KR100951001B1 - New multi-substituted tetrahydrofuran derivatives and method for manufacturing the same - Google Patents

Abstract

The present invention relates to a novel multi-substituted tetrahydrofuran derivative expressed in various structures in physiologically active natural products and pharmaceuticals, and to a stereoselective synthesis method for preparing the derivative, according to the present invention. It is possible to provide a new polysubstituted tetrahydrofuran and its derivatives, which are important structures of.

Polysubstituted Tetrahydrofuran Derivatives, Stereoselective Synthesis Method, Bioactive Natural Products

Description

New polysubstituted tetrahydrofuran derivatives and a method for preparing the same {NEW MULTI-SUBSTITUTED TETRAHYDROFURAN DERIVATIVES AND METHOD FOR MANUFACTURING THE SAME}

The present invention relates to novel multi-substituted tetrahydrofuran derivatives expressed in various structures in physiologically active natural products and pharmaceuticals, and to stereoselective synthesis methods for preparing the derivatives.

Heterocycles with highly asymmetric carbons, especially oxcycles containing oxygen, are monomers that are frequently found in natural and bioactive substances and are used in compounds that exhibit various physiological activities such as anticancer agents, antibiotics, and pesticides. It is known as a basic skeleton that appears and is known to be useful as a raw material of drugs or bioactive substances.

Most of these compounds are prepared from cyclic compounds. Therefore, the development of how efficiently and how effective they are is critical. In recent years, a great deal of research has been conducted on various transition metal catalysts, but from the economic and industrial standpoints, no suitable synthesis has been developed (Zeni, G .; Larock, RC Chem . Rev. 2006, 106 , 4644-4680; Transition). Metals for Organic Synthesis Beller, M .; Bolm, C. Eds .; Weinheim, 2004. (c) Trost, BM; Toste, D. Chem . Rev. 2001, 101 , 2067-2096).

Tetrahydrofuran, one of the most commonly found, is well known for its basic structure that makes up many bioactive substances (Review, Reviews: Faul, MM; Huff, BE Chem . Rev. 2000, 100 , 2407-2474; Saleem, M .; Kim, HJ; Ali, MS; Lee, YS Nat. Prod . Rep . 2005, 22 , 696-716). For example, Pharmamycins (Famamycins; Friedman, Doron; Besonov, Alex; Tamarkin, Dov; Eini, Meir. US Pat. Appl. Publ. 2006, US Ser.No. 532,618; Hashimoto, M .; Kozone, I .; Kawaide, H .; Abe, H .; Natsume, M. Journal of Antibiotics 2005, 58 , 722-730) are attracting much attention to research on the development of next-generation drugs due to their unique antibiotic action. In addition, numerous biologically active natural or synthetic tetrahydrofuran derivatives are known.

Accordingly, various synthesis methods have been introduced (Review, Reviews: Wolfe, JP Eur . J. Org . Chem . 2007, 571-581; Kang, EJ; Lee, E. Chem . Rev. 2005, 105 , 4348-4378; Boivin, TL Tetrahedron 1987, 43 , 3309-3362). Many methods of tetrahydrofuran synthesis have focused on the formation of carbon-oxygen bonds. However, this method can efficiently form tetrahydrofuran rings, but it is pointed out that there are problems in introducing various functional groups and stereoselectivity. Accordingly, it was expected that carbon-carbon bonds using Oxonium intermediates could overcome this problem.

In order to meet the above expectations, studies on the synthesis of tetrahydrofuran of various structures have been conducted (Jaques, T .; Marko, IE; Prospisil, J. In Multicomponent). Reactions Zhu, J .; Bienayme, H. Eds .; Wiley-VCH: Weinheim, 2005 pp. 398-452; Loh, T.-P .; Hu, Q.-Y .; Tan, K.-T .; Cheng, H.-S. Org . Lett . 2001, 3 , 2669-2672; Loh, T.-P .; Hu, Q.-Y .; Ma, L.-T. J. Am . Chem . Soc . 2001, 123 , 2450-2451; Mohr, P. Tetrahedron Lett . 1993, 34 , 6251-6254), so far, the synthesis method has been pointed out as a problem in the applicability and utility due to 1) structurally complex starting materials 2) low stereoselectivity 3) functional group limitation.

In the present invention, to provide a new complex multi-substituted tetra- hydrofuran compound is rich in application.

