Method for the synthesis of solid heterogeneous chiral catalysts and their use in stereoselective reactions

Abstract

This invention describes the methodology to produce solid heterogeneous chiral organocatalysts that can be used in condensation reactions. The catalysts can be recovered in a simple manner by filtration and can also be reused.

Claims

1. A method for obtaining a compound of formula (I):
---OSiC.sub.3H.sub.6NHR.sub.1OCO(CNH)R.sub.2R.sub.2].sub.X[OSi].sub.Y--- Formula (I), wherein R.sub.1 is an aliphatic chain of the formula (CH2).sub.n-; n represents an integer from 0 to 9; X and Y have a proportion of from 1:1 to 1:20; OCO(CNH)R.sub.2R.sub.2 represents an -amino acid selected from the group consisting of ##STR00010## the method comprising: protecting an amino group of the -amino acid by reacting the -amino acid with di-tert-butyl carbonate to obtain a protected -amino acid; (ii) reacting a carboxyl group of the protected -amino acid with aminopropyltriethoxysilane (APTES) to obtain a protected and silanized -amino acid; (iii) polymerizing the protected and silanized -amino acid by reacting with a silicon alkoxide, and optionally an acid catalyst or a base catalyst, to obtain a polymerized product, wherein a ratio of the protected and silanized -amino acid to the silicon alkoxide is in a range of 1:1 to 1:20; and (iv) deprotecting the amino group of the -amino acid in the polymerized product with an acid selected from the group consisting of trifluoroacetic acid and 3M hydrochloric acid in ethyl acetate, thereby obtaining the compound of formula (I).

2. The method according to claim 1, wherein step (i) comprises adding 0.5 to 3.0 equivalents of di-tert-butyl carbonate to a 0.1 M to 0.2 M solution of the -amino acid in aqueous 1,4-dioxane at a temperature from 0 C. to 30 C., wherein the aqueous 1,4-dioxane has a ratio by volume of water: 1,4-dioxane of 1:0.5 to 1:2.

3. The method according to claim 2, further comprising adding 0.3 to 3.0 equivalents of triethylamine to the reaction mixture of step (i) and reacting at a temperature of 20 C. to 40 C. for 12 to 72 hours.

4. The method according to claim 1, wherein step (ii) comprises: adding 0.5 to 3.0 equivalents of potassium carbonate and 0.5 to 3.0 equivalents of O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate to a 0.1 M to 2.0 M solution of the protected -amino acid in a solvent selected from the group consisting of acetonitrile and methanol under nitrogen at temperature of 0 C. to 40 C. for a period of 10 to 60 minutes to obtain a reaction mixture; and adding 0.5 to 5.0 equivalents of APTES to the reaction mixture, and reacting for a period of 12 to 72 hours at a temperature of 20 C. to 40 C. to obtain the protected and silanized -amino acid.

5. The method according to claim 4, wherein the protected and silanized -amino acid is purified and washed with acetonitrile or methanol.

6. The method according to claim 1, wherein step (iii) comprises: adding potassium carbonate or acetic acid to a 0.1 M to 2.0 M solution of the protected and silanized -amino acid in ethanol or methanol at a temperature of 40 C. to 80 C., wherein 0.1 to 3.0 equivalents of the potassium carbonate or acetic acid are added relative to the protected and silanized -amino acid to obtain a reaction mixture; incubating the reaction mixture for 0.1 to 12 hours; slowly adding 1.0 to 20 equivalents of silicon alkoxide to the reaction mixture, followed by slowly adding 30 to 100 equivalents of water; and continuously stirring the reaction mixture for 0.4 to 24 hours at 40 to 80 C., thereby obtaining the polymerized product.

7. The method according to claim 6, further comprising incubating the polymerized product at a temperature 20 to 30 C. for a period of 24 to 72 hours, and drying the polymerized product at a temperature of 40 to 90 C. for 24 to 72 hours until a dried solid polymerized product is obtained.

8. The method according to claim 6, further comprising a step of purifying and washing the polymerized product with methanol and dichloromethane.

9. The method according to claim 1, wherein in step (iv), 0.1 mL to 5 mL of the acid per 1 g of the polymerized product is added.

10. A method for obtaining a compound of formula (I):
---[OSiC.sub.3H.sub.6NHR.sub.1OCO(CNH)R.sub.2R.sub.2].sub.X[OSi].sub.Y--- Formula (I), wherein R.sub.1 is an aliphatic chain of the formula n represents an integer from 0 to 9; X and Y have a proportion of from 1:1 to 1:20; OCO(CNH)R.sub.2R.sub.2 represents an -amino acid selected from the group consisting of ##STR00011## the method comprising: (i) protecting an amino group of the -amino acid by reacting the -amino acid with di-tert-butyl carbonate to obtain a protected -amino acid; (ii) polymerizing aminopropyltriethoxysilane (APTES) with a silicon alkoxide to obtain a solid matrix; (iii) reacting the solid matrix with the protected -amino acid to obtain a polymerized product; and (iv) protecting, the amino group of the -amino acid in the polymerized product with an acid selected from the group consisting of trifluoroacetic acid and 3M hydrochloric acid in ethyl acetate, thereby obtaining the compound of formula (I).

