JPH09249653A - Electrophilic asymmetric fluorinating reagent - Google Patents

Abstract

(57) [Summary] [Structure] Novel optically active N-fluoro-3,3-dialkyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative and its electrophilic fluorine It relates to a stereospecific fluorination method characterized by being used as a fluorination reagent. [Effect] According to the present invention, it becomes possible to stereospecifically produce an optically active monofluoro compound which can be expected to have various physiological activities.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the synthesis of an asymmetric fluorinating reagent which is useful in the field of synthetic organic chemistry including drug development and is excellent in selectivity and reaction characteristics, and asymmetric fluorinating using the same. It is about the method.

[0002]

2. Description of the Related Art Organic halogen compounds, especially organic fluorine compounds, have come into the limelight as physiologically active substances because of the steric and electronic specificity of halogen atoms. For the purpose of introducing a fluorine atom into an organic compound, in particular, a physiologically active substance or an existing drug, improvement of physical properties,
The enhancement of pharmacological effects, the expression of different pharmacological effects, and the separation of side effects are considered. However, from the viewpoint of synthetic chemistry, most of the currently known fluorine-containing drugs do not cause any stereochemistry problems because of severe restrictions on the means for introducing a fluorine atom, and their synthesis is not possible. It is a relatively easy trifluoromethylated derivative or aromatic fluorinated derivative. However, since aliphatic monofluoro compounds, as represented by fluorinated steroids, have great potential from the viewpoint of manifestation of pharmacological action, they can be said to be extremely promising compounds in the field of drug development. . In the case of such a chiral compound in which a fluorine atom is directly connected to the asymmetric center, the configuration of the fluorine atom poses a serious problem. The reason is that the steric factor is greatly involved in the mutual relationship between the drug and the receptor, which is the first-step behavior for expressing the pharmacological action. Therefore, when synthesizing a fluorine-containing compound with the drug development in mind, it is not only regioselective for the mother molecule,
It is extremely important to stereo-selectively fluorinate.

[0003]

However, until now, the synthesis of a fluorine-containing chiral compound in which a fluorine atom is directly bonded to an asymmetric center has relied on very limited means. The reason is that it is difficult to apply means such as optical resolution that has been frequently used conventionally because of the steric and electronic specificity of the fluorine atom. Under such circumstances, the development of new means for efficiently obtaining an optically active monofluoro compound has been a proposition for many years. As a new means to overcome this problem, it is necessary to develop an electrophilic fluorinating reagent having an asymmetric induction ability in the molecule. The conventional asymmetric fluorination method utilizing the three-dimensional structure of the substrate not only requires the preparation of an optically active substrate in advance, but this method is applicable only to substrates with a very limited structure. , Lacks generality. Therefore, contrary to such conventional methods, it is the most important issue to develop an asymmetric fluorination method based on a new concept of incorporating some asymmetric induction function in the fluorination reagent side. .

[0004]

Means for Solving the Problems The inventors of the present invention have conducted earnest research on the basis of such a current situation, and as a result, the following general formula (R
¹ and R ² are the same as defined above)

Embedded image That the optically active N-fluoro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative represented by the formula (1) meets this purpose, and that they can be excellent stereoselective fluorinating reagents Was confirmed, and the present invention was completed. That is, the present invention relates to the general formula

Embedded image (Wherein R ¹ and R ² are the same as defined above), and a novel optically active N-fluoro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative and Novel optically active N-fluoro-
2,3-dihydro-1,2-benzisothiazole
The present invention relates to a novel method for asymmetric fluorination, which comprises using a 1,1-dioxide derivative as a fluorinating reagent in an electrophilic reaction mode.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION Optically active N-fluoro-2,3-dihydro-as an asymmetric fluorinating reagent according to the present invention
The 1,2-benzisothiazole 1,1-dioxide derivative is produced by the following method. First, saccharin (1), which can be obtained at low cost, is used as the starting material. In the first step, one suitable alkyl group or two different alkyl groups are introduced into the 3-position of saccharin to form a chiral molecule. That is, an alkyl Grignard reagent or an alkyl lithium reagent corresponding to the R ¹ group is allowed to act on saccharin in ether or tetrahydrofuran to give a corresponding imine form (2-4). Methods reported previously (Abramovitch et al., Tetrahed
Ron, 1996, 52, 3339, Oppolzer et al., Tetrah.
edron Lett. 1991, 32, 4893, Oppolzer et al.
Tetrahedron Lett. 1990, 31, 4117, etc.), these are hydrogenated in a suitable manner to give 3-monoalkyl substituents. In addition, the imine body (2-
The 4) is further reacted with an alkyl Grignard reagent or an alkyllithium reagent corresponding to the R ² group to obtain a 3,3-dialkyl-substituted compound (5-9).
There is no particular limitation on the order of introducing the R ¹ group and the R ² group when synthesizing the 3,3-dialkyl compound. The R ¹ group and R ² group can be selected from C _{1 to} C ₁₀ chain and cyclic alkyl groups such as methyl group, ethyl group, isopropyl group, t-butyl group and cyclohexyl group, alkenyl groups, Examples include an alkynyl group or a substituted or unsubstituted aryl group such as a phenyl group, and an aralkyl group such as a benzyl group.

