JP2007222850A - Diels-alder reaction catalyst and method for producing asymmetric cyclized addition product - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a Diels-Alder reaction catalyst suitable for such an asymmetric Diels-Alder reaction that α-acyloxyacrolein is converted into dienophile. <P>SOLUTION: A toluene solution of (S)-1,1'-binaphtyl-2,2'-diamine (0.02 mmol) and Tf<SB>2</SB>NH (0.038 mmol) is prepared and toluene is distilled and removed under reduced pressure to obtain the catalyst. The obtained catalyst is dissolved in propionitrile (0.8 mL), water is added to catalyst-dissolved propionitril and then α-(cyclohexanecarbonyloxy)acrolein (0.4 mmol) is added to water-added propionitril to obtain a solution. After the obtained solution is cooled to -78°C, cyclopentadiene (1.6 mmol) is added slowly to the cooled solution and the cyclopentadiene-added solution is agitated at -78°C for 24 hours to obtain a reactive mixture. After triethylamine is added to the reactive mixture to stop the reaction, the temperature of the reaction-stopped mixture is raised to room temperature and a reaction solvent is distilled and removed under reduced pressure to obtain an exo-form body of a cyclized addition product with high enantio-selectivity. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a Diels-Alder reaction catalyst and a method for producing an asymmetric cycloaddition product using the same.

The enantioselective Diels-Alder reaction is one of the most important carbon-carbon bond formation reactions in synthetic chemistry because it can construct a cycloaddition product having an asymmetric carbon. On the other hand, α-acyloxyacrolein is effective as an active dienophile for Diels-Alder reaction, and the cycloaddition product obtained by Diels-Alder reaction of this α-acyloxyacrolein with an appropriate diene has an acyloxy group And formyl group can be converted into various functional groups, it can be used as a key synthesis intermediate for many useful compounds including prostaglandin E2, and its usefulness in synthetic chemistry is extremely high. In addition, α-acyloxyacroleins are easy to synthesize and can exist stably at room temperature. Furthermore, it is considered that the reactivity of α-acyloxyacroleins can be controlled by the type of acyloxy group. As described above, α-acyloxyacroleins have various advantages as dienophiles for asymmetric Diels-Alder reaction, but at present, they have succeeded in asymmetric Diels-Alder reaction of α-acyloxyacroleins. As far as the present inventors know, there are only reports of Non-Patent Document 1. In Non-Patent Document 1, an asymmetric Diels-Alder reaction of α-acyloxyacroleins was successfully achieved by using an ammonium salt of a chiral primary amine obtained from a dipeptide as a catalyst.
J. Am. Chem. Soc., 2005, vol127, p10504-10505

  However, in Non-Patent Document 1, the Diels-Alder reaction between a cyclopentadiene-based diene and α-acyloxyacrolein that gives a product that can be converted into a useful compound such as prostaglandin has sufficient enantioselectivity. It was not expensive.

  The present invention has been made to solve such problems, and one of the objects is to provide a Diels-Alder reaction catalyst suitable for an asymmetric Diels-Alder reaction using α-acyloxyacrolein as a dienophile. To do. Another object of the present invention is to provide a method for producing an asymmetric cycloaddition product capable of producing an asymmetric cycloaddition product with high enantioselectivity using the Diels-Alder reaction catalyst. .

  In order to achieve the above-mentioned object, the present inventors examined Diels-Alder reaction between cyclopentadiene and various α-acyloxyacroleins in the presence of salts formed by various diamines and strong acids. However, when the Diels-Alder reaction is carried out in the presence of an ammonium salt formed by optically active 1,1′-binaphthyl-2,2′-diamine and trifluoromethanesulfonimide, the asymmetric ring is highly enantioselectively selected. It was found that a chemical addition product was obtained, and the present invention was completed.

