JP2002363180A - Eudistomin synthetic intermediate and method for synthesizing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an eudistomin intermediate compound improved with the yield and stereospecific selectivity in the forming process of a 7-membered oxathiazepine skeleton, a method for producing the same intermediate, and a new eudistomin analog compound. SOLUTION: This eudistomin synthetic intermediate is expressed by the general formula (I) (wherein, R<1> to R<4> are each H, a lower alkyl or the like; R<5> is H; R<6> is H, silyl or the like; R<7> is H, a lower alkyl or the like), in which the absolute stereospecific configurations at 1 and 10th positions are (1S, 10R), (1R, 10S), (1S, 10S) or (1R, 10R). As a concrete example of the compound, a compound expressed by the formula II (wherein, Boc is a substituting group such as tertiary butoxycarbonyl, etc.), can be sited.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a highly stereoselective compound using an aldehyde represented by the general formula C, which can be easily synthesized by defining the configuration of the corresponding amino acid in any compound having an absolute configuration. The present invention relates to four diastereomers of a eudistmin synthetic intermediate synthesized by a reaction and a method for producing the same.

[0002]

2. Description of the Related Art Eudistmins are a group of compounds isolated from a sea squirt in the Caribbean and whose structure has already been determined (Reference 1), and a tetrahydro-β-carboline derivative having a characteristic oxathiazepine ring (general formula D) ). Among them, eudystomins C (compounds in which R ¹ is H, R ² is OH and R ³ is Br in Formula D) and E (in Formula D, R ¹ is Br, R ² is OH and R
³ is H) is reported to exhibit strong antiviral activity, and is expected as a lead compound of antiviral agents. To date, total synthesis has been achieved by several groups (2, 3). However, there are problems with the yield and stereoselectivity, especially with respect to the stereoselective construction of the 7-membered oxthiazepine skeleton, and no commercially available synthetic method capable of supplying compounds has been realized.

[0003]

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[0004] The invention described in the above-mentioned reference 2 discloses a pictet-Spengler of nitrone obtained from N-hydroxytryptamine and aminoaldehyde.
The characteristic feature lies in the construction of a 7-membered oxthiazepine structure using the Pummerer reaction of methyl sulfide with the key step of the ngler) reaction as a key step. Is extremely inefficient.
Further, the invention described in Document 3 is characterized in that the basic skeleton of udistmin is constructed at once by a reductive cyclization reaction of O-alkylhydroxylamine having an ester group at the terminal, but it is derived from amino acids. There is a problem that the control of the stereochemistry at the 1-position due to the influence of the stereochemistry of the amino group is opposite to the stereostructure of natural eudistmin. In any prior art, the efficiency of the synthesis route,
There is a problem that the structure selectivity of the three-dimensional structure, in other words, the diastereoselectivity is not good.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a eudistmin which can improve the above-mentioned problems of the prior art and has a high yield and a high stereoselectivity. It is an object of the present invention to provide an intermediate for synthesizing udidistmin having improved yields, including selective construction, and a method for synthesizing the intermediate. Although a synthesis reaction in which the Pictet-Spengler reaction is one step of the eudistmin synthesis process is known,
There is a problem that the structure selectivity and the yield are not good depending on the compound used as a reaction raw material for the reaction. Therefore, the present inventors started by examining the starting materials, and started from the starting materials capable of producing a novel eudistmin synthetic intermediate capable of synthesizing the eudistmin analog, which is the final object, by controlling the three-dimensional structure at a high degree. The object of the present invention was solved by establishing a method for synthesizing a body.

[0006]

