JP2000281670A - A new synthetic intermediate for corrole sewing machine and production method - Google Patents

Abstract

(57) Abstract: A dehydroaminolactone represented by the following formula I, a method for producing the same, and a method for producing a cholor sewing machine using dehydroaminolactone as a raw material. Embedded image [Effect] By using an inexpensive and easily available optically active natural product as a starting material and further combining inconsistencies, it is possible to produce inexpensively and mass-produce dehydroaminolactone, which is an important key compound, and optically active corrole sewing machine. Provide the law.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an important intermediate of the antibacterial substance cholor sewing machine and a method for producing the same, and a method for producing an optically active cholor sewing machine.

[0002]

2. Description of the Related Art Antibiotics play an important role as a remedy for infectious diseases, and one of them is known as corrole sewing machine (JP-A-10-306094). Koror sewing machines are produced by marine bacteria of the genus Pseudoalteromonas, and are characterized by having antibacterial activity only against gram-negative marine bacteria. Conventionally, a koror sewing machine has been produced by a fermentation method, but its titer is not so high, and a purification method from a culture solution requires multiple steps, making mass production difficult. Therefore, an inexpensive and easy manufacturing method is required.
In general, in the case of a compound having an asymmetric point as a physiologically active substance, there is a case where only one enantiomer has an activity and the optical isomer has little or no physiological activity. Against this background, the present inventors have attempted chemical synthesis of an optically active cholor sewing machine from an optically active substance that is available at a low cost.

[0003]

SUMMARY OF THE INVENTION The present invention uses an optically active natural product that is inexpensive and easily available as a starting material, and further combines an optically active natural product with dehydroaminolactone, which is an important key compound, by using an optically active natural product. An object of the present invention is to provide an inexpensive and mass-producible production method of a koror sewing machine.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have used lactic acid or malic acid as an optically active starting material and further combined means of inconsistency. As a result, a chemical synthesis method of optically active corrole sewing machine was found, and the present invention was completed.
That is, a first aspect of the present invention is dehydroaminolactone, which is a synthetic intermediate of cholor sewing machine.

A second aspect of the present invention is characterized in that an aldol reaction of an optically active aldehyde with a glycine ester is performed to convert the optically active aldehyde into an optically active lactone, and then the amino-protecting group of the optically active lactone is eliminated. A method for producing the above dehydroaminolactone. Further, a third aspect of the present invention is a method for producing a color roll sewing machine, which comprises condensing an optically active carboxylic acid with the above dehydroaminolactone.

[0006]

DETAILED DESCRIPTION OF THE INVENTION Hereinafter, the first to third inventions will be described in detail. The solvent used for the reaction described below is an inert solvent, but unless otherwise specified, tetrahydrofuran, ether solvents such as ethyl ether, amide solvents such as dimethylformamide, chloroform, Halogen solvents such as methylene chloride, sulphoxide solvents such as dimethyl sulfoxide,
Alcohol solvents such as methanol and ethanol, alkyl solvents such as hexane and pentane, aromatic solvents such as benzene and toluene, water and the like are used alone or in combination. The reaction temperature is from -150 ° C to 100 ° C, and the reaction is performed within this range unless otherwise specified. The reaction time is usually completed in 1 hour to 240 hours, but unless otherwise specified, the reaction is completed within this range. In order to isolate the target substance from such a reaction solution, a post-treatment method usually used in organic chemistry, such as extraction with an organic solvent, is performed, and chromatographic chromatography such as silica gel column chromatography or preparative HPLC is used alone or in combination. It can be purified. The numbers assigned to the compounds correspond to the numbers shown in FIGS. (A) First invention The first invention relates to dehydroaminolactone represented by the following formula I.

[0007]

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This compound can be produced, for example, by the method of the second invention described later, but may be produced by another method. This compound is not only a key compound for the synthesis of cholor sewing machine, but also an important intermediate which enables the synthesis of derivatives and the induction of other physiologically active substances. (B) Second invention The second invention is to cause an aldol reaction of an optically active aldehyde represented by the following formula II with a glycine ester represented by the following formula III to give an optically active lactone represented by the following formula IV The present invention also relates to a method for producing the above dehydroaminolactone, which comprises, after conversion, removing a protective group for the amino group of the optically active lactone.