Since (5-9) obtained at this stage is a racemate, it is converted into the corresponding optically active form by performing optical resolution by an appropriate method. For example, the sulfonamide moiety is protected by (+)-camphorsulfonylation or mentoxyacetylation of these sulfonamide moieties, and then the resulting mixture of two diastereomers is subjected to a suitable method such as column chromatography. Separated and purified with
Subsequent deprotection of these protecting groups can give both the two optically active forms, namely the enantiomers. The thus obtained optically active 3-monoalkyl-substituted or 3,3-dialkyl-substituted 2,3-dihydro-1,
2-Benzisothiazole 1,1-dioxide derivative was treated with fluorine gas or perchloryl fluoride gas to give N-
The corresponding optically active N-fluoro derivative (10-12) can be obtained by fluorinating. Also, N-
If N-chlorination or N-bromination is applied instead of fluorination, the corresponding N-chloro compound or N-bromo compound can be similarly obtained.

Then, the optically active N-fluoro-2,3-dihydro-1,2-benzisothiazole thus obtained.
The stereoselective fluorination reaction using the 1,1-dioxide derivative (10-12) will be described. The target substance for performing the stereoselective fluorination reaction is not particularly limited as long as it can be asymmetrically fluorinated by undergoing an electrophilic fluorination reaction, but in the examples of the present application, 2-methyl Active methylene compounds such as -1-tetralone and 2-benzyl-1-tetralone were used. By reacting these starting materials with the optically active fluorinating reagent of the present invention in the presence of a suitable base such as lithium diisopropylamide in a solvent such as tetrahydrofuran, a stereoselective conversion to the active methylene moiety is achieved. Monofluorination can be applied. In this case, the stereochemistry of the introduced fluorine atom depends on the three-dimensional structure of the fluorinating reagent to be used. A fluoro compound can be obtained. The invention is explained in more detail by the examples described below.

[0008]

【Example】

1. Preparation of 3-monoalkyl-1,2-benzisothiazole 1,1-dioxide derivative (2-4) 3-Methyl-1,2-benzisothiazole 1,1-
Synthesis of Dioxide (2) To a solution of saccharin (3.30 g, 18 mmol) in ether (100 ml) was added freshly prepared methylmagnesium iodide (6.6 g, 40 mmol) at 0 ° C. to give 16 Stir for hours. The reaction is stopped by adding water and the aqueous layer is brought to pH 1 with 10% HCl. After separating the organic layer, the aqueous layer is extracted twice with ether (100 ml). The combined organic layers are washed with 10% sodium thiosulfate and then saturated brine, dried over magnesium sulfate, and the solvent is evaporated. The residue is purified by recrystallization (methanol), 3-
Methyl compound (2) was obtained as colorless crystals (2.09 g,
Yield 64%). Physical and spectral data are shown below. mp 219-220 ° C (methanol) ¹ H-NMR (δppm): 2.67 (3H, s, CH ₃ ), 7.69 −7.93
(4H, m, Arom) IR (KBr) (νcm ^-1 ): 1559 (C = N), 1321 (SO ₂ ), 1173 (S
O ₂ ) .MS m / z: 181 (M ⁺ ), 117 (M ⁺ —SO ₂ ) 3-t-butyl-1,2-benzisothiazole 1,
Synthesis of 1-dioxide (3) The 3-t-butyl compound (3) was obtained as a colorless solid in the same manner as the above-mentioned reaction procedure (yield 64%). Physical and spectral data are shown below. mp 130 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 1.53 (9H, s, tBu), 7.70-7.94
(4H, m, Arom) IR (KBr) (νcm ^-1 ): 1546 (C = N), 1335 (SO ₂ ), 1173 (S
O ₂ ). MS m / z 223 (M ⁺ ), 208 (M ⁺ —CH ₃ ) 3-phenyl-1,2-benzisothiazole 1,1
-Synthesis of Dioxide (4) In the same manner as the above-mentioned reaction procedure, 3-phenyl compound (4)
Was obtained as a colorless solid (yield 61%). Physical and spectral data are shown below. mp 170 ° C (methanol / ethyl acetate) ¹ H-NMR (δppm): 7.59 −8.04 (9H, m, Arom) IR (KBr) (νcm ⁻¹ ): 1719 (C = N), 1326 (SO ₂ ), 1169 (S
O ₂ ) .MS m / z 243 (M ⁺ ), 179 (M ⁺ −SO ₂ ).