The first aspect of the present invention is an intermediate for synthesizing eudistmin having four diastereomeric structures represented by the above-mentioned general formula A. Are numbered in the Rine shown in FIG.
According to the method used by Hart et al. In the general formula A, the numbering of the eudistmin skeleton is extended and numbered. ]. The second aspect of the present invention is the above general formula B
From the compound of formula 1 and the aldehyde of formula 1
This is a method for producing the compound of the general formula A by a Pictet-Spengler reaction, preferably using halogen-substituted acetic acid as an acid and using toluene or benzene as a reaction solvent (1S, 10R) and (1S).
R, 10S) in a highly selective manner and using (1S, 10S) and (1R, 10R) absolute compounds using formic acid as the acid and acetonitrile as the reaction solvent. This is a method for highly selectively producing a compound of the general formula A having a steric configuration (FIG. 2). A third aspect of the present invention is characterized in that the 7-position represented by the general formula 1 is OR ³ (R ³ is H, a lower alkylsulfonyl group, an arylsulfonyl group or a trifluoromethanesulfonyl group). The present invention relates to a eudistmin analog compound which can be synthesized as various intermediates, for example, a compound obtained by introducing a residue bonding to carbon at the 7-position by a Suzuki coupling reaction, and which is useful as an intermediate.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail. A. The present invention relates to a compound represented by the general formula A obtained by reacting the compound of the general formula B with the general formula C, in particular, the compound 1 (where Boc is a substituent such as tert-butoxycarbonyl). (1) It is characterized in that a useful intermediate capable of synthesizing a eudistmin analog having a desired configuration by controlling the configuration at the 1- and 10-positions can be produced.

[0008]

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B. In addition, the novel udistmin analog of the general formula 1 has a feature that the substituent at the 7-position can be easily converted into various substituents. It is an important compound in considering the characteristics as such.

[0010]

Example 1 In the general formula B, R ¹ is hydrogen, R ² is a methoxy group, R ³ is Br, and R ⁷ is H. Compound 3 contained in general formula A is synthesized.

[0011]

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[0012]

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The compound 2 (1.25 g, 3.62 mm)
ol), the aldehyde 1 (1.07 g, 4.36 mm)
ol) in a toluene solution of dichloroacetic acid (0.0
30 ml, 0.362 mmol) was added dropwise. 1 at the same temperature
After stirring for 5 minutes, the reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.01 g (quant, 11: 1 dr) of a colorless oily compound 3 from a fraction eluted with hexane / ethyl acetate (4/1).

Physical properties of compound 3: IR (film, c
m ^-1 ) 3469, 3359, 2978, 2981, 16
99, 1366, 1171, 852, 759; ¹ H-N
MR (400 MHz, CDCl ₃ ) δ 1.50 (s, 6
H), 1.54 (s, 9H), 2.26 (s, 3H),
2.72-2.82 (m, 1H), 2.84-2.96
(M, 1H), 3.04-3.16 (m, 1H), 3.0.
67-3.76 (m, 1H), 3.77-3.83
(M, 1H), 3.91 (s, 3H), 4.06-4.
15 (m, 1H), 4.57-4.63 (m, 1H),
4.64-4.70 (m, 1H), 4.81 (d, J =
11.6 Hz, 1 H), 4.85 (d, J = 11.6 H)
z, 1H), 6.94 (s, 1H), 7.50 (s, 1
H), 8.26 (brs, 1H); ¹³ C-NMR (10
0MHz, CDCl ₃₎ δ15.6,19.8,26.
9, 28.4, 52.1, 56.8, 63.8, 64.
7, 64.9, 77.9, 81.2, 95.1, 10
0.6, 106.8, 110.2, 115.3, 12
6.1, 131.5, 131.8, 150.1.

Example 2 In the same manner as in Example 1, the 6-position of compound 3
Compound 4 is obtained in which Me and 7-Br are hydrogen. Physical properties of compound 4: IR (film, cm ^-1 ) 3472,
1700, 1254, 1171, 1095, 853, 7
41; ¹ H NMR (400 MHz, CDCl ₃ ) δ1.
50 (s, 6H), 1.55 (s, 9H), 2.26
(S, 3H), 2.77-2.97 (m, 2H), 3.
05-3.15 (m, 1H), 3.67-3.75
(M, 1H), 3.83 (dd, J = 3.7, 9.5H
z, 1H), 4.09 (dd, J = 7.8, 9.5H
z, 1H), 4.70 (brs, 2H), 7.09 (d
dd, J = 0.8, 7.8, 7.8 Hz, 1H), 7.
15 (ddd, J = 1.2, 7.8, 7.8 Hz, 1
H), 7.29 (d, J = 7.8 Hz, 1H), 7.4
7 (d, J = 7.8 Hz, 1H), 8.32 (brs,
1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) δ
15.6, 19.9, 26.8, 28.5, 52.4,
58.2, 63.8, 64.9, 77.9, 81.1,
95.1, 110.3, 110.9, 118.1, 11
9.4,121.8,126.3,136.3,15
3.9.