[0009]

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[0010]

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[0011]

[Formula 10]

Here, R ¹ in formulas III and IV represents an alkyl group having 1 to 6 carbon atoms, and R 2 represents a substituted methylene group. Examples of the substituent for R ² include a phenyl group, a nitrophenyl group, and a naphthyl group. Examples of the catalyst for causing the aldol reaction of the optically active aldehyde with the glycine ester include, but are not limited to, lithium diisopropylamide, butyllithium and the like. The method for removing the protecting group for the amino group may be determined according to the type of the protecting group.For example, when a benzylidene group is used as the protecting group, a mild acid such as acetic acid-water is used. As a result, the protecting group can be eliminated.

As shown in FIG. 1, the optically active aldehyde is produced from (S) -lactic acid (5) and pivalaldehyde (6) as raw materials through the following first to fourth steps. It may be manufactured by another method. First step: (S) -lactic acid (5) and pivalaldehyde (6) are condensed using an organic acid such as p-toluenesulfonic acid or an inorganic acid such as sulfuric acid alone or as a mixture, and optically active dioxilanone ( Convert to 8). At this time, the compound (7) which is an optical isomer is also by-produced.

Second step: The compound (8) is treated with a strong base such as lithium diisopropylamide and reacted with an alkylating agent such as ethyl iodide to give an optically active compound.
Convert to (9). Third step: Dioxolanone (9) is reduced with a reducing agent such as lithium aluminum hydride or DIBAL to convert it into optically active lactol (10). Fourth step: Compound (10) is solvolyzed with a weak base such as potassium carbonate in methanol to give an optically active aldehyde (11).
Convert to

In addition, instead of (S) -lactic acid in the first step, (R)
-By using lactic acid or other alkyl iodide instead of ethyl iodide in the second step, it is possible to change the chemical structure of the optically active aldehyde to be produced. Body and analogs can be manufactured. (C) Third invention The third invention relates to a method for producing a color roll sewing machine, which comprises condensing an optically active carboxylic acid represented by the following formula V with dehydroaminolactone represented by the following formula I. is there.

[0016]

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[0017]

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Here, R ³ in the formula V represents a linear alkyl group having 1 to 20 carbon atoms. The condensation of the optically active carboxylic acid with dehydroaminolactone can be performed by using a suitable condensing agent. Suitable condensing agents include, for example, water-soluble carbodiimide, dicyclohexylcarbodiimide and the like. As shown in FIG. 4, the optically active carboxylic acid is produced from the iodoolefin (3) and the tin compound (4) as raw materials through the following first to third steps, but is produced by another method. You may.

First step: The iodoolefin (3) is coupled with the tin compound (4) for 6 days at room temperature in the presence of a palladium catalyst such as trisdibenzylideneacetonylpalladium and trifurylphosphine, to give an optically active diene. Convert to (24). Second step: The compound (24) is treated with a fluoride such as tributylammonium fluoride to remove the TBS protecting group and convert to an optically active ester (25) (in the figure, R = C ₈ H ₁₇ ; R may be another group.). Third step: Compound (25) is hydrolyzed with a base such as lithium hydroxide to convert to optically active carboxylic acid (26). As shown in FIG. 2, the iodoolefin (3) is produced through the following first to sixth steps using (R) -malic acid (14) as a raw material, but may be produced by another method. Good.

First step: (R) -malic acid (14) is reduced with sodium borohydride or borohydride dimethyl sulfide or a mixture thereof to obtain an optically active diol (1).
Reduce to 5). Second step: Compound (15) is reacted with trityl chloride in pyridine with dimethylaminopyridine as a catalyst to protect a primary hydroxyl group with a trityl group, thereby obtaining an optically active alcohol (16). Third step: Compound (16) is reacted with t-butyldimethylsilyl (TBS) chloride using imidazole as a base to protect a secondary hydroxyl group with a TBS group, and to form an optically active ester (1
Convert to 7).

Fourth step: The trityl group of the compound (17) is selectively detritylated using diethylaluminum chloride to be converted to an optically active alcohol (18). Fifth step: Triethylamine is added as a base to compound (18), and gently oxidized with oxalyl chloride and dimethyl sulfoxide to convert to optically active aldehyde (19). Sixth step: Sodium bistrimethylsilylamide is added to compound (19), and methylenetriphenylphosphonyl iodide is reacted with the compound, to give an optically active cis-iodoolefin (3) which is a target product of this step. Convert. In addition, an optical isomer can be obtained by using (S) -malic acid instead of (R) -malic acid in the first step.