In addition, the present invention provides a polysubstituted tetra-hydro which can introduce various functional groups through concise stereoselective synthesis that can sequentially proceed several chemical transformations in one vessel by a transition metal catalyst from an easily obtained starting material. It is intended to provide a method for preparing a furan compound.

In order to achieve the above object, the present invention provides a polysubstituted tetra-hydrofuran compound represented by the following formula (1).

[Formula 1]

Where R ¹ and R ² is C ₁ to C ₂₀ alkyl, C ₆ to C ₉ allyl or C ₆ to C ₉ aralkyl.

Preferably the R ¹ _May be selected from the group consisting of PhCH ₂ CH ₂ , n- C ₅ H ₁₁ , Me, Me ₂ CH and Ph, wherein R ² is PhCH ₂ CH ₂ , Me, ClCH _2, and Me ₂ CH may be selected from the group consisting of.

The compound represented by Chemical Formula 1 may be prepared by using the compound represented by Chemical Formula 2 as a starting material.

[Formula 2]

Here, R ¹ is as defined in the formula (1).

The compound represented by Chemical Formula 2 may be represented as in Scheme 1 applying the prior art. In other words, homopropargyl alcohols (homopropargyl alcohols) in the conventional method (Yu, C.-M .; Yoon, S.-K .; Choi, H.-S .; Baek, K. Chem .. Commun synthesized by 1997, 763-764), and it Klein chopping methods (such as, Calogeropoulou, T. et al J. Med Chem 2005, 48, 5203-5214;... Pyo, S .; Skowron III, JF; Cha, JK Tetrahedron Lett . 1992, 33 , 4703-4706) was converted to the corresponding allene alcohol compound. Then, the obtained allene alcohol was reacted in the presence of chlorotrimethylsilane (Me ₃ SiCl) and triethylamine (Et ₃ N) to synthesize the compound of Formula 2.

Scheme 1

The present invention also provides a tetra-hydrofuran derivative represented by the following formula (3) to (5).

(3)

[Formula 4]

[Chemical Formula 5]

R ¹ in Formulas 3 to 5 And R ² is as defined in Formula 1 above.

In addition, the present invention (a) mixing and dissolving the starting material represented by the formula (2) in the reaction flask in the reaction flask, (b) the catalyst represented by the following formula (6) and the compound represented by the formula (7) in the reactor to the intermediate It provides a method for producing a polysubstituted tetra-hydrofuran compound comprising the step of, and (c) adding the compound represented by the formula (8) and (9) to the reactor to complete the reaction.

[Formula 6]

[Formula 7]

[Formula 8]

Here, R ² is as defined in the formula (1).

[Formula 9]

Although it does not specifically limit as a solvent which melt | dissolves the said starting material, It is preferable that it is tetrahydrofuran.

The step (b) is preferably reacted for 2 to 4 hours at -10 to 10 ℃, more preferably can be reacted for 2.5 to 3.5 hours at -5 to 5 ℃.

In this case, the addition amount of the compound represented by the formula (7) is not particularly limited, but is preferably added in 0.9 to 1.8 equivalents relative to the compound represented by the formula (2).

The step (c) is preferably reacted at -90 to -60 ° C for 3 to 5 hours, more preferably at -85 to -70 ° C for 3.5 to 4.5 hours. It is most preferable to proceed especially at -78 degreeC.

In this case, although the addition amount of the compound represented by the said Formula (9) is not specifically limited, It is preferable to add in 1-2 equivalents with respect to the compound represented by Formula (2).

According to the present invention, a new polysubstituted tetrahydrofuran and its derivatives, which are important structures of the bioactive substance, can be provided by a simple method.

In addition, the production method according to the present invention can be a simple one-pot reaction to thereby increase efficiency.

The present invention provides a compound represented by the formula (1) is expected to be applicable to include a variety of functional groups prepared stereoselectively from the compound represented by the formula (2) can be easily obtained as in Scheme 2.

Scheme 2

The method for preparing polysubstituted tetrahydrofuran according to the present invention can be summarized by the following Scheme 3.

