KR101732485B1

KR101732485B1 - -Novel cyclic tolan compound preparation thereof and -sheet prepared from the same

Info

Publication number: KR101732485B1
Application number: KR1020160013518A
Authority: KR
Inventors: 조동규
Original assignee: 인하대학교 산학협력단
Priority date: 2016-02-03
Filing date: 2016-02-03
Publication date: 2017-05-04

Abstract

The present invention relates to a novel cyclic tolan compound, a preparation thereof, and a -sheet prepared from the same. A large-ring tolan compound according to the present invention limits the free rotation of two phenyl groups on both ends of tolan by introducing an ether chain, and induces the formation of a flat structure. Therefore, the large-ring tolan compound according to the present invention can have two effects including: an effect of limiting the free rotation of the phenyl groups unlike existing acyclic tolan compounds, thereby preventing the radiationless energy loss through the rotation of the phenyl group when emitting energy after exiting the tolan compound; and a fluorescent effect 1,000 times greater than existing tolan compounds by moving increased charges through the flat surface.

Description

The present invention relates to a novel cyclotoluene compound, a process for producing the same, and a β-sheet prepared from the same,

The present invention relates to a novel cyclotoluene compound, a process for producing the same, and a β-sheet produced therefrom.

Diphenylacetylene, known as tollan, has numerous conformers around the acetylene axis.

The structure and properties of the toluene heterogeneous bodies have been studied as skeletons, switches, sensors, poles and β-turn mimics of the rotating body. Among them, Tollan, studied as a β-turn analogue, (Non-Patent Document 1), a β-turn analogue can be prepared by forming a complementary peptide chain which is linked to the phenyl group at both terminals of the tolan by hydrogen bonding.

The β-turn analogue is advantageous in that the β-turn analogue can be more stably prepared by further enhancing the hydrogen bond interaction between two peptide chains continuously attached to the phenyl group at both ends of the tolane, - It can be used for the qualitative study of the sheet structure. However, when the tolan is used as a starting material in the production of the β-turn analogue, the two phenyl groups of the tolan are converted to acetylene Can be rotated about the axis, which hinders the production of the β-turn analogue.

Accordingly, the present inventors have made efforts to overcome the disadvantages and limitations of the above-mentioned tallane, and have found that the novel cyclotoluene compound according to the present invention inhibits the free rotation of two phenyl groups of tolane, Turn analogues and β-sheets which are more stable than those in the case of the present invention, and since two phenyl groups and acetylenes can be positioned on a single plane, it has been found that unprecedented excellent fluorescence can be used as a fluorescent material, Thereby completing the invention.

Kemp, D. S .; Li, Z. Q. Tetrahedron Lett. 1995, 36, 4175.

It is an object of the present invention to provide a cyclic tolane compound.

Another object of the present invention is to provide a process for producing the cyclic tolan compound.

Still another object of the present invention is to provide a motif for the production of a β-sheet protein structure containing the cyclic tolan compound.

Another object of the present invention is to provide a fluorescent substance for detecting a biomolecule containing the cyclic tolane compound.

In order to achieve the above object,

The present invention provides a compound represented by the following formula (1).

[Chemical Formula 1]

Wherein R ¹ is hydrogen or straight or branched alkyl of _1-5 C;

Wherein R ² is hydrogen or C _1-5 straight or branched chain alkylcarbonyl; And

And n is an integer of 1 to 4.

The present invention also relates to a process for producing a compound represented by the formula (1)

A step of iodinating a compound represented by formula (2) to prepare a compound represented by formula (3) (step 1);

Preparing a compound represented by the formula (4) (step 2) by subjecting the compound represented by the formula (3) prepared in the step 1 to a sonogashira coupling reaction with trimethylsily-acetylene;

A step (3) of preparing a compound represented by the formula (5) by subjecting the compound represented by the formula (4) prepared in the step 2 to a desilylation reaction and an acetylation reaction;

Reacting a compound represented by the formula (5) prepared in the above step 3 with a compound represented by the formula (6) to prepare a compound represented by the formula (7) (step 4);

(Step 5) of preparing a compound represented by the formula (9) through a compound represented by the formula (8) and Williamson ether synthesis according to the compound (7) prepared in the step 4;

A step of deacetylating the compound represented by the formula (9) prepared in the step 5 to prepare a compound represented by the formula (10) (step 6);

A step of cyclizing the compound represented by the formula (10) prepared in the step 6 to prepare a compound represented by the formula (11) (step 7); And

And a step (8) of producing a compound represented by the formula (1) by a reduction reaction of the compound represented by the formula (11) prepared in the step (7)

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ and n are as defined in Formula 1;

R ² is hydrogen; And

X is halogen.

Further, the present invention relates to a process for the preparation of

There is provided a process for preparing a compound represented by the above formula (1), comprising the step of acylating a compound represented by the formula (1a) to prepare a compound represented by the formula (1)

[Reaction Scheme 2]

In the above Reaction Scheme 2,

The compounds represented by formulas (1) and (1a) are included in the compound represented by formula (1); And

R ¹ , R ² and n are independently as defined in the above formula (1).

Also, as shown in the following Reaction Scheme 3,

There is provided a process for preparing a compound represented by the above formula (1), comprising the step of hydrolyzing a compound represented by the formula (1a) to prepare a compound represented by the formula (1b)

[Reaction Scheme 3]

In Scheme 3,

The compounds represented by formulas (Ia) and (Ib) are included in the compound represented by formula (1); And

R ¹ and n are independently as defined in the above formula (1).

Further, the present invention provides a compound represented by the above formula (11): < EMI ID =

And R < ¹ > and n are independently as defined in formula (1).