The tin compound (4) is, as shown in FIG.
The following first products are made from allylic alcohol (20).
Although it is manufactured through the fourth step, it may be manufactured by another method. First step: Tetraisopropylpyroxytitanium and (+)-tartaric acid are added to the allylic alcohol (20), and t-butyl hydroperoxide is added in the presence of molecular sieves.
After reacting for a day (sharpless oxidation), it is converted to an optically active epoxy alcohol (21) (in the figure, R = C ₈ H ₁₇ , but R may be another group). Second step: Compound (21) is reacted with 2,6-lutidine as a base and trifluoroacetic anhydride to form triflate, and then reacted with lithium acetylide using dimethylpropyleneurea as a catalyst for 10 days to obtain an optically active alkyne ( Two
Convert to 2).

Third step: Compound (22) is brominated with silver nitrate as a catalyst using N-bromosuccinimide or the like in acetone to convert into optically active bromoacetylene (23). Fourth step: Tributyltin hydride is added to compound (23) in the presence of a palladium catalyst such as bistriphenylphosphine dichloropalladium to convert to optically active tin compound (4). By using (-)-tartaric acid instead of (+)-tartaric acid in the first step, optical isomers and various analogs can be synthesized.

[0024]

The present invention will now be described in detail with reference to examples. [Example 1] Production of dioxolanone (7, 8) Distilled (S) -lactic acid (10.4 g, 115 mmol), pivalaldehyde
(25 ml, 231 mmol), para-toluenesulfonic acid monohydrate
(0.24 g, 1.26 mmol), concentrated sulfuric acid (1 drop), and pentane (50 m
The mixture of l) was heated to reflux to remove water formed by azeotropic distillation. The solvent was removed and the mixture was purified by flash column chromatography and medium pressure column chromatography, and dioxolanone 7 (70.7 mol, 61%) and dioxolanone 8 (7.2 m
mol, 6.3%). The purity of each diastereomer was determined to be greater than 100 to 1 by GC analysis (Chira
ldex G-AT, column temperature, 45 ° C). 7: ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.97 (9H, s), 1.46 (3
H, d, J = 6.8Hz), 4.35 (1H, qd, J = 6.8, 1.0Hz), 5.1
4 (1H, d, J = 1.0 Hz) .8: ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.96 (9H, s), 1.46 (3
H, d, J = 6.4Hz), 4.47 (1H, qd, J = 6.8, 1.0Hz), 5.3
0 (1H, d, J = 1.0Hz).

Example 2 Preparation of dioxolanone (9) Dioxolanone 8 (3.65 mmol) in tetrahydrofuran (TH
F) (5 ml) solution with lithium diisopropylamide (4.7 mmo
l) was added dropwise to a solution of THF (21 ml) at -80 ° C and stirred for 40 minutes. Ethyl iodide (1.5 ml, 18 mmol) was added, and the temperature was raised to -20 ° C over 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by flash column chromatography to obtain dioxolanone 9 (561 mg, 3.01 mmol, 83%). ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.95 (9H, s), 1.00 (3H,
t, J = 7.4Hz), 1.42 (3H, s), 1.70-1.80 (2H, m), 5.1
9 (1H, s).

Example 3 Production of Lactol (10) Isobutylaluminum hydride (0.94 M hexane solution, 5.0 ml, 4.7 mmol) was added dropwise to a dichloromethane solution of dioxolanone 9 (560 mg, 3.0 mmol) at -70 ° C. Stirred for 20 minutes. A saturated aqueous solution of Rochelle salt was added to the reaction solution, extracted with diethyl ether, and the organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by flash column chromatography.
(469 mg, 2.49 mmol, 83%) was obtained as a 1: 1 mixture of diastereomers. Diastereomer A: ¹ H NMR (200 MHz, CDCl ₃ ): δ1.01
(9H, s), 1.05 (3H, t, J = 7.4Hz), 1.31 (3H, s), 1.4
5-1.93 (2H, m), 2.43 (1H, d, J = 8.8Hz), 4.74 (1H,
s), 5.08 (1H, d, J = 8.8Hz). Diastereomer B: ¹ H NMR (200MHz, CDCl ₃ ): δ 0.99
(9H, s), 0.90-1.00 (3H, m), 1.29 (3H, s), 1.45-1.
93 (2H, m), 2.93 (1H, d, J = 4.4Hz), 4.97 (1H, s),
5.20 (1H, d, J = 4.4Hz).

Example 4 Production of Aldehyde (11) Lactol 10 (469 mg, 2.49 mmol) in anhydrous methanol (5 m
l) Potassium carbonate (68 mg, 0.49 mmol) was added to the solution at room temperature and stirred for 2 hours. Florisil column chromatography (pentane-diethyl ether) of the reaction mixture as it is
And concentrated to give aldehyde 11 (1.38 mmol, 55%).

