl acetate), 5 (colorless oil, 677 mg, yield 69% from 11 )
Got

NMR (500 MHz, CDCl ₃ ): δ 4.27 (ddd like,
1H, HO-CCC H -O-), 3.86 (m, 1H, CH ₃ -C H -O-), 3.77
(m, 2H, HO-C H _2- ), 3.54 (ddd like, 1H, CH ₃ -CH-), 3.3
4 (s, 3H, OCH ₃ ), 2.07 (m, 1H, HO-CC H- ), 1.97, 1.8
0 (each m, 1H × 2, -CH- (eq)), 1.65, 1.52 (ddd, 1H × 2
, -CH- (ax)), 1.24 (d, J = 6.4Hz, 3H, CH _3- ). [Α]
_D ^22.5 -42.6 ° (c, 2.47; CHCl ₃₎

[0034]

INDUSTRIAL APPLICABILITY The macrolide synthesis intermediate synthesized according to the present invention can be used for the synthesis of macrolides such as swinholide A, bisteonellide A and C. The macrolide that can be produced by the synthetic intermediate of the present invention is a compound having remarkable antitumor activity and antibacterial activity, and can be used as an antitumor agent or an antibacterial agent.

The macrolide synthetic intermediate of the present invention can stereoselectively produce a desired macrolide in high yield and high purity.

Claims (3)

[Claims] 1. A macrolide synthesis intermediate of formula I. [Chemical 1] 2. A macrolide synthetic intermediate of formula II. [Chemical 2] 3. A macrolide synthetic intermediate of formula III. [Chemical 3]