Example 3 In the same manner as in Example 1, the 6-position of compound 3
Me is hydrogen, 7th-Br is MsO (Ms is methanesulfo
Nyl) is obtained. Physical properties of compound 5: IR (film, cm^-1) 2979,
2935, 1748, 1697, 1478, 1375,
1181,967,836,757;¹H-NMR (4
00 MHz, CDCl_Three) Δ1.43-1.72 (m,
15H), 2.04 (d, J = 5.9 Hz, 3H),
2.21 (s, 3H), 2.53 (dd, J = 6.0,
16.4 Hz, 1H), 2.93-3.05 (m, 1
H), 3.13 (s, 3H), 3.39-3.58.
(M, 1H), 3.68 (dd, J = 6.0, 14.8)
Hz, 1H), 4.15-4.30 (m, 1H), 4.
46 (dd, J = 2.0, 9.0 Hz, 1H), 4.5
6-4.61 (m, 1H), 4.85 (d, J = 11.
0 Hz, 1H), 4.89 (d, J = 11.0 Hz, 1
H), 4.94-5.06 (m, 1H), 6.77.
(Q, J = 5.9 Hz, 2H), 7.21-7.23
(M, 1H), 7.41-7.49 (m, 1H), 8.
09 (brs, 1H); ¹³C-NMR (100 MHz,
CDCl_Three) Δ 15.0, 25.4, 27.7, 28.
4, 37.0, 58.6, 58.8, 64.3, 77.
2,77.9,80.0,83.4,95.2,11
0.8, 116.9, 117.7, 118.7, 12
8.7, 134.9, 146.6, 146.7, 14
9.1.

Reference Example 1 Here, a schematic process for synthesizing a eudistmin analog from the compound 3 will be described. First, H of the amino group at the 9-position is converted to ACE (alpha-chloroethoxycarbonyl). The MTM (methylthiomethyl) group of the obtained compound is converted into a chloromethyl ether group, and thioacetate is formed. The udistmin analog 7 was formed from the obtained compound 6 by forming a 7-membered oxthiazepine ring in reaction 1 shown below.
Can be synthesized.

[0018]

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The ring forming reaction was performed as follows.
A methanol solution of compound 6 (1.15 g, 1.58 mmol) and potassium carbonate (1.09 g, 7.90 mmol) was heated under reflux for 15 minutes. The reaction solution was cooled to room temperature, diluted with methylene chloride, and washed with a saturated aqueous solution of ammonium chloride. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 498 mg (65%) of a colorless powder of Compound 7 from a fraction eluted with hexane / ethyl acetate (1/1). Even after the ring-forming reaction,
“0013” which is a key reaction for determining the three-dimensional structure
In (7), the configuration of (1S, 10R) formed by reacting an R-form aldehyde synthesized from the corresponding amino acid with dichloroacetic acid using a toluene solvent was also maintained in the compound 7.

Physical properties of compound 7: IR (film, c
m ^-1 ) 3338,1685,1497,1164,10
40,829,757; ¹ H-NMR (400 MHz,
_{CDCl 3) δ1.19 (s, 9H} ), 2.72-2.
85 (m, 2H), 2.88-3.00 (m, 1H),
3.06-3.19 (m, 1H), 3.30 (d, J =
14.4 Hz, 1H), 3.56-3.63 (m, 1
H), 3.90 (s, 1H), 4.10 (brs, 1
H), 4.59-4.67 (m, 1H), 4.79.
(D, J = 8.8 Hz, 1H), 4.93 (d, J =
8.8 Hz, 1H), 6.89 (s, 1H), 7.46
(S, 1H), 8.58 (brs, 1H); ¹³ C-NM
R (100 MHz, CDCl ₃ ) δ 20.7, 28.
0, 32.4, 48.5, 54.8, 56.7, 69.
5,70.9,80.1,100.3,106.7,1
09.3, 115.7, 125.9, 132.1, 13
2.4, 149.8, 156.1.

Example 4 The udistmin analog 8 in which the 7-position was substituted with MsO- (where Ms is methanesulfonyl) was obtained in the same manner as in the above-mentioned Reference Example by using the above-mentioned Compound 5.