Example 5 Preparation of Lactone (13) Activated molecular sieves 4A was added to a solution of glycine derivative 12 (245 mg, 1.52 mmol) in THF (1 ml), and the mixture was added at room temperature.
Stir for hours and dry. The supernatant of this solution was placed in a solution of lithium diisopropylamide (1.66 mmol) in THF (2 ml) at -80 °.
C was added dropwise. Aldehyde 11 (1.38mmol) in THF (0.5ml)
Add activated molecular sieves 4A to the solution and add 1
Stir for hours and dry, then drop the supernatant of this solution into the previous reaction solution, followed by hexamethylphosphoramide (HMPA)
(0.8 ml, 4.6 mmol) was added dropwise. After the temperature was raised to 10 ° C. over 6 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by flash column chromatography (-hexane / hexane containing 1% triethylamine).
Ethyl acetate) lactone 13 was obtained (135 mg, 530 mmol, 35%).

¹ H NMR (500 MHz, CDCl ₃ ): δ 0.93 (3H, t,
J = 7.5Hz), 1.51 (3H, s), 1.81 (1H, dq, J = 14.5,
7.5Hz), 1.88 (1H, dq, J = 14.5, 7.5Hz), 7.11 (1H,
s), 7.42-7.50 (3H, m), 7.84-7.90 (2H, m), 9.19 (1
^{. H, s) 13 C NMR} (125MHz, CDCl 3): δ8.12, 24.06, 32.00, 85.
28, 128.69, 129.03, 132.08, 135.85, 137.76, 145.83,
165.37, 168.70.IR (neat): ν 2975, 2934, 1755, 1613, 1577, 1452,
1376, 1314, 1191, 1091, 996, 950, 754, 692cm ^-1 . [Α] _D ³⁰ -5.8 (c 0.47 CHCl ₃ ).

Example 6 Preparation of amine (2, compound I) Lactone 13 (57 mmol) was added to THF (0.8 ml), water (0.4 ml), and acetic acid.
(20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. After dilution with ethyl acetate, the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed and the residue was purified by flash column chromatography (containing 1% triethylamine-hexane / ethyl acetate).
Amine 2 was obtained (6.7 mg, 48 mmol, 83%). ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.86 (3H, t, J = 7.3 Hz),
1.42 (3H, s), 1.62-1.85 (2H, m), 3.64 (2H, bs), 5.
81 (1H, s) .IR (film): ν 3463, 3366, 2975, 2932, 2882, 1747,
1673, 1598, 1456, 1345, 1317, 1227, 1114, 1030, 9
95, 948, 920, 786 cm ^-1 . [Α] _D ³⁰ -21.4 ° (c 0.39, CHCl ₃ ).

Example 7 Preparation of alcohol (16) Borane dimethyl sulfide complex (10 M, 2.0 ml, 20 m) was added to a solution of dimethyl (R) -malic acid ((+)-14) in THF (38 ml).
mol) was added dropwise at room temperature and stirred for 1 hour. Reaction solution at 0 ° C
And stirred for 10 minutes. Sodium borohydride (37 mg, 1.0 mmol) was added to this solution, and the mixture was stirred at room temperature for 1 hour. Methanol (5 ml) and para-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) were added, stirred for 30 minutes, and concentrated.
Toluene (4 ml) and methanol (4 ml) were added to the obtained residue, and the mixture was concentrated. This operation was repeated twice to remove trimethylboric acid, thereby obtaining diol 15 as a crude product. ¹ H NMR (200 MHz, CDCl ₃ ): δ 2.43 (1 H, dd, J = 16.2,
5.0Hz), 2.56 (1H, dd, J = 16.2, 7.2Hz), 2.88 (1H, b
s), 3.43-3.75 (3H, m), 3.71 (3H, s), 4.02-4.20 (1
H, m). [Α] _D ²⁹ + 22.9 ° (c 1.02, CHCl ₃ ).

The crude product, diol 15, was dissolved in pyridine (8 ml), trityl chloride (8.0 g, 29 mmol) and 4-dimethylaminopyridine (69 mg, 0.57 mmol) were added, and the mixture was stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with hexane-ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated saline. After drying the organic layer over anhydrous magnesium sulfate, the solvent was removed and the residue was purified by flash column chromatography.
mol, 82%, two steps). ¹ H NMR (200 MHz, CDCl ₃ ): δ 2.43-2.67 (2H, m), 2.93
(1H, d, J = 3.8Hz), 3.18 (2H, d, J = 5.4Hz), 3.68 (3
H, s), 4.15-4.31 (1H, m), 7.25-7.51 (15H, m). [Α] _D ²⁸ + 5.5 ° (c 0.89, CHCl ₃ ).