The present invention also provides a motif for the production of a β-sheet protein structure containing the compound represented by the above formula (1).

Further, the present invention provides a biomolecule-detecting phosphor containing the compound represented by the above formula (1).

The large cyclotoluene compound according to the present invention introduces an ether chain to induce the formation of a planar structure as well as restricting the free rotation of the two phenyl groups at both ends of the tolun. From the above, it can be seen that the large cyclotoluene compound according to the present invention can exhibit two effects. First, unlike the conventional non-cyclotoluene compound for exciting the tolane compound and releasing energy, by restricting the free rotation of the phenyl group, The non-radiant energy loss can be prevented, and the elevated charge transfer can be performed due to the planar structure, so that the effect of fluorescence is 1000 times or more as compared with the conventional tolan compound.

1 shows the X-ray crystal structure of the tolane compound (Example 3) according to the present invention.
FIG. 2 (a) is a graph showing the results of a comparison between a large cyclotoluene compound (Example 2-3) according to the present invention in CH ₂ Cl ₂ , a β-hairpin (Example 5-7) and a non-cyclotoluene compound 2 shows the standardized UV-visible light absorption spectrum of a large ring tortolane compound (Example 2-3) according to the present invention in CH ₂ Cl ₂ , a β-hairpin (Example 5-7) and the non-cyclotoluene compound (Comparative Example 1).

Hereinafter, the present invention will be described in detail.

[Chemical Formula 1]

Wherein R ¹ is hydrogen or straight or branched alkyl of _1-5 C;

And n is an integer of 1 to 4.

More preferably, wherein R ¹ is hydrogen or straight or branched alkyl of _1-3 C;

Wherein R ² is hydrogen or C _1-3 straight or branched alkyl-carbonyl, and; And

And n is an integer of 1 to 3.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ and n are as defined in Formula 1;

R ² is hydrogen; And

X is halogen.

Further, the present invention relates to a process for the preparation of

[Reaction Scheme 2]

In the above Reaction Scheme 2,

R ¹ , R ² and n are independently as defined in the above formula (1).

Also, as shown in the following Reaction Scheme 3,

[Reaction Scheme 3]

In Scheme 3,

R ¹ and n are independently as defined in the above formula (1).

And R < ¹ > and n are independently as defined in formula (1).

As a result of X-ray photoelectron spectroscopic analysis to analyze the structure of the large cyclotoluene compound according to the present invention, it was found that the large cyclotoluene compound had two phenyl groups of the ether chain linked with the free chain of the phenyl group based on the acetylene axis It can be confirmed that it is effectively restricted. It is also confirmed that a large cyclotoluene compound is located on one plane, and that the planarity as described above is attributable to the back angle of two phenyl groups (see Experimental Example 1 below).

In order to evaluate the structural stability of the β-hairpin prepared from the large cyclotoluene compound of the present invention, the temperature constant of the amide NH 2 hydrogen atoms in the DMSO-d ₆ of the β-hairpin prepared from the large cyclotoluene compound according to the present invention Value was compared with the temperature constant value of a conventional non-cyclotoluene compound (toluene designed by Kemp). As a result, the large cyclotoluene compound according to the present invention was found to have a large cyclotolane 11- close to strengthen the hydrogen bonding interaction between CO and NH ^tol ^tol a distance and has the effect of stabilizing the structure of the (hydrogen bonds between amide and carbonyl group is a hydrogen bond is as strong as that observed in the ring-penta-peptide), β- hairpins (See Experimental Example 2 below).

In order to evaluate the optical properties and properties of the large cyclotoluene compound according to the present invention, the standardized absorption and fluorescence spectrum experiments of the large cyclotoluene compound according to the present invention were conducted. As a result, the large cyclotoluene compound according to the present invention was found to have a Unlike the conventional toluene compounds, the free rotation of the tolan is restricted to reduce the loss of non-radiant energy due to the rotation of the phenyl group, and the planar structure is induced to increase the inter-charge mobility It has an effect of having a strong fluorescence of about 1000 times or more than that of a conventional tolan compound (see Experimental Example 3).

Therefore, the large cyclotoluene compound according to the present invention can be usefully used as a structurally stable? -Capped hairpin motif rather than the conventional non-cyclotoluene compound, and the large cyclotoluene compound according to the present invention can be used as a non- And thus has a remarkable fluorescence which can not be found, and can be usefully used as a phosphor containing the phosphor. Specifically, the large cyclotoluene compound according to the present invention can be usefully used as a motive in the production of β-hairpin, β-sheet, β-turn analogue and β-type secondary protein, Organic light emitting diodes and phosphors for biosensor detection.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited thereto.

< Example 1> Big loop Tollan Preparation of compounds 1

The central core of diacetylene (tolane) was prepared using the Sonogashira coupling reaction.

Step 1: Preparation of methyl 3-hydroxy-2-iodobenzoate of Produce

As described above, methyl 2-amino-3-hydroxybenzoate (1.00 g, 5.98 mmol) was dissolved in 40 mL of 15% sulfuric acid. 1 mL of sodium nitrite (0.45 g, 6.58 mmol) dissolved in water at 0 DEG C was added to the sulfuric acid solution and the reaction mixture was stirred at room temperature for 20 minutes. Water soluble potassium iodide (4.47 g, 26.91 mmol) was added to the reaction solution and the reaction mixture was stirred at 60 < 0 > C for 1.5 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with Na ₂ S ₂ O ₃ , dried over anhydrous Na ₂ SO ₄ and evaporated. The residue was flash-chromatographed on silica gel (DCM / hexane, 4.5 / 1) to give a light brown solid of methyl 3-hydroxy-2-iodobenzoate (0.86 g, 52%).

mp: 58-60 [deg.] C; ^{1 H-NMR (500 MHz,} CDCl 3) [ppm] 3.90 (s, 3H), 5.31 (bs, 1H), 7.09 (dd, J = 8.1, 1.6 Hz, 1H), 7.24 (m, 1H), 7.32 (dd, J = 7.8,1.2 Hz, 1H); ¹³ C-NMR (125 MHz, CDCl ₃ ) [ppm] 52.7, 86.9, 118.1, 123.3, 129.6, 135.7, 156.0, 167.1; HRMS-ESI: m / z [ M -H] - calcd for C 8 H 6 IO 3: 276.9362; found: 276.9356.