[0022]

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Physical properties of compound 8: IR (film, c
m ^-1 ) 3329, 2976, 2925, 2848, 16
86, 1497, 1365, 1180, 1112, 83
5,754; ¹ H-NMR (400 MHz, CDCl ₃ )
δ 1.17 (s, 9H), 2.77-2.83 (m, 2
H), 2.90-3.00 (m, 1H), 3.07
(S, 3H), 3.09-3.19 (m, 1H), 3.
32 (d, J = 14.4 Hz, 1H), 3.58-3.
62 (m, 1H), 4.14 (brs, 1H), 4.6
3-4.71 (m, 1H), 4.80 (d, J = 9.0)
Hz, 1H), 4.94 (d, J = 9.0 Hz, 1
H), 5.72 (d, J = 10.5 Hz, 1H), 7.
00 (dd, J = 2.2, 8.5 Hz, 1H), 7.2
4 (d, J = 2.2 Hz, 1H), 7.43 (d, J =
8.5 Hz, 1H), 8.90 (brs, 1H); ¹³ C
-NMR (100 MHz, CDCl ₃ ) δ 20.7, 2
8.1, 32.5, 36.8, 48.6, 54.9, 6
9.5, 71.0, 80.2, 105.1, 109.
5, 113.7, 118.8, 125.4, 132.
7, 136.8, 144.9, 156.2.

Example 4 'The compound 8' was prepared by removing the protecting group (Boc) from the compound 8 by the following method.

[0025]

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Compound 8 (11.0 mg, 0.0234 m
mol) and NaI (16.7 mg, 0.117 mm)
chloro) in a CH ₃ CN solution (6.0 μL, 0.0468 mmol) at room temperature under an argon atmosphere. The reaction mixture is poured into saturated NaHCO ₃ and then extracted with ethyl acetate. Extracts washed with brine, dried over Na ₂ SO _4. Filtration and concentration on a rotary evaporator gave a crude product. The crude product was purified by thin-layer chromatography for purification (using a mixture of 10% methanol in CH ₂ Cl ₂ ) to give compound 8 ′. Physical properties of compound 8 ': [α] D-94.6- (c0.6
2, MeOH); IR (film, cm ^-1 ) 3377,
3168, 2919, 1559, 1473, 1178,
1100, 955, 839, 750; ¹ H-NMR (4
00 MHz, CDCl ₃ ) δ 1.95 (brs, 2
H), 2.72-2.85 (m, 1H), 3.06-
3.13 (m, 1H), 3.14 (s, 3H), 3.2
9 (d, J = 14.4 Hz, 1H), 3.53-3.6
1 (m, 2H), 4.06 (brs, 1H), 4.78
(D, J = 9.0 Hz, 1H), 4.91 (d, J =
9.0 Hz, 1H), 7.00 (dd, J = 2.2,
8.6 Hz, 1 H), 7.30 (d, J = 2.2 Hz,
1H), 7.42 (d, J = 8.6 Hz, 1H), 8.
90 (brs, 1H); ¹³ C-NMR (100 MHz,
CDCl ₃₎ δ20.9,34.1,37.0,50.
6,53.8, 69.6, 71.5, 105.3, 11
0.7, 113.9, 118.9, 125.5, 13
2.7, 136.7, 144.8.

Example 5 From the compound 8, Ms was synthesized by the following synthesis method.
The compound 9 to be H is obtained. Compound 8 (20.7 m
g, 0.0441 mmol) of methanol (0.5 m
L) Add KOH (60.4 g, 0.882 mmol) to the solution
Add. The reaction mixture is heated at reflux for 15 minutes. After cooling,
The reaction mixture is brought to saturated NH_FourPour into Cl solution and add CH_TwoCl _Twoso
Extract. The extract is washed with brine and Na_TwoSO_FourAbove
Dry, filter and then dry under reduced pressure. Compound 9
Compounds were purified by thin-layer chromatography for purification (in hexane).
Using a solvent mixture of 40% ethyl acetate
Obtained.