2.3 Preparation of 3,3-dialkyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative (5-9) 3-Methyl-3-isopropyl-2,3-dihydro −
Synthesis of 1,2-benzisothiazole 1,1-dioxide (5) 3-methyl derivative (2) (1.20 g, 7.1) synthesized above
isopropylmagnesium bromide (1.35 g) prepared in a nitrogen atmosphere in an ether solution (35 ml) of
Equivalent, 9.2 mmol) is added at 0 ° C. and stirred for 3 hours.
Water and 10% HCl are added sequentially to bring the aqueous layer to pH 1.
After separating the organic layer, the aqueous layer is extracted three times with ethyl acetate (50 ml). Combine the organic layers with 10% sodium thiosulfate,
Then, it is washed with saturated saline and dried over magnesium sulfate, and then the solvent is distilled off. The residue was purified by column chromatography (n-hexane / ethyl acetate = 2: 1) and recrystallized (ethyl acetate / n-hexane),
84 g of the target compound (5) was obtained (yield 49%). Physical and spectral data are shown below. mp 83.5-84 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 0.75 (3H, d, J = 6.6 Hz, iPro), 1.08
(3H, d, J = 6.6Hz, iPro), 1.63 (3H, s, CH ₃ ), 2.14 (1
H, sept, J = 6.6Hz, CH), 4.38 (1H, bs, NH), 7.35 (1H,
d, J = 7.7Hz, Arom), 7.53 (1H, td, J = 7.1, 1.1Hz, Aro
m), 7.64 (1H, td, J = 7.7, 1.1Hz, Arom), 7.76 (1H, dd,
J = 7.7, 1.1Hz, Arom) IR (KBr) (νcm ^-1 ): 3285 (NH), 1158 (SO ₂ N) MS m / z 226 (M ⁺ +1), 210 (M ⁺ -Me), 182 (M ⁺ -iPr) Anal.Calcd for C ₁₁ H ₁₅ NO ₂ S: C, 58.64; H, 6.71; N,
6.22; Found: C, 58.39; H, 6.61; N, 5.92 3-Cyclohexyl-3-methyl-2,3-dihydro-
1,2-Benzisothiazole 1,1-dioxide (6) In the same manner as the above-mentioned reaction procedure, 3-cyclohexyl-
The 3-methyl derivative (6) was obtained as a colorless solid (yield 60
%). Physical and spectral data are shown below. mp 181-183 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 0.98-2.02 (11H, cHex), 1.61 (3H, s,
CH ₃ ), 4.34 (1H, bs, NH), 7.33 (1H, d, J = 7.8Hz, Aro
m), 7.51 (1H, t, J = 7.4Hz, Arom), 7.63 (1H, t, J = 7.3H
z, Arom), 7.75 (1H, d, J = 7.8Hz, Arom) IR (KBr) (νcm ^-1 ): 3242 (NH), 1276 (SO ₂ ), 1155 (SO ₂ N) MS m / z 266 (M ⁺ +1), 244 (M ⁺ -CH ₃ ), 182 (M ⁺ -C
₆ H ₁₁ ) Anal.Calcd for C ₁₄ H ₁₉ NO ₂ S: C, 63.36; H, 7.22; N,
5.28; Found: C, 63.02; H, 7.19; N, 5.20 3-tbutyl-3-methyl-2,3-dihydro-1,2.
-Benzisothiazole 1,1-dioxide (7) A 3-tbutyl-3-form (7) was obtained in the same manner as the above-described reaction procedure (yield 46%). Physical and spectral data are shown below. mp 178-180 ° C (methylene chloride / carbon tetrachloride) ¹ H-NMR (δppm): 1.05 (9H, s, tBu), 1.65 (3H, s, C
H ₃ ), 4.46 (1H, bs, NH), 7.49−7.79 (4H, m, Arom) IR (KBr) (νcm ⁻¹ ): 3260 (NH), 1291 (SO ₂ ), 1176 (SO
₂ N) MS m / z 240 (M ⁺ 1), 224 (M ⁺ −CH ₃ ), 182 (M ⁺ −tBu) Anal.Calcd for C ₁₂ H ₁₇ NO ₂ S: C, 60.2; H, 7.16; N,
5.85; Found: C, 59.64; H, 7.08; N, 5.78 3-Methyl-3-phenyl-2,3-dihydro-1,2
-Benzisothiazole 1,1-dioxide (8) The 3-methyl-3-phenyl derivative (8) was obtained as a colorless solid (yield 39%) in the same manner as the above-mentioned reaction procedure. Physical and spectral data are shown below. mp 117-118 ° C. (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 2.07 (3H, s, CH ₃ ), 4.83 (1H, bs, N
H), 7.20−7.82 (9H, m, Arom) IR (KBr) (νcm ⁻¹ ): 3237 (NH), 1312 (SO ₂ ), 1179 (SO ₂ N) MS m / z: 260 (M ⁺ 1 ), 259 (M ⁺ ), 244 (M ⁺ −CH ₃ ), 18
2 (M ⁺ −Ph) Anal. Calcd for C ₁₄ H ₁₃ NO ₂ S: C, 64.8; H, 5.05; N,
5.40; Found: C, 64.53; H, 4.96; N, 5.26 3-benzyl-methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (9) In the same manner as the above-mentioned reaction procedure. , 3-Benzyl-3-methyl derivative (9) (40% yield) was obtained as a colorless solid. The physical data is shown below. mp 151 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 1.58 (3H, s, CH ₃ ), 3.03 (1H, d, J = 1
3.7Hz, PhCHaHb), 3.19 (1H, d, J = 13.7Hz, PhCHaHb),
4.44 (1H, bs, NH), 7.21-7.40 (6H, m, Arom), 7.55 (1
H, ddd, J = 7.4, 7.4, 1.1 Hz, Arom), 7.66 (1H, ddd, J
= 7.69, 7.69, 1.10Hz, Arom), 7.77 (1H, d, J = 7.69Hz,
Arom) IR (KBr) (νcm ^-1 ): 3262 (NH), 1276, 1161, 1132 (SO ₂
N) MS m / z: 274 (M ⁺ +1), 273 (M ⁺ ), 258 (M ⁺ −CH ₃ ),
182 (M ⁺ −Bn), 91 (Bn ⁺

