JP2006193529A - Intermediate for intermediate producing vinblastines by coupling reaction with vindoline - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an intermediate useful for synthesis of indole derivatives which is the one component in synthesis of (+)-vinblastines. <P>SOLUTION: The compound represented by general formula C is useful for synthesis of the intermediate which enables synthesis of an eleven membered ring useful for synthesis of the indole derivatives by using radical cyclization of a thioanilide. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to an intermediate useful for forming a carbomethoxybervanamine site constituting one indole ring derivative, which is useful for the total synthesis of vinblastine.

  The natural product vinblastine (1), an alkaloid extracted from the oleander plant (Catharanthus roseus), has been found to have a strong anti-cancer effect and is currently used as a treatment for malignant lymphoma and choriocarcinoma (Non-Patent Document 1). In addition, many derivatives using vinblastine as a lead compound have been searched and synthesized for the purpose of creating a new pharmaceutical (Non-patent Document 2). However, most of these derivatives currently rely on semisynthesis from vinblastine derived from nature or its analogs. There is a limit to the chemical conversion of natural products, and a broad systematic structure-activity relationship cannot be investigated. In order to synthesize derivatives more efficiently and systematically, it is necessary to make the raw material vinblastine readily available without depending on nature, and for that purpose, to establish an efficient total synthesis of vinblastine. Is indispensable. Vinblastine (X) can be viewed as a bisindole compound in which two indole moieties, vindrin and carbomethoxybervanamine (Y), are bound.

Therefore, it is important to establish a complete synthesis method for each indole derivative. However, the vinblastine can be supplied enough to efficiently synthesize vinblastine even in the synthesis of the compound constituting the Bindrin site, which is the one compound. It was not like that. Under such circumstances, the present inventors have already proposed an efficient synthesis method of (−)-bindrin (Patent Document 1 (Japanese Patent Application No. 2000-335349, November 7, 2000)). ). Another problem is that the compound (Y) is used as a derivative of the other indole derivative (referred to as the upper unit), and the reaction with the opposite stereoselectivity proceeds even if vindrin is introduced into the compound (Y). (Non-patent Document 3).

Therefore, if an indole derivative that constitutes the upper unit capable of introducing vindoline is designed in a state where stereoselectivity is desired, and if a method for total synthesis of the derivative cannot be established, vinblastine derivatives are efficiently synthesized. The desired problem cannot be solved.

Regarding the design of the indole derivative constituting the upper unit, Schill et al. Have reported that vindrin can be introduced with a desired stereoselectivity when a compound (Z) having an 11-membered ring with an open piperidine ring is used (non-selective). Patent Document 4).

However, the process up to the synthesis of the 11-membered ring compound is complicated, and the synthesis of vinblastine using the compound (Z) is far from an efficient synthesis method in terms of yield. I don't get it.

Noble, R.A. L. Beer, C .; T.A. Cuts, J .; H. Ann. N. Y. Acad. Sci. 1958, 76, 882. Blasko, G.M. Cordell, G .; A. Kuehne, M .; E. Marko, I .; Borman, L .; S. Pearce, H .; L. McCorack, J .; J. et al. Neuss, N .; Neuss, M .; N. The Alkaloids; Brossi, A .; Suffness, M .; Ed. Academic Press: New York, 1990; Vol 37. Kutney, J.M. P. Beck, J .; Bylsma, F .; Cook, J .; Cretney, W .; J. et al. Fuji, K .; Imhof, R .; Treasurywala, A .; M.M. Helv. Chim. Acta 1975, 58, 1690. Schill, G.M. Priester, C .; U. Windhovel, U .; F. Fritz, H .; Helv. Chim. Acta 1986, 69, 438. Tokuyama, H .; Yamashita, T .; Reding, M .; T.A. Kaburagi, Y .; Fukuyama, T .; J. et al. Am. Chem. Soc. 1999, 121, 3791. Fujiwara, A.A. Kan, T .; Fukuyama, T .; Synlett 2000, 1667. Martinelli, M.M. J. et al. Nayar, N .; K. Moher, E .; D. Dhokte, U .; P. Pawlak, J .; M.M. Vaidyanathan, R .; Org. Lett. 1999, 1, 447. Yoshida, Y. et al. Shimonishi, K .; Sakakura, Y .; Okada, S .; Aso, N .; Tanabbe, Y .; Synthesis 1999, 1633. a) Kuehne, M .; E. Matton, P .; A. Bornmann, W .; G. J. et al. Org. Chem. 1991, 56, 513. b) Magnus, P .; Mendoza, j. S. Stamford, A .; Ladlow, M .; Willis, P .; J. et al. Am. Chem. Soc. 1992, 114, 10232. Men, J. et al. L. Taylor, W .; I. Expertia 1965, 21, 508. Japanese Patent Application No. 2000-335349 (November 7, 2000) (Japanese Patent No. 3446176)

The subject of the present invention relates to a compound of the general formula C, which is an important intermediate in the process of producing an intermediate for the efficient synthesis of vinblastine of the general formula A. This problem is to solve the problem of the compound of the general formula A, that is, based on the knowledge of the above-mentioned Schill et al. (1) Establish an efficient and highly stereoselective synthesis method of the upper unit. In this case, (2) to provide a method capable of synthesizing an upper unit derivative having high versatility capable of synthesizing various vinblastine analogs and (3) improved stereochemistry control in vindoline introduction. . In order to solve the above-mentioned problems, the present inventors conducted an indole synthesis method using a radical cyclization reaction of thioanilide developed by the present inventors (Non-patent Document 5) and intramolecular alkylation of 2-nitrobenzenesulfonamide. The combination of the medium and large ring synthesis methods used (Non-patent Document 6) was studied. During the study, it was found that when the above reactions were used in combination, the compound forming the upper unit could be synthesized under relatively mild conditions. Accordingly, when these reactions are used in combination, various functional groups can coexist in each reaction component, and therefore, the explanation of solving the basic problems (1) and (2) above will be explained. You will understand it.

  The present invention is an intermediate useful for the production of the general formula A consisting of the general formula C.

The compound of the general formula C of the present invention is obtained by synthesizing the thioanilide of the general formula C by reacting with the compound 1 using the compound of the compound B as a starting material, and synthesizing the compound of the general formula D, radical ring of thioanilides This is a method of synthesizing the compound of the general formula A by using a chemical reaction. Preferably, it is a compound useful for the method of synthesizing the compound of the general formula A, which comprises synthesizing the general formula A using a medium ring formation reaction of the general formula D. That is, the indole synthesis method using radical cyclization reaction of thioanilide and the medium macrocycle synthesis method using intramolecular alkylation of substituted or unsubstituted arylsulfonamides such as 2-nitrobenzenesulfonamide developed by the present inventors It is a compound useful for the method of synthesizing the compound of the general formula A, which comprises a combination of two reactions based on the above formula.

The indole derivative of the general formula A is obtained by treating the indole derivative of the general formula A with tert-butyl hypochlorite at the 3-position of the indole and treating the resulting chlorinated product with trifluoroacetic acid in the presence of vindolines. Stereoselective coupling of bindrins yields compounds of general formula E, followed by removal of the trifluoroacetyl group and substituted or unsubstituted arylsulfonyl groups, such as 2-nitrobenzenesulfonyl groups, and the construction of piperidine rings. Thus, the compound is useful for the method of synthesizing (+)-vinblastine represented by the general formula F.

As an effect of the invention, the indole synthesis method using radical cyclization reaction of thioanilide and the medium macrocycle synthesis method using intramolecular alkylation of substituted or unsubstituted arylsulfonamides, such as 2-nitrobenzenesulfonamide 2 It can be mentioned that a compound useful for the method of synthesizing the compound of the general formula A, characterized by comprising a combination of two reactions, was provided.

The present invention will be described in more detail.
A. The characteristics of the present invention will be explained by sequentially describing the starting materials containing the general formula C, intermediates and methods for producing vinblastine.
1. A thioanilide of general formula C is synthesized by reacting a compound in which two hydroxyl groups of general formula B are protected, a silyl ether, and the isothiocyanate of compound 1. The synthesis process is as follows. An ethyl group as a preferred group of R _5, a methyl group as a preferred group of R ₆ , a combination of a t-butyl group and two phenyl groups as a preferred group of R 10, an ethyl group as a preferred group of R ₁₁ , and R ₁₂ A methyl group can be mentioned as a preferable group of R 4, and a tetrahydropyranyl group can be mentioned as a preferable group of R ₁₃ .

2. Radical cyclization reaction of the thioanilide compound of general formula C in THF in the presence of (Bu) ₃ SnH and Et ₃ B at room temperature gives indole compound 2. The process is as follows. Here, toluene, benzene, acetonitrile or dioxane may be used instead of THF. Instead of using Et ₃ B in THF at room temperature, AIBN can also be used in toluene or benzene at 80 ° C. Also, instead of using (Bu) ₃ SnH and Et ₃ B in THF at room temperature, hypophosphorous acid, triethylamine and AIBN can be used in n-propanol at 90 ° C.

3, then compound 2 is reacted at room temperature in CH ₂ Cl ₂ in the presence of Boc ₂ O, Et ₃ N and 4-dimethylaminopyridine (DMAP), followed by treatment at 80 ° C. in aqueous acetic acid. , Introduction of a protecting group (Boc) and deprotection give compound 3. This process is as follows. Here, acetonitrile can be used instead of CH ₂ Cl ₂ . The concentration of the aqueous acetic acid solution can be selected arbitrarily, but 95% is particularly preferable. Further, instead of using an acetic acid aqueous solution at 80 ° C., a protonic acid such as camphorsulfonic acid or p-toluenesulfonic acid can be used in a lower alcohol solvent.