Physical properties of compound 9: IR (film, c
m ^-1 ) 3344, 2970, 2844, 168, 163
4,1498,1366,1164,1038,78
7; ¹ H-NMR (400 MHz, CDCl ₃ ) δ1.1
9 (s, 9H), 2.72-2.78 (m, 2H),
2.78-2.99 (m, 1H), 3.10-3.18
(M, 1H), 3.25-3.36 (m, 1H), 3.
53-3.63 (m, 1H), 4.11 (brs, 1
H), 4.56-4.65 (m, 1H), 4.80.
(D, J = 9.0 Hz, 1H), 4.93 (d, J =
9.0 Hz, 1H), 5.26 (brs, 1H), 5.
70 (d, J = 10.0 Hz, 1H), 6.64 (d
d, J = 2.2, 8.6 Hz, 1H), 6.71 (d,
J = 2.2 Hz, 1H), 7.22-7.26 (m, 1
H), 8.44 (brs, 1H); ¹³ C-NMR (10
0MHz, CDCl ₃₎ δ20.8,28.1,32.
5,48.8,54.9,69.5,71.0,80.
1,977.4,109.1,109.4,118.6,
120.9, 122.8, 129.4, 138.1, 1
51.9.

Example 5 'Compound 9' obtained by removing the protecting group (Boc) from Compound 9 is obtained in the same manner as in the preparation of Compound 8 '. Physical properties of compound 9 ': [α] D-93.7- (c0.3
7, MeOH); IR (film, cm ^-1 ) 3281
2918, 1633, 1457, 1151, 1038,
832,722; ¹ H-NMR (400 MHz, CD ₃ O
D) δ2.58-2.65 (m, 1H), 2.69-
2.80 (m, 2H), 2.94-3.04 (m, 1
H), 3.11-3.19 (m, 1H), 3.41-
3.48 (m, 2H), 3.95 (brs, 1H),
4.68 (d, J = 9.0 Hz, 1H), 4.80
(D, J = 9.0 Hz, 1H), 6.47 (dd, J =
2.0, 8.5 Hz, 1H), 6.64 (d, J = 2.
0 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1
H); ¹³ C-NMR (100 MHz, CD ₃ OD) δ2
1.8, 34.0, 50.8, 55.2, 71.3, 7
2.0, 97.9, 110.1, 111.2, 119.
3,121.6,130.0,140.1,154.
3.

Example 6 OH of compound 9 was converted to trifluoromethanesulfonyl (T
f) Compound 10 is synthesized by the following method. This compound is useful as a raw material for a coupling reaction using a transition metal catalyst, particularly a Suzuki coupling reaction, a Sonogashira coupling reaction, a Stille coupling reaction, and a Heck reaction. Synthesis of compound 10. Compound 9 (18.9 mg, 0.1 mg).
0483 mmol) in CH ₂ Cl ₂ solution.
2 μL, 0.145 mmol) and trifluoromethanesulfonic anhydride (12 μL, 0.0725 mmol)
l) at 0 ° C. The reaction mixture is warmed to room temperature, poured into saturated NaHCO ₃ and then extracted with CH ₂ Cl ₂ . Extracts washed with brine, dried over MgSO _4, filtered and evaporated under reduced pressure. Compound 10 was obtained by thin layer chromatography for purification (using a mixture of 20% ethyl acetate in hexane).

Physical properties of compound 10: IR (film, cm
^-1 ) 3321, 976, 1685, 1498, 136
7,1143,1097,948,868,757; ¹
H-NMR (400 MHz, CDCl ₃ ) δ 1.17
(S, 9H), 2.79-2.84 (m, 2H), 2.
90-3.01 (m, 1H), 3.11-3.18
(M, 1H), 3.33 (d, J = 14.4 Hz, 1
H), 3.59-3.63 (m, 1H), 4.11 (b
rs, 1H), 4.62-4.71 (m, 1H), 4.
80 (d, J = 9.0 Hz, 1H), 4.94 (d, J
= 9.0 Hz, 1H), 5.74 (d, J = 10.5H)
z, 1H), 6.98 (dd, J = 2.2, 8.8H)
z, 1H), 7.22 (d, J = 2.2 Hz, 1H),
7.42 (d, J = 8.8 Hz, 1H), 8.95 (b
rs, 1H); ¹³ C-NMR (100 MHz, CDCl
₃ ) δ 20.7, 28.1, 32.5, 48.6, 5
5.0, 69.6, 71.1, 80.5, 104.6,
109.8, 112.9, 119.0, 120.5, 1
26.2, 133.5, 136.6, 145.4, 15
6.3.