11. The method according to claim 10, wherein step (ii) comprises: slowly adding 1.0 to 20 equivalents of the silicon alkoxide to a 0.1 M to 2.0 M solution of APTES in ethanol or methanol at a temperature of 40 to 80 C. to obtain a reaction mixture; slowly adding 30 to 100 equivalents of water to the reaction mixture; and continuously stirring the reaction mixture at a temperature of 40 to 80 C. for 0.1 to 12 hours to obtain a solid matrix.

12. The method according to claim 11, further comprising incubating the solid matrix at a temperature of 20 to 30 C. for 24 to 72 hours, and drying the solid matrix at a temperature of 40 to 90 C. for 24 to 72 hours until a dried solid matrix is obtained.

13. The method according to claim 10, wherein step (iii) comprises: adding 0.5 to 3.0 equivalents of potassium carbonate and 0.5 to 3.0 equivalents of O-(benzotriazole-1-i1)-N,N,N,N-tetramethyluronium-tetrafluoroborate to a 0.1 M to 1.5 M solution of the protected -amino acid in acetonitrile or methanol under nitrogen at a temperature of 0 C. to 40 C. to obtain a reaction mixture; stirring the reaction mixture for 10 minutes to 60 minutes; adding to the reaction mixture the solid matrix obtained in step (ii) in a mass:volume (g/mL) ratio of 1:5 to 1:40; and incubating the reaction mixture at a temperature of 20 C. to 40 C. for 12 to 72 hours, thereby obtaining the polymerized product.

14. The method according to claim 13, further comprising purifying and washing the polymerized product with acetonitrile or methanol.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The solid heterogeneous chiral catalyst obtained by any of these methodologies can be used in reactions for forming carbon-carbon bonds of a chiral nature, such as aldol condensation, Mannich condensation, Michael addition and Henry reaction using aqueous reaction mediums or organic mediums. The reactions can be done at temperatures from 78 C. to 40 C.

EXAMPLES

Example 1

Synthesis of a Solid Heterogeneous Chiral Catalyst Based on L-Proline

(2) ##STR00001##
Protection Reaction with Boc of the Amino Group of L-Proline (1)

(3) 1.1 equivalents of BOC.sub.2O were added to a 0.5M solution of L-proline (1) in a mixture of distilled water and 1,4-dioxane (1:1) at a temperature of 0 C. Once the mixture was homogenized, 1.1 equivalents of TEA were slowly added. The reaction mixture was continuously stirred for 12 hours at 25 C. The reaction mixture was partially concentrated, and the solution extracted with ethyl acetate. The organic phase was separated and dried with anhydrous sodium sulphate. The solution was concentrated in order to obtain N-Boc L-proline (2) in 98% yield. The product was not purified and was subjected to the following reaction as crude.

(4) ##STR00002##
Silanization Reaction of the Compound (2) with APTES

(5) 1.0 equivalent of potassium carbonate and 1.5 equivalents of TBTU were added to a 0.2M solution of the compound (2) in acetonitrile at 0 C. while subjected to a nitrogen atmosphere. The mixture was continuously stirred for 60 minutes and 1.0 equivalent of APTES was later added. The reaction mixture was kept at 25 C. for 12 hours. The reaction mixture was concentrated, and to the resulting viscous product ethyl acetate was added and the suspension filtered. The resulting solution was concentrated, producing a lightly-yellow viscous liquid (3).

(6) ##STR00003##
Polymerization Reaction of the Compound (3)

(7) 0.5 equivalent of potassium carbonate and 3.0 equivalents of tetraethyl orthosilicate (TEOS) were added to a 0.3M solution of the compound (3) in ethanol. The reaction mixture was heated at 70 C. for 2 hours. 30 equivalents of distilled water were slowly added to the reaction mixture at 70 C. The reaction mixture was continuously stirred at 70 C. until a gel was formed. The reaction mixture was left to stand at 25 C. while vented for 24 to 72 hours. The gel was dried at 60 C. for 48 hours. The solid was pulverized and the powder washed with methanol and dichloromethane in order to obtain a yellowish powder corresponding to compound (4).