Step 2: methyl 3-hydroxy-2 - (( Trimethylsilyl ) Ethynyl ) Benzoate Produce

Methyl 3-hydroxy-2-iodobenzoate (0.55 g, 1.98 mmol) prepared in step 1 above was added to 12 mL of Et ₃ N (Triethylamine) under nitrogen gas and Pd (PPh ₃ ) ₂ Cl ₂ (0.042 g, 0.059 mmol), trimethylsilylacetylene (0.6 mL, 3.96 mmol), and CuI (0.006 gm 0.03 mmol) are added to the solution. This solution is heated at 60 占 폚 for 2 hours. The reaction mixture is cooled to room temperature and passed through a Celite pad to remove the insoluble material. The filtrate was evaporated to dryness and the residue was flash chromatographed on silica gel (EA / hexane, 1/4 4.5) to give methyl 3-hydroxy-2- ((trimethylsilyl) ethynyl) benzoate (0.408 g, 83 %).

^{1 H-NMR (400 MHz,} CDCl 3) [ppm] 0.25 (s, 9H), 3.85 (s, 3H), 6.35 (s, 1H), 7.09 (dd, J = 8.2, 1.2 Hz, 1H), 7.24 (m, 1 H), 7.47 (dd, J = 7.8, 1.2 Hz, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) [ppm] 0.1, 52.3, 97.8, 108.0, 109.6, 118.4, 122.7, 129.7, 132.0, 158.2, 166.3; HRMS-ESI: m / z [ M - H] - calcd for C 13 H 15 O 3 Si: 247.0790; found: 247.0779.

Step 3: Methyl 3-acetoxy-2-ethynyl Benzoate Produce

Triethylamine (0.5 mL, 3.46 mmol) and DMAP (4-Dimethylaminopyridine) were added to a solution of methyl 3-hydroxy-2- ((trimethylsilyl) ethynyl) benzoate (0.43 g, 1.73 mmol) in 10 mL of DCM (dichloromethane). To give the reaction mixture was cooled to 0 ℃, after adding dropwise to Ac ₂ O (0.35mLm 3.63 mmol) the lower limit, was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous NaHCO ₃ solution and extracted with DCM. Dry the combined organic layer over anhydrous Na ₂ SO ₄ and, was evaporated and dissolved in dried later, the 10 mL THF. 1 M Bu ₄ NF (0.15 mL, 18 mmol) was added to the solution under nitrogen at 0 < 0 > C. After stirring for 30 min, the mixture was poured into a saturated solution of NH ₄ Cl and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na ₂ SO _4, evaporated to dryness. The resulting residue was purified by silica gel (EA / hexane, 1 / 2.25) to give methyl 3-acetoxy-2-ethynylbenzoate (0.348 g, 92%) as a light brown solid.

mp: 62-64 DEG C; ^{1 H-NMR (400 MHz,} CDCl 3) [ppm] 2.37 (s, 3H), 3.59 (s, 1H), 3.94 (s, 3H), 7.29 (dd, J = 8.1, 1.2 Hz, 1H), 7.43 (dd, J = 8.1, 7.9 Hz, 1H), 7.86 (dd, J = 7.9, 1.2 Hz, 1H), 13 C-NMR (100 MHz, CDCl 3) [ppm] 21.0, 52.6, 76.7, 87.7, 117.1 , 126.3, 128.1, 129.3, 134.4, 153.8, 165.9, 168.9; HRMS-ESI: m / z [M + Na] ⁺ calcd for C ₁₂ H ₁₀ NaO ₄ : 241.0477; found: 241.0481.

Step 4: methyl 3- Acetoxy -2 - ((2-hydroxy-6- Nitrophenyl ) Ethynyl ) Benzoate Produce

2-Iodo-3-nitrophenol (0.34 g, 128 mmol) was added to a solution of 8-mL anhydrous toluene prepared by dissolving methyl 3-acetoxy-2-ethynylbenzoate (0.28 g, 0.8 mL of triethylamine was added to the solution. 5 minutes to give remove the gas of the product mixture, Pd in a nitrogen gas _{(PPh 3) 2 Cl 2 (} 0.027 g, 0.038 mmol), PPh 3 (0.034 g, 0.128 mmol) and CuI (0.004 g, 0.019 mmol) solution for Lt; / RTI > The resulting mixture is heated at 60 < 0 > C for 5 hours. After cooling the reaction to room temperature, the reaction mixture is poured into a saturated aqueous NaCl solution and extracted with ethyl acetate. The organic layer is dried over anhydrous Na ₂ SO ₄ and evaporated to dryness. The residue was purified by silica gel (DCM / hexane / EA, 1 / 1.4 / 0.5) to give methyl 3-acetoxy-2 - ((2-hydroxy-6-nitrophenyl) ethynyl) benzoate 0.210 g, 46%).

mp: 194-196 [deg.] C; ¹ H-NMR (400 MHz, CDCl ₃ ) [ppm] 2.54 (s, 3H), 4.01 (s, 3H), 7.32 (dd, J = 8.3, 1.2 Hz, (dd, J = 8.1, 8.1 Hz, 1H), 7.70 (dd, J = 8.1, 1.2 Hz, 1H), 8.05 (dd, J = 7.9, 1.3 Hz, 1H), 9.17 ¹³ C-NMR (100 MHz, CDCl ₃ ) [ppm] 21.3, 53.3, 91.3, 95.7, 105.2, 116.4, 118.1, 121.2, 127.7, 128.8, 129.6, 130.2, 131.6, 148.9, 152.9, 161.0, 166.3, 169.6; HRMS-ESI: m / z [M + Na] ⁺ calcd for C ₁₈ H ₁₃ N NaO ₇ : 378.0590; found: 378.0590.