Example 7 Compound 11 obtained by converting TfO- of compound 10 to p-methoxyphenyl and removing the protecting group (Boc) is synthesized by the following method (so-called Suzuki coupling method). Synthesis of compound 11. Compound 10 (8.7 mg, 0.01
66 mmol) and 4-methoxyphenylboronic acid (5.1mg, 0.0332mmol dioxane) (0.3 mL) - saturated Na ₂ CO ₃ (0.1mL) was added _{Pd (PPh 3) 4 (2.0mg} , 0 .00166mmo
l) was added. The mixture was heated at 80 C for 15 minutes. After cooling, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over MgSO _4. Filtration and concentration on a rotary evaporator gave a crude product. The crude product was purified by thin layer chromatography for purification (using a mixture of 20% ethyl acetate in hexane) to give the desired product.
The desired product and NaI (12.5 mg, 0.06
Chlorotrimethylsilane (4.5 μL, 0.0332 mmol) was added to a 64 mmol CH ₃ CN (0.5 mL) solution.
l) was added at room temperature under a stream of argon. The reaction mixture was poured into saturated NaHCO ₃ and then extracted with ethyl acetate. Extracts washed with brine, dried over Na ₂ SO _4. A crude product was obtained by filtration and concentration on a rotary evaporator. The crude product was purified by thin layer chromatography for purification (using a mixture of 10% methanol in CH ₂ Cl ₂ ) to give compound 11.

Physical properties of compound 11: [α] D-154.3
-(C 0.55, MeOH); IR (film, cm ^-1 )
3111, 2916, 2838, 1509, 1465,
1245, 1179, 1037, 823, 734; ¹ H
-NMR (400MHz, CDCl ₃₎ δ2.39-
2.50 (m, 1H), 2.69-2.98 (m, 5
H), 3.05-3.14 (m, 1H), 3.16.
(D, J = 14.9 Hz, 1H), 3.46-3.53
(M, 1H), 3.86 (s, 3H), 4.07 (br
s, 1H), 4.62 (d, J = 9.0 Hz, 1H),
4.82 (d, J = 9.0 Hz, 1H), 6.98
(D, J = 8.8 Hz, 2H), 7.35 (dd, J =
1.5, 8.2 Hz, 1H), 7.47 (d, J = 8.
2Hz, 1H), 7.70 (brs, 1H), 8.96
(Brs, 1H); ¹³ C-NMR (100 MHz, CD
Cl ₃ ) 20.5, 33.1, 50.3, 53.7,
55.7, 68.5, 71.1, 109.9, 114.
2,116.1,118.5,119.7,124.
6, 130.4, 134.3, 135.9, 137.
2,149.6,153.7.

Example 8 Compound 12 was obtained by removing the protecting group (Boc) from the above-mentioned Compound 9 by converting hydrogen to an allyl group by the following method. Synthesis of compound 12. Compound 9 (12.5 mg, 0.03
19 mmol), tetrabutylammonium iodide (23.6 mg, 0.0638 mmol) and powdered K ₂ CO ₃ (22.1 g, 0.160 mmol) solution.
Allyl bromide (28 μL, 0.319 mmol) is added. The mixture is heated at reflux for 30 minutes. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated NH ₄ Cl, M
It is dried over gSO _4. A crude product was obtained by filtration and concentration on a rotary evaporator. The crude product was subjected to thin layer chromatography for purification (using a mixture of 20% ethyl acetate in hexane) to give the desired product. The desired product and NaI (23.9 mg, 0.
To a solution of 160 mmol of CH ₃ CN (0.5 mL) was added chlorotrimethylsilane (8.1 μL, 0.0638 mmol).
l) was added at room temperature under a stream of argon. The reaction mixture was poured into saturated NaHCO ₃ and then extracted with ethyl acetate. Extracts washed with brine, dried over Na ₂ SO _4. A crude product was obtained by filtration and concentration on a rotary evaporator. The crude product was purified by thin layer chromatography for purification (using a mixture of 10% methanol in CH ₂ Cl ₂ ) to give compound 12.