3. Racemic Resolution The 3,3-dialkyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative synthesized in Example 2 is condensed with camphorsulfonyl chloride and the resulting diastereomers are separated. Racemic resolution was performed by the method of removing the camphorsulfonyl portion. The racemic resolution of the 3-monoalkyl-substituted product was according to the method described in the literature (Oppolzer et al., Supra). 3-1. Synthesis of N-camphorsulfonyl derivative 2-camphorsulfonyl-3-methyl-3-methylethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (13a, b) Synthesis 3-methyl- 3-isopropyl body (5) (3.0, 1
3.3 mmol) was dissolved in THF (50 ml) and the solution was added to 60 ° C at 0 ° C.
% Sodium hydride (NaH) (0.64g, 16mmo
l) Add and stir for 1 hour. Then, at -80 ℃ 10-
(+)-Camphorsulfonyl chloride (3.5g, 14mm
ol) is added, the temperature is gradually raised, and the mixture is stirred at room temperature for 3 hours.
Stop the reaction by adding water and add 10% HCl to adjust the pH.
Let it be 1. The mixture is extracted 3 times with ethyl acetate (50 ml), the organic layer is dried over magnesium sulfate, and the solvent is evaporated. The residue was subjected to column chromatography (chloroform / ethyl acetate = 9: 1) to obtain 3.68 g of a diastereomeric mixture (13a, b) (yield 63%).
Further, both diastereomers were separated by repeating column chromatography (chloroform / ethyl acetate = 9: 1) and recrystallization (methylene chloride / n-hexane), and a low polar isomer (13a) (1.47 g, Yield 25
%), Highly polar isomer (13b) (1.77 g, yield 30)
%) As colorless crystals. Physical and spectral data are shown below. Low polarity isomer (13a) mp 224-227 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 0.85 (3H, d, J = 7.1Hz, iPro), 0.86
(3H, s, gem CH ₃ ), 1.15 (3H, d, J = 7.1Hz, iPro), 1.18
(3H, s, gem CH ₃ ), 1.43 −1.52 (1H, m, bornyl), 1.72
−1.81 (1H, m, bornyl), 1.97 (1H, d, J = 18.1Hz, borny
l), 2.04−2.15 (2H, m, bornyl), 2.11 (3H, s, CH ₃ ),
2.35 −2.43 (1H, m, bornyl), 2.54 −2.64 (1H, m, bor
nyl), 2.91 (1H, J = 6.87Hz, CH), 3.69 −3.80 (2H, ABq,
SO ₂ CH ₂ ), 7.46 (1H, d, J = 7.69Hz, Arom), 7.58−7.63
(1H, m, Arom), 7.67 −7.73 (1H, m, Arom), 7.83 (1H,
d, J = 7.69Hz, Arom) IR (KBr) (νcm ^-1 ): 1744 (C = O), 1329 (SO ₂ ), 1188 (SO
₂ N) MS m / z: 440 (M ⁺ +1), 439 (M ⁺ ), 396 (M ⁺ -iPr) Highly polar isomer (13b) mp 214-215 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 0.81 (3H, d, J = 7.1Hz, iPro), 0.99 (3
H, s, gem CH ₃ ), 1.18 (3H, d, J = 6.6Hz, iPro), 1.24 (3
H, s, gem CH ₃ ), 1.38−1.45 (1H, m, bornyl), 1.60 −
1.68 (1H, m, bornyl), 1.94 (1H, d, J = 18.7Hz, borny
l), 2.04 (3H, s, CH ₃ ), 2.05−2.13 (2H, m, bornyl),
2.39 −2.60 (2H, m, bornyl), 2.95 (1H, J = 6.87Hz, C
H), 3.43 (1H, d, J = 14.8Hz, SO ₂ CHaHb), 4.09 (1H, d, J
= 14.8Hz, SO ₂ CHaHb), 7.45 (1H, d, J = 7.69Hz, Arom),
7.58−7.63 (1H, m, Arom), 7.67−7.72 (1H, td, J = 7.
7, 1.1Hz, Arom), 7.83 (1H, dd, J = 7.7, 1.6 Hz, Arom) IR (KBr) (νcm ^-1 ): 1746 (C = O), 1365 (SO ₂ N), 1331 (S
O ₂ ), 1190 (SO ₂ N) MS m / z: 440 (M ⁺ +1), 439 (M ⁺ ), 396 (M ⁺ −iPr)