Step 5: Preparation of methyl 3-acetoxy-2 - ((2- (3-bromopropoxy) -6-nitrophenyl) ethynyl) benzoate

Dichloropropane (0.2 mL, 2.04 mmol) and K ₂ CO ₃ (0.14 g, 1.02 mmol) were added to a solution of methyl 3-acetoxy-2 - ((2- -6-nitrophenyl) ethynyl) benzoate (0.18 g, 0.51 mmol) in 7 mL of DMF. The mixture was stirred at 50-60 < 0 > C for 2 hours. The reaction mixture was poured into a saturated aqueous solution of NH ₄ Cl and extracted with ethyl acetate. The organic layer was dried dried with anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by silica gel (DCM / hexane / EA, 1/1 / .08) to give methyl 3-acetoxy-2 - ((2- (3- bromomethoxy) ) Benzoate (0.164 g, 68%).

^{1 H-NMR (500 MHz,} CDCl 3) [ppm] 2.33 (s, 3H), 2.39 (m, 2H), 3.64 (t, J = 6.3, 2H), 3.89 (s, 3H), 4.23 (t, J = 5.7,2H), 7.15 (d, J = 8.3 Hz, 1H), 7.41 (m, 2H), 7.29 (dd, J = 8.1, 1.2 Hz, 1H) ), 7.85 (dd, J = 7.9, 1.2 Hz, 1 H); ^{13 C-NMR (125 MHz,} CDCl 3) [ppm] 21.0, 30.3, 32.2, 52.5, 67.4, 89.7, 94.2, 108.3, 116.2, 116.5, 117.5, 126.4, 128.0, 129.2, 129.6, 133.6, 151.4, 152.8, 160.8, 165.6, 169.2; HRMS-ESI: m / z [M + Na] ⁺ calcd for C ₂₁ H ₁₈ BrN NaO ₇ : 498.0164; found: 498.0165.

Step 6: methyl 2 - ((2- (3- Bromophore Foxy ) -6- Nitrophenyl ) Ethynyl ) -3- Hydroxybenzoate Produce

(Ethynyl (2- (3-bromo isoquinoline by) -6-nitrophenyl _{Morph)) - K 2 CO 3 (} 0.072 g, 0.52 mmol) for one, methyl 3-acetoxy--2 prepared as described in Step 5 at room temperature Benzoate (0.125 g, 0.26 mmol) in 6 mL of dissolved methanol. The mixture was stirred for 30 minutes. The reaction mixture was neutralized with 1 N HCl and the resulting solution was concentrated by removal of methanol. The residue was partitioned with ethyl acetate and water. The organic layer was dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by silica gel (EA / hexane, 1 / 2.5) to give methyl 2 - ((2- (3-bromopropoxy) -6- nitrophenyl) ethynyl) -3-hydroxybenzoate as a yellow solid Acetate (0.102 g, 89%).

mp: 94-96 [deg.] C; 1H-NMR (400 MHz, CDCl 3) [ppm] 2.55 (m, 2H), 3.69 (t, J = 6.2, 2H), 4.0 (s, 3H), 4.37 (t, J = 5.9, 2H), 7.21 (dd, J = 8.2, 1.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.2, 7.8 Hz, 1H), 7.46 J = 7.8, 1.2 Hz, 1H), 7.77 (dd, J = 8.3, 1.0 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) [ppm] 30.2 32.0, 52.6, 68.1, 92.3, 95.9, 108.4, 109.1, 116.4, 117.4, 119.0, 122.9, 129.0, 130.6, 131.4, 150.0, 159.4, 160.4, 166.1 ; HRMS-ESI: m / z [ M + Na] + calcd for C1 9 H 16 BrNNaO 6: 456.0059; found: 456.0061.

Step 7: Big loop Tollan Preparation of compounds

K ₂ CO ₃ (0.048 g, 0.345 mmol) was added to a solution of methyl 2 - ((2- (3-bromoproxy) -6-nitrophenyl) ethynyl) -3-hydroxy Benzoate (0.108 g, 0.23 mmol) in 5 mL of anhydrous DMF. The mixture was heated at 50-60 < 0 > C for 1.5 h. The reaction mixture was poured into a saturated aqueous NH ₄ Cl solution and extracted with ethyl acetate. The organic layer was dried dried with anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by silica gel (EA / hexane, 1/2) to give the desired compound (0.074 g, 91%) as a yellow solid.

mp: 138-139 [deg.] C; ^{1 H-NMR (500 MHz,} CDCl 3) [ppm] 2.12 (m, 2H), 4.27 (t, J = 5.0, 2H), 3.98 (s, 3H), 4.34 (t, J = 5.0, 2H), 7.26 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (m, 3H), 7.74 (dd, J = 7.8, 1.3 Hz, 1H), 7.81 (m, 1H); ¹³ C-NMR (125 MHz, CDCl ³ ) [ppm] 30.0 52.6, 70.1, 70.6, 89.9, 96.5, 114.0, 117.1, 120.3, 126.0, 126.6, 127.3, 129.3, 130.1, 133.7, 149.9, 162.3, 162.5, 166.6 ; HRMS-ESI: m / z [ M + Na] + calcd for C 19 H 15 NNaO 6: 376.0797; found: 376.0800.