Example 8 Preparation of TBS ether (17) Alcohol 16 (5.72 g, 15.2 mmol) and imidazole (1.56
g, 23 mmol) in DMF (5 ml) was added with t-butyldimethylsilane chloride (TBSCl) (2.51 g, 17 mmol) at room temperature and stirred for 2 hours. The mixture was extracted with hexane-ethyl acetate, and the organic layer was washed with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed and purified by flash column chromatography to obtain TBS ether 17 (6.57 g, 13.4 mmol, 88%). ¹ H NMR (200 MHz, CDCl ₃ ): δ-0.08 (3H, s), -0.02 (3
H, s), 0.80 (9H, s), 2.47 (1H, dd, J = 15.0, 8.2H
z), 2.75 (1H, dd, J = 15.0, 4.4Hz), 3.63 (3H, s),
4.20-4.32 (1H, m), 7.18-7.50 (5H, m) .IR (neat): ν 2929, 2857, 1741, 1490, 1449, 1255,
1171, 1076, 1002, 837, 778, 632 cm ^-1 . [Α] _D ²⁸ + 19.1 ° (c 1.00, CHCl ₃ ).

Example 9 Production of alcohol (18) A solution of (1.33 g, 2.71 mmol) in dichloromethane (14 ml) was mixed with diethyl aluminum chloride (0.95 M hexane solution, 8.5 ml,
8.1 mmol) was added dropwise at -80 ° C, and the mixture was stirred for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by flash column chromatography to remove alcohol 18 (501 mg, 2.0 mmo).
l, 74%) to obtain the starting material TBS ether 17 (0.42 mmol,
15%). ¹ H NMR (200 MHz, CDCl ₃ ): δ0.07 (3H, s), 0.10 (3H,
s), 0.88 (9H, s), 1.91 (1H, dd, J = 7.2, 6.0Hz), 2.5
5 (1H, d, J = 6.4Hz), 3.51-3.67 (1H, m), 3.68 (3H,
s), 4.15-4.26 (1H, m) .IR (neat): ν 3473, 3058, 2951, 1738, 1597, 1491,
1449, 1219, 1172, 1074, 1002, 766, 748, 707, 633
cm ^-1 .

Example 10 Cis-iodoolefin
Preparation of (3) To a solution of dimethyl sulfoxide (DMSO) (1.2 ml, 17 mmol) in dichloromethane (30 ml) was added oxalic acid chloride (0.88 ml, 9.9
mmol) at -80 ° C, followed by alcohol 18 (817m
g, 3.29 mmol) in dichloromethane (3.0 ml) was added dropwise. After stirring for 15 minutes, triethylamine (4.6 ml, 33
mmol) and the temperature was raised to -50 ° C over 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by florisil column chromatography to obtain aldehyde 19, which was used immediately in the next reaction.

(Ph ₃ PCH ₂ I) I (2.79 g, 5.3 mmol) in THF (8.0
ml) solution at room temperature with sodium hexamethyldisilazide (1
M THF solution, 4.9 ml, 4.9 mmol) and stirred for 1 minute.
After cooling to -60 ° C, HMPA (1.2 ml) was added and the mixture was cooled to -100 ° C. A solution of aldehyde 19 in THF (2 ml) was added dropwise, the temperature was raised to -70 ° C over 40 minutes, and the mixture was further stirred at 0 ° C for 40 minutes. Hexane was added to the reaction solution, the resulting precipitate was removed by filtration, the solvent was removed, and the mixture was purified by flash column chromatography to obtain cis-iodoolefin 3 (673 mg, 1.8
(2 mmol, 55%, two steps). Olefin Z / E ratio is ¹ H
NMR (200 MHz) determined 7: 1.

¹ H NMR (200 MHz, CDCl ₃ ): δ0.05 (3H,
s), 0.09 (3H, s), 0.85 (9H, s), 2.46 (1H, dd, J = 1
4.6, 5.4Hz), 2.55 (1H, dd, J = 14.6, 7.8Hz), 3.69
(3H, s), 4.52 (1H, dtd, J = 7.2, 5.4 1.6Hz), 6.21-6.
38 (2H, m) .IR (neat): ν 2953, 2930, 2857, 1743, 1610, 1472,
1436, 1361, 1259, 1200, 1154, 1093, 953, 837, 77
9, 722 cm ^-1 . [Α] _D ³⁰ -41.2 ° (c 1.22, CHCl ₃ ).