(8) ##STR00004##
Deprotection or Activation Reaction of the Compound (4)

(9) 0.1 mL of trifluoroacetic acid was added to a suspension of the compound (4) in dichloromethane using 1 g of solid per 10 mL of solvent. The reaction mixture was kept at 0 C. and stirred for 3 hours. The reaction mixture was decanted and the solid neutralized with an aqueous solution of NaHCO.sub.3 at 10%. The activated heterogeneous chiral catalyst was filtered and washed with distilled water. The catalyst was dried at 80 C. for 48 hours obtaining a fine powder with a slightly yellowish coloring. If preferred, the catalyst (5) can be used in aqueous reactions without previously drying.

(10) The solid heterogeneous chiral catalyst or compound (5) was characterized by nuclear magnetic resonance of .sup.13C in the solid state, and the signals corresponding to the expected catalyst were observed: .sup.13C cross polarization magic angle spinning (CP-MAS) NMR (16 kHz, CDCl.sub.3) ppm: =9.7 (CA), 24 (CB), 30.7 (CC), 41.1 (CD), 46.5 (CE), 60.9 (CF), 174.8 (CG). The elemental analysis indicates the presence of 31.5% by weight of the organic catalyst in the heterogeneous chiral catalyst.

Example 2

Synthesis of a Solid Catalyst Based on L-Proline

(11) Stage I was carried out as described in Example 1 in order to obtain N-Boc L-proline (2). Later, the esterification of N-Boc L-proline (2) with 9-bromononanol was done in order to obtain the compound (6). The reaction proceeds as follows:

(12) ##STR00005##
Esterification of N-Boc L-Propline

(13) 1.0 equivalent of potassium carbonate and 1.5 equivalents of TBTU were added to a 0.2M solution of N-Boc L-proline (2) in acetonitrile at 0 C. under a nitrogen atmosphere. The reaction mixture was stirred for 60 minutes. 1.0 equivalent of 9-bromononanol is added to the reaction mixture. The reaction mixture was stirred for 12 hours. The reaction mixture was concentrated and the product was purified by column chromatography using silica gel as the immobile phase and a mixture of hexanes/ethyl acetate (3/1) as mobile phase in order to obtain the compound (6) in 92% yield.

(14) The compound (6) was subjected to Stage II:

(15) ##STR00006##
Silanization Reaction of the Compound (6) with APTES

(16) 1.0 equivalent of potassium carbonate and 1.0 equivalent of APTES are added to a 0.2M solution of the compound (6) in methanol at ambient temperature under a nitrogen atmosphere. The reaction mixture, while being stirred, was heated to 60 C. for 12 hours. The reaction mixture was concentrated and the unpurified compound (8) was used in the following reaction. Compound (7) was subjected to Stage III of inorganic polymerization as in Example 1, but 6.0 equivalents of TEOS were used.

(17) Compound (7) was subjected to Stage III:

(18) ##STR00007##
Polymerization Reaction of Compound (7)

(19) 0.5 equivalents of potassium carbonate and 6.0 equivalents of TEOS were added to a 0.3M solution of compound (7) in ethanol. The reaction mixture was heated to 70 C. for 2 hours. 30 equivalents of distilled water were slowly added to the reaction mixture at 70 C. The reaction mixture was continuously stirred at 70 C. until a gel was formed. The reaction mixture was left to stand at 25 C. while vented for 24 to 72 hours. The gel was dried at 60 C. for 48 hours. The solid was pulverized and the powder was washed with methanol and dichloromethane in order to obtain a yellowish powder corresponding to compound (8).

(20) Compound (8) is subjected to Stage 1V.

(21) ##STR00008##
Deprotection or Activation Reaction of the Compound (8)

(22) 0.1 mL of trifluoroacetic acid was added to a suspension of the compound (8) in dichloromethane using 1.0 g of solid per 10 mL of solvent. The reaction mixture was stirred at 0 C. for 3 hours. The reaction mixture was decanted and the solid was neutralized with an aqueous solution of NaHCO.sub.3 at 10%. The activated heterogeneous chiral catalyst was filtered and washed with distilled water. The catalyst was dried at 80 C. for 48 hours, producing a fine powder with a slightly yellowish coloring. If preferred, the catalyst (9) can be used in aqueous reactions without previous drying.

(23) The catalyst (9) was characterized by nuclear magnetic resonance of C.sup.13, in which the signals corresponding to the expected catalyst were observed: .sup.13C CP MAS NMR (16 kHz, CDCl.sub.3) ppm: =9.8 (Ca), 20.5 (Cb), 28.7 (Cc), 43.9 (Cd), 49.1 (Ce), 51.8 (Cf), 59.7 (Cg), 67.5 (Ch), 162 (Ci). The elemental analysis indicated the presence of 21% by weight of the organic catalyst in the final solid.

(24) This example shows that Stages I, II, III and IV described in this invention are always present to carry out the synthesis of solid catalysts with modified -amino acids, although modification of the -amino acids implies additional reaction steps. In order to obtain the solid heterogeneous chiral catalyst, it is necessary to include each and every one of the Stages I, II, III and IV or alternatively Stages I, V, VI and IV described in the methodology of the invention.