  That is, the Diels-Alder reaction catalyst of the present invention is a catalyst used for an asymmetric Diels-Alder reaction in which α-acyloxyacroleins are used as a dienophile, and is a diamine represented by Formula (1) or Formula (2). And a salt with a strong acid having a valence of 3 or more adjacent to the proton as an active ingredient.

(In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen, or a hydrocarbon group which may have a substituent)

  The method for producing an asymmetric cycloaddition product of the present invention comprises a Diels-Alder reaction between a diene and an α-acyloxyacrolein as a dienophile in the presence of the above-described Diels-Alder reaction catalyst of the present invention. To produce the corresponding asymmetric cycloaddition product.

  According to the Diels-Alder reaction catalyst and the method for producing an asymmetric cycloaddition product of the present invention, the asymmetric Diels-Alder reaction using α-acyloxyacrolein as a dienophile can be suitably advanced. Highly enantioselective asymmetric cycloaddition products can be produced. In particular, when a cyclic diene such as cyclopentadiene or cyclohexadiene is used as the diene, an asymmetric cycloaddition product can be obtained with high enantioselectivity. Since the Diels-Alder reaction catalyst of the present invention has higher activity than the catalyst of Non-Patent Document 1, the asymmetric Diels-Alder reaction can be suitably advanced at a low temperature with a small amount of catalyst.

In the Diels-Alder reaction catalyst of the present invention, R ¹ , R ² , R ³ , and R ⁴ in the formulas (1) and (2) are each independently hydrogen, halogen, or a hydrocarbon having a substituent. It is a group. Here, examples of the halogen include fluorine, chlorine, bromine and iodine. Further, the hydrocarbon group is not particularly limited, but examples thereof include saturated aliphatic groups such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, s-butyl group, and t-butyl group. Hydrocarbon group; unsaturated aliphatic hydrocarbon group such as vinyl group, 1-propenyl group, allyl group and 2-propenyl group; alicyclic hydrocarbon group such as cyclopentyl group, cyclohexyl group and 1-cyclohexenyl group; phenyl And aromatic hydrocarbon groups such as a group, tolyl group, xylyl group, mesityl group, benzyl group and phenethyl group. The substituent of the hydrocarbon group is not particularly limited. For example, the saturated aliphatic hydrocarbon group, the unsaturated aliphatic hydrocarbon group, the alicyclic hydrocarbon group, and the aromatic hydrocarbon group described above. In addition, an alkoxy group, an alkoxycarbonyl group, an acyloxy group, a nitro group, a cyano group, a halogen, and the like can be given.

  In the Diels-Alder reaction catalyst of the present invention, the diamine is preferably an (S) isomer or an (R) isomer of 1,1'-binaphthyl-2,2'-diamine. This is because this diamine is commercially available and therefore very easy to obtain. The Diels-Alder reaction catalyst containing a salt of a diamine and a strong acid as an active ingredient is very effective when a cyclic diene such as cyclopentadiene or cyclohexadiene is used as a diene and an α-acyloxyacrolein is used as a dienophile. This is because an asymmetric cycloaddition product can be obtained with high enantioselectivity.

In the Diels-Alder reaction catalyst of the present invention, the strong acid is not particularly limited as long as the valence of an adjacent element is 3 or more (for example, nitrogen, carbon, boron, etc.), but is preferably a super strong acid. One or more selected from the group consisting of perfluoroalkanesulfonylimide, tris (perfluoroalkanesulfonyl) methane, pentafluorophenylbis (perfluoroalkanesulfonyl) methane and tetrakis [3,5-bis (perfluoroalkyl) phenyl] borate A compound is preferred. Here, the carbon number of the perfluoroalkane (alkyl) is not particularly limited, but one or two is preferable. Specifically, trifluoromethanesulfonylimide (hereinafter referred to as Tf ₂ NH), tris (trifluoromethanesulfonyl) methane, pentafluorophenylbis (trifluoromethanesulfonyl) methane and tetrakis [3,5-bis (trifluoromethyl) phenyl] Borate and the like are preferred. The mixing molar ratio of diamine and strong acid is preferably diamine: strong acid = 1: 1 to 2, more preferably diamine: strong acid = 1: 1.8 to 2, and diamine: strong acid = 1: 1. .9 is more preferable.