2-Camphorsulfonyl-3-cyclohexyl-3-methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (14a, b) In the same manner as the above-mentioned reaction procedure, 3- Cyclohexyl
From 3-methyl derivative (6) to 2-camphorsulfonyl-3
-Cyclohexyl-3-methyl derivative low polar isomer (14a) (yield 28%) and high polar isomer (14a)
b) (27% yield) was obtained as colorless crystals. Physical and spectral data are shown below. Low polar isomer (14a) mp 288-289 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 0.33 -2.59 (20H, cHex, bornyl),
0.86 (3H, s, gem CH ₃ ), 1.17 (3H, s, gem CH ₃ ), 2.10 (3
H, s, CH ₃ ), 3.72 −3.73 (2H, ABq, CH ₂ ), 7.45 (1H, d,
J = 7.7Hz, Arom), 7.59 (1H, t, J = 7.7Hz, Arom), 7.69
(1H, t, J = 7.7Hz, Arom), 7.81 (1H, d, J = 7.7Hz, Arom) IR (KBr) (νcm ^-1 ): 1748 (C = O), 1361 (SO ₂ ), 1331 (S
O ₂ ), 1190 (SO ₂ N) MS m / z: 480 (M ⁺ +1), 396 (M ⁺ −cHex), 396 (M ⁺ ) Highly polar isomer (14b) mp 275−278 ℃ (Chloride Methylene / n-hexane) ¹ H-NMR (δppm): 0.33 −2.63 (20H, cHex, bornyl),
0.97 (3H, s, gem CH ₃ ), 1.23 (3H, s, gem CH ₃ ), 2.02 (3
H, s, CH ₃ ), 3.46 (1H, d, J = 14.29Hz, CH ₂ ), 4.00 (1H,
d, J = 14.29Hz, CH ₂ ), 7.44 (1H, d, J = 8.2Hz, Arom), 7.
60 (1H, t, J = 7.7Hz, Arom), 7.70 (1H, td, J = 7.7, 1.7H
z, Arom), 7.81 (1H, dd, J = 8.2, 1.6Hz, Arom) IR (KBr) (νcm ^-1 ): 1748 (C = O), 1356 (SO ₂ ), 1332 (S
O ₂ ), 1189 (SO ₂ N) MS m / z: 480 (M ⁺ +1), 396 (M ⁺ −cHex)

3-2. Synthesis of optically active 2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivatives (5) and (6) by removal of N-camphorsulfonyl group Optically active 3-methyl-3-isopropyl-2, Synthesis of 3-dihydro-1,2-benzisothiazole 1,1-dioxide ((+)-5) and ((-)-5) 2-camphorsulfonyl-3-methyl-3 at 0 ° C.
-Isopropyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (13a, 950m
g, 2.2 mmol), concentrated sulfuric acid (8 ml), water (1 ml) and ethanol (1 ml) are mixed and stirred in an oil bath at 85-95 ° C. for 1.5 hours. After neutralizing by adding saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted three times with ether (30 ml), and the organic layer is washed with saturated aqueous sodium hydrogen carbonate solution. After drying over magnesium sulfate, the solvent was distilled off to obtain (+)-3-methyl-3-isopropyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((+)-5). The crude product of was quantitatively (645 mg) obtained as a colorless solid. Physical and spectral data are shown below. mp 137-138 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 0.75 (3H, d, J = 6.6Hz, iPro), 1.08
(3H, d, J = 6.6Hz, iPro), 1.63 (3H, s, CH ₃ ), 2.14 (1
H, sept, J = 6.6Hz, CH), 4.38 (1H, bs, NH), 7.35 (1H,
d, J = 7.7Hz, Arom), 7.53 (1H, td, J = 7.1, 1.1Hz, Aro
m), 7.64 (1H, td, J = 7.7, 1.1Hz, Arom), 7.76 (1H, dd,
J = 7.7, 1.1Hz, Arom) IR (KBr) (νcm ^-1 ): 3244 (NH), 2979 (CH ₃ ), 1273, 115
6, 1137 (SO ₂ N) MS m / z: 226 (M ⁺ +1), 210 (M ⁺ −Me), 182 (M ⁺ −iPro) [α] 26 / D +47.9 ° (c = 0.95, Chloroform) In the same manner as the above-mentioned reaction procedure, the highly polar isomer (13
The crude product from (b) to ((-)-5) was quantitatively obtained as a colorless solid. Physical and spectral data are shown below. mp 138 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 0.75 (3H, d, J = 6.6Hz, iPro), 1.08
(3H, d, J = 6.6Hz, iPro), 1.63 (3H, s, CH ₃ ), 2.14 (1
H, sept, J = 6.6Hz, CH), 4.38 (1H, bs, NH), 7.35 (1H,
d, J = 7.7Hz, Arom), 7.53 (1H, td, J = 7.1, 1.1Hz, Aro
m), 7.64 (1H, td, J = 7.7, 1.1Hz, Arom), 7.76 (1H, dd,
J = 7.7, 1.1Hz, Arom) IR (KBr) (νcm ^-1 ): 3244 (NH), 2979 (CH ₃ ), 1273, 115
6, 1137 (SO ₂ N) MS m / z: 226 (M ⁺ +1), 210 (M ⁺ −Me), 182 (M ⁺ −iPro) [α] 26 / D -48.5 ° (c = 1.01, (Chloroform)