4. The primary hydroxyl group of the 1,2-diol of compound 3 so that the step of forming the 11-membered ring of the general formula A can utilize the formation reaction of the medium-large ring using the alkylation reaction of Ns amide Is selectively tosylated at room temperature in a CH ₂ Cl ₂ solution containing tosyl chloride (TsCl), Bu ₂ SnO, Et ₃ N (Non-Patent Document 7), and then MHCO ₃ (M is Na or K). Epoxide compound 4 is obtained by heating to 80 ° C. in DMF in the presence of. This process is as follows. Here, instead of TsCl, a substituted or unsubstituted aryl sulfonic acid chloride can also be used.

5. Next, the compound 4 is converted to R ₇ SO ₂ NH ₂ , such as NsNH ₂ , an azodicarboxylic acid derivative such as diethyl azodicarboxylic acid (DEAD), and the remaining primary hydroxyl group in toluene in the presence of Ph ₃ P at room temperature. On the other hand, sulfonamide is introduced by Mitsunobu reaction to obtain a compound of general formula D which is a cyclization precursor. This process is as follows. The compound intermediate into which the sulfonamide is introduced is a key compound for forming an 11-membered ring.

6. The compound of the general formula D is heated to 90 ° C. in DMF or acetonitrile in which M ₂ CO ₃ (M is Na, K or Cs) is present, and the medium ring formation reaction proceeds regioselectively, Ring compound 5 was obtained. This process is as follows.

7. Treatment of compound 5 in CH ₂ Cl ₂ in the presence of trifluoroacetic acid (TFA) at room temperature, in CH ₃ CN-toluene mixture with TsCl and Me ₂ N (CH ₂ ) ₃ NMe ₂ The compound A is treated by deprotection and introduction of a protecting group by a step of treating at room temperature (Non-Patent Document 8) and a step of treating at room temperature in a CH ₂ Cl ₂ solution of trifluoroacetic anhydride (TFAA) and pyridine. obtain. This process is as follows. Here, instead of TsCl, a substituted or unsubstituted aryl sulfonic acid chloride can also be used. Further, in place of Me ₂ N (CH ₂ ) ₃ NMe ₂ , a tertiary amine such as pyridine, triethylamine or diisopropylethylamine can be used. Further, the ratio of the CH ₃ CN-toluene mixed solution can be arbitrarily selected, and CH ₂ Cl ₂ can be used instead.

B. A synthesis example of the compound of general formula B, which is a raw material compound of the present invention, will be described. A series of reaction steps are summarized as follows.

I. First, synthesis of a compound contained in the general formula B which is a synthetic raw material.
Reference example 1
The process for producing the carboxylic acid 2 from the known starting material 1 is as follows.

Propionic acid (0.86 mL, 11.58 mmol) was added to a solution of alcohol 1 (199.5 g, 2.316 mol) in triethyl orthoacetate (849 mL), and the mixture was stirred at 135 ° C. The ethanol produced was collected in a dropping funnel attached to the flask. When production of ethanol was not observed, the reaction solution was cooled to 80 ° C. or lower, and the contents of the separatory funnel were returned to the reaction solution. The above operation was continued until the starting alcohol disappeared. After confirming the disappearance of the starting alcohol, water (100 mL) was added to the reaction solution at room temperature. After stirring at room temperature for 2.5 hours, an aqueous solution of potassium hydroxide (390 g, 6.95 mol) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and further at room temperature overnight. The reaction solution was neutralized with concentrated hydrochloric acid, and the organic layer was separated and extracted with dichloromethane. The organic layers were matched and dried over anhydrous magnesium sulfate. After concentrating the reaction solution at normal pressure, the residue was distilled under reduced pressure to obtain carboxylic acid 2 (boiling point 93-96 ° C., 247.5 g, 83.38%) as a colorless liquid.

Properties of carboxylic acid 2;
IR (film): 3083, 2968, 1712, 1649, 1438, 1415, 1296, 892 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 11.63 (brs, 1H), 4.78 (d, J = 0. 4 Hz, 1H), 4.73 (d, J = 0.4 Hz, 1H), 2.52 (t, J = 7.7 Hz, 2H), 2.36 (t, J = 7.7 Hz, 2H), 2.05 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 180.2, 149.4, 108.3 32.6, 30.7, 29.0, 12.3; analysis; calculated value (Anal. Calcdfor) C ₇ H ₁₂ O: C, 65.60, H, 9.44; analysis result (Found) C, 65.50, H, 9.37.

The process for producing the imide 3 from the carboxylic acid 2 is as follows.

Pivalic acid chloride (26.93 mL, 220.0 mmol) was added dropwise to a diethyl ether solution (1 L) of carboxylic acid 2 (28.20 g, 220.0 mmol) and triethylamine (30.66 ml, 220.0 mmol) under ice cooling. . After stirring at the same temperature for 40 minutes, the mixture was cooled to −78 ° C. (mixed acid anhydride diethyl ether solution). On the other hand, n-butyllithium (2.46M n-hexane solution, 81.3 mL, 200 mmol) was added dropwise to a tetrahydrofuran solution (500 mL) of oxazolidinone (35.44 g, 200 mmol) at -78 ° C. This solution was added dropwise to the mixed acid anhydride diethyl ether solution using a cannula. After completion of dropping, the mixture was stirred at -78 ° C for 50 minutes, and further stirred at 0 ° C for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and extracted with ethyl acetate. The organic layers were matched, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (2-12% ethyl acetate / n-hexane) to give imide 3 (51.0 g, 88.7%) as a colorless oil. .

Properties of imide 3:
[Α] ²⁶ _D- 52.0 (c1.15, CHCl ₃ ); IR (film) 3029, 2966, 2921, 1783, 1701, 1648, 1454, 1388, 1353, 1212, 1110, 892, 762, 743 703 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.33 (t, J = 7.0 Hz, 2H), 7.27 (t, J = 7.0 Hz, 1H), 7.20 (d, J = 7.0 Hz, 2H), 4.79 (d, J = 1.1 Hz, 1H), 4.77 (d, J = 1.1 Hz, 1H), 4.67 (ddt, J = 9.8, 8) .3, 3.2 Hz, 1H), 4.19 (dd, J = 9.0, 8.3 Hz, 1H), 4.15 (dd, J = 9.0, 3.2 Hz, 1H), 3. 29 (dd, J = 13.5, 3.2 Hz, 1H), 3.14 (d dd, J = 17.0, 8.8, 6.8 Hz, 1H), 3.06 (dddd, J = 7.0, 8.4, 7.2 Hz, 1H), 2.76 (dd, J = 13.5, 9.8 Hz, 1H), 2.42 (m, 2H), 2.09 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 172.9, 153.4, 149.6, 135.3, 129.4, 128.9, 127.3, 108.4, 66.2, 55.2, 37. 9, 34.0, 30.4, 29.0, 12.3.

The process for producing the adduct 4 from the imide 3 is as follows.

Titanium tetrachloride (16.0 mL, 145.5 mmol) was added dropwise to a dichloromethane solution (265 mL) of titanium tetraisopropoxide (14.4 mL, 48.5 mmol). This solution was added dropwise to a dichloromethane solution (176 mL) of imide 3 (50.7 g, 176 mmol) and diisopropylethylamine (45.8 mL, 265 mmol) under ice cooling. After stirring at the same temperature for 40 minutes, acrylonitrile (34.8 mL, 529 mmol) was added dropwise to the reaction solution, and the mixture was further stirred at the same temperature for 9 and a half hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the organic layer was separated and extracted with ethyl acetate. The organic layers were matched, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (5-12% ethyl acetate / n-hexane) to give adduct 4 (42.3 g, 70.4%) as a colorless oil. It was.

Physical properties of adduct 4;
[Α] ²⁶ _D- 36.4 (c 0.978, CHCl ₃ ); IR (film) 3029, 2967, 2935, 2247, 1779, 1695, 1646, 1453, 1389, 1351, 1291, 1211, 1113, 1014 902, 762, 742, 703 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.35 (t, J = 7.0 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7. 22 (d, J = 7.0 Hz, 2H), 4.83 (d, J = 1.4 Hz, 1H), 4.75 (d, J = 1.4 Hz, 1H), 4.65 (m, ¹ H), 4.19 (m, 2H), 4.09 (ddt, J = 12.0, 7.3, 4.4 Hz, ¹ H), 3.34 (dd, J = 13.4, 3. 4 Hz, 1 H), 2.78 (dd, J = 13. , 10.0 Hz, 1 H), 2.49 (dd, J = 14.0, 7.0 Hz, 1 H), 2.38 (m, 2 H), 2.15 (dd, J = 14.0, 7. 6 Hz, 1H), 2.08 (m, 1H), 2.04 (q, J = 7.3 Hz, 2H), 1.90 (m, 1H), 1.03 (t, J = 7.3 Hz, ¹³ C NMR (CDCl ₃ , 100 MHz) 174.7, 153.1, 147.6, 135.2, 129.4, 129.0, 127.4, 119.1, 110.9, 66.4 , 55.6, 40.5, 39.0, 38.1, 28.3, 27.1, 15.1, 12.2;

The method for producing the alcohol 5 from the adduct 4 is as follows.

Sodium borohydride (22.6 g, 597.4 mmol) was dissolved in water (150 mL) and added dropwise to a tetrahydrofuran solution (300 mL) of adduct 4 (50.84 g, 149.3 mmol) under ice cooling. The mixture was warmed to room temperature and stirred as it was overnight. Hydrochloric acid was added to the reaction solution under ice cooling to adjust the pH to about 5, and then extracted three times with ethyl acetate. The matched organic layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and then dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (25-35% ethyl acetate / n-hexane) to give alcohol 5 (22.9 g, 91.7%) as a colorless oil. .