Example 11 Epoxy alcohol (21)
In the presence of activated molecular sieves 4A (2.7 g), in a dichloromethane solution of diethyl (+)-tartaric acid (0.85 ml, 4.9 mmol), titanium tetraisopropoxide (1.05 ml, 3.5
mmol) at 0 ° C. The solution was cooled to -40 ° C and t-
Butyl hydroperoxide (7.0 M dichloromethane solution,
10 ml, 70 mmol) followed by allylic alcohol 20 (6.0
A solution of 1 g (35.2 mmol) in dichloromethane (15 ml) was added.
After stirring for 20 hours, t-butyl hydroperoxide (5
ml, 35 mmol) and stirred for 2 days. Add water to this reaction solution
(20 ml) and a 30% aqueous sodium hydroxide solution (4 ml) saturated with sodium chloride were added, and the mixture was stirred at room temperature for 20 minutes. After dilution with diethyl ether, the precipitate was removed by filtration, extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by silica gel column chromatography. Epoxy alcohol 21 (87% ee, determined by HPLC analysis, CHIRALCEL OD, hexane / 2-propanol = 4
0, RI detector). Recrystallized from pentane (350 mL) to give pure epoxy alcohol 21 (4.37 g, 23.4 mmol, 67%,
99% ee).

Example 12 Preparation of alkyne (22) A solution of epoxy alcohol 21 (51.2 mg, 275 mmol) and 2,6-lutidine (70 ml, 830 mmol) in dichloromethane (2 ml) was mixed with trifluoromethanesulfonic anhydride (95 ml). , 560 mmol) in dichloromethane (1 ml) was added at -20 ° C and stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and after extraction with diethyl ether, the organic layer was washed with a saturated aqueous solution of ammonium chloride and saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The crude product of triflate obtained by removing the solvent was not generated, and only dehydration by azeotropic distillation with toluene was performed, and the resultant was directly used for the next reaction.

Acetylene gas was blown into THF (3 ml) at −80 ° C. for 1 hour, followed by a solution of n-butyllithium (1.5 M hexane solution, 0.53 ml) in THF (1.0 ml) and 1,3-dimethyl -3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU)
(0.9 ml) was added. A solution of triflate in THF (1.0 ml) was added, and the temperature was raised to 0 ° C. over 10 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with hexane-ethyl acetate, and the organic layer was washed with a saturated aqueous ammonium chloride solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by flash column chromatography to obtain alkyne 22 (24.4 mg, 126 mmol, 46%). ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.88 (3H, t, J = 7.0 Hz),
1.12-1.68 (14H, m), 2.01 (1H, t, J = 7.5Hz), 2.28 (1
H, ddd, J = 17.0, 7.4, 3.0Hz), 2.59 (1H, ddd, J = 17.
0, 5.4, 2.4Hz), 2.92-3.02 (1H, m), 3.15 (1H, ddd,
J = 7.4, 5.4, 3.8Hz).

Example 13 Production of bromoalkyne (23) N-bromosuccinimide (670 mg, 3.8 mmol) and silver nitrate (27 mg, 1 mmol) were added to a solution of alkyne 22 (3.07 mmol) in acetone (12 ml).
60 mmol) at room temperature and stirred for 1.5 hours. Extracted with hexane-ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by flash column chromatography.
5 mg, 2.18 mmol, 71%). _{^{1 H NMR (200MHz, CDCl 3}} ): δ0.88 (3H, t, J = 6.8Hz),
1.12-1.60 (14H, m), 2.30 (1H, dd, J = 17.0, 6.8Hz),
2.61 (1H, dd, J = 17.0, 5.2Hz), 2.90-3.01 (1H, m), 3.
13 (1H, ddd, J = 7.4, 5.8, 4.4Hz) .IR (neat): ν 2926, 2856, 2222, 1465, 1379, 1291,
1200, 977, 918, 826,775 cm ^-1 . [Α] _D ³⁰ + 48.2 ° (c 1.06, CHCl ₃ ).

Example 14 Trans-vinyl tin (4)
Manufacturing bromo alkyne 23 (531mg, 1.94mmol) and tributyltin hydride _{(1.3ml, 4.9mmol) PdCl 2 (} PP in THF (4 ml) solution of
h ₃ ) ₂ (14 mg, 19 mmol) was added at room temperature and stirred for 5 minutes. After removing the solvent, the product was purified by flash column chromatography (hexane-ethyl acetate containing 1% triethylamine),
Trans-vinyl tin 4 was obtained (277 mg, 570 mmol, 29%). The olefin E / Z ratio was determined to be 7 to 1 from ¹ H NMR (200 MHz). ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.70-1.05 (18H, m), 1.10
-1.60 (26H, m), 2.29 (1H, ddd, J = 14.8, 6.4, 4.4H
z), 2.45 (1H, ddd, J = 14.8, 6.4, 4.4Hz), 2.93-3.05
(2H, m), 5.87-6.13 (2H, m).