Scheme 3

That is, while advancing the reaction under anhydrous N ₂ atmosphere, the compound represented by Chemical Formula 2 was placed in a reaction flask in a reaction flask, and then tetrahydrofuran (THF) was added as a solvent. After the addition of the compound represented by the formula (7) and the catalyst represented by the formula (6) to the mixture in the reaction vessel and the reaction was carried out. Then, after cooling the intermediate produced by the above method, the compound represented by the formula (8) was added. Then, the compound represented by the formula (9) diluted in tetrahydrofuran (THF) was added dropwise through the cannula and the reaction proceeded. The reaction proceeded by adding NaHCO ₃ aqueous solution to terminate the reaction, followed by extraction with Et ₂ O and drying with MgSO ₄ . After distilling the solvent under reduced pressure, the compound may be purified by silica gel chromatography to obtain a compound represented by Chemical Formula 1.

The synthesized derivatives of formula I can be converted to other compounds which are more useful by chemical conversion of the functional groups. Specific examples are as in Scheme 4 below.

Scheme 4

For example, the vinyl tin group of Formula 1 could be converted into an iodovinyl compound of Formula 3 by N-Iodosuccinimide (NIS). This compound of Formula 3 could be converted into an ester of Formula 4, which is rich in applicability by palladium-catalyzed carbonylation (Similar examples, Martin, LD; Stille, JK J. Org . Chem . 1982, 47 , 3630 -3633). In addition, it can be converted to the formula (5) under the strong base NaHMDS (Sodium hexamethyldisilazide) conditions.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are merely specific examples of the present invention, and the protection scope of the present invention is not limited to the following Examples.

Example 1

(2R, 3R, 5S) -2,5- dependency ethyl-3- (1'-trimethyl stearyl carbonyl) -vinyl tetrahydrofuran ((2 R, 3 R, 5 S) -2,5-Diphenethyl-3- Preparation of (1′-trimethylstannyl) -vinyltetrahydrofuran)

In anhydrous N ₂ atmosphere, a compound represented by Chemical Formula 2 (wherein R ¹ = PhCH ₂ CH ₂ , 1 equivalent) was weighed into a reaction vessel, and tetrahydrofuran (THF) was added as a solvent. Hexamethylditin (1.3 equiv) and π-allylPdCl ₂ (0.005 equiv) were added to the mixture in the reaction vessel and reacted at 0 ° C. for 3 hours.

And after cooling to -78 ℃ aldehyde of formula 8 (but, R ² = PhCH ₂ CH ₂ ) was added. Then, TMSOTf diluted in tetrahydrofuran (THF) at -78 ° C was added dropwise through the cannula, and the reaction was reacted at -78 ° C for 4 hours. At this time, an aqueous NaHCO ₃ solution was added to terminate the reaction, followed by extraction with Et ₂ O and drying with MgSO ₄ . The solvent was distilled under reduced pressure and purified by silica gel chromatography to obtain a compound represented by the following formula.

Yield: 83%

TLC, Rf = 0.72 (3: 1, Hexanes / EtOAc)

IR (film): 3026, 2945, 1608, 1042, 766, 694 cm ^-1

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.13-7.31 (m, 10H), 5.67 (s, 1H), 5.26 (s, 1H), 3.89-3.99 (m, 2H), 3.16-3.25 (m, 1H), 2.55-2.89 (m, 4H), 1.81-2.07 (m, 3H), 1.67 (dt, J = 12.2 Hz, 10.3 Hz, 1H), 1.44-1.52 (m, 2H), 0.12 (s. 9H )

¹³ C NMR (125 MHz, CDCl ₃ ) δ 153.7, 142.9, 142.6, 129.0, 128.9, 128.8, 128.7, 126.2, 126.1, 125.8, 80.2, 78.6, 52.5, 39.2, 36.0, 35.4, 33.2, 33.1, -8.3

MS (ESI) m / z (rel intensity) 470 (M ⁺ , 5), 455 (100)

[Example 2]

(2R, 3R, 5S) -2-Methyl-5-phenethyl-3- (1′-trimethylstenyl) -vinyl-tetrahydrofuran ((2 R *, 3 R *, 5 S * ) -2- Preparation of Methyl-5-phenethyl-3- (1′- trimethylstannyl) vinyltetrahydrofuran)

R ¹ = PH ₂ CH ₂ CH ₂ , R ² A compound represented by the following formula was prepared in the same manner as in Example 1 except that = Me.

