EP1381462A1

EP1381462A1 - Polymer-bound catalyst for the enantioselective aldol or mannich reaction

Info

Publication number: EP1381462A1
Application number: EP02722246A
Authority: EP
Inventors: Jens WÖLTINGER; Hans-Peter Krimmer; Dietmar Reichert; Juan Jose Almena Perea; Karlheinz Drauz; Andreas Karau
Original assignee: Degussa GmbH
Current assignee: Evonik Operations GmbH
Priority date: 2001-04-26
Filing date: 2002-03-20
Publication date: 2004-01-21
Also published as: WO2002087759A1; WO2002087759B1; DE10120456A1; US20040198591A1; JP2004528174A

Abstract

The invention relates to catalysts for the enantioselective aldol or Mannich reaction. Said catalysts have an increased molecular weight by being bound to a polymer and as active units that enantioselectively catalyse the aldol or Mannich reaction comprise a compound of general formula (I). The invention also relates to a method for the production and use of said catalysts.

Description

Polymer-bound catalyst for the enantioselective

Aldol / annich reaction

The present invention is directed to a catalyst for the enantioselective aldol or Mannich reaction. In particular, the invention relates to catalysts which, on the one hand, have a molecular weight increase due to attachment to a polymer and, on the other hand, have an amino acid as the active unit which catalyzes the aldol or Mannich reaction enantioselectively. In particular, compounds of the general formula (I) are meant here.

Polymer-enlarged chiral catalysts are important tools for the synthesis of enantiomerically enriched organic compounds, especially on an industrial scale, because on the one hand, because of their catalytic activity and their ability to recycle and reuse, they help to produce the desired products in an extremely cost-effective manner.

Numerous chiral catalysts for the asymmetric aldol or Mannich reaction have also been described in the literature. Some of them also concern polymer-enlarged Lewis acids, which can be used in the so-called Mukaiyama reaction. The yields and ee values achieved in this way sometimes remain significantly below those of the monomer-catalyzed variant (A. Mandoli et al., Tetrahedron: Asymmetry 1998, 9, 1479f). The suitability of proline for the enantioselective catalysis of aldol or Mannich reactions is sufficiently known from the prior art (List et al. J. Am. Chem. Soc. 2000, 122, 9336f; ibid, 2000, 122, 2395; Hajos et al. 1974, 39, 1615f .; Wiechert et al. Angew. Chem., Int. Ed. Engl. 1971, 10, 496). So far, the successful use of such polymer-enlarged catalysts has not been reported.

There is therefore still a need for polymer-enlarged catalysts for use in the organic catalytic aldol or Mannich reaction for the synthesis of chiral compounds.

The object of the present invention was therefore to provide further polymer-enlarged catalysts which are able to catalyze the enantioselective aldol or Mannich reaction.

This object is achieved by the invention with the features of the present claim 1. Advantageous embodiments of the invention are protected in the dependent claims dependent on claim 1. Claim 7 relates to a preferred production process and claims 8 to 10 the use of the catalysts according to the invention.

The fact that polymer-enlarged catalysts having one or more of the structures of the general formula (I) as the active unit which determines the chiral induction

provides where m, n independently represent 0.1, 2, 3.4 X represents CH ₂ , 0, S, N, CHO, CH H, CHS, RH, (-C-C ₈ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, (C ₆ -C ₁₈ ) aryl, (C ₇ - Cιg) aralkyl means, you get the opportunity to work in catalytically To use processes in which the desired products can be obtained in very excellent yields and with high enantiomeric excesses. The catalysts can be separated very well from the low molecular weight compounds by the polymer connection, for example by filtration, and are thus accessible to the extremely simple, but no less advantageous, recycling desired by the invention.

Further preferred compounds of the general formula (I) are those in which n = 2 and m = 1, where X represents an oxygen atom.

A catalyst according to the invention is particularly preferred in which the active unit which determines the chiral induction has one or more of the structures of the general formula (II)

has, the free valence on the alcohol oxygen atom symbolizing the connection to a polymer.