Synthesis of optically active 3-cyclohexyl-3-methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((+)-6 and (-)-6) 2-camphorsulfonyl -3-cyclohexyl-3-
Methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (14a) (660 mg, 1.
38 mmol), THF (5 ml) and 2N lithium hydroxide (20 ml) are mixed and heated under reflux for 2 hours. 10% H
Cl was added and the mixture was extracted with ethyl acetate (40 ml × 3 times), the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off to give 3-cyclohexyl-3-methyl 2,3-dihydrobenzisothiazole 1,1-dioxide ((+)-
6) Obtained as a colorless solid (301 mg, 91% yield). Physical and spectral data are shown below. mp 221 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 0.98-2.02 (11H, cHex), 1.61 (3H, s,
CH ₃ ), 4.34 (1H, bs, NH), 7.33 (1H, d, J = 7.8Hz, Aro
m), 7.51 (1H, t, J = 7.4Hz, Arom), 7.63 (1H, t, J = 7.3H
z, Arom), 7.75 (1H, d, J = 7.8Hz, Arom) IR (KBr) (νcm ^-1 ): 3243 (NH), 2931 (CH ₃ ), 1276, 1155
(SO ₂ N) MS m / z: 265 (M ⁺ ), 244 (M ⁺ −Me), 182 (M ⁺ −cHex) [α] 29 / D +29.5 ° (c = 0.97, chloroform) Reaction described above In the same manner as the operation, the highly polar isomer (14
((-)-6) was obtained as a colorless solid from b) (yield 9
8%). Physical and spectral data are shown below. mp 221-223 ° C (ethyl acetate / n-hexane) ¹ H-NMR (δppm): 0.98-2.02 (11H, cHex), 1.61 (3H, s,
CH ₃ ), 4.34 (1H, bs, NH), 7.33 (1H, d, J = 7.8Hz, Ph),
7.51 (1H, t, J = 7.4Hz, Ph), 7.63 (1H, t, J = 7.3Hz, P
h), 7.75 (1H, d, J = 7.8Hz, Ph) IR (KBr) (νcm ^-1 ): 3244 (NH), 2931 (CH ₃ ), 1276, 115
6, 1135 (SO ₂ N) MS m / z 265 (M ⁺ ), 244 (M ⁺ −Me), 182 (M ⁺ −cHex) [α] 29 / D -28.6 ° (c = 1.01, chloroform)

4. Synthesis of N-fluorinated compound (10-1
2) 2-fluoro-3-methyl-3-isopropyl-2,3
-Dihydro-1,2-benzisothiazole 1,1-
Synthesis of Dioxide ((+)-10 and (-)-10) The crude dialkyl compound ((+)-5) synthesized according to Example 3-2 (645 mg) and potassium fluoride (380 mg, 6. 5 mmol) as CHCl ₃ / CFCl ₃
= 1: 1 mixed solvent (30 ml). The reaction solution was -4
While maintaining the temperature at 0 ° C., 10% (He) fluorine gas is introduced for 90 minutes. The reaction solution was naturally filtered to remove insolubles, the resulting solution was concentrated, and the residue was purified by column chromatography to give an N-fluoro compound ((+)
-10) 345 mg was obtained as a colorless solid (yield 66
%). Physical and spectral data are shown below. mp 57-58 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 1.02 (3H, dd, J = 6.8, 1.2 Hz, iPr
o), 1.10 (3H, d, J = 6.8Hz, 1.65 (3H, d, J = 5.4Hz, CH ₃ ),
2.34 (1H, sept, J = 6.8Hz, CH), 7.38 (1H, d, J = 7.8Hz,
Arom), 7.57 (1H, t, J = 7.6Hz, Arom), 7.70 (1H, t, J =
7.3Hz, Arom), 7.81 (1H, d, J = 7.8Hz, Arom) ¹⁹ F-NMR (δppm): -57.2 (s, NF) IR (KBr) (νcm ^-1 ): 1366, 1189 (SO ₂ ) MS m / z 243 (M ⁺ ), 224 (M ⁺ −F), 200 (M ⁺ −iPro) [α] 29 / D +11.5 ° (c = 1.01, chloroform) From the crude product of ((-)-5), an N-fluoro compound ((-)-10) was obtained as a colorless solid (yield 61%). Physical and spectral data are shown below. mp 56-57 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 1.02 (3H, dd, J = 6.8, 1.2Hz, iPro),
1.10 (3H, d, J = 6.8Hz, 1.65 (3H, d, J = 5.4Hz, CH ₃ ), 2.
34 (1H, sept, J = 6.8Hz, CH), 7.38 (1H, d, J = 7.8Hz, Ar
om), 7.57 (1H, t, J = 7.6Hz, Arom), 7.70 (1H, t, J = 7.3
Hz, Arom), 7.81 (1H, d, J = 7.8Hz, Arom) ¹⁹ F-NMR (δppm): -57.2 (s, NF) IR (KBr) (νcm ^-1 ): 1366, 1184 (SO ₂ N ) MS m / z 243 (M ⁺ ), 224 (M ⁺ −F), 200 (M ⁺ −iPro) [α] 29 / D -10.6 ° (c = 1.03, chloroform)