Yield: 77%

TLC, R f 0.69 (3: 1, Hexanes / EtOAc)

IR (film) 3027, 2971, 1601, 1082, 917, 768, 699 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.15-7.30 (m, 10H), 5.70 (s, 1H), 5.29 (s, 1H), 4.17 (p, J = 6.5 Hz, 1H), 3.83-3.93 (m, 1H), 3.14-3.23 (m, 1H), 2.62-2.82 (m, 2H), 1.78-2.05 (m, 3H), 1.67 (dt, J = 11.8 Hz, 10.3 Hz, 1H), 0.95 ( d, J = 6.5 Hz, 3H), 0.16 (s. 9H)

¹³ C NMR (125 MHz, CDCl ₃ ): δ 154.2, 142.5, 128.8, 128.7, 126.1, 125.8, 78.5, 76.9, 52.6, 38.8, 35.8, 33.1, 19.3, -8.3

MS (ESI) m / z (rel intensity) 380 (M ⁺ , 10), 365 (100)

Example 3

(2R, 3R, 5S) -5- pentyl-2-phenethyl-3- (1'-trimethyl stearyl carbonyl) -vinyl tetrahydrofuran ((2 R *, 3 R *, 5 S *) -5-Pentyl Preparation of -2-phenethyl-3- (1′-trimethylstannyl) vinyl tetrahydrofuran)

A compound represented by the following formula was prepared in the same manner as in Example 1 except that R ¹ = nC ₅ H ₁₁ and R ² = PhCH ₂ CH ₂ ).

　

　

Yield: 75%

TLC, R f : 0.74 (3: 1, Hexanes / EtOAc)

IR (film) 3026, 2953, 1601, 1108, 919, 769, 669 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23-7.28 (m, 2H), 7.13-7.17 (m, 3H), 5.67 (s, 1H), 5.25 (s, 1H), 3.86-3.97 (m, 2H ), 3.15-3.24 (m, 1H), 2.77-2.87 (m, 1H), 2.52-2.62 (m, 1H), 1.97-2.05 (m, 1H), 1.26-1.75 (m, 11H), 0.91 (t , J = 6.5 Hz, 3H), 0.12 (s. 9H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 153.9, 143.1, 128.9, 128.7, 126.0, 125.8, 80.1, 79.5, 52.5, 37.4, 36.0, 35.4, 33.0, 32.4, 26.5, 23.1, 14.5, -8.3

MS (ESI) m / z (rel. Intensity): 436 (M ⁺ , 9), 421 (100)

Example 4

(2R, 3R, 5S) -2-Methyl-5-pentyl-3- (1′-trimethylstenyl) -vinyl-tetrahydrofuran ((2 R *, 3 R *, 5 S * ) -2-Methyl Preparation of -5-pentyl-3- (1′-trimethylstannyl) -vinyl-tetrahydrofuran)

A compound represented by the following formula was prepared in the same manner as in Example 1 except that R ¹ = nC ₅ H ₁₁ and R ² = Me.

Yield: 71%

TLC, R f 0.62 (3: 1, Hexanes / EtOAc)

IR (film) 2956, 2925, 1087, 916 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.69 (t, J = 2.4 Hz, 1H), 5.29 (t, J = 1.9 Hz, 1H), 4.15 (p, J = 8.4 Hz, 1H), 3.80- 3.89 (m, 1H), 3.17 (m, 1H), 2.00 (m, 1H), 1.25-1.72 (m, 9H), 0.92 (d, J = 8.4 Hz, 3H), 0.86 (t, J = 9.2 Hz , 3H), 0.16 (s, 9H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 156.6, 128.0, 81.6, 79.1, 54.8, 39.3, 38.3, 34.7, 28.7, 25.3, 21.5, 16.7, -6.0

MS (ESI) m / z (rel. Intensity) 346 (M ⁺ , 8), 331 (100)

Example 5

(2S, 3R, 5S) -2- ( chloromethyl) -5-pentyl-3- (1'-trimethyl stearyl carbonyl) -vinyl tetrahydrofuran ((2 S *, 3 R *, 5 S *) -2 Preparation of-(Chloromethyl) -5-pentyl-3- (1′-trimethylstannyl) -vinyltetrahydrofuran)

A compound represented by the following formula was prepared in the same manner as in Example 1 except that R ¹ = nC ₅ H ₁₁ and R ² = CH ₂ Cl.