Example 15 Production of diene (24) Pd_Two(dba)_Three・ CHCl_Three(14.9mg, 14mmol) and (2-furyl)_ThreeP (1
3.4mg, 58mmol) N-methylpyrrolidinone (NMP) (0.3ml)
The solution was stirred for 10 minutes and the iodoolefin 3 (232 mg, 6
27 mmol). NM of vinyl tin 4 (277mg, 570mmol)
P (0.5ml) solution over 20 hours using syringe pump
And dropped. 23 hours later, additional Pd_Two(dba) _Three・ CHCl_Three(14.5
mg, 14mmol) and (2-furyl)_ThreeP (13.5mg, 58mmol) NMP
(0.2 ml) solution was added and stirred for 5 days. Hexane-acetic acid
The mixture was extracted with chill, and the organic layer was washed with water and saturated saline. anhydrous
After drying over magnesium sulfate, remove the solvent and flash column
Purified by chromatography, diene 24 (192 mmol, 34%)
Obtained.¹ H NMR (200MHz, CDCl_Three): δ0.01 (3H, s), 0.04 (3H,
s), 0.84 (9H, s), 0.80-0.90 (3H, m), 1.20-1.60 (14
H, m), 2.24-2.50 (3H, m), 2.50-2.62 (1H, m), 2.88-
3.02 (2H, m), 5.04 (1H, td, J = 8.8, 4.8Hz), 5.32
(1H, dd, J = 9.2,8.8Hz), 5.75 (1H, dt, J = 15.2, 6.8
Hz), 5.94 (1H, t, J = 11.0Hz), 6.44 (1H, dd, J = 15.
2, 11.2Hz).

Example 16 Preparation of Alcohol (25) To a solution of diene 24 (192 mmol) in THF (1.0 ml) was added tetrabutylammonium fluoride (1.0 M THF solution, 290 ml, 290 m 2).
mol) and stirred at room temperature for 6 hours. After removing the solvent, purification was performed by flash column chromatography to remove alcohol 25 (48.
9 mg, 151 mmol, 78%). _{^{1 H NMR (200MHz, CDCl 3}} ): δ0.88 (3H, t, J = 6.4Hz),
1.20-1.60 (14H, m), 2.28-2.45 (2H, m), 2.51 (1H, d
d, J = 16.5, 4.4Hz), 2.60 (1H, dd, J = 16.5, 7.6Hz),
2.79 (1H, d, J = 3.5Hz), 2.91-3.04 (2H, m), 3.72
(3H, s), 4.92-5.08 (1H, m), 5.38 (1H, dd, J = 11.2,
8.2Hz), 5.79 (1H, dt, J = 15.2, 6.8Hz), 6.06 (1H,
t, J = 11.0Hz), 6.47 (1H, dd, J = 15.2, 11.2Hz) .IR (neat): ν 3456, 2925, 2856, 1738, 1656, 1438,
1379, 1357, 1274, 1167, 1038, 990, 951,845, 822,
724 cm ^-1 . [Α] _D ²⁹ -10.5 ° (c 0.58, CHCl3).

Example 17 Production of Carboxylic Acid (26) To a solution of alcohol 25 (5.9 mg, 18 mmol) in methanol (0.3 ml) was added lithium hydroxide (1.0 M aqueous solution, 37 ml, 37 mmol), and the mixture was stirred at room temperature for 6.5 hours. Stirred for hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. After removal of the solvent, purification was performed by flash column chromatography to remove carboxylic acid 26 (4.6 mg, 15 mmol, 81%).
Obtained. ¹ H NMR (200 MHz, CDCl ₃ ): δ 0.88 (3H, t, J = 7.4 Hz),
1.20-1.60 (14H, m), 2.28-2.42 (2H, m), 2.50-2.68
(2H, m), 2.92-3.08 (2H, m), 4.90-5.10 (2H, m), 5.3
8 (1H, t, J = 10.2Hz), 5.80 (1H, dt, J = 15.2, 7.1H
z), 6.06 (1H, t, J = 10.7Hz), 6.48 (1H, dd, J = 14.6,
12.2Hz).