2-fluoro-3-cyclohexyl-3-
Methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((+)-11 and (-)
Synthesis of -11) Dialkyl derivative ((+)
The N-fluoro form ((+)-11) was obtained from -6) as a colorless solid (yield 94%). Physical and spectral data are shown below. mp 126-127 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 1.11-2.05 (11H, cHex), 1.65 (3H, d,
J = 5.91Hz, CH ₃ ), 7.34 (1H, d, J = 7.8Hz, Arom), 7.56
(1H, t, J = 7.6Hz, Arom), 7.69 (1H, t, J = 7.6Hz, Arom),
7.81 (1H, d, J = 7.8Hz, Arom) ¹⁹ F-NMR (δppm): -58.5 (s, NF) IR (KBr) (νcm ^-1 ): 2932 (CH ₂ ), 1359, 1186 (SO ₂ ) MS m / z: 283 (M ⁺ ), 264 (M ⁺ −F), 200 (M ⁺ −cHex) [α] 29 / D +48.0 ° (c = 0.95, chloroform) Dialkyl compound ((-)-
The N-fluoro compound ((-)-11) was obtained from 6) as a colorless solid (yield 66%. Physical data and spectrum data are shown below: mp 126-127 ° C (methylene chloride / n-hexane) ¹ H-NMR (δppm): 1.11-2.05 (11H, cHex), 1.65 (3H, d,
J = 5.91Hz, CH ₃ ), 7.34 (1H, d, J = 7.8Hz, Arom), 7.56
(1H, t, J = 7.6Hz, Arom), 7.69 (1H, t, J = 7.6Hz, Arom),
7.81 (1H, d, J = 7.8Hz, Arom) ¹⁹ F-NMR (δppm): -58.5 (s, NF) IR (KBr) (νcm ^-1 ): 2932 (CH ₂ ), 1358, 1339, 1186 ( S
O ₂ ) MS m / z: 283 (M ⁺ ), 264 (M ⁺ −F), 200 (M ⁺ −cHex) [α] 29 / D -49.2 ° (c = 1.05, chloroform)

Synthesis of 2-fluoro-3-tbutyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((+)-12 and (-)-12) and the reaction procedure described above. Similarly, in the literature known (Oppolz
er et al.) Compound (+)-3-t-butyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide to N-fluoro form ((+)-12) (yield 82%) Obtained as a colorless oil. Physical and spectral data are shown below. ¹ H-NMR (δppm): 1.19 (9H, s, tBu), 4.68 (1H, d, J = 4
0.3Hz, CH), 7.54-7.94 (4H, m, Arom) ¹⁹ F-NMR (δppm): -14.4 (bm) IR (KBr) (νcm ^-1 ): 2975 (CH ₂ ), 1367, 1186 (SO ₂ N) MS m / z: 244 (M ⁺ +1), 224 (M ⁺ −F), 223 (M ⁺ −HF) [α] 27 / D +47.3 ° (c = 0.21, chloroform) Reaction described above In the same manner as the procedure, known compounds in the literature (see above)
Oppolzer et al.) (-)-3-t-butyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide from N-fluoro body ((-)-12) (yield 85%) as an oil Obtained as a substance. Physical and spectral data are shown below. ¹ H-NMR (δppm): 1.19 (9H, s, tBu), 4.68 (1H, d, J = 4
0.3Hz, CH), 7.54−7.94 (4H, m, Arom) ¹⁹ F-NMR (δppm): -14.4 (bm) IR (KBr) (νcm ^-1 ): 2976 (CH ₂ ), 1367, 1338, 1186 (SO ₂
N) MS m / z: 244 (M ⁺ +1), 224 (M ⁺ −F), 223 (M ⁺ −HF) [α] 27 / D -50.0 ° (c = 0.65, chloroform)

5. Asymmetric fluorination reaction Optical purity (ee value) described below is based on chiral cell OB.
Alternatively, it was determined by high performance liquid chromatography (solvent; n-hexane / isopropanol) using OJ (Daicel Chemical Industry Co., Ltd.). 2-Fluoro-2-methyl-1-tetralone (see; Di
fferding et al., Helv. Chim. Acta, 1989, 72, 12
48 and Davis et al., Tetrahedron Lett., 1991.
32,1631) Synthesis of lithium diisopropylamide (LDA, 0.3 mmol)
2-Methyl-1-tetralone (40 mg, 0.25 mmol) was added to a THF (5 ml) solution of the above at −70 to −80 ° C.
Stir for 30 minutes at -40 to 0 ° C. Reaction temperature -40 to -50 ℃
Cooled to (+)-3-cyclohexyl-3-methyl-2-fluoro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((+)-11)
(78 mg, 0.28 mmol) is added and stirred for 2 hours. Then, the temperature is gradually raised to 0 ° C., and a saturated ammonium chloride solution (3 ml) is added to stop the reaction. Ethyl acetate extraction (10 ml × 3 times) is performed, the organic layer is dried over magnesium sulfate, and the solvent is evaporated. The obtained residue was subjected to preparative thin layer chromatography (n-hexane / ethyl acetate = 2:
Purification according to 1) gave the desired optically active monofluoro compound as a colorless oil (36 mg, yield 81%, optical purity 80%). The spectrum data is shown below. ¹ H-NMR (δppm): 1.60 (3H, d, J = 22.2Hz, Me), 2.21-
2.57 (2H, m, CH ₂ ), 2.95−3.23 (3H, m, CH ₂ ), 7.25 (1H,
d, J = 7.6 Hz, Arom), 7.35 (1H, t, J = 7.5 Hz, Arom),
7.53 (1H, td, J = 7.6, 1.2Hz, Arom), 8.07 (1H, d, J = 7.
8Hz, Arom) ¹⁹ F-NMR (δppm): −153.1 (qdd, J = 22.1, 16.6, 9.2Hz) MS m / z: 179 (M ⁺ +1), 178 (M ⁺ )