Yield: 69%

TLC, R f 0.65 (3: 1, Hexanes / EtOAc)

IR (film) 2957, 2928, 1461, 1110 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.77 (t, J = 1.9 Hz, 1H), 5.34 (t, J = 1.9 Hz, 1H), 4.16 (m, 1H), 3.95 (m, 1H), 3.21 -3.38 (m, 3H), 2.04 (m, 1H), 1.25-1.80 (m, 9H), 0.89 (t, J = 6.8 Hz, 3H), 0.18 (s, 9H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 152.4, 126.9, 80.7, 79.9, 51.9, 46.8, 36.6, 36.1, 32.3, 26.2, 23.0, 14.5, -8.3

MS (ESI) m / z (rel. Intensity) 403 (M + Na ⁺ , 5), 380 (M ⁺ , 60), 365 (30), 345 (11)

Example 6

(2R, 3R, 5S) -5-Methyl-2-phenethyl-3- (1′-trimethylstenyl) -vinyltetrahydrofuran ((2 R *, 3 R *, 5 S * ) -5-Methyl Preparation of -2-phenethyl-3- (1′-trimethylstannyl) -viyl-tetrahydrofuran)

A compound represented by the following formula was prepared in the same manner as in Example 1, except that R ¹ = Me, R ² = PH ₂ CH ₂ CH ₂ .

Yield: 87%

TLC, R f 0.69 (3: 1, Hexanes / EtOAc)

IR (flim) 3024, 2970, 1603, 1089, 909, 763, 695 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ7.23-7.28 (m, 2H), 7.13-7.18 (m, 3H), 5.67 (s, 1H), 5.25 (s, 1H), 3.89-4.09 (m, 2H), 3.21 (m, 1H), 2.78-2.87 (m, 1H), 2.53-2.63 (m, 1H), 2.02-2.10 (m, 1H), 1.46-1.65 (m, 3H), 1.33 (d, J = 6.1 Hz, 3H), 0.13 (s, 9H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 154.2, 143.0, 128.9, 128.7, 126.0, 125.9, 80.6, 75.2, 52.9, 38.3, 35.4, 33.0, 22.3, -8.2

MS (ESI) m / z (rel. Intensity) 413 (65), 380 (M ⁺ , 7), 365 (9), 245 (100)

Example 7

(2R, 3R, 5R) -5- isopropyl-2-phenethyl-3- (1'-trimethyl stearyl carbonyl) -vinyl tetrahydrofuran ((2 R *, 3 R *, 5 R *) -5- Preparation of Isopropyl-2-phenethyl-3- (1′-trimethylstannyl) vinyl-tetrahydrofuran)

However, except that R ¹ = Me ₂ CH, R ² = PH ₂ CH ₂ CH ₂ A compound represented by the following formula was prepared in the same manner as in Example 1.

Yield: 76%

TLC, R f 0.75 (3: 1, Hexanes / EtOAc)

IR (film) 3020, 2968, 2872, 11018, 921, 765, 672 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23-7.28 (m, 2H), 7.12-7.17 (m, 3H), 5.68 (t, J = 2.4 Hz, 1H), 5.26 (s, 1H), 3.95- 4.01 (m, 1H), 3.59-3.66 (m, 1H), 3.18-3.26 (m, 1H), 2.78-2.88 (m, 1H), 2.51-2.59 (dt, J = 18.4 Hz, 11.2 Hz, 1H) , 1.88-1.96 (m, 1H), 1.63-1.76 (m, 2H), 1.38-1.45 (m, 2H), 1.05 (d, J = 9.2 Hz, 3H), 0.90 (d, J = 9.2 Hz, 3H ), 0.11 (s. 9H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 153.3, 143.1, 128.9, 128.7, 126.0, 125.5, 85.1, 79.8, 52.4, 35.5, 34.9, 33.1, 20.2, 19.1, -8.4

MS (ESI) m / z (rel. Intensity) 408 (M ⁺ , 5), 393 (100), 384 (10)

Example 8

(2R, 3R, 5R) -2- phenethyl-5-phenyl-3- (1'-trimethyl stearyl carbonyl) -vinyl tetrahydrofuran ((2 R *, 3 R *, 5 R *) -2-Phenethyl Preparation of -5-phenyl-3- (1′-trimethylstannyl) vinyl-tetrahydrofuran)

A compound represented by the following formula was prepared in the same manner as in Example 1, except that R ¹ = Ph, R ² = PH ₂ CH ₂ CH ₂ .