  The Diels-Alder reaction catalyst of the present invention is obtained by mixing a diamine represented by formula (1) or formula (2) and a strong acid in a low polarity solvent such as toluene or xylene and then distilling off the solvent under reduced pressure. Can be separated.

In the method for producing an asymmetric cycloaddition product of the present invention, the diene is not particularly limited. For example, when a cyclic diene such as cyclopentadiene or cyclohexadiene is used, the exo / endo is compared with the conventional one. The selectivity and the enantioselectivity of the compound are preferable. Moreover, as (alpha) -acyloxy acrolein which is a dienophile, the compound shown, for example by Formula (3) can be used. Many α-acyloxyacroleins are easy to handle because they can be stored at room temperature. In the formula (3), the hydrocarbon group is not particularly limited, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an s-butyl group, and a t-butyl group. Saturated aliphatic hydrocarbon group: unsaturated aliphatic hydrocarbon group such as vinyl group, 1-propenyl group, allyl group, 2-propenyl group; alicyclic carbon group such as cyclopentyl group, cyclohexyl group, 1-cyclohexenyl group A hydrogen group; an aromatic hydrocarbon group such as a phenyl group, a tolyl group, a xylyl group, a mesityl group, a benzyl group, and a phenethyl group. The substituent of the hydrocarbon group is not particularly limited. For example, the saturated aliphatic hydrocarbon group, the unsaturated aliphatic hydrocarbon group, the alicyclic hydrocarbon group, and the aromatic hydrocarbon group described above. In addition, an alkoxy group, an alkoxycarbonyl group, an acyloxy group, a nitro group, a cyano group, a halogen, and the like can be given. The substituent selected as R ⁵ is preferably selected in consideration of the yield and enantioselectivity depending on the type of diene and catalyst used in the reaction.

(In the formula, R ⁵ is a hydrocarbon group which may have a substituent, and R ⁶ and R ⁷ are each independently hydrogen or a hydrocarbon group which may have a substituent)

  In the method for producing an asymmetric cycloaddition product of the present invention, the amount of Diels-Alder reaction catalyst used is not particularly limited. For example, 0.1% of diene and dienophile having a smaller number of moles. -30 mol% is preferable, 0.5-20 mol% is more preferable, and 1-10 mol% is especially preferable. If it is less than 0.1 mol% with respect to dienophile, the yield and enantioselectivity of the Diels-Alder reaction may be reduced, which is not preferable. If it exceeds 30 mol%, the results are not greatly improved and it is not economical. It is not preferable.

  In the method for producing an asymmetric cycloaddition product of the present invention, it is preferable that 1 to 20 mol% of water is present with respect to the smaller number of moles of diene and dienophile. This is because the presence of water in the reaction system facilitates the Diels-Alder reaction. In the reaction system, the reaction may proceed satisfactorily without the presence of water. For example, in a reaction system using a nitroalkane solvent such as nitroethane, the reaction may proceed well without water.

  In the method for producing an asymmetric cycloaddition product of the present invention, the reaction temperature is not particularly limited, and may be appropriately set, for example, in the range of −100 ° C. to room temperature (about 25 ° C.). Enantioselectivity -100 ° C to 0 ° C is preferable, and -100 ° C to -50 ° C is more preferable.

  In the method for producing an asymmetric cycloaddition product of the present invention, a nitrile solvent or a nitroalkane solvent that does not solidify during the reaction is preferably used as a reaction solvent. For example, the nitrile solvent includes propionitrile, and the nitroalkane solvent includes nitroethane.