Physical properties of compound 12: [α] D-98.5- (c0.45, MeOH); IR (film, cm ^-1 )
3246, 2921, 1507, 1271, 1154
1031, 817, 773; ¹ H-NMR (400 MH
_{z, CDCl 3) δ2.39 (brs} , 2H), 2.7
0-2.90 (m, 2H), 3.03-3.13 (m,
1H), 3.18 (d, J = 14.9 Hz, 1H),
3.44-3.51 (m, 1H), 3.71-3.78
(M, 1H), 4.05 (brs, 1H), 4.58
(D, J = 5.4 Hz, 2H), 4.65 (d, J =
9.0 Hz, 1H), 4.84 (d, J = 9.0 Hz,
1H), 5.29 (dd, J = 1.4, 10.5 Hz,
1H), 5.48 (dd, J = 1.4 Hz, 18.0H
z, 1H), 6.08 (ddt, J = 5.4, 10.
5,18.0 Hz, 1H), 6.81 (dd, J = 2.
0, 8.6 Hz, 1H), 7.12 (d, J = 2.0H)
z, 1H), 7.32 (d, J = 8.6 Hz, 1H),
8.99 (brs, 1H); ¹³ C-NMR (100 MH
z, CDCl ₃ ) δ 20.6, 33.2, 50.2, 5
3.7, 68.5, 69.4, 71.1, 96.5, 1
10.2, 110.8, 117.7, 118.9, 12
0.2, 128.7, 133.4, 137.4, 15
5.7.

Example 9 Compound 13 in which TfO of Compound 10 is replaced by -CO ₂ Me group
Is synthesized by the following method. Compound 10 (7.4 m
g, 0.0141 mmol) and Et ₃ N (10 m
L, 0.0705 mmol) of methanol (0.4 m
L) -DMF (0.0141 mmol) solution in PdCl
₂ (dppf) (1.1 mg, 0.00141 mmol)
l) CO atmosphere (1 atm = 0.101325 MPa)
Added below. The reaction mixture was heated at 80 C for 15 minutes.
After cooling, the reaction mixture is diluted with ethyl acetate, washed with brine, dried over MgSO _4. Filtration and concentration on a rotary evaporator gave a crude product. The crude product was purified by thin layer chromatography for purification (using a mixture of 20% ethyl acetate in hexane) to give compound 13 (3.7).
mg, 60% yield).

Physical properties of compound 13: [α] D-78.4- (c 0.15, MeOH); IR (film, cm ^-1 )
3326, 2925, 1714, 1505, 1321,
1211, 1164, 1089, 767; ¹ H-NMR
(400 MHz, CDCl ₃ ) δ 1.16 (s, 9
H), 2.79-2.88 (m, 2H), 2.92-
3.03 (m, 1H), 3.11-3.20 (m, 1
H), 3.33 (d, J = 14.0 Hz, 1H);
91 (s, 3H), 4.16 (brs, 1H), 4.6
4-4.71 (m, 1H), 4.81 (d, J = 9.0
Hz, 1H), 4.95 (d, J = 9.0 Hz, 1
H), 5.72 (d, J = 10.5 Hz, 1H), 7.
44 (d, J = 8.3 Hz, 1H), 7.77 (d, J
= 8.3 Hz, 1H), 8.04 (s, 1H), 8.8
6 (brs, 1H); ¹³ C-NMR (100 MHz, C
DCl ₃₎ δ20.7,28.1,32.5,48.
6, 51.9, 54.9, 69.7, 71.1, 80.
3, 109.7, 113.6, 117.5, 120.
6, 129.8, 134.6, 138.6, 148.
7, 156.2, 168.2.

Reference list: Reference 1: Rinehart, KL, Jr .; Kobayashi, J .; Harbo
ur, GC; Hughes, RG, Jr .; Mizsak, SA; Scahi
ll, TAJAm. Chem. Soc., 1984, 106, 1524., Reference 2: M. Nakagawa et al., J. Chem. Soc., Perkin 1,348.
7 (2000), Reference 3: PHHHermkens et al., Tetrahedron, 49, 2325
(1993), Reference 4: PHHHermkens et al., J. Org. Chem., 55, 3998-
3946 (1990),

[0039]

As described above, the use of the intermediate of the present invention has an excellent effect of improving the yield and stereoselectivity of the step of forming a 7-membered oxthiazepine skeleton, and The novel udistmin analogs can be synthesized into compounds into which various substituents have been introduced, and thus have an excellent effect of being useful for examining the substituents and functions of eudystomin analogs.