Yield: 67%

TLC, R f 0.73 (3: 1, Hexanes / EtOAc)

IR (film) 3027, 2923, 1602, 1052, 756, 698 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.42 (m, 4H), 7.25-7.30 (m, 3H), 7.15-7.21 (m, 3H), 5.67 (t, J = 1.9 Hz, 1H), 5.28 (t, J = 1.9 Hz, 1H), 5.02 (dd, J = 14.4 Hz, 5.5 Hz, 1H), 4.16-4.24 (m, 1H), 3.38-3.46 (m, 1H), 2.92-3.02 (m , 1H), 2.63-2.73 (m, 1H), 2.26-2.34 (m, 1H), 1.92-2.04 (m, 1H), 1.46-1.68 (m, 2H), 0.12 (s. 9H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 152.7, 143.6, 142.8, 129.0, 128.7, 127.6, 126.1, 125.9, 81.0, 80.4, 52.7, 38.7, 35.7, 33.1, -8.4

MS (ESI) m / z (rel. Intensity) 443 (5), 442 (M ⁺ , 5), 427 (100), 395 (10)

Example 9

(2R, 3R, 5R) -2- isopropyl-5-phenyl-3- (1'-trimethyl stearyl carbonyl) -vinyl tetrahydrofuran ((2 R *, 3 R *, 5 R *) -2-Isopropyl Preparation of -5-phenyl-3- (1′-trimethylstannyl) vinyl-tetrahydrofuran)

A compound represented by the following formula was prepared in the same manner as in Example 1 except that R ¹ = Ph and R ² = Me ₂ CH.

Yield: 53%

TLC, R f 0.73 (3: 1, Hexanes / EtOAc)

IR (film) 3031, 2958, 2926, 1602, 1086, 750, 700 cm ^-1

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34-7.42 (m, 4H), 7.25-7.30 (m, 3H), 7.15-7.21 (m, 3H), 5.67 (t, J = 1.9 Hz, 1H), 5.28 (t, J = 1.9 Hz, 1H), 5.02 (dd, J = 14.4 Hz, 5.5 Hz, 1H), 4.16-4.24 (m, 1H), 3.38-3.46 (m, 1H), 2.92-3.02 (m , 1H), 2.63-2.73 (m, 1H), 2.26-2.34 (m, 1H), 1.92-2.04 (m, 1H), 1.46-1.68 (m, 2H), 0.12 (s. 9H)

¹³ C NMR (75 MHz, CDCl ₃ ) δ 155.4, 142.4, 128.3, 127.1, 126.4, 125.8, 87.8, 79.5, 52.3, 41.1, 29.4, 19.9, 19.6, -7.9

GC / MS (EI) m / z (rel intensity) 380 (M ⁺ , 5), 365 (100), 293 (77), 165 (43), 143 (75)

Example # 10

(2 R *, 3 R * , 5 S *) - 3- (1- iodo-vinyl) -5-pentyl-2-phenethyl-tetrahydro-furan ((2 R *, 3 R *, 5 S *) Preparation of -3- (1-Iodovinyl) -5-pentyl-2-phenethyl-tetrahydrofuran)

(2R, 3R, 5S) -5-pentyl-2-phenethyl-3- (1′-trimethylstenyl) -vinyltetrahydrofuran (44.8 mg, 0.103 mmol) in CH ₂ Cl ₂ was added to the reaction vessel. Add at 78 ° C. N-Iodosuccinimide (46.3 mg, 0.206 mmol) was added.

Thereafter, the mixed solution was reacted at -78 ° C for 2 hours and again at -40 ° C for 20 minutes. And the mixed solution was reacted at room temperature. At this time, water was added to terminate the reaction, followed by extraction with CH ₂ Cl ₂ and drying with Na ₂ S ₂ O ₃ . The solvent was distilled under reduced pressure and purified by silica gel chromatography to obtain a compound represented by the following formula.