[Α] ²⁷ _D -1.56 (c 0.960, CHCl ₃ ); IR (film) 3449, 3078, 2965, 2931, 2249, 1644, 1450, 1328, 1037, 984, 895 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 4.84 (d, J = 1.5 Hz, 1H), 4.77 (d, J = 1.5 Hz, 1H), 3.64 (dd, J = 10.9, 4.4 Hz, 1H), 3.55 (dd, J = 10.9, 5.4 Hz, 1H), 2.46 (t, J = 7.3 Hz, 2H), 2.13 (dd, J = 14.0, 7 .7 Hz, 1H), 2.03 (q, J = 7.4 Hz, 2H), 2.02 (dd, J = 14.0, 7.8 Hz, 1H), 1.87 (m, 1H), 1 .74 (m, 2H), 1.05 (t, J = 7.4Hz, 3H); 13 _{NMR (CDCl 3, 100MHz) 148.6,120.0,110.3,64.4,38.2,37.0,28.1,27.0,15.0,12.1} ;

A method for producing silyl ether 6 from alcohol 5 is as follows.

To a solution of alcohol 5 (22.8 g, 136.3 mmol) and imidazole (13.92 g, 204.5 mmol) in dimethylformamide (136 mL) was added dropwise t-butyldiphenylsilane chloride (39.0 mL) at room temperature. Stir for 1 hour. The reaction mixture was diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether, and the matched organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (0-2% ethyl acetate / n-hexane) to give silyl ether 6 (50.6 g, 91.5%) as a colorless oil. It was.

Physical properties of silyl ether 6;
[Α] ²³ _D +6.49 (c1.99, CHCl ₃ ); IR (film) 3071, 2961, 2931, 2858, 2246, 1644, 1589, 1471, 1428, 1112, 1083, 894, 823, 741, 703 , 614, 505 cm ⁻¹ ; ¹ HNMR (CDCl 3, 400 MHz) 7.64 (d, J = 7.3 Hz, 4H), 7.44 (t, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 4H), 4.76 (d, J = 1.4 Hz, 1H), 4.67 (d, J = 1.4 Hz, 1H), 3.56 (dd, J = 9.4). , 3.4 Hz, 1H), 3.53 (dd, J = 9.4, 4.2 Hz, 1H), 2.30 (ddd, J = 16.8, 8.3, 6.3 Hz, 1H), 2.23 (dd, J = 16.8, 7.3 Hz, 1 ), 2.15 (dd, J = 13.9, 6.6 Hz, 1H), 1.94 (dd, J = 13.9, 7.6 Hz, 1H), 1.93 (q, J = 7. 3 CHz (2H), 1.79 m, 1 H), 1.74 (m, 2 H), 1.06 (s, 9 H), 0.99 (t, J = 7.3 Hz, 3 H); ¹³ C NMR (CDCl 3 100MHz) 148.5, 135.6, 135.6, 133.4, 133.4, 129.8, 129.8, 127.8, 127.7, 120.0, 110.3, 65.3 38.2, 37.4, 28.2, 27.2, 26.9, 19.3, 15.0, 12.0;

A method for producing isoxazoline 7 from silyl ether 6 is as follows.

Diisobutylaluminum hydride (DIBAL) (1.0 M toluene solution, 88.9 mL, 88.9 mmol) was added dropwise to a dichloromethane solution (90 mL) of silyl ether 6 (32.8 g, 80.9 mmol) at −78 ° C. For 20 minutes. A dichloromethane solution of acetic acid (20 mL) was added to the reaction solution, and then the temperature was raised to room temperature. After liquid separation with ethyl acetate-dilute hydrochloric acid, the aqueous layer was extracted with ethyl acetate. The matched organic layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. Concentrated under reduced pressure. The residue was dissolved in ethanol (120 mL), sodium acetate (13.27 g, 161.7 mmol) and hydroxylamine hydrochloride (8.43 g, 121.3 mmol) were added, and the mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The matched organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (404 mL), aqueous sodium hypochlorite solution (about 5%, 190 mL) was added dropwise at room temperature, and the mixture was stirred for 3 and a half hours. Under ice-cooling, sodium sulfite was added to the reaction solution and stirred for a while at room temperature, and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the matched organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (5-8% ethyl acetate / n-hexane) to give isoxazoline 7 (20.0 g, 58.7%) as a yellow oil. .

Physical properties of isoxazoline 7;
[Α] ²⁵ _D +8.5 (c2.06, CHCl ₃ ); IR (film) 3070, 2931, 2858, 1471, 1428, 1388, 1112, 1063, 846, 823, 741, 704, 614 cm ⁻¹ ; 1HNMR (CDCl ₃ , 400 MHz) 7.63 (d, J = 7.4 Hz, 4H), 7.44 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 4H) , 4.27 (d, J = 8.0 Hz, 1H), 3.77 (d, J = 8.0 Hz, 1H), 3.52 (dd, J = 9.3, 5.4 Hz, 1H), 3.48 (dd, J = 9.3, 5.5 Hz, 1H), 2.67 (ddd, J = 13.9, 4.9, 2.2 Hz, 1H), 2.15 (td, J = 13.9, 5.4 Hz, 1H), 2.08 (dt, J = 13.0, 2. Hz, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.67 (dq, J = 14.1, 7.5 Hz, 1H), 1.49 (dq, J = 14.1, 7.5 Hz, 1H), 1.20 (t, J = 13.0 Hz, 1H), 1.18 (qd, J = 13.9, 4.9 Hz, 1H), 1.05 (s) , 9H), 0.89 (t, J = 7.5 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 162.5, 135.5, 135.5, 133.6, 133.5, 129.7 , 129.7, 127.6, 127.6, 79.0, 68.0, 55.1, 39.1, 35.7, 29.5, 26.8, 26.4, 22.0, 19 .2, 8.3;

A method for producing hydroxyketone 8 from isoxazoline 7 is as follows.

A suspension of isoxazoline 7 (17.4 g, 41.3 mmol) and zinc powder (27.0 g, 413 mmol) in acetic acid (165 mL) was stirred at room temperature for 4 hours. After the reaction solution was diluted with dichloromethane, zinc powder was removed using a celite column. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and then neutralized by adding solid sodium hydrogen carbonate. After separating the organic layer, the aqueous layer was extracted with dichloromethane. The matched organic layer was washed with water and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (10-15% ethyl acetate / n-hexane) to give hydroxyketone 8 (11.6 g, 66.4%) as a pale yellow oil. Obtained.

Physical properties of hydroxyketone 8;
[Α] ²⁶ _D +54.4 (c1.40, CHCl ₃ ); IR (film) 3489, 3070, 2931, 2858, 1699, 1471, 1427, 1389, 1191, 1112, 1056, 997, 823, 741, 703 , 614, 506 cm ⁻¹ ; ¹ HNMR (CDCl 3, 400 MHz) 7.65 (d, J = 7.4 Hz, 4H), 7.44 (t, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 4H), 3.67 (dd, J = 11.5, 7.3 Hz, 1H), 3.55 (dd, J = 8.8, 4.9 Hz, 1H), 3.51 (Dd, J = 8.8, 5.2 Hz, 1H), 3.33 (dd, J = 11.5, 6.8 Hz, 1H), 2.51 (td, J = 14.6, 6.6 Hz) , 0H), 2.48 (dd, J = 7.3, 6. Hz, 1H), 2.28 (ddd, J = 14.6, 4.6, 2.4 Hz, 1H), 2.12 (m, 2H), 1.83 (dq, J = 15.4, 7 .6 Hz, 1H), 1.75 dq, J = 15.0, 3.9 Hz, 1H), 1.52 (dq, J = 15.4, 7.6 Hz, 1H), 1.38 t, J = 15. 0 Hz, 1H), 1.32 (qd, J = 14.6, 3.7 Hz, 1H), 1.06 (s, 9H), 0.84 (t, J = 7.6 Hz, 3H); ¹³ CNMR (CDCl ₃ , 100 MHz) 218.5, 135.6, 135.6, 133.7, 133.6, 129.7, 129.7, 127.7, 127.6768, 65.9, 52. 6, 38.3, 34.8, 34.4, 29.5, 26.9, 25.4, 19.3, 7.7;

The method for producing diol 9 from hydroxyketone 8 is as follows.

A solution of hydroxyketone 8 (10.66 g, 25.10 mmol) and m-chloroperbenzoic acid (mCPBA) (17.32 g, 75.29 mmol) in acetic acid (62.8 mL) was stirred at room temperature for 41 hours. Dimethyl sulfide (5.53 mL, 75.3 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred for 20 minutes, and then the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and then with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was dissolved in methanol (77 mL), potassium carbonate (3.82 g, 27.6 mmol) was added, and the mixture was stirred at room temperature for 45 min. The reaction solution was diluted with diethyl ether, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The matched organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (20-40% ethyl acetate / n-hexane) to give diol 9 (9.49 g, 80.0%) as a yellow oil. .

Physical properties of diol 9;
[Α] ²⁷ _D +10.0 (c1.50, CHCl ₃ ); IR (film) 3441, 3071, 2932, 2859, 1738, 1462, 1428, 1362, 1172, 1112, 1071, 823, 741, 704, 614 , 504 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.67 (m, 4H), 7.43 (t, J = 6.7 Hz, 2H), 7.40 (t, J = 6.7 Hz, 4H) ), 3.64 (s, 3H), 3.57 (dd, J = 10.0, 4.6 Hz, 1H), 3.51 (s, 1H), 3.46 (brs, 2H), 3. 42 (dd, J = 10.0, 7.7 Hz, 0H), 2.23 (t, J = 7.4 Hz, 2H), 2.09 (m, 1H), 1.82 (m, 1H), 1.63-1.48 (m, 9H), 1.06 (s, 9 H), 0.88 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 174.4, 135.7, 135.6, 132.9, 132.9, 129.9, 129.9, 127.8, 127.8, 74.0, 68.4, 67.5, 51.6, 38.5, 35.2, 31.4, 30.2, 28.1, 26. 8, 19.1, 8.1;

A method for producing the target silyl ether 10 from the diol 9 is as follows.