Polymer enlargement:

The polymer enlargement can be chosen freely within the scope of the invention. It is limited on the one hand by practicality and cost considerations, and on the other hand by technical framework conditions (retention, solubility, etc.). Some polymer enlargements for catalysts are known from the prior art (Reetz et al., Angew. Chem. 1997, 109, 1559f .; Seebach et al. , Helv. Chim Acta 1996, 79, 1710f. _; Kragl et al. , Appl. Chem. 1996, 108, 684f. _; Schurig et al. , Chem. Ber./Recueil 1997, 130, 879f .; Bolm et al. , Appl. Chem. 1997, 109, 113 f. ; Bolm et al. Eur. J. Org. Chem. 1998, 21f .; Baystone et al. in Specialty Chemicals 224f .; Salvadori et al. , Tetrahedron: Asymmetry 1998, 9, 1479; Wandrey et al. , Tetrahedron: Asymmetry 1997, 8, 1529f .; ibid. 1997, 8, 1975f .; Togni et al. J. Am. Chem. Soc. 1998, 120, 10274f., Salvadori et al., Tetrahedron Lett. 1996, 37, 3375f; WHERE

98/22415; in particular DE 19910691.6; Janda et al., J. Am. Chem. Soc. 1998, 120, 9481f .; Andersson et al. , Chem. Commun. 1996, 1135f .; Janda et al. , Soluble Polymers 1999, 1, 1; Janda et al. , Chem. Rev. 1997, 97, 489; Geckler et al., Adv. Polym. Be. 1995, 121, 31; White et al. , in "The Chemistry of Organic Silicon Conpounds" Wiley, Chichester, 1989, 1289; Schuberth et al., Macromol. Rapid Commun. 1998, 19, 309; Sharma et al., Synthesis 1997, 1217; "Functional Polymers" Ed. : R. Arshady, ASC, Washington, 1996; "Internship of Macromolecular Substances", D. Braun et al., VCH-Wiley, Weinheim 1999).

The polymer enlargement is preferably formed by polyacrylates, polyacrylamides, polyvinylpyrrolidinones, polysiloxanes, polybutadienes, polyisoprenes, polyalkanes, polystyrenes, polyoxazolines or polyethers or mixtures thereof. In a very particularly preferred embodiment, polystyrenes are used to build up the polymer enlargement.

left:

A linker can be installed between the actual active unit and the polymer enlargement. The

Linker serves to build up a distance between the active unit and the polymer in order to reduce or eliminate mutual interactions which are disadvantageous for the reaction. The linker can in principle be free by the expert to get voted. They are to be selected according to the criteria of how well they are to be coupled to the polymer / monomer on the one hand and to the active unit on the other. Suitable linkers can be found, inter alia, in the references mentioned above under the heading polymer enlargement.

In the context of the invention, these active units of the formulas (I) and (II) are advantageously selected directly or preferably via a linker from the group a) -Si (R ₂ ) - b) - (SiR ₂ -0) _n - n = l-10000 c) - (CHR-CHR-O) _n - n = l-10000 d) - (X) n- n = l-20 e) Z- (X) _n - n = 0-20 f ) - (X) _n -W n = 0-20 g) Z- (X) _n -W n = 0-20 where

R is H, (-C ₈ -C) alkyl, (C ₆ -C ₈ ) aryl, (C ₇ -C ₁₉ ) aralkyl,

((-CC ₈ ) alkyl) ₃ - (C ₆ -C ₁₈ ) aryl, X means ( ₆ -C ₈ ) arylene, (-C ₈ ) alkylene, (-C ₈ ) -

Alkenylene, ((-C ₈ -C ₈ ) alkyl) ₃ - (C ₆ -C ₈ ) arylene, (C ₇ -C ₉ ) -

aralkylene,

Z, W independently of one another mean -C (= 0) 0-,

-C (= 0) H-, -C (= 0) -, NR, 0, CHR, CH ₂ , C = S, S, PR, bound to the polymer enlargement.

Further preferred compounds that can be used as linkers are shown in the following scheme:

However, linkers such as e.g. B. 1,4'-biphenyl, 1,2-ethylene, 1,3-propylene, PEG- (2-10), oc, ω-siloxanylene or 1,4-phenylene as well as α, (0-1,4- Bisethylene benzene or linker, which, starting from siloxanes of the general formula IV

R: Me, Et n = 0-10

are available. These can be found under

Hydrosilylation conditions (overview of the hydrosilylation reaction by Ojima in The Chemistry of Organic Silicon Compounds, 1989 John Wiley & Sons Ltd., 1480 - 1526) easily bind to any double bonds present in the polymers and suitable functional groups of the active centers.