Yield: 93%

TLC, Rf: 0.55 (15: 1, Hexanes / EtOAc)

IR (film) 3024, 2952, 1065, 770, 693, 665 cm-1

1 H NMR (400 MHz, CDCl ₃ ) δ 7.17-7.30 (m, 5H), 6.09 (s, 1H), 5.84 (s, 1H), 3.90-4.04 (m, 2H), 3.18-3.26 (m, 1H) , 2.83-2.92 (m, 1H), 2.60-2.71 (m, 1H), 2.04-2.16 (m, 1H), 1.25-1.79 (m, 9H), 0.89 (t, J = 6.9 Hz, 3H)

13C NMR (125 MHz, CDCl ₃ ) δ 145.0, 131.2, 130.9, 128.8, 128.3, 112.0, 82.6, 81.9, 57.9, 39.4, 39.2, 35.9, 35.2, 34.5, 28.6, 25.3, 16.7

MS (ESI) m / z (rel. Intensity) 421 (M + Na ⁺ , 20), 399 (72), 398 (M +, 5), 253 (100)

Anal. Calcd for C ₁₉ H ₂₇ IO: C, 57.29; H, 6.83; I, 31.86; O, 4.02. Found: C, 57.57 H, 6.61.

Example 11

Methyl 2 - {(2 R *, 3 S *, 5 S *) - 5- pentyl-2-phenethyl-tetrahydro-furan-3-yl} acrylate (Methyl 2 - {(2 R *, 3 S * , 5 S *)-5-pentyl-2-phenethyl-tetrahydrofuran-3-yl} acrylate)

To the autoclave flask was added Pd (PPh 3) 4 (5.4 mg, 5 mol%) and potassium carbonei (K 2 CO 3) (39.4 mg, 0.282 mol). And (2 R *, 3 R *, 5 S *)-3- (1-iodovinyl) -5-pentyl-2-phenethyl-tetrahydrofuran (37.8 mg, 0.094 mmol) in methanol (3 mL) Was added. Thereafter, the mixture was reacted for 3 hours in an oil bath which was previously heated to 70 ° C. under CO gas (200 psi). At this time, the volatiles were blown off and purified by silica gel chromatography to obtain a compound represented by the following formula.

Yield: 83%

TLC, R f : 0.38 (15: 1, Hexanes / EtOAc)

IR (film) 3021, 2949, 2855, 1720, 1602, 1205, 1054, 767, 695 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.27 (m, 2H), 7.12-7.17 (m, 3H),

6.29 (s, 1H), 5.60 (s, 1H), 4.12-4.19 (m, 1H), 3.88-3.97 (m, 1H), 3.72 (s, 3H), 3.42-3.50 (m, 1H), 2.74- 2.84 (m, 1H), 2.49-2.59 (m, 1H), 2.03-2.11 (m, 1H), 1.28-1.76 (m, 11H), 0.91 (t, J = 6.9 Hz, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 170.2, 145.2, 142.2, 131.1, 130.9, 128.3, 81.7, 81.2, 54.6, 46.2, 39.2, 38.6, 37.3, 35.1, 34.6, 28.6, 25.3, 16.7, 2.6

MS (ESI) m / z (rel intensity) 354 (M + Na ⁺ , 11), 331 (100), 330 (M ⁺ , 5), 281 (63)

Anal. Calcd for C ₂₁ H ₃₀ O ₃ : C, 76.33; H, 9. 15; O, 14.52. Found: C, 76.18 H, 9.32.

Example 12

(2 R *, 3 S * , 5 S *) - 3-ethynyl-5-pentyl-2-phenethyl-tetrahydro-furan ((2 R *, 3 S *, 5 S *) - 3-Ethynyl- Preparation of 5-pentyl-2-phenethyl-tetrahydrofuran)

In a reaction vessel at 0 ℃ in DMF (2.4ml) (2 R * , 3 R *, 5 S *) - 3- (1- iodo-vinyl) -5-pentyl-2-phenethyl-tetrahydro-furan (46mg , 0.116 mmol) and 1.0 M NaHMDS (sodium hexamethyldisilazide) in THF (0.2 ml, 0.20 mmol) were added slowly for 5 minutes. After that, the reaction was carried out for 5 hours. At this time, water was added to terminate the reaction, followed by extraction with EA and drying with MgSO 4. The solvent was distilled under reduced pressure and purified by silica gel chromatography to obtain a compound represented by the following formula.