[Example 1]
(S) -1,1′-binaphthyl-2,2′-diamine (Wako Pure Chemical Industries, 0.02 mmol) and Tf ₂ NH (Aldrich, 0.038 mmol, 1.9 equivalents relative to the diamine) After the toluene solution was prepared, the catalyst obtained by distilling off toluene under reduced pressure was dissolved in propionitrile (0.8 mL), water (10 mol% with respect to diamine) was added, and α- ( Cyclohexanecarbonyloxy) acrolein (0.4 mmol) was added. The solution was cooled to −78 ° C., cyclopentadiene (1.6 mmol) was slowly added, and the mixture was stirred at −78 ° C. for 24 hours. After stopping the reaction by adding triethylamine to the reaction mixture, the temperature was raised to room temperature, and the reaction solvent was distilled off under reduced pressure. The product was purified by a silica gel column (developing solvent: hexane-ethyl acetate) and subjected to ¹ H NMR analysis to obtain an exo form (9.53 ppm, s, 1 H, C H 2 O) and an end form (9.38 ppm, s, 1H, C H 2 O). The results are shown in Table 1. The exo spectrum data is as follows. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.12-1.51 (m, 7H), 1.55-1.81 (m, 4H), 1.81-2.00 (m, 2H), 2 .30 (tt, J = 3.6, 10.8 Hz, 1H), 2.50 (dd, J = 3.6, 12.9 Hz, 1H), 2.96 (m, 1H), 3.16 ( m, 1H), 6.08 (dd, J = 3.0, 5.7 Hz, 1H), 6.42 (dd, J = 3.0, 5.7 Hz, 1H), 9.53 (s, 1H) ) (Unit: ppm).

On the other hand, the resulting product was reduced to 2-hydroxy-2-hydroxymethylbicyclo [2.2.1] -5-heptene in THF using 2 equivalents of lithium aluminum hydride at 0 ° C. The reduction product is a known compound obtained by benzoylating a primary hydroxyl group (hydroxyl group at the 2-position) using 1.3 equivalents of benzoyl chloride and 2 equivalents of N, N-diisopropylethylamine in CHCl ₃ at 0 ° C. Conversion to (2-hydroxybicyclo [2.2.1] -5-hepten-2-yl) methylbenzoate, its enantioselectivity was determined by chiral HPLC analysis. The results are shown in Table 1. The HPLC analysis conditions and retention time are as follows. HPLC analysis conditions: Daicel Chemical OJ-H column (φ4.6 × 250 mm) manufactured by Daicel Chemical Industries, Ltd., hexane-isopropyl alcohol (40: 1), flow rate 1 mL / min, retention time: 20.9 ((2R ) -Exo isomer) min, 23.4 ((2S) -exo isomer) min.

Further, after preparing a toluene solution of (S) -1,1′-binaphthyl-2,2′-diamine (0.02 mmol) and Tf ₂ NH (0.04 mmol, 2 equivalents relative to diamine), toluene was reduced in pressure. The spectrum data of the catalyst (see formula (4)) obtained by distilling off is as follows. ¹ H NMR (300 MHz, CD ₃ CN) δ 7.08 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 7.5, 8.4 Hz, 2H), 7.71 (d , J = 8.4 Hz, 2H), 7.73 (dd, J = 7.5, 8.4 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H), 8.39 (d, J = 8.4 Hz, 2H) (unit: ppm). ¹³ C NMR (125 MHz, CD ₃ CN) δ 120.2 (q, J = 320 Hz), 121.6, 124.7, 125.5, 127.9, 128.8, 129.3, 129.6, 132 6, 133.2, 134.2 (unit: ppm).

[Example 2]
In Example 2, the reaction was performed in the same manner as in Example 1 except that 2 equivalents of Tf ₂ NH was used with respect to (S) -1,1′-binaphthyl-2,2′-diamine. The results are shown in Table 1.