Abbreviations List Boc: Tertiary butoxycarbonyl Me: Methyl Ns: Orthonitrobenzene honsulfonyl DEAD: Diethyl azodicarboxylate PPh ₃ : Triphenylphosphine TFA: Trifluoroacetic acid Me ₂ S: Dimethyl sulfide PhSH: Thio phenol DMF: dimethyl carbonate iPr ₂ Net: diisopropylethylamine AcSH: thio acetic acid AcOH: acetic acid Ms: methanesulfonyl ACE: alpha chloroethoxycarbonyl TMSCl: trimethylsilyl chloride Tf ₂ O: trifluoromethane nick anhydride PdCl ₂ (dppf ): Dichloropalladium diphenylphosphinoferrocene

[Brief description of the drawings]

Fig. 1 Method of assigning the order of eudistmin skeleton by Reinhart et al.

FIG. 2 shows four isomers of the general formula A based on the difference in the steric structure at positions 1 and 10.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07M 7:00 C07M 7:00 (72) Inventor Hidetoshi Tokuyama 8-5-11-202 Machiya, Arakawa-ku, Tokyo (72) Inventor Tohru Yamashita 4-1-1 Yushima, Bunka-ku, Tokyo 202 Kobayashi Corp. F-term (reference) 4C050 AA01 BB04 CC07 EE02 FF01 GG02 GG03 HH04 4C086 AA03 CB05 CB31 HA24 MA01 NA14 ZB33 4H006 AA02 AB84 AC81

Claims (4)

[Claims] In the structure represented by the general formula A, the 1-position
And the absolute configuration at the 10-position is (1S, 10R), (1
R, 10S), (1S, 10S) or (1R, 10S)
R) is a dystomin synthetic intermediate. Embedded image(Where R¹, R^Two, And R^ThreeIs H, lower alkyl
Group, lower alkoxy group, halogen, lower perfluoroa
Alkyl group, lower alkylthio group, hydroxy group, amino
Group, mono- or di-alkyl or acylamino group, low
Independent of a higher alkyl or arylsulfonyloxy group
Is a group selected for R^FourIs alkoxycarbonyl
Group, acyl group, lower alkyl or arylsulfonyl
Represents a group. R ⁶Is H, silyl group, acyl group, or other
May form an acetal structure with the lower alcohol.
Also, R^FiveIs H or R⁶And intramolecular acetal structure
May be implemented. Me is a methyl group, R⁷Is H, alkyl
Group, alkoxycarbonyl group, lower alkyl or ant
-Rusulfonyl group. 2. Pictet-Spengler from compounds of general formula B and aldehydes of formula C
A method for producing the compound of the general formula A by a reaction. Embedded image Embedded image (In the general formulas B and C, R ¹ , R ² , R ³ , R ⁴ , R
⁵ , R ⁶ and R ⁷ are the same as in the general formula A. ) 3. The method according to claim 1, wherein a halogen-substituted acetic acid is used as an acid and toluene or benzene is used as a reaction solvent.
2. The compound of the general formula A showing the absolute configuration of (1S, 10R) and (1R, 10S) described in (1) in a highly selective manner, and using formic acid as an acid and acetonitrile as a reaction solvent. A method for highly selectively producing a compound of the general formula A showing the absolute configuration of (1S, 10S) and (1R, 10R) described in (1). 4. At least 7 position represented by the general formula 1 is O
A udestomin analog which is R ³ . Embedded image (R ¹ and R ² are each the same in the general formula A in which R ¹ and R ^2, R ³ is H, lower alkylsulfonyloxy group, arylsulfonyloxy group or a trifluoromethanesulfonyl group, R ⁴ is an alkoxycarbonyl group, an acyl group , Lower alkyl or arylsulfonyl group, R ⁷ is H, alkyl group, alkoxycarbonyl group,
Shows a lower alkyl or arylsulfonyl group. )