< Example 2> Big loop Tollan Preparation of compounds 2

Fe powder (0.14 g, 2.55 mmol) was added to the suspension of gaseous acid (0.4 mL), ethanol (8 mL) and water (0.6 mL) in which the objective compound prepared in Example 1 was dissolved. The present tan liquid was heated at 70 DEG C for 1 hour. After cooling to room temperature, the reaction mixture was filtered to remove the Fe residue, which was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by silica gel (DCM / hexane, 3/1) to give the desired compound (0.068 g, 83%) as a light yellow solid.

mp: 169-171 DEG C; ^{1 H-NMR (400 MHz,} CD 2 Cl 2) [ppm] 2.12 (tt, J = 5.0, 5.0, 2H), 3.92 (s, 3H), 4.18 (m, 4H), 4.70 (bs, 2H), 8.15 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 8.2 Hz, 1H), 7.08 = 6.7, 2.3 Hz, 1H); ¹³ C-NMR (100 MHz, CDCl ₃ ) [ppm] 30.0 52.6 70.1 70.6 89.9 96.5 114.0 117.1 120.3 126.0 126.6 127.3 129.3 130.1 133.7 149.9 162.3 162.5 166.6 ; HRMS-ESI: m / z [M + Na] ⁺ calcd for C ₁₉ H ₁₇ N Na O ₄ : 346.1055; found: 346.1059.

< Example 3> Big loop Tollan Preparation of compounds 3

(0.03 g, 0.092 mmol), triethylamine (0.05 mL, 0.368 mmol) prepared in Example 2, and DMAP (0.03 mL, 0.368 mmol) were added dropwise at 0 째 C under nitrogen gas at 0 째 C Was added to 7 mL of DCM. After the addition step was complete, the reaction mixture was stirred for at least 30 minutes. The reaction mixture was poured to give a saturated aqueous solution of NaHCO ₃ and extracted with DCM. The organic layer was dried dried with anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by silica gel (DCM / EA, 20/1) to give the desired compound as a white solid (0.032 g, 94%).

mp: 191-197 [deg.] C; ^{1 H-NMR (400 MHz,} CDCl 3) [ppm] 2.13 (m, 2H), 2.40 (s, 3H), 3.91 (s, 3H), 4.43 (t, J = 5.0 Hz, 2H), 4.47 (t J = 8.1 Hz, 1H), 7.32 (m, 2H), 7.83 (m, 1H) 8.29 (d, J = d, J = 8.5 Hz, 1 H), 8.83 (s, 1 H); ¹³ C-NMR (100 MHz, CDCl ₃ ) [ppm] 24.7, 31.4, 52.5, 69.1, 69.6, 92.9, 96.8, 115.0, 116.9, 119.2, 126.5, 127.1, 129.2, 131.0, 131.2, 141.6, 152.1, 165.9 169.8; HRMS-ESI: m / z [M + Na] ⁺ calcd for C ₂₁ H ₁₉ N Na O ₅ : 388.116. ; found: 388.1161.

< Example 4> Big loop Tollan Preparation of compound 4

(0.15 g, 0.464 mmol) prepared in Example 2 was dissolved in a mixed solution of methanol (5 mL) and THF (2 mL). LiOH (0.089 g, 3.71 mmol in 1.5 mL of H ₂ O) was added to the solution and heated at 40 ° C for 4 hours. After evaporation of the organic solvent, the remaining mixture was diluted in water. The aqueous layer was washed with ether to remove unnecessary adducts. The aqueous layer was made to pH 5.0 using HCl (1M) and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was purified by silica gel (DCM / MeOH, 19/1) to give the title compound as a white solid (0.128 g, 89%).

mp: 196-197 [deg.] C; ^{1 H-NMR (400 MHz,} DMSO-d6) [ppm] 2.03 (m, 2H), 4.32 (t, J = 4.8 Hz, 2H), 4.35 (t, J = 4.8 Hz, 2H), 5.66 (s, (Dd, J = 7.9, 0.9 Hz, 1H), 6.49 (dd, J = 8.2, 0.9 Hz, 1H), 7.00 ), 7.71 (d, J = 7.5 Hz, 1 H); ¹³ C-NMR (100 MHz, DMSO-d6) [ppm] 30.5, 68.3, 68.6, 93.4, 95.3, 100.7, 108.8, 109.2, 117.8, 124.8, 126.0, 128.3, 130.4, 136.1, 151.2, 160.0, ; ; HRMS-ESI: m / z [ M - H] + calcd for C 18 H 14 NO 4: 308.0923; found: 308.0910.