Diethyl 9 (5.532 g, 11.70 mmol), imidazole (2.39 g, 35.11 mmol) in dimethylformamide solution (23.4 mL), and triethylsilane chloride (TESCl) (2.35 ml, 14.0 mmol) at room temperature. Was added and stirred for 1 hour. After confirming disappearance of the raw materials, trimethylsilane chloride (1.78 ml, 14.0 mmol) was added to the reaction solution, and the mixture was further stirred for 40 minutes. The reaction mixture was partitioned between diethyl ether and water, and the aqueous layer was extracted with diethyl ether. The matched organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (0-2% ethyl acetate / n-hexane) to give silyl ether 10 (7.13 g, 92.4%) as a colorless oil. It was.

Physical properties of silyl ether 10;
[Α] ²⁸ _D -3.48 (c1.04, CHCl ₃ ); IR (film) 2955, 2878, 1742, 1461, 1430, 1249, 1168, 1109, 1011, 839, 741, 704, 612 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.66 (d, J = 6.7 Hz, 4H), 7.41 (t, J = 6.7 Hz, 2H), 7.36 (t, J = 6.7 Hz, 4H), 3.65 (s, 3H), 3.63 (dd, J = 10.0, 4.4 Hz, 1H), 3.47 (dd, J = 10.0, 6.1 Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H), 3.37 (d, J = 9.8 Hz, 1H), 2.27 (dd, J = 9.0, 7.3 Hz, 1H), 1 .81 (m, 3H), 1.55 (m, 2H), 1.41 (dq, J = 1) 3.9, 7.4 Hz, 1 H), 1.25 (dd, J = 14.4, 4.9 Hz, 1 H), 1.05 (s, 9 H), 0.95 (t, J = 7.9 Hz) , 9H), 0.77 (t, J = 7.4 Hz, 3H), 0.59 (q, J = 7.9 Hz, 6H), 0.01 (s, 9H); ¹³ CNMR (CDCl ₃ , 100 MHz) ) 174.6, 135.7, 133.9, 129.5, 127.6, 79.2, 68.0, 67.0, 51.4, 36.9, 35.5, 31.7, 31 6, 29.9, 27.8, 26.9, 8.3, 6.9, 4.4, 2.6;

II. Synthesis of compounds contained in general formulas C, D and A using as a raw material the compounds synthesized in I, contained in the compounds of general formula B.
Example 1
a. Synthesis of thioanilide 12 contained in general formula C from isothiocyanate 11 corresponding to a compound in which all of R _{1 to} R ₄ are H in silyl ether 10 and compound 1. The synthesis process is as follows.

To a tetrahydrofuran solution (THF) (40.5 ml) of diisopropylamine (3.17 mL, 22.5 mmol), n-butyllithium (1.46 M hexane solution, 13.5 mL, 19.7 mmol) was added dropwise under ice cooling. After stirring for 10 minutes, the mixture was cooled to -78 ° C. A tetrahydrofuran solution (40.5 mL) of silyl ether 10 (9.269 g, 14.06 mmol) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 1 hour. A tetrahydrofuran solution (15 mL) of isothiocyanate 11 (3.872 g, 14.06 mmol) was added dropwise to the reaction solution. The temperature was raised to 0 ° C. for 50 minutes at the same temperature, the mixture was stirred for 15 minutes, diluted with diethyl ether, and saturated aqueous ammonium chloride solution was added. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The matched organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (5-10% ethyl acetate / n-hexane) to give thioanilide 12 (9.95 g, 75.7%) as a yellow oil. .

Physical properties of thioanilide 12;
¹ HNMR (CDCl ₃ , 400 MHz) 9.78 (s, (1/4) 1H), 9.74 (s, (1/4) 1H), 9.63 (s, (1/4) 1H), 9.60 (s, (1/4) 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.67 (m, 5H), 7.38 (m, 8H), 6.50 (D, J = 11.5 Hz, 1H) 6.00 (ddd, J = 11.5, 6.4, 3.9 Hz, 1H), 4.60 (t, J = 3.4 Hz, 1H), 3 .43 (ddd, J = 12.7, 5.8, 1.9 Hz, 1H), 4.16 (m, (1/2) 1H), 4.09 (ddd, J = 12.7, 7. 1, 1.6 Hz, 1 H), 4.03 (m, (1/2) 1 H), 3.81 (m, 2 H), 3.74 (s, 3 H), 3.57 (m, 1 H), 3.49-3.40 (m, 3H) 2.24 (m, 2H), 1.93 (m, (1/2) 1H), 1.82 (m, 1H + (1/2) 1H), 1.68 (m, 2H), 1.53 (M, 4H), 1.44-1.20 (m, 3H), 1.07 (s, (1/2) 9H), 1.05 (s, (1/2) 9H), 0.94 (T, J = 7.9 Hz, 9H), 0.79 (t, J = 7.3 Hz, (1/2) 3H), 0.77 (t, J = 7.3 Hz, (1/2) 3H ), 0.59 (q, J = 7.9 Hz, (1/2) 6H), 0.58 (q, J = 7.9 Hz, (1/2) 6H), 0.01 (s, (1 / 2) 9H), 0.00 (s, (1/2) 9H);

The step of obtaining indole compound 13 contained in compound 2 by radical cyclization reaction of thioanilide 12 is as follows.

To a tetrahydrofuran solution (369 ml) of thioanilide 12 (8.628 g, 9.233 mmol) and tributyltin hydride (4.97 ml, 18.47 mmol) at room temperature, triethylborane (1.0 M hexane solution, 1.85 ml, 1. 85 mmol) was added dropwise and stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The matched organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (2-8% ethyl acetate / n-hexane) to give indole 13 (5.51 g, 66.1%) as a yellow oil. .

Physical properties of indole 13;
¹ H NMR (CDCl ₃ , 400 MHz) 8.68 (s, (1/4) 1 H), 8.65 (s, (1/4) 1 H), 8.39 (s, (1/2) 1 H), 7.61 (m, 6H), 7.37 (m, 6H), 7.12 (m1H), 7.06 (m, 1H), 4.54 (m, (1/2) 1H), 4. 51 (m, (1/2) 1H), 4.12 (m, 1H), 3.96 (m, 1H), 3.83 (m, 1H), 3.66 (s, (1/2) 3H), 3.63 (s, (1/2) 3H), 3.50 (m, 3H), 3.39 (m, 3H), 3.31 (m, 1H), 2.96 (m, 2H), 2.85 (m, 1H), 2.33 (m, 1H), 2.23 (m, 1H), 2.13 (m, 1H), 1.79 (m, 2H), 1. 60-1.37 (m, 4H), 1.27 (m, 2H) 1.06 (s, (1/2) 9H), 1.05 (s, (1/2) 9H), 0.99-0.81 (m, 9H), 0.74 (t, J = 7 .2 HzH (1/2) 3H), 0.67 (t, J = 7.2 Hz, (1/4) 3H), 0.66 (t, J = 7.2 Hz, (1/4) 3H), 0.56 (m, 6H), 0.11 (s, (1/4) 9H), 0.10 (s, (1/4) 9H), 0.00 (s, (1/4) 9H) , -0.01 (s, (1/4) 9H);

Compound 14 containing a protecting group from indole 13 is obtained by the following steps.

Indole 13 (6.055 g, 6.709 mmol), triethylamine (1.40 mL, 10.1 mmol) in dichloromethane (16.8 mL) and Boc2O (2.93 g, 13.4 mmol), 4-dimethylaminopyridine (82 mg, 0.67 mmol) was added and stirred at room temperature overnight. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The matched organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (3-8% ethyl acetate / n-hexane) to give silyl ether compound 14 (5.83 g, 86.7%) as a yellow oil. Obtained.

Physical properties of silyl ether compound 14:
¹ HNMR (CDCl ₃ , 400 MHz) 7.95 (m, 1H), 7.67 (m, 3H), 7.53 (t, J = 8.3 Hz, 2H), 7.37 (m, 6H), 7.21 (m, 2H), 4.57 (m, 1H), 4.51 (m, 1H), 4.23 (m, (1/2) 1H), 4.12 (m, (1 / 2) 1H), 3.92 (m, (1/2) 1H), 3.85 (m, (1/2) 1H), 3.82 (m, 1H), 3.70 (m, 1H) , 3.60 (s, (1/2) 3H), 3.59 (s, (1/4) 3H), 3.58 (s, (1/4) 3H), 3.57 (m, 2H) ), 3.43 (m, 3H), 3.19 (m, 2H), 2.92 (m, 2H), 2.82 (m, 2H), 2.53 (m, (1/2) 1H ), 2.12 (m, (1/2) 1H), 1.86 (m, H), 1.64 (s, (1/4) 9H), 1.60 (s, (1/4) 9H), 1.57 (s, (1/2) 9H), 1.72-1 .40 (m, 4H), 1.28 (m, 2H), 1.27 (brs, (1/2) 9H), 1.06 (s, (1/2) 9H), 0.93 (t , J = 8.0 Hz, (1/4) 9H), 0.89 (t, J = 8.0 Hz, (1/4) 9H), 0.85 (t, J = 8.0 Hz, (1 / 4) 9H), 0.84 (t, J = 8.0 Hz, (1/4) 9H), 0.74 (t, J = 7.2 Hz, (1/2) 3H), 0.65 (t , J = 7.2 Hz, (1/2) 3H), 0.56 (q, J = 8.0 Hz, (1/2) 6H), 0.45 (q, J = 8.0 Hz, (1 / 4) 6H), 0.44 (q, J = 8.0 Hz, (1/4) 6H), -0.0 (S, (1/2) 9H), - 0.10 (s, (1/4) 9H), - 0.11 (s, (1/4) 9H);

The process for producing the triol compound 15 contained in the compound 3 from the silyl ether compound 14 is as follows.