Example 18 Preparation of Korol Sewing Machine (1) Carboxylic acid 26 (4.6 mg, 15 mmol) and amine 2 (3.3 mg, 2
3mmol) in DMF (50 ml) solution, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCHCl) (4.
6 mg, 24 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (3.9 mg, 29 mmol) were added at room temperature. After stirring for 10 hours, the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was removed and purified by flash column chromatography to obtain cholor sewing machine 1 (2.7 mg, 6.2 mmol,
Amine 2 was recovered (1.9 mg, 14 mmol, 58%). Further, the geometric isomer of kororum sewing machine 1 was analyzed by HPLC (CHIRALCEL O
Purification with D, hexane / 2-propanol = 30) gave pure corrolecin 1 (2.1 mg, 4.8 mmol). The optically active cholor sewing machine thus obtained had all the physical properties corresponding to those of the natural cholor sewing machine.

¹ H NMR (600 MHz, CDCl ₃ ): δ 0.88 (3H, t,
J = 7.2Hz), 0.90 (3H, t, J = 7.5Hz), 1.23-1.46 (12
H, m), 1.49 (3H, s), 1.50-1.56 (2H, m), 1.79 (1H,
dq, J = 14.2, 7.4Hz), 1.86 (1H, dq, J = 14.2, 7.4H
z), 2.35 (1H, t, J = 6.5Hz), 2.57 (1H, dd, J = 15.7,
3.2Hz), 2.62 (1H, dd, J = 15.7, 8.6Hz), 2.68 (1H,
d, J = 2.9Hz), 2.97 (1H, td, J = 5.9, 4.2Hz), 2.99 (1
H, td, J = 6.2, 4.2Hz), 5.04-5.08 (1H, m), 5.40 (1
H, t, J = 9.7Hz), 5.84 (1H, dt, J = 15.1, 6.7Hz), 6.0
9 (1H, t, J = 10.9Hz), 6.46 (1H, dd, J = 15.0, 11.2H
. z), 7.36 (1H, s), 8.22 (1H, bs) 13 C NMR (150MHz, CDCl 3): δ8.22, 14.09, 22.65, 24.
27, 26.58, 27.77, 29.21, 29.507, 29.511, 31.45, 3
1.83, 32.05, 43.34, 55.79, 57.16, 64.74, 88.48, 12
4.52, 126.69, 129.43, 130.94, 132.89, 134.11, 169.
18, 170.21.

[0048]

According to the present invention, an optically active natural product, which is inexpensive and easily available, is used as a starting material, and further, by combining inconsistent components, dehydroaminolactone, which is an important key compound, and an optically active corrole sewing machine can be produced at low cost. And a production method capable of mass production.

[Brief description of the drawings]

FIG. 1 is a diagram showing a synthesis route of dehydroaminolactone.

FIG. 2 Optically active cis used as a raw material for the synthesis of koror sewing machine
FIG. 3 is a view showing a synthesis route of -iodoolefin.

FIG. 3 is a view showing a synthesis route of a tin compound as a raw material for synthesizing a corrole sewing machine.

FIG. 4 is a diagram showing a route for synthesizing a cholor sewing machine from dehydroaminolactone, an optically active cis-iodoolefin, and a tin compound.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hisatoshi Uehara Aoba, Aoba-ku, Aoba-ku, Sendai City, Miyagi Prefecture Within the Graduate School of Science, Tohoku University (72) Inventor Kenichi Mochida 1900 Soedoshicho, Shimizu-shi, Shizuoka Marine Biotechnology Co., Ltd. Within the Research Laboratory Shimizu Research Laboratory (72) Inventor Kazuhiro Yoshikawa 1900 Sodesoshi-cho, Shimizu City, Shizuoka Prefecture Marine Biotechnology Research Laboratory, Inc. Shimizu Research Laboratory F-term (reference) 4C063 AA01 BB04 CC75 DD71

Claims (3)

[Claims] 1. A dehydroaminolactone represented by the following formula I: Embedded image 2. An optically active aldehyde represented by the following formula II is converted to a glycine ester represented by the following formula III (wherein R ¹
Represents an alkyl group having 1 to 6 carbon atoms, R ² represents a substituted methylene group) and causes an aldol reaction, and an optically active lactone represented by the following formula IV (wherein R ² represents a substituted methylene group)
2. The method for producing dehydroaminolactone according to claim 1, wherein the protecting group for the amino group of the optically active lactone is eliminated after the conversion into the compound. Embedded image Embedded image Embedded image 3. An optically active carboxylic acid represented by the following formula V (wherein R ³ represents a linear alkyl group having 1 to 20 carbon atoms).
Is condensed with a dehydroaminolactone represented by the following formula I: Embedded image Embedded image