< Example 5 > Preparation of beta-hairpin 1

Diisopropylethylamine (0.068 mL, 0.388 mmol) and HATU (0.492 g, 1.29 mmol) were added to a solution of the compound prepared in Example 4 (0.1 g, 0.323 mmol) in DCM (3 mL) and DMF (0.3 mL). After the reaction mixture was stirred for 1 hour, a mixed solution of DMF (0.9 mL) and DCM (0.3 mL) in which (S) -2-amino-N-methylpropanamide (0.132 g, 1.29 mmol) Was added to the reaction mixture. The resulting solution was stirred for two hours. The reaction mixture was poured into 0.1 M HCl (10 mL) aqueous solution and the product was extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Purification by silica gel (DCM / MeOH, 20/1) afforded the desired compound as a white solid (0.102 g, 79%).

mp: 52-53 [deg.] C; _{^{[α] D 25 = -6.3 (}} c = 0.1, CHCl 3); ^{1 H-NMR (400 MHz,} CDCl 3) [ppm] 1.52 (d, J = 6.9 Hz, 3H). (M, 2H), 4.73 (td, J = 7.1, 2.0 Hz, 1H), 6.58 (m, (D, J = 7.9 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H) , 7.84 (d, J = 7.4 Hz, 1 H); ^{13 C-NMR (100 MHz,} CDCl 3) [ppm] 18.6, 26.6, 30.6, 50.1, 70.0, 70.2, 93.5, 95.4, 103.9, 112.3, 112.9, 115.9, 125.1, 125.3, 129.5, 131.2, 135.4, 147.3, 161.5, 162.4, 166.6, 173.4; HRMS-ESI: m / z [ M + Na] + calcd for C 22 H 23 N 3 O 4 Na: 416.1586; found: 416.1588.

< Example 6> Production of β-hairpin 2

Oxalyl chloride (0.025 mL) was added to a solution of (S) -2-acetylamino-3-methylbutyric acid (0.043 g, 0.27 mmol) in DCM (1 mL) and DMF Was slowly added to the mixed solution. After 15 minutes, a mixed solution of DCM (0.5 ml) and Et ₃ N (0.04 mL) in which the compound prepared in Example 5 (0.07 g, 0.178 mmol) was dissolved at 0 ° C was added dropwise And stirred for 30 minutes. The reaction was carefully diluted with water and extracted with DCM. The organic layer was dried dried with anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by silica gel (DCM / MeOH, 25/1) to give the desired compound as a white solid (0.072 g, 76%).

mp: 267-268 [deg.] C; _{^{[α] D 25 = +222.9 (}} c = 0.1, CHCl 3); ¹ H-NMR (400 MHz, CDCl ₃ ) [ppm] 0.99 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 2H), 4.77 (m, 2H), 5.36 (m, 2H), 2.32 (m, J = 7.6 Hz, 1H), 7.28 (m, 1H), 7.34 (t, 2H), 6.49 (d, J = 9.0 Hz, 1H) J = 7.8 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 6.1 Hz, 1H), 8.30 (m, 1H), 8.92 ^{13 C-NMR (125 MHz,} CDCl 3) [ppm] 17.3, 19.2, 20.5, 23.7, 26.0, 31.4, 33.0, 48.5, 58.1, 68.7, 69.1, 91.1, 97.3, 107.1, 114.7, 117.1, 117.3, 122.7, 125.2, 129.3, 130.6, 136.5, 140.6, 160.7, 161.1, 165.7, 170.4, 170.9, 173.5; HRMS-ESI: m / z [M + Na] ⁺ calcd for C ₂₉ H ₃₄ N ₄ O ₆ Na: 557.2376; found: 557.2378.

< Example 7 > Production of β-hairpin 3

The β-hairpin was prepared by using the larger ringtallol compound prepared in Example 3 as follows.

The compound (0.10 g, 0.309 mmol) prepared in Example 3 was dissolved in a mixed solution of methanol (2.5 mL) and THF (1 mL). 3N NaOH (aq) (1 mL, 3 mmol) was added to the solution and stirred overnight at room temperature. After evaporation of the organic solvent, the remaining mixture was diluted with water. The aqueous layer was washed with ether to remove unnecessary adducts. The aqueous layer was made up to pH 5.0 with HCl (1M) and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude product was used in the next reaction without purification. Diisopropylethylamine (0.21 mL, 1.23 mmol) and HATU (0.467 g, 1.23 mmol) were added to a mixed solution of DCM (2 mL) and DMF (0.2 mL) in which the crude product was dissolved under nitrogen gas. Diethylamine HCl (0.10 g, 1.23 mmol) was dissolved in the reaction mixture. The resulting solution was stirred for 2 hours. The reaction mixture was poured into 0.1 M HCl (10 mL) and the product was extracted with DCM. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel (EA / Hexane, 6/1) to give the desired compound (0.095 g, 81%) as a white solid.

mp: 202-205 [deg.] C; ^{1 H-NMR (400 MHz,} Acetone-d 6) [ppm] 2.13 (m, 2H), 2.81 (s, 3H), 3.01 (s, 3H), 3.15 (s, 3H), 4.39 (t, J = J = 8.0 Hz, 1H), 7.24 (dd, J = 7.8, 4.6 Hz, 2H), 7.32 (t, J = 8.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.28 (s, 1H); ^{13 C-NMR (125 MHz,} MeOH-d 4) [ppm] 24.1,31.8, 35.4, 39.2, 70.9, 71.1, 91.7, 95.0, 111.5, 116.3, 119.6, 119.8, 123.3, 124.6, 128.2, 131.5, 140.2, 140.6, 148.5, 162.9, 171.7, 171.8; HRMS-EI: m / z [ M] + calcd for C 22 H 22 N 2 O 4: 378.1580; found: 378.1577.

< Comparative Example 1> without a collar Tollan Preparation of compounds

The unglobled tollan compounds which were devised by Kemp were prepared as follows. In the same manner as in Example 2, the nitro group was reduced to an amine group, and then the amine group was treated with methylcarbonyl Lt; / RTI > to produce the desired compound.

< Comparative Example 2> without a collar From Tollan Preparation of β-hairpin

The procedure of Example 1 was repeated except that the step 5 and the step 7 were carried out. After the nitro group was reduced to an amine group as in the case of Example 2, the production methods of Examples 4 to 6 were sequentially performed To give the desired compound.