A solution of silyl ether compound 14 (184 mg, 0.184 mmol) in acetic acid-water (95: 5) (7.4 mL) was stirred at 80 degrees for 30 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (20-80% ethyl acetate / n-hexane) to give triol 15 (101 mg, 75%) as a pale yellow oil. The isomers were separated by thin layer silica gel chromatography and instrument data were measured.

Physical properties of Triol 15;
I, low polar isomer [α] ²⁶ _D +78 (c 0.57, CHCl ₃ ); IR (film) 3423, 2934, 2860, 1731, 1457, 1431, 1366, 1325, 1231, 1163, 1131, 1113, 1047 , 910, 823, 738, 705, 614 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.96 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.8 Hz, 2H) 7.62 (d, J = 7.8 Hz, 2H), 7.44 (m, 3H), 7.37 (m, 3H), 7.30 (td, J = 7.8, 1.2 Hz, 1H), 7.23 (dd, J = 7.8, 1.2 Hz, 1H), 4.05 (t, J = 6.3 Hz, 1H), 3.74 (m, 1H), 3.68 ( m, 1H), 3.61 (s, 3H), 3.60 (Dd, J = 9.9, 4.9 Hz, 1H), 3.36 (dd, J = 9.9, 7.9 Hz, 1H), 3.28 (s, 2H), 2.82 (dt, J = 14.4, 4.3 Hz, 1H), 2.67 (ddd, J = 14.4, 9.0, 5.6 Hz, 1H), 2.42 (dt, J = 13.7, 6. 3 Hz, 1 H), 1.87 (m, 1 H), 1.79 (ddd, J = 13.7, 7.3, 5.6 Hz, 1 H), 1.63 (s, 9 H), 1.62 ( dd, J = 15.0, 5.9 Hz, 1H), 1.50 (dd, J = 15.0, 4.3 Hz, 1H), 1.34 (q, J = 7.6 Hz, 2H), 1 .03 (s, 9H), 0.75 (t, J = 7.6 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 173.2, 150.4, 135.8, 135.7, ¹³ 5.6, 135.5, 132.9, 132.8, 129.9, 129.8, 129.1, 127.8, 127.8, 124.6, 122.7, 118.6, 117. 8, 115.9, 84.4, 73.8, 68.6, 67.2, 61.7, 52.2, 41.3, 38.6, 34.1, 34.0, 30.0, 28.2, 27.7, 26.8, 19.1, 7.8;

II, highly polar isomer [α] ^26.5 _D- 59 (c0.47, CHCl ₃ ); IR (film) 3430, 2934, 2863, 1728, 1458, 1430, 1366, 1326, 1230, 1163, 1131 1116, 1048, 910, 738, 705, 614 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.93 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 2H) ), 7.58 (d, J = 8.1 Hz, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 8.1 Hz, 2H), 7.32 (T, J = 8.1 Hz, 4H), 7.26 (dd, J = 8.0, 1.0 Hz, 1H), 7.23 (td, J = 8.0, 1.0 Hz, 1H), 3.96 (brs, 1H), 3.66 (m, 2H) 3.63 (s, 3H), 3.55 (dd, J = 10.2, 4.2 Hz, 1H), 3.51 (d, J = 11.0 Hz, 1H), 3.47 (d, J = 11.0 Hz, 1 H), 3.37 (dd, J = 10.2, 8.4 Hz, 1 H), 2.74 (dt, J = 14.4, 4.7 Hz, 1 H), 2.58 ( ddd, J = 14.4, 8.3, 6.4 Hz, 1H), 2.47 (ddd, J = 14.7, 6.8, 5.1 Hz, 1H), 1.98 (m, 1H) 1.68 (dd, J = 14.9, 5.9 Hz, 1H), 1.61 (dd, J = 14.9, 7.1 Hz, 1H), 1.60 (m, 2H), 1. 60 (s, 9H), 1.45 (ddd, J = 14.7, 7.6, 4.9 Hz, 1H), 0.98 (s, 9H), 0.91 (t, J = 7.4 Hz) , 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 173.5, 150.3, 135.8, 135.6, 135.6, 135.6, 132.9, 132.8, 129.8, 129.8, 129.2 , 127.8, 127.7, 124.5, 122.7, 118.6, 116.9, 115.9, 84.4, 74.2, 68.9, 67.6, 61.8, 52 3, 42.0, 39.2, 35.6, 34.9, 30.2, 28.1, 27.7, 26.7, 19.0, 8.2;

The process for producing the tosylate compound 16 from the triol compound 15 is as follows.

P-Toluenesulfonic acid chloride (40 mg, 0.212 mmol) was added to a suspension of triol 15 (148 mg, 0.202 mmol), triethylamine (84 μL, 0.606 mmol), dibutyltin oxide (15 mg, 0.061 mmol) in dichloromethane (2 mL). ) And stirred at room temperature for 20 hours. The solid was removed using a celite column and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25-40% ethyl acetate / n-hexane) to give tosylate 16 (149 mg, 83.2%) as a pale yellow oil. The isomers were separated by thin layer silica gel chromatography and instrument data was measured.

Physical properties of tosylate 16;
I, low polar isomer [α] ²⁴ _D +73 (c0.41, CHCl ₃ ); IR (film) 3543, 3397, 2934, 1731, 1597, 1457, 1431, 1364, 1325, 1253, 1232, 1175, 1130 , 1113, 1044, 973, 911, 842, 821, 740, 705, 667, 615, 555 cm −1; 1H NMR (CDCl 3, 400 MHz) 7.96 (d, J = 8.3 Hz, 1H), 7.68 ( d, J = 8.1 Hz, 2H), 7.50 (m, 5H), 7.39 (m, 2H), 7.32 (td, J = 7.3, 1.2 Hz, 1H), 7. 29 (t, J = 7.3 Hz, 4H), 7.26 (dd, J = 7.3, 1.2 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 3.96 (Brs, 1H), 3. 3 (d, J = 9.2 Hz, 1H), 3.79 (d, J = 9.2 Hz, 1H), 3.69 (m, 2H), 3.63 (s, 3H), 3.47 ( dd, J = 10.3, 3.8 Hz, 1H), 3.33 (dd, J = 10.3, 8.3 Hz, 1H), 2.90 (dt, J = 14.4, 4.5 Hz, 1H), 2.65 (ddd, J = 14.4, 9.0, 6.1 Hz, 1H), 2.41 (ddd, J = 15.9, 6.1, 4.6 Hz, 1H), 2 .37 (s, 2H), 1.83 (m, 1H), 1.69 (dd, J = 14.9, 4.4 Hz, 1H), 1.61 (m, 1H), 1.58 (s , 9H), 1.51 (m, 1H), 1.00 (m, 2H), 0.91 (s, 9H), 0.79 (t, J = 7.6 Hz, 3H); ¹³ CNMR (CDCl _3, 100MH ) 173.2, 150.3, 144.7, 135.7, 135.5, 135.5, 135.4, 132.6, 132.5, 132.5, 129.9, 129.8, 129 .8, 129.3, 128.0, 127.8, 127.8, 124.5, 122.7, 118.8, 117.5, 116.0, 84.4, 73.1, 72.4 , 68.9, 61.8, 52.3, 41.8, 40.2, 35.3, 34.7, 30.5, 28.1, 27.8, 26.7, 21.6, 19 0.0, 7.5;

II, highly polar isomer [α] ²⁵ _D- 20 (c 0.57, CHCl ₃ ); IR (film) 3416, 2934, 1729, 1597, 1457, 1431, 1364, 1325, 1254, 1231, 1175, 1131 1112, 1045, 974, 912, 841, 821, 739, 705, 667, 614, 556, 508 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.96 (d, J = 7.6 Hz, 1H), 7 .68 (d, J = 8.3 Hz, 2H), 7.61 (m, 4H), 7.47 (t, J = 7.6 Hz, 1H), 7.43 (m, 2H), 7.37 (M, 4H), 7.29 (td, J = 7.6, 1.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.23 (dd, J = 7. 6, 1.2 Hz, 1 H), 3 98 (t, J = 5.5 Hz, 1H), 3.82 (d, J = 9.3 Hz, 1H), 3.74 (m, 2H), 3.64 (d, J = 9.3 Hz, 1H) ), 3.63 (dd, J = 10.0, 2.3 Hz, 1H), 3.61 (s, 3H), 3.33 (dd, J = 10.0, 8.3 Hz, 1H), 2 .92 (dt, J = 14.2, 5.2 Hz, 1H), 2.72 (dt, J = 14.2, 8.0 Hz, 1H), 2.41 (s, 2H), 2.40 ( m, 1H), 1.98 (m, 1H), 1.65 (m, 1H), 1.61 (s, 9H), 1.58 (m, 2H), 1.37 (dq, J = 14) .4, 7.4 Hz, 1 H), 1.31 (dq, J = 14.4, 7.4 Hz, 1 H), 1.00 (s, 9 H), 0.68 (t, J = 7.4 Hz, 3H); ¹³ C NMR (CD Cl ₃ , 100 MHz) 172.9, 150.3, 144.9, 135.8, 135.7, 135.6, 135.6, 132.5, 132.5, 132.5, 132.4, 130 0.0, 129.9, 129.3, 128.0, 127.9, 127.8, 124.4, 122.6, 118.6, 117.4, 116.0, 84.3, 72.9 72.0, 68.8, 61.8, 52.1, 41.2, 39.4, 34.5, 34.2, 30.5, 28.1, 28.0, 26.8, 21 .6, 19.1, 7.3;

The process for producing the epoxide 17 contained in the compound 4 from the tosylate 16 is as follows.

A dimethylformamide suspension (2.7 mL) of tosylate 16 (238 mg, 0.269 mmol) and sodium hydrogen carbonate (113 mg, 1.343 mmol) was stirred at 90 ° C. for 2.5 hours. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether. The matched organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (25-40% ethyl acetate / n-hexane) to give epoxide 17 (176 mg, 91.8%) as a white foamy solid. The isomers were separated by thin layer silica gel chromatography and instrument data was measured.