Synthesis of 2-benzyl-2-fluoro-1-tetralone To a solution of LDA (0.3 mmol) in THF (5 ml), -70
2-benzyl-1-tetralone (59 mg, 0.2
5 mmol) and stir at -40 to 0 ° C for 30 minutes. The reaction solution was cooled to −40 to −50 ° C., and (+)-2-fluoro-3-cyclohexyl-3-methyl-2,3-dihydro-1,2-benzisothiazole 1,1 dioxide ((+) -11) (70.8 mg, 0.25 mmol) was added and the mixture was stirred for 1.5 hours, then the temperature was gradually raised to 0 ° C, and a saturated ammonium chloride solution (3 ml) was added to stop the reaction.
Ether extraction (10 ml × 3 times) is performed, the organic layer is dried over magnesium sulfate, and the solvent is distilled off. The obtained residue was purified by column chromatography and preparative thin layer chromatography (n-hexane / ethyl acetate = 2: 1) to obtain the desired optically active monofluoro compound as a colorless oily substance (32 mg, Yield 50%, optical purity 86
%). The spectrum data is shown below. ¹ H-NMR (δppm): 2.04-2.35 (2H, m), 2.96-3.14 (3H,
m, CHaCHb), 3.32 (1H, dd, J = 17.3, 14.9Hz, CHaCHb),
7.26 −7.57 (7H, m, Ph, Arom), 8.10 (1H, d, J = 7.8 H
z, Arom) ¹⁹ F-NMR (δppm): −158 (dddd, J = 31.3, 16.6, 16.5, 5.
5 Hz) The above reaction using (-)-2-fluoro-3-isoprolyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((-)-12) as a fluorinating agent. In the same manner as the procedure, the target optically active monofluoro compound was obtained as a colorless oily substance (yield 18%, optical purity 58%). The spectrum data is ((+)-1
Consistent with that of the reaction product using 1).

Ethyl 1-fluoro-2-oxocyclopentanoate (see; Lerman et al., J. Org. Chem., 1983, 4).
Synthesis of 8,724) 60% NaH (15.3 g, 0.38 mmol) in THF (5 ml) was treated with ethyl 2-oxocyclopentanoate (5
Add 0 mg, 0.32 mmol) and stir for 15 minutes. 0 ° C
And (-)-2-fluoro-3-isopropyl-3-methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((-)-10) (93 mg, 0.
(38 mmol) and stirred for 2 hours, and then saturated ammonium chloride solution (3 ml) is added to stop the reaction. After extraction with ether (3 times 10 ml), the organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was subjected to column chromatography and preparative thin layer chromatography (n-hexane / ethyl acetate = 2: 1). The desired optically active monofluoro compound was obtained as a colorless oily substance (22 m
g, yield 40%, optical purity 48%). The spectrum data is shown below. ¹ H-NMR (δppm): 1.32 (3H, t, J = 7.1Hz, CH3), 2.08 −
2.64 (2H, m), 4.29 (2H, q, J = 7.1Hz, CH ₂ ) ¹⁹ F-NMR (δppm): -164.6 (t, J = 20.2Hz) α-fluoro-α-methylbenzoyl ethyl acetate Synthesis To a solution of 60% NaH (15.0 mg, 0.38 mmol) in THF (5 ml), ethyl α-methylbenzoyl acetate (67
mg, 0.32 mmol) and stirred for 15 minutes. -40 ° C
And (-)-2-fluoro-3-isopropyl-3-methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide ((-)-10) 93 mg, 0.3
(8 mmol) was added and the mixture was stirred for 1.5 hours, then the temperature was gradually raised to 0 ° C., and saturated ammonium chloride solution (3 ml) was added to stop the reaction. Ether extraction (10 ml × 3 times) was performed, the organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain a residue, which was subjected to column chromatography and preparative thin layer chromatography (n-hexane / ethyl acetate =).
2: 1) to obtain the desired optically active monofluoro compound as a colorless oily substance (38 mg, yield 48%, optical purity 28%). The spectrum data is shown below. ¹ H-NMR (δppm): 1.20 (3H, t, J = 7.1Hz, OCH ₂ CH ₃ ), 1.8
7 (3H, d, J = 22.7Hz, CH ₃ ), 4.26 (2H, qd, J = 7.1, 1.7H
z, CH ₂ ), 7.48 (2H, d, J = 7.8Hz, Arom), 7.43−7.62 (1
H, m, Arom), 8.05 (2H, d, J = 8.3Hz, Arom) ¹⁹ F-NMR (δppm): -152.3 (t, J = 20Hz)

Claims (2)

[Claims] 1. A compound of the general formula (In the formula, R ¹ and R ² are different from each other and are hydrogen, or a C _{1 to} C ₁₀ chain or cyclic alkyl group, alkenyl group, alkynyl group, or substituted or unsubstituted phenyl group, aryl group, or substituted Or an unsubstituted aralkyl group), which is a novel optically active N-fluoro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative 2. A compound of the general formula (In the formula, R ¹ and R ² are different from each other and are hydrogen, or a C _{1 to} C ₁₀ chain or cyclic alkyl group, alkenyl group, alkynyl group, or substituted or unsubstituted phenyl group, aryl group, or substituted Alternatively, a novel optically active N-fluoro-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide derivative represented by (showing an unsubstituted aralkyl group) is used as a fluorinating reagent in an electrophilic reaction mode. A novel asymmetric fluorination method characterized by being used.