The structures of the larger cyclotoluene compounds prepared in Examples 1 to 4 are shown in Table 1 below.

Example rescue One

2

3

4

< Experimental Example 1> X-ray analysis

In order to analyze the structure of the large cyclotoluene compound according to the present invention, X-ray film analysis was performed.

The single crystal of Example 3 prepared by carefully evaporating and drying a mixed solution of ethyl acetate and n-hexane dissolved in Example 3 was analyzed by X-ray diffraction, and the results are shown in FIG.

1 shows the X-ray crystal structure of the tolane compound (Example 3) according to the present invention.

Referring to FIG. 1, the single crystal structure of Example 3 can be confirmed. It is confirmed that the large cyclotoluene compound (Example 3) effectively restrains the free rotation of the phenyl group based on the acetylene axis since the double phenyl group is linked by the ether chain . It was also confirmed that the large cyclotoluene compound (Example 3) was located on one plane, and the planarity as described above was confirmed to be attributed to the back angle of the two phenyl groups.

< Experimental Example 2> Evaluation of structure stability of β-hairpin

In order to evaluate the stability of the β-hairpin structure prepared from the larger cyclotoluene compound and the conventional non-cyclotoluene compound according to the present invention, the following experiment was conducted.

The stability constants of the β-hairpin structure were compared by comparing the temperature constants of the amide NH 3 hydrogen atoms in DMSO-d ₆ of the compounds of Example 3, Example 6, Comparative Example 1 and Comparative Example 2, Respectively.

NH ^tol NH ^ala NH ^val NH ^CH3 Comparative Example 1 -2.7 - - - Comparative Example 2 -3.1 -5.9 -5.3 -4.5 Example 3 -2.4 - - - Example 6 -1.5 -6.0 -5.6 -4.7

Table 2 shows that when the non-cyclotoluene compound (Comparative Example 1) was produced from the? -Barthin (Comparative Example 2), the temperature constant value of the NH ^tol hydrogen atom was -2.7 ppb / K (Comparative Example 1) to -3.1 ppb / K (Comparative Example 2), while the larger ring tallane compound (Example 3) showed a temperature constant value of NH ^tol hydrogen atom of -2.4 ppb / K (Example 3) to -1.5 ppb / K (Example 6). The temperature constant value of the high NH ^tol hydrogen atom of Example 6 as described above was unprecedented in the non-ring β-hairpin. This high temperature constant value of NH ^tol is due to the fact that the 11-membered ring of the larger ring-thiol compound is brought close to the distance between the two peptide chains, thereby increasing the hydrogen bonding interaction between CO ^tol and NH ^tol , Stabilize hairpin structure.

Therefore, when a large cyclotoluene compound according to the present invention is used for the production of? -Hexafine, it is possible to produce a? - hairpin structure that is more stable than a conventional non-cyclotoluene compound and can be used as a?

< Experimental Example 3> Evaluation of optical characteristics

In order to evaluate the optical properties and properties of the large cyclotoluene compound according to the present invention, the following experiment was conducted.

The standardized absorption and fluorescence spectra of the large cyclotoluene compound (Example 2-3), β-hairpin (Example 5-7) and non-cyclotoluene compound (Comparative Example 1) prepared therefrom according to the present invention were evaluated The absorption band and the emission band of the compound were determined and the compound was excited by irradiation of light of the absorption wavelength band of each compound in two solvents of CH ₂ Cl ₂ and CH ₃ CN and the quantum yield of the light emitted by the compound was measured using coumarin 120 120). The results are shown in FIG. 2 and Table 3.

FIG. 2 (a) is a graph showing the results of a comparison between a large cyclotoluene compound (Example 2-3) according to the present invention in CH ₂ Cl ₂ , a β-hairpin (Example 5-7) and a non-cyclotoluene compound 2 shows the standardized UV-visible light absorption spectrum of a large ring tortolane compound (Example 2-3) according to the present invention in CH ₂ Cl ₂ , a β-hairpin (Example 5-7) and the non-cyclotoluene compound (Comparative Example 1).

Referring to FIG. 2 (a), the absorption wavelength band of each compound can be known. Referring to FIG. 2 (b), the respective ^em _max is known. The mobile (ICT) - Example 3 and Example 7 of the ^em λ _max values embodiments than the two respective blue as much as 47nm and 63nm - appears to be shifted, the movement of the emission spectrum in the wavelength of this dark is the charge in the molecule It is commonly observed in molecules.

Comparative Example 1 Example 2 Example 3 Example 5 Example 6 Example 7 ^abs λ _max (nm) 334 363 341 345 336 318 竜 (cm ^-1 M ^-1 ) 16100 12700 14300 10386 19700 21667 ^em ? _max (nm) 419 453 406 456 390 390 Stokes shift (nm) 85 90 65 107 54 72 Φ (%) 0.03 14 33 44 3 1.2 Φ (%) ^a 0.02 3 29 25 2 0.5

^Abs λ _max in Table 3 represents the maximum absorption wavelength band of the absorption spectrum;

ε (cm ^-1 M ^-1 ) represents the permittivity;

^em ? _max represents the maximum emission wavelength band of the emission spectrum;

The stokes shift represents the difference (nm) between ^em ? _Max and ^abs ? _Max ;

? (%) Shows the relative quantum yield of the compound to coumarin 120 in CH ₂ Cl ₂ ; And

? (%) ^A represents the relative quantum yield of the compound to coumarin 120 in CH ₃ CN.