Physical properties of epoxide 17; I,
Low polar isomer [α] ²³ _D +93 (c 0.31, CHCl ₃ ); IR (film) 3456, 2934, 2859, 1731, 1588, 1458, 1431, 1364, 1324, 1254, 1229, 1164, 1130, 1113 , 1049, 1004, 910, 822, 741, 705, 616 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.98 (d, J = 7.7 Hz, 1H), 7.64 (m, 4H), 7 .43 (m, 3H), 7.36 (m, 4H), 7.29 (td, J = 7.7, 1.2 Hz, 1H), 7.23 (td, J = 7.7, 1. 2 Hz, 1H), 4.01 (dd, J = 9.9, 4.3 Hz, 1H), 3.68 (m, 2H), 3.66 (s, 3H), 3.55 (dd, J = (10.2, 4.1 Hz, 1H) 3.47 (dd, J = 10.2, 4.7 Hz, 1H), 2.82 (dt, J = 14.7, 3.9 Hz, 1H), 2.55 (m, 2H), 2. 34 (d, J = 4.7 Hz, 1H), 2.27 (d, J = 4.7 Hz, 1H), 2.11 (dd, J = 9.6, 3.8 Hz, 1H), 2.05 (Ddd, J = 14.7, 9.8, 3.4 Hz, 1H), 1.66 (m, 1H), 1.65 (s, 9H), 1.44 (brs, 1H), 1.21 (Qd, J = 7.4, 3.6 Hz, 2H), 1.05 (s, 9H), 0.64 (t, J = 7.4 Hz, 3H); ¹³ CNMR (CDCl ₃ , 100 MHz) 173. 0, 150.3, 136.0, 135.8, 135.6, 135.1, 133.5, 133.5, 129.8, 129.7, 129.7, 127 7, 127.7, 124.5, 122.7, 118.5, 118.3, 116.0, 84.4, 65.9, 61.7, 58.7, 52.1, 51.6 41.8, 36.2, 35.0, 31.8, 28.2, 27.8, 26.9, 26.5, 19.3, 8.5;

II, highly polar isomer [α] ²⁴ _D 62 (c0.36, CHCl ₃ ); IR (film) 3455, 2934, 2859, 1730, 1458, 1431, 1365, 1325, 1253, 1229, 1164, 1130, 1112 , 1079, 1008, 910, 823, 742, 705, 615 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 7.9 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8. 0 Hz, 4H), 7.50-7.20 (m, 9H), 4.14 (t, J = 6.8 Hz, 1H), 3.76 (m, 2H), 3.65 (s, 3H) 3.47 (d, J = 4.6 Hz, 2H), 2.93 (dt, J = 14.4, 4.3 Hz, 1H), 2.80 (ddd, J = 14.4, 9.0) , 5.9 Hz, 1 H), 2.45 (d dd, J = 14.2, 6.8, 4.6 Hz, 1H), 2.42 (d, J = 4.6 Hz, 1H), 2.40 (d, J = 4.6 Hz, 1H), 2 .27 (dd, J = 9.5, 4.4 Hz, 1H), 2.09 (ddd, J = 14.2, 7.3, 4.9 Hz, 1H), 1.63 (s, 9H), 1.62 (m, 1H), 1.39 (m, 2H), 1.06 (m, 1H), 0.90 (s, 9H), 0.76 (t, J = 7.6 Hz, 3H) ¹³ C NMR (CDCl ₃ , 100 MHz) 173.2, 150.4, 135.9, 135.8, 135.6, 135.6, 133.6, 133.4, 129.6, 129.6, 129; .3, 127.6, 127.5, 124.5, 122.7, 118.5, 117.6, 116.1, 84.4, 66.7, 61.9 , 59.1, 52.3, 52.2, 41.7, 36.3, 36.0, 33.6, 28.1, 28.1, 26.8, 26.7, 19.1, 8 .7;

A method for synthesizing the nosylamide 18 contained in the general formula D by introducing sulfonamide into the epoxide 17 is as follows.

Diethylazodica arbonic acid (40%) was added to a toluene suspension (6 mL) of epoxide 17 (171 mg, 0.240 mmol), 2-nitrobenzenesulfonamide (97 mg, 0.48 mmol) and triphenylphosphine (94 mg, 0.36 mmol). Of toluene solution, 0.163 mL, 0.359 mmol) was added dropwise at room temperature and stirred for 20 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (20-22.5% ethyl acetate / n-hexane) to give nosylamide 18 (187 mg, 86.9%) as a yellow foamy solid. It was.

IR (film) cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 8.04 (dd, J = 8.0, 4.0 Hz, (1/2) 1 H), 7.97 (dd, J = 6. 8, 4.0 Hz, (1/2) 1 H), 7.94 (d, J = 8.8 Hz, (1/2) 1 H), 7.91 (d, J = 8.0 Hz, (1/2 ) 1H), 7.70-7.50 (m, 6H), 7.46-7.36 (m, 4H), 7.34-7.32 (m, 2H), 7.23-7.17. (M, 2H + (1/2) 1H), 7.13 (d, J = 6.8 Hz, (1/2) 1H), 7.09 (t, J = 7.4 Hz, (1/2) 1H ), 7.00 (t, J = 7.2 Hz, (1/2) 1H), 5.73 (dd, J = 6.8, 4.0 Hz, (1/2) 1H), 5.48 ( dd, J = 6.8, 2.8 Hz, ( 1/2) 1H), 4.07 (m, (1/2) 1H), 3.87 (m, (1/2) 1H), 3.71 (s, (1/2) 3H), 3 .68 (s, (1/2) 3H), 3.53 (dd, J = 10.8, 4.8 Hz, (1/2) 1H), 3.47-3.32 (m, 2H), 3.24 (m, 1H), 2.95 (m, (1/2) 1H), 2.92 (ddd, J = 14.8, 5.6, 4.0 Hz, (1/2) 1H) , 2.84 (dd, J = 16.8, 8.0 Hz, (1/2) 1H), 2.75 (dt, J = 14.8, 4.8 Hz, (1/2) 1H), 2 .59 (ddd, J = 14.8, 10.0, 4.8 Hz, (1/2) 1H), 2.48 (d, J = 4.8 Hz, (1/2) 1H), 2.44 (M, 2H), 2.42 (d, J = 4.8 Hz, (1/2) 1H) , 2.36 (d, J = 4.0 Hz, (1/2) 1H), 2.30 (d, J = 4.0 Hz, (1/2) 1H), 2.05 (m, 1H), 1.67 (s, (1/2) 1H), 1.64 (s, (1/2) 1H), 1.62 (m, 1H), 1.45 (m, 1H), 1.27 ( m, 2H), 1.05 (s, (1/2) 9H), 0.88 (s, (1/2) 9H), 0.74 (t, J = 7.8 Hz, (1/2) 3H), 0.65 (t, J = 7.8 Hz, (1/2) 3H);

The process of producing the 11-membered ring compound 19 contained in the compound 5 by causing the nosylamide 18 to undergo a medium-membered ring formation reaction is as follows.

A suspension of nosylamide 18 (113 mg, 0.126 mmol) and potassium carbonate (35 mg, 0.25 mmol) in dimethylformamide (2.5 mL) was stirred at 90 degrees for 13 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted 3 times with diethyl ether. The matched organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (20-25% ethyl acetate / n-hexane) to give 11-membered ring compound 19 (80 mg, 71%) as a yellow foamy solid. .

Physical properties of 11-membered ring compound 19;
IR (film) 3397, 3071, 2934, 2859, 1731, 1546, 1459, 1432, 1367, 1327, 1235, 1165, 1115, 910, 735, 705, 581 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 8. 04 (d, J = 8.3 Hz, 1H), 7.93 (m, (1/2) 1H), 7.89 (d, J = 7.1 Hz, (1/2) 1H), 7.78 -7.16 (m, 13H + (1/2) 1H), 7.13 (d, J = 7.3 Hz, (1/2) 1H), 7.11 (d, J = 7.3 Hz, (1 / 2) 1H), 6.77 (brs, (1/2) 3H), 4.83 (s, (1/2) 1H), 4.31 (brs, (1/2) 1H), 4. 23 (m, (1/2) 2H), 3.82-3.19 (m, 4H + (1/2) H), 3.60 (s, (1/2) 3H), 3.56 (s, (1/2) 3H), 3.12 (m, (1/2) 1H), 2.98 (m) , 1H), 2.88 (d, J = 14.9 Hz, (1/2) 1H), 2.75 (m, (1/2) 1H), 2.51-1.71 (m, 3H) , 1.64 (s, (1/2) 9H), 1.61 (s, (1/2) 9H), 1.42-1.15 (m, 4H), 1.06 (s, (1 / 2) 9H), 0.98 (s, (1/2) 9H), 0.89 (t, J = 7.6 Hz, (1/2) 3H), 0.68 (t, J = 7. 6Hz, (1/2) 3H);

The process of producing the diol 20 having an 11-membered ring by deprotecting the 11-membered ring compound 19 is as follows.

To a dichloromethane solution (2 mL) of 11-membered ring compound 19 (124 mg, 0.138 mmol) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred for 2 hours. After concentration under reduced pressure, the residue was dissolved in methanol (3 mL), triethylamine (0.2 mL) was added, and the mixture was stirred at room temperature for 1 hr. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (50-100% ethyl acetate / n-hexane) to give diol 20 (71 mg, 92%) as a pale yellow oil. The isomers were separated by thin layer silica gel chromatography and instrument data was measured.