[Example 3]
Example 3 was the same as Example 1 except that 1 equivalent of Tf ₂ NH was used with respect to (S) -1,1′-binaphthyl-2,2′-diamine and no water was added. The reaction was carried out. The results are shown in Table 1.

[Example 4]
In Example 4, the reaction was performed in the same manner as in Example 1 except that α- (cyclopentanecarbonyloxy) acrolein was used instead of α- (cyclohexanecarbonyloxy) acrolein. The results are shown in Table 1.

As is apparent from Table 1, in any Diels-Alder reaction of Examples 1 to 4, the cycloaddition product was obtained in a high yield (72 to 99%). In addition, the cycloaddition product was obtained with high selectivity to the exo isomer, and the (2S) isomer was obtained with high selectivity. Since the enantioselectivity of the product is used in excess of Tf 2 _NH respect diamine may be lowered, was considered to use 1.9 equivalents of Tf 2 _NH respect diamine is suitable. Moreover, in Example 3, it is thought that what formed one ammonium in diamine formed ammonium salt acted as a catalyst.

[Examples 5 to 7]
In Examples 5 to 7, various α-acyloxyacroleins shown in Table 2 were used by changing the diamine to (S) -6,6′-dibromo-1,1′-binaphthyl-2,2′-diamine. The reaction was conducted in the same manner as in Example 1 except that water was not added and the reaction was carried out with the reaction time shown in Table 2. The results are shown in Table 2. (S) -6,6′-dibromo-1,1′-binaphthyl-2,2′-diamine was prepared as follows. That is, first, N-bromosuccinimide (3 mmol) was added to a 1,4-dioxane (1 mL) solution of (S) -1,1′-binaphthyl-2,2′-diamine (1 mmol) and acetic acid (2 mmol). In addition, the mixture was stirred at room temperature for 12 hours. Subsequently, the reaction solution was diluted with ethyl acetate, and 10% aqueous sodium thiosulfate solution was added. Thereafter, the mixture was allowed to stand until liquid separation, and the organic layer was washed with 1M aqueous sodium hydroxide solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified with a silica gel column (developing solvent: toluene-ethyl acetate) to collect (S) -6,6′-dibromo-1,1′-binaphthyl-2,2′-diamine. Obtained at a rate of 41%.

  As is clear from Table 2, the cycloaddition product was obtained in high yield (78 to> 99%) in any Diels-Alder reaction of Examples 5-7. In addition, the cycloaddition product was obtained with high selectivity to the exo isomer, and the (2S) isomer was obtained with high selectivity.

[Example 8]
In Example 8, the reaction was performed in the same manner as in Example 1 except that the diene was changed to cyclohexadiene and the reaction time was changed to 48 hours. The reaction product is purified by a silica gel column (developing solvent: hexane-ethyl acetate) and subjected to ¹ H NMR analysis to obtain an exo form (9.38 ppm, s, 1 H, C H 2 O) and an end form (9.29 ppm). , S, 1H, C H 2 O). The results are shown in Table 3. The spectrum data of the end body is as follows. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.10-1.71 (m, 10H), 1.71-1.85 (m, 2H), 1.85-2.02 (m, 2H), 2 .09 (tdd, J = 3.0, 9.3, 12.6 Hz, 1H), 2.30 (td, J = 3.0, 14.1 Hz, 1H), 2.39 (tt, J = 3.6, 10.8 Hz, 1H), 2.74 (m, 1H), 2.85 (m, 1H), 6.03 (t, J = 7.2 Hz, 1H), 6.40 (t, J = 7.2 Hz, 1H), 9.29 (s, 1H) (unit: ppm).

  On the other hand, the obtained product was converted into (2-hydroxybicyclo [2.2.2] -5-octen-2-yl) methylbenzoate in the same manner as in Example 1, and the enantioselectivity was converted to chiral. Determined by HPLC analysis. The results are shown in Table 3. The HPLC analysis conditions and retention time are as follows. HPLC analysis conditions: Daicel Chemical OD-H column (φ4.6 × 250 mm) manufactured by Daicel Chemical Industries, Ltd., hexane-isopropyl alcohol (40: 1), flow rate 1 mL / min, retention time: 13.6 ((2R ) -Exo isomer) min, 16.9 ((2S) -exo isomer) min.