As shown in Table 3, it can be seen that the quantum yield of the large cyclotoluene compound according to the present invention and the β-hairpin produced therefrom is remarkably increased (about 1000 times). In addition, the fluorescence quantum yield tends to decrease in the order of Example 5> Example 3> Example 2> Example 6> Example 7> Comparative Example 1 in CH ₂ Cl _2, where the first functional group of the two peptide chains Amide groups, quantum yields were found to decrease significantly and the quantum yields of Example 2 and Example 5 were found to decrease in CH ₃ CN solvents which are more polar than CH ₂ Cl ₂ . This quantum yield tendency is due to the preferential interaction between the polar solvent and the potent ICT compound in the excited state. In addition, a relatively large stroke movement was observed in Example 2 and Example 5, and it can be seen that the large cyclotolane of Example 2 and Example 5 is an ICT compound having a relatively large charge-transporting property.

In conclusion, the large quantum yields observed from the larger cyclotoluene compounds suggest that the cyclic structure introduced into the larger cyclotolan compound blocks the non-radiative loss of the excitation energy by limiting the rotation of the phenyl group with respect to the acetylenic axis, And thus the energy of the excited electrons can be efficiently emitted to the light. As shown in FIG.

Therefore, a large cyclotoluene compound introducing a chain linking two phenyl groups of tolane has a structure that is structurally planar, unlike a conventional non-cyclotoluene compound, and has strong fluorescence of about 1000 times or more than that of a conventional non-cyclotoluene compound. The phosphor can be advantageously used as a phosphor.

As can be seen from Experimental Examples 1 to 3, the large cyclotoluene compound according to the present invention introduces an ether chain to induce the formation of a planar structure as well as restricting free rotation of two phenyl groups on both ends of the tolgan. From the above, it can be seen that the large cyclotoluene compound according to the present invention can exhibit two effects. First, unlike the conventional non-cyclotoluene compound for releasing energy after exciting a tolan compound, by restricting the free rotation of the phenyl group, It is possible to prevent non-radiant energy loss, and it is possible to increase the charge transfer due to the planar structure, thereby emitting light 1000 times or more. Accordingly, the present invention can be effectively used as a phosphor containing a large cyclotoluene compound according to the present invention, preferably as an organic light emitting diode and a biomolecule-detecting phosphor, and the large cyclotoluene compound according to the present invention can be used as a large cyclotoluene compound Hairpin, β-sheet, β-turn analogues and β-2 analogs which are more structurally stable than conventional methods in the production of β-hairpin, β-sheet, β-turn analogues and β- And can be usefully used as β-hairpin, β-sheet, β-turn analogue and β-type secondary protein motif.

Claims

A compound represented by the following formula (1):
[Chemical Formula 1]

(Wherein R ¹ is hydrogen or straight or branched alkyl of _1-5 C;
Wherein R ² is hydrogen or C _1-5 straight or branched chain alkylcarbonyl; And
And n is an integer of 1 to 4).

The method according to claim 1,
Wherein R < ¹ > is hydrogen or _C1-3 straight or branched chain alkyl;
Wherein R ² is hydrogen or C _1-3 straight or branched alkyl-carbonyl, and; And
Wherein n is an integer from 1 to 3.

The method according to claim 1,
Wherein the compound is any one selected from the group consisting of the following compounds:

,

And

.

As shown in Scheme 1 below,
A step of iodinating a compound represented by formula (2) to prepare a compound represented by formula (3) (step 1);
Preparing a compound represented by the formula (4) (step 2) by subjecting the compound represented by the formula (3) prepared in the step 1 to a sonogashira coupling reaction with trimethylsily-acetylene;
A step (3) of preparing a compound represented by the formula (5) by subjecting the compound represented by the formula (4) prepared in the step 2 to a desilylation reaction and an acetylation reaction;
Reacting a compound represented by the formula (5) prepared in the above step 3 with a compound represented by the formula (6) to prepare a compound represented by the formula (7) (step 4);
(Step 5) of preparing a compound represented by the formula (9) through a compound represented by the formula (8) and Williamson ether synthesis according to the compound (7) prepared in the step 4;
A step of deacetylating the compound represented by the formula (9) prepared in the step 5 to prepare a compound represented by the formula (10) (step 6);
A step of cyclizing the compound represented by the formula (10) prepared in the step 6 to prepare a compound represented by the formula (11) (step 7); And
A process for producing a compound represented by the formula (1) as set forth in claim 1, comprising the step of reducing the compound represented by the formula (11) prepared in the step 7 to prepare a compound represented by the formula (1)
[Reaction Scheme 1]

(In the above Reaction Scheme 1,
R ¹ and n are as defined in formula (1) of claim 1;
R ² is hydrogen; And
And X is halogen.

As shown in Reaction Scheme 2 below,
(1), comprising the step of acylating a compound represented by the formula (1a) to prepare a compound represented by the formula (1)
[Reaction Scheme 2]

(In the above Reaction Scheme 2,
R ¹ , R ² and n are independently as defined in formula (1) of claim 1.

As shown in Scheme 3 below,
A process for producing a compound represented by the general formula (1) as set forth in claim 1, comprising the step of hydrolyzing a compound represented by the formula (1a) to prepare a compound represented by the formula (1b)
[Reaction Scheme 3]

(In the above scheme 3,
R ¹ and n are independently as defined in formula (1) of claim 1).

The compound represented by the general formula (11) of claim 4:

(Wherein R < ¹ > and n are independently as defined in formula (1) of claim 1).

A motif for producing a β-sheet protein structure containing the compound represented by the general formula (1) of claim 1.

A fluorescent substance for detecting biomolecules containing a compound represented by the general formula (1) of claim 1.