Example 3

Use of Catalyst (5) in the Aldol Condensation of 4-Nitrobenzaldehyde with Acetone

(25) ##STR00009##
Aldol Condensation Catalyzed with Catalyst (5)

(26) Acetone (11, 3.305 mmol) and 0.1 g of catalyst (5) were added to a 0.3M solution of 4-nitrobenzaldehyde (10, 0.661 mmol) in a phosphate buffer pH=7 (0.05M) at 25 C. The reaction mixture was kept stirring at 25 C. for 2 hours. The suspension was filtered, and the solution was partially concentrated and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and concentrated with a vacuum. The product was purified by column chromatography n order to obtain the -hydroxyketone compound (12) in 98% yield with an enantiomeric excess of 79% corresponding to the (S)-enantiomer.

Example 4

Use of Catalyst (5) in the Aldol Condensation Reaction of 3-Nitrobenzaldehyde with Acetone

(27) This reaction with 3-nitrobenzaldehyde used the same reaction conditions used in Example 3 in 3 hours. The corresponding -hydroxyketone product was obtained in 92% yield and in 64% enantiomeric excess of the (S)-enantiomer.

Example 5

Use of Catalyst (5) in the Reaction of Aldol Condensation of Isatin with Acetone

(28) This reaction with isatin used the same reaction conditions used in Example 3 in 3 hours. The corresponding -hydroxyketone product was obtained in 76% yield and 84% enantiomeric excess of the (R)-enantiomer.

Example 6

Use of Catalyst (9) in the Aldol Condensation Reaction of 4-Nitrobenzaldehyde with Acetone

(29) This reaction with catalyst (9) used the same reaction conditions used in Example 3 in 4 hours. The corresponding -hydroxyketone product was obtained in 75% yield and in 69% enantiomeric excess of the (S)-enantiomer.

Example 7

Use of Catalyst (9) in the Aldol Condensation Reaction of 3-Nitrobenzaldehyde with Acetone

(30) This reaction with catalyst (9) and 3-nitrobenzaldehyde used the same reaction conditions used in Example 3 in 4 hours. The corresponding -hydroxyketone product was obtained in 67% yield and in 55% enantiomeric excess of the (S)-enantiomer.

Example 8

Use of Catalyst (9) in the Aldol Condensation Reaction of Isatin with Acetone

(31) This reaction with catalyst (9) and isatin used the same reaction conditions used in Example 3 in 6 hours. The corresponding -hydroxyketone product was obtained in 58% yield and 76% enantiomeric excess of the (R)-enantiomer.

Example 9

Reusing Catalyst (5) in the Aldol Condensation Reaction of 4-Nitrobenzaldehyde with Acetone

(32) The aldol condensation reaction of 4-nitrobenzaldehyde with acetone was done using catalyst (5) as described in Example 3. The catalyst (5) was filtered, washed with acetone, and added to a new 0.3M solution of 4-nitrobenzaldehyde (0.661 mmol) in a phosphate buffer pH=7 (0.05M) at 25 C. with acetone (3.305 mmol). This reusing process was repeated for several cycles, obtaining the results shown in Table 1.

(33) TABLE-US-00001 TABLE 1 Reusing of catalyst (5) with 4-nitrobenzaldehyde and acetone 4-nitrobenzaldehyde Results Reuse Yield Time Enantiomeric excess (%) 0 98% 2 h 79 (S)-() 1 96% 2 h 79 (S)-() 2 92% >2 h 79 (S)-() 3 82% >2 h 76 (S)-() 4 80% 3 h 69 (S)-()

Example 10

Reusing Catalyst (9) in the Aldol Condensation Reaction of 4-Nitrobenzaldehyde with Acetone

(34) The aldol condensation reaction of 4-nitrobenzaldehyde with acetone was done using catalyst (9) as described in Example 3. The catalyst (9) was filtered, washed with acetone, and added to a new solution of 0.3M of 4-nitrobenzaldehyde (0.661 mmol) in a phosphate buffer (0.05M) at 25 C. with acetone (3.305 mmol). This reusing process was repeated for several cycles, obtaining the results shown in Table 2.

(35) TABLE-US-00002 TABLE 2 Reusing of catalyst (9) with 4-nitrobenzaldehyde and acetone 4-nitrobenzaldehyde Results Reuse Yield Time Enantiomeric excess (%) 0 75% 4 h 69 (S)-() 1 70% 4 h 66 (S)-() 2 70% 5 h 63 (S)-() 3 66% 6 h 59 (S)-()

(36) It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

(37) Having described my invention sufficiently, I claim as my property what is contained in the following claims.