[Example 9]
In Example 9, the reaction was performed in the same manner as in Example 8 except that the reaction solvent was changed from propionitrile to nitroethane and no water was added. The results are shown in Table 3.

[Example 10]
In Example 10, the reaction solvent was changed from propionitrile to nitroethane, water was not added, and diamine was used in an amount of 5 mol% with respect to α-acyloxyacrolein. The reaction was performed. The results are shown in Table 3.

[Example 11]
In Example 11, α- (cyclopentanecarbonyloxy) acrolein was used instead of α- (cyclohexanecarbonyloxy) acrolein, the reaction solvent was changed from propionitrile to nitroethane, and no water was added. The reaction was carried out in the same manner as in Example 8 except that the reaction time was 24 hours. The results are shown in Table 3.

  As is apparent from Table 3, in any Diels-Alder reaction of Examples 8 to 11, the cycloaddition product was obtained in a high yield (90 to> 99%). In addition, the cycloaddition product was obtained with high selectivity for the endo form, and the (2S) form was obtained with high selectivity for the endo form. Furthermore, when the reaction solvent was changed from propionitrile to nitroethane, the reactivity was improved, and the reaction proceeded efficiently without adding water.

  The present invention can be used mainly in the pharmaceutical and chemical industries, and can be used, for example, in producing various cyclic compounds used as intermediates for pharmaceuticals, agricultural chemicals, and cosmetics.

Claims (9)

A catalyst used in an asymmetric Diels-Alder reaction using α-acyloxyacrolein as a dienophile,
A Diels-Alder reaction catalyst containing, as an active ingredient, a salt of a diamine represented by formula (1) or formula (2) and a strong acid having an valence of 3 or more adjacent to the proton.

(Wherein R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, halogen or a hydrocarbon group which may have a substituent)   The Diels-Alder reaction catalyst according to claim 1, wherein the diamine is an (S) isomer or an (R) isomer of 1,1'-binaphthyl-2,2'-diamine.   1 wherein the strong acid is selected from the group consisting of perfluoroalkanesulfonylimide, tris (perfluoroalkanesulfonyl) methane, pentafluorophenylbis (perfluoroalkanesulfonyl) methane and tetrakis [3,5-bis (perfluoroalkyl) phenyl] borate The Diels-Alder reaction catalyst according to claim 1 or 2, which is a compound of more than one species.   A corresponding asymmetric cycloaddition reaction by proceeding a Diels-Alder reaction between a diene and an α-acyloxyacrolein as a dienophile in the presence of the Diels-Alder reaction catalyst according to claim 1. A method for producing an asymmetric cycloaddition product for producing a product.   The method for producing an asymmetric cycloaddition product according to claim 4, wherein the diene is cyclopentadiene or cyclohexadiene.   The method for producing an asymmetric cycloaddition product according to claim 4 or 5, wherein 0.1 to 30 mol% of the Diels-Alder reaction catalyst is used relative to the diene or the dienophile having a smaller number of moles.   The asymmetric cycloaddition according to any one of claims 4 to 6, wherein the Diels-Alder reaction is allowed to proceed in the presence of 1 to 20 mol% of water with respect to the diene or the dienophile having a smaller number of moles. Product manufacturing method.   The method for producing an asymmetric cycloaddition product according to any one of claims 4 to 7, wherein the Diels-Alder reaction is allowed to proceed at -100 ° C to -50 ° C.   The method for producing an asymmetric cycloaddition product according to any one of claims 4 to 8, wherein a nitrile solvent or a nitroalkane solvent that does not solidify during the reaction is used as a reaction solvent.