Yield: 90%

TLC, R f : 0.41 (15: 1, Hexanes / EtOAc)

IR (film) 3298, 3026, 2958, 2152, 1605, 1080, 767, 702 cm ^-1

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.15-7.30 (m, 5H), 3.73-3.82 (m, 2H) 2.98-3.06 (m, 1H), 2.67-2.84 (m, 2H), 2.29-2.38 (m , 1H), 2.13 (d, J = 2.7 Hz, 1H), 1.98-2.06 (m, 2H), 1.25-1.73 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H)

¹³ C NMR (125 MHz, CDCl ₃ ) δ 131.1, 130.9, 128.4, 86.8, 81.9, 81.4, 73.8, 41.9, 38.8, 36.9, 36.3, 35.1, 34.6, 28.6, 25.3, 16.7, 2.6

MS (ESI) m / z (rel. Intensity) 271 (100), 270 (M ⁺ , 4), 155 (29)

Anal. Calcd for C ₁₉ H ₂₆ O: C, 84.39; H, 9.69; O, 5.92. Found: C, 84.31 H, 9.92.

Claims (14)

Polysubstituted tetra-hydrofuran compound represented by the following formula (1): [Formula 1]

R ¹ and R ² is C ₁ to C ₂₀ alkyl, C ₆ to C ₉ allyl or C ₆ to C ₉ aralkyl. The method of claim 1, R ¹ Is selected from the group consisting of PhCH ₂ CH ₂ , n- C ₅ H ₁₁ , Me, Me ₂ CH and Ph, wherein R ² is PhCH ₂ CH ₂ , Me, ClCH _{2 ,} and Multi-substituted tetra-hydrofuran compound, characterized in that selected from the group consisting of Me ₂ CH. The method of claim 1, The compound of Formula 1 is a polysubstituted tetra-hydrofuran compound, characterized in that prepared from the compound represented by the formula (2): [Formula 2]

Here, R ¹ is as defined in the formula (1). A polysubstituted tetra-hydrofuran compound represented by the following Chemical Formulas 3 to 5, which is derived from the compound of Chemical Formula 1 according to claim 1: (3)

[Formula 4]

[Chemical Formula 5]

R ¹ in Formulas 3 to 5 And R ² is as defined in Formula 1 above. (a) dissolving the starting material represented by the formula (2) in a solvent to dissolve it, (b) adding a catalyst represented by the following formula (6) and a compound represented by the formula (7) to a reactor to form an intermediate, and (c Method for preparing a polysubstituted tetra- hydrofuran compound comprising the step of completing the reaction by adding a compound represented by the formula (8) and (9) to the reactor: [Formula 6]

[Formula 7]

[Formula 8]

Here, R ² is as defined in the formula (1). [Formula 9]

The method of claim 5, The solvent used in step (a) is a method for producing a polysubstituted tetra-hydrofuran compound, characterized in that tetrahydrofuran. The method of claim 5, The step (b) is a method for producing a polysubstituted tetra-hydrofuran compound, characterized in that the reaction for 2 to 4 hours at -10 ~ 10 ℃. The method of claim 5, The addition amount of the compound represented by the formula (7) is a method for producing a polysubstituted tetra-hydrofuran compound, characterized in that the addition of 0.9 to 1.8 equivalents relative to the compound represented by the formula (2). The method of claim 5, The step (c) is a method for producing a polysubstituted tetra-hydrofuran compound, characterized in that for 3 to 5 hours at -90 ~ -60 ℃. The method of claim 5, The amount of the compound represented by the formula (9) is 1 to 2 equivalents to the compound represented by the formula (2) The method for producing a polysubstituted tetra-hydrofuran compound. A method for preparing a compound represented by the following Chemical Formula 3, wherein the compound according to claim 1 is mixed with NIS (N-Iodosuccinimide) under CH ₂ Cl ₂ and the temperature is changed. (3)

Where R ¹ And R ² is as defined in Formula 1 above. The method of claim 11, The reaction may include (1) proceeding at -85 to -70 ° C, (2) proceeding at -45 to -35 ° C, and (3) proceeding at room temperature. Method for preparing a compound represented by: A method for preparing a compound represented by the following Chemical Formula 4, wherein the compound represented by Chemical Formula 3 prepared according to claim 11 is carbonylated under a palladium catalyst. [Formula 4]

Where R ¹ And R ² is as defined in Formula 1 above. A method for preparing a compound represented by the following Chemical Formula 5, wherein the compound represented by Chemical Formula 4 prepared according to claim 13 is reacted under a strong base NaHMDS (Sodium hexamethyldisilazide) condition. [Chemical Formula 5]

Where R ¹ And R ² is as defined in Formula 1 above.