Physical properties of diol 20;
I, low polar isomer [α] ²² _D- 89 (c 0.37, CHCl ₃ ); IR (film) 3389, 2947, 1728, 1545, 1460, 1439, 1370, 1341, 1167, 910, 734, 580 cm ^{− 1} ; ¹ HNMR (CDCl ₃ , 400 MHz) 8.76 (s, 1H), 7.93 (dd, J = 7.6, 1.2 Hz, 1H), 7.72 (td, J = 7.6) 1.2 Hz, 1H), 7.67 (td, J = 7.6, 1.2 Hz, 1H), 7.62 (dd, J = 7.6, 1.2 Hz, 1H), 7.42 (d , J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.15 (td, J = 8.0, 1.0 Hz, 1H), 7.05 (td, J = 8.0, 1.0 Hz, 1H), 4.17 (dd, J = 12.8, 3.3) Hz, 1H), 4.07 (ddd, J = 15.1, 8.5, 6.6 Hz, 1H), 3.74 (s, 3H), 3.58 (d, J = 14.4 Hz, 1H) ), 3.51 (dd, J = 10.9, 4.0 Hz, 1H), 3.46 (dd, J = 10.9, 6.3 Hz, 1H), 3.40 (dt, J = 15. 1, 7.9 Hz, 1 H), 3.11 (m, 2 H), 3.10 (d, J = 14.4 Hz, 1 H), 2.97 (ddd, J = 15.4, 6.6, 3 .3 Hz, 1H), 2.19 (d, J = 15.4 Hz, 1H), 2.10 (t, J = 12.1 Hz, 1H), 1.77-1.63 (m, 4H), 0 _{^{.98 (t, J = 7.4Hz,}} 3H); 13 CNMR (CDCl 3, 100MHz) 174.3,148.9,136.0,133.9,131.5,131 3, 130.5, 129.8, 127.2, 124.2, 122.5, 119.8, 118.6, 112.6, 111.2, 74.3, 68.3, 60.4, 53.6, 52.6, 39.4, 37.9, 37.2, 33.7, 33.6, 26.4, 7.4;

II, highly polar isomer [α] ²³ _D +21 (c0.24, CHCl ₃ ); IR (film) 3385, 2930, 1726, 1546, 1461, 1440, 1372, 1347, 1166, 909, 735, 581 cm ^{−1 1} H NMR (CDCl ₃ , 400 MHz) 8.56 (s, 1H), 7.98 (dd, J = 7.7, 1.5 Hz, 1H), 7.76 (td, J = 7.7, 1 .5 Hz, 1H), 7.72 (td, J = 7.7, 1.5 Hz, 1H), 7.64 (dd, J = 7.7, 1.5 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.08 (t, J = 7.9 Hz) , 1H), 4.15 (dd, J = 10.0, 2.4 Hz, 1H), 4.0 (M, 1H), 3.70 (s, 3H), 3.58 (dd, J = 10.8, 6.1 Hz, 1H), 3.54 (dd, J = 10.8, 5.7 Hz, 1H), 3.40 (d, J = 15.4 Hz, 1H), 3.31 (m, 3H), 2.77 (d, J = 15.4 Hz, 1H), 2.44 (m, 1H) , 2.17 (dt, J = 13.9, 2.4 Hz, 1H), 1.80 (dt, J = 13.9, 10.8 Hz, 1H), 1.05 (m, 4H),. 40 (t, J = 7.4 Hz, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz) 174.3, 149.0, 136.0, 134.1, 132.4, 131.5, 131.0, 130 3,127.6,124.2,122.5,119.8,118.6,111.1,110.8,73.0,68.6, 1.8,53.9,52.5,42.2,37.5,37.5,36.0,34.6,25.6,7.1;

The process for producing tosylate 21 by tosylation to diol 20 is as follows.

To a toluene-acetonitrile solution (1 mL-1 mL) of diol 20 (57.0 mg, 0.102 mmol) and tetramethyldiaminopropane (26 μL, 0.15 mmol), p-toluenesulfonic acid chloride (22 mg, 0.11 mmol) at room temperature. ) Was added and stirred for 3 hours. The solid was removed using a celite column and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-50% ethyl acetate / n-hexane) to give tosylate 21 (55 mg, 75%) as a pale yellow oil.

Physical properties of tosylate 21;
IR (film) 3514, 3393, 2956, 1728, 1595, 1546, 1461, 1440, 1354, 1173, 962, 754, 667, 580 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 8.67 (s, (1 / 2) 1H), 8.51 (s, (1/2) 1H), 7.89 (d, J = 8.0 Hz, (1/2) 1H), 7.81 (d, J = 8. 0 Hz, (1/2) 1H), 7.77 (d, J = 8.0 Hz, (1/2) 2H), 7.73-7.57 (m, 4H), 7.43 (d, J = 7.1 Hz, 1H), 7.36 (d, J = 7.1 Hz, 1H), 7.32 (d, J = 8.0 Hz, (1/2) 2H), 7.18 (t, J = 7.1 Hz, (1/2) 1H), 7.16 (t, J = 7.1 Hz, (1/2) 1H), 7.11 ( d, J = 8.0 Hz, (1/2) 2H), 7.06 (t, J = 7.1 Hz, (1/2) 1H), 7.04 (t, J = 7.1 Hz, (1 / 2) 1H), 4.23-4.07 (m, 2H), 3.92 (dd, J = 9.5, 6.6 Hz, (1/2) 1H), 3.86 (dd, J = 9.8, 7.1 Hz, (1/2) 1H), 3.80 (m, (1/2) 1H), 3.70 (s, (1/2) 3H), 3.69 (s) , (1/2) 3H), 3.38 (d, J = 15.0 Hz, 1H), 3.25 (m, 1H), 3.17 (m, (1/2) 1H), 3.10 (M, (1/2) 1H), 2.97 (d, J = 15.0 Hz, (1/2) 1H), 2.63 (d, J = 15.0 Hz, (1/2) 1H) , 2.50 (m, (1/2) 1H), 2.42 (s, (1/2) 3H), 2.32 (s, (1/2) 3H), 2.21 (dt, J = 13.9, 1.5 Hz, (1/2) 1H), 1.94 (d, J = 15.9 Hz, (1/2) 1H), 1.83 (m, 1H), 1.49 (m, 2H), 1.28 (m, 2H), 1.02 (m, 2H), 0.77 (t, J = 7.4 Hz, (1/2) 3H), 0.37 (t, J = 7.4 Hz, (1/2) 3H);

The step of esterifying tosylate 21 with trifluoroacetic anhydride to produce ester 22 contained in general formula A is as follows.

To a solution of tosylate 21 (55 mg, 0.077 mmol) and pyridine (62 μL, 0.77 mmol) in dichloromethane (2 mL) was added trifluoroacetic anhydride (44 μL, 0.31 mmol) at room temperature, and the mixture was stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The matched organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (20-40% ethyl acetate / n-hexane) to give ester 22 (49 mg, 79%) as a pale yellow oil.

IR (film) 3397, 2953, 1781, 1730, 1595, 1548, 1461, 1441, 1366, 1222, 1173, 965, 930, 817, 754, 667, 580, 556 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 8.74 (s, (1/2) 1H), 8.63 (s, (1/2) 1H), 7.93 (dd, J = 7.3, 1.8 Hz, (1/2) 1H ), 7.73 (m, 3H + (1/2) 1H), 7.64 (dd, J = 7.3, 1.8 Hz, (1/2) 1H), 7.58 (dd, J = 7) .3, 1.8 Hz, (1/2) 1 H), 7.53 (d, J = 8.4 Hz, (1/2) 2 H), 7.36 (m, 3 H), 7.20 (t, J = 7.4 Hz, (1/2) 1H), 7.18 (t, J = 7.4 Hz, (1/2) H), 7.08 (t, J = 7.4 Hz, (1/2) 1H), 7.06 (t, J = 7.4 Hz, (1/2) 1H), 6.99 (d, J = 8.4 Hz, (1/2) 2H), 4.49 (d, J = 16.4 Hz, (1/2) 1H), 4.14 (m, 1H + (1/2) 1H), 4. 05 (d, J = 10.5 Hz, (1/2) 1H), 3.87 (m, 1H + (1/2) 1H), 3.74 (s, (1/2) 3H), 3.71 (S, (1/2) 3H), 3.38-3.08 (m, 3H), 2.78 (m, 1H), 2.64 (d, J = 16.1 Hz, (1/2) 1H), 2.42 (s, (1/2) 3H), 2.25 (s, (1/2) 3H), 2.16 (m, 1H + (1/2) 1H), 2.00 ( d, J = 14.2 Hz, (1/2) 1H), 1.90 (d, J = 1) .1 Hz, (1/2) 1 H), 1.85-1.52 (m, 3 H), 1.67 (brs, 1 H), 1.02 (m, (1/2) 1 H), 0.88 (T, J = 7.4 Hz, (1/2) 1H), 0.77 (t, J = 7.4 Hz, (1/2) 3H), 0.62 (d, J = 15.6 Hz, ( 1/2) 1H), 0.25 (t, J = 7.4 Hz, (1/2) 3H);

 (+)-Vinblastine is synthesized by coupling vindolines to the compound of general formula A synthesized in III, II, and then removing the trifluoroacetyl group and Ns, and further constructing a piperidine ring. how to. Example 3a The process of synthesizing vinblastine precursor 23 contained in general formula E by coupling vindrin to ester 22 contained in general formula A is as follows.

To a dichloromethane solution (0.4 mL) of ester 22 (10 mg, 0.012 mmol), a dichloromethane solution of t-butyl hypochlorite (1.5 μl, 0.013 mmol) was added dropwise under ice cooling, followed by stirring for 15 minutes. The reaction solution was directly purified by thin layer silica gel chromatography to obtain chloroindolenin. To a dichloromethane solution (0.5 mL) of chloroindolenine and vindoline (5.6 mg, 0.012 mmol) was added trifluoroacetic acid (10 μL, 0.12 mol) under ice-cooling, followed by stirring at the same temperature for 10 minutes, and at room temperature. Stir for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The matched organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give compound 23 (12.5 mg, 80.4%) as a colorless oily compound.

Physical properties of compound 23;
[Α] ²⁸ _D +27 (c 0.32, CHCl ₃ ); IR (film) 3414, 2952, 2879, 1778, 1740, 1614, 1548, 1498, 1461, 1434, 1396, 1226, 1175, 1043, 913, 817 , 734, 668, 580, 554 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 10.56 (brs, 1H), 9.42 (brs, 1H), 7.86 (dd, J = 7.8, 1 .2 Hz, 1H), 7.78 (td, J = 7.8, 1.2 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.70 (td, J = 7. 8, 1.2 Hz, 1H), 7.64 (dd, J = 7.8, 1.2 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J = 7.3 Hz, 1H) ), 7.32 (d, J = 8 .3 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H) 5.91 (dd, J = 10.2, 3.7 Hz, 1H), 5.81 (dd, J = 10.2, 3.7 Hz, 1H), 5.57 (s, 1H), 5. 27 (d, J = 10.2 Hz, 1H), 4.12 (d, J = 9.7 Hz, 1H), 3.90 (d, J = 16.0 Hz, 1H), 3.80 (s, 3H) ), 3.79 (m, 1H), 3.71 (s, 3H), 3.64 (d, J = 9.7 Hz, 1H), 3.44 (s, 3H), 3.44 (m, 1H), 3.36 (t, J = 7.3 Hz, 1H), 3.29 (m, 1H), 3.16 (dd, J = 16.0, 6.1 Hz, 1H), 3.04 ( d, J = 16.6 Hz, 1H 2.94 (t, J = 12.2 Hz, 1H), 2.82 (m, 2H), 2.81 (s, 1H), 2.70 (m, 1H), 2.63 (s, 3H) ), 2.54 (m, 2H), 2.41 (s, 3H), 2.09 (s, 3H), 1.89 (m, 3H), 1.71 (m, 2H), 1.58 (Brs, 2H), 1.30 (m, 3H), 0.59 (t, J = 7.4 Hz, 3H), 0.43 (t, J = 7.3 Hz, 3H); ¹³ CNMR (CDCl ₃ , 100 MHz) 177.1, 177.0, 172.3, 170.9, 158.5, 155.8, 155.4, 155.0, 153.2, 148.8, 145.0, 135.1 134.5, 134.0, 132.4, 131.6, 131.3, 130.2, 129.9, 128.0, 127.7, 127 7, 125.4, 124.6, 124.0, 122.5, 121.6, 120.1, 119.0, 117.5, 115.1, 112.2, 111.1, 108.4. 94.4, 94.1, 77.2, 72.9, 68.0, 55.7, 54.1, 53.0, 52.8, 52.6, 52.4, 51.0, 50. 7, 43.4, 39.5, 37.8, 37.7, 31.6, 30.7, 29.3, 25.2, 21.6, 21.1, 8.8, 7.0;

The step of producing vinblastine precursor 24 detrifluoroacetylated from compound 23 is as follows.

To a methanol solution (1 mL) of compound 23 (12.5 mg, 0.0100 mmol), triethylamine (12 μL) was added dropwise at room temperature and stirred for 45 minutes. Concentration under reduced pressure gave Compound 24 (10 mg, 90%) as a white solid.

[Α] ²⁵ _D +57 (c 0.30, CHCl ₃ ); IR (film) 3750, 3464, 3414, 2951, 1739, 1614, 1545, 1500, 1459, 1434, 1358, 1250, 1174, 1042, 964, 914 , 837, 739, 667, 581, 556 cm ⁻¹ ; ¹ HNMR (CDCl ₃ , 400 MHz) 10.99 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.79 (d , J = 8.1 Hz, 2H), 7.75 (d, J = 7.7 Hz, 1H), 7.68 (t, J = 7.7 Hz, 2H), 7.58 (s, 1H), 7 .43 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8Hz, 1H), 7.0 2 (t, J = 7.8 Hz, 1H), 5.86 (s, 1H), 5.81 (dd, J = 10.1, 4.4 Hz, 1H), 5.64 (s, 1H), 5.27 (d, J = 10.1 Hz, 1H), 3.95 (dd, J = 15.0, 5.6 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 1H) ), 3.73 (dd, J = 9.3, 6.6 Hz, 1H), 3.66 (d, J = 9.3 Hz, 1H), 3.55 (s, 3H), 3.50 (m) , 2H), 3.43 (s, 3H), 3.35 (m, 2H), 3.04 (m, 1H), 2.94 (s, 1H), 2.83 (m, 2H), 2 .67 (m, 1H), 2.60 (s, 3H), 2.52 (dt, J = 14.4, 4.4 Hz, 1H), 2.44 (s, 3H), 2.09 (s , 3H), 1.95 (dd, J = 15.1. 9.8 Hz, 1 H), 1.72 (dq, J = 14.4, 7.3 Hz, 1 H), 1.41 (d, J = 14.9 Hz, 1 H), 1.38-1.26 (m , 6H), 1.08 (dq, J = 14.4, 7.3 Hz, 1H), 0.99 (dq, J = 14.4, 7.3 Hz, 1H), 0.86 (m, 1H) , 0.62 (t, J = 7.3 Hz, 3H), 0.55 (t, J = 7.3 Hz, 3H); ¹³ CNMR (CDCl ₃ , 100 MHz) 176.7, 172.7, 171.0 , 157.7, 153.4, 148.8, 144.8, 137.8, 134.1, 133.9, 132.9, 131.1, 130.5, 130.1, 129.8, 128 0.0, 127.4, 126.1, 124.8, 124.0, 122.6, 122.2, 120.8, 119 6, 117.3, 111.7, 106.7, 93.6, 83.3, 79.1, 76.2, 7.1, 73.4, 68.1, 64.6, 55.6, 54.1, 53.0, 52.8, 52.3, 52.2, 50.9, 50.3, 45.6, 43.6, 43.4, 40.1, 38.5, 37. 7, 35.7, 31.6, 29.7, 29.0, 26.9, 21.6, 21.1, 9.1, 6.9;

The reaction for producing (+)-vinblastine by radical cyclization reaction of Compound 24 is as follows.

To an acetonitrile solution of Compound 24 (16 mg, 0.014 mmol), 1,8-diazabicyclo [5.4.0] undecene (DBU) (3 μL, 0.02 mmol), mercaptoethanol (1 μL, 0.01 mmol) under ice cooling. Was added dropwise and stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The matched organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to obtain a cyclization precursor (9.0 mg, 67%) as a yellow oil. To an acetone solution (0.3 mL) of the cyclization precursor (2.0 mg, 0.0020 mmol), a saturated aqueous sodium hydrogen carbonate solution (0.3 mL) was added and stirred overnight. The reaction mixture was partitioned between ethyl acetate and saturated brine, and the aqueous layer was extracted with ethyl acetate. The matched organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give vinblastine (25, 1.3 mg, 79%) as a white solid. Various device data was consistent with literature values (Non-Patent Document 9).

As described above, through the intermediate represented by the general formula A of the present invention, the coupling reaction of two indole compounds and the subsequent indole ring formation reaction proceed efficiently in a stereochemically selective manner. In addition, it is possible to obtain a natural vinblastine with high efficiency, and it is possible to design a compound C that can be produced under mild conditions. Is brought about.

Abbreviation;
AIBN = azobisisobutyronitrile Bn = benzyl Boc = t-butoxycarbonyl group DBU = 1,8-diazabicycloundecene DEAD = diethylazodicarboxylic acid DIBAL = diisobutylaluminum hydride DMAP = 4-dimethylaminopyridine DMF = Dimethylformamide Et = ethyl group LDA = lithium diisopropylamide Me = methyl group Ns = 2-nitrobenzenesulfonyl group Ph = phenyl group Py = pyridine TBDPS = t-butyldiphenylsilyl group TES = triethylsilyl group TFA = trifluoroacetyl group or tri Fluoroacetate TFAA = trifluoroacetic anhydride THF = tetrahydrofuran THP = tetrahydropyranyl group TMS = trimethylsilyl group Ts = p-to Ensuruhoniru based on

  Establishing a commercial synthesis process for (+)-vinblastine by establishing an intermediate design that enables efficient production of the synthesis of (+)-vinblastine, which has been found useful as an anticancer agent, etc. It is clear that you can contribute to

Claims (1)

Intermediate for production of general formula A consisting of general formula C.

(In formula C, R ₁ , R ₂ , R ₃ and R ₄ are H, lower alkyl group, lower alkoxy group, halogen, lower perfluoroalkyl group, lower alkylthio group, hydroxy group, amino group, mono- or di- A group independently selected from an alkyl or acylamino group, a lower alkyl or arylsulfonyloxy group, R ₅ is H or a lower alkyl group or a substituted or unsubstituted aryl group, and R ₆ is an alkyl group having up to 4 carbon atoms. , R ₁₀ is independently selected from an alkyl group having up to 4 carbon atoms and an aryl group which may have a substituent, and the three groups selected for each group may be the same or different. also, R _11, R ₁₂ is independently selected from an aryl group which may have an alkyl group and substituents having up to 4 carbon atoms, and, in each group -Option by three groups may .R ₁₃ be the same or different is an acetal structure and trialkylsilyl group, tetrahydropyranyl group or other lower alcohols.)

Wherein R ₁ , R ₂ , R ₃ and R ₄ are H, lower alkyl group, lower alkoxy group, halogen, lower perfluoroalkyl group, lower alkylthio group, hydroxy group, amino group, mono- or di-alkyl. Or an acylamino group, a lower alkyl group or an arylsulfonyloxy group independently selected from R ₅ is H or a lower alkyl group or a substituted or unsubstituted aryl group, R ₆ is an alkyl group having up to 4 carbon atoms, R ₇ and R ₈ are substituted or unsubstituted aryl groups, and R ₉ is an acyl group or a trialkylsilyl group.)
The numbering in the naming of Bindrins is based on the method proposed by Men et al. (Non-patent Document 10)