The size of the polymer enlargement should be such that the catalyst dissolves in the solvent to be used, so that one can work in a homogeneous phase. The catalyst according to the invention is therefore preferably a homogeneously soluble one. Thereby it is possible to avoid negative effects that occur due to the phase changes of the substrates and products that would otherwise be necessary when using heterogeneous catalysts. The polymer-enlarged catalysts can have an average molecular weight in the range from 1,000 to 1,000,000, preferably 5,000 to 500,000, particularly preferably 5,000 to 300,000, g / mol.

It is within the scope of the invention that, according to the knowledge of a person skilled in the art, the abovementioned constituents of the polymer-enlarged catalysts (I) (polymer, linker, active center / unit) can be combined in any way with a view to optimal reaction control.

Combination of polymer enlargement to linker / active unit:

In principle there are two approaches how the linker / active unit can be attached to the polymer enlargement: a) the active unit which is responsible for the chiral induction is bound with a linked linker or directly to a monomer and this is copolymerized with further unmodified monomers, or b ) the active chiral induction unit is bound via a linker or directly to the finished polymer.

Possibly. polymers can be prepared according to a) or b) and these can be block copolymerized with other polymers which likewise have the active units which determine the chiral induction or which do not have them.

In principle, the same applies to the number of

Linker / active units per monomer in the polymer, that as many such catalytically active units as possible should find space on a polymer, so that the conversion per polymer is thereby increased. On the other hand However, the units should be at such a distance from each other that a mutual negative influence on the reactivity (TOF, selectivity) is minimized or does not even take place. The distance between the linker / active centers in the polymer should therefore preferably be in the range of 1-200 monomer units, preferably 5-25 monomer units.

In an advantageous embodiment, those locations in the polymer or monomer to be polymerized are used to connect the linker / active unit that are easy to functionalize or allow existing functionality to be used for the connection. For example, heteroatoms or unsaturated carbon atoms are preferably suitable for establishing the bond.

For example, In the case of styrene / polystyrene, the aromatics present can be used as connection points to the linkers / active units. Functionalities can be linked well to these aromatics, preferably in the 3-, 4-, 5-position, particularly preferably the 4-position, via normal aromatic chemistry. However, it is also advantageous to mix the mixture to be polymerized, e.g. Mix in already functionalized monomer and, after the polymerization, bind the linker to the functionalities present in the polystyrene. For this purpose, e.g. para-hydroxy, para-chloromethyl or para-aminostyrene derivatives are suitable.

In the case of the polyacrylates, an acid group or ester group is present in the monomer component, to which the linker or the active unit can be attached preferably via an ester or amide bond before or after the polymerization.

Polysiloxanes as an increase in molecular weight (increase in polymer) are preferably built up in such a way that in addition to dimethylsilane units Hydromethylsilane units are present. At these points, the linker / active units can then still be coupled via hydrosilylation. These can preferably be linked to the functionalities envisaged in the polymer under hydrosilylation conditions (overview of the hydrosilylation reaction by Ojima in The Chemistry of Organic Silicon Compounds, 1989 John Wiley & Sons Ltd., 1480-1526).

Suitable polysiloxanes modified in this way are known in the literature ("Siloxane polymers and copolymers", White et al., In Ed. S. Patai "The Chemistry of Organic Silicon Compounds" Wiley, Chichester, 1989, 46, 2954; C. Wandrey et al. TH: Asymmetry 1997, 8, 1975).

Combination of linker / polymer to active unit:

For the active units according to the invention, the polymer enlargement may be linked. via the linker, preferably via the ring, although obviously a free nitrogen function in the 1-position and a free acid group are essential for the successful implementation of the substrates (List et al. J. Am. Chem. Soc. 2000, 122, 9336f; ibid , 2000, 122, 2395; Hajos et al. 1974, 39, 1615f.).

In the case of a carbocyclic ring, the link is preferably established via a C-C linkage, preferably so far from the points of the compound which are essential for the reaction that there are no negative influences on the reaction itself. If there is another nitrogen atom in the carbocycle, the connection to the polymer / linker is very particularly preferably carried out via this 3-bonded nitrogen atom. If a CHS or CHO or CHNH function is present, the connection to the polymer / linker can be carried out successfully and simply via the heteroatoms themselves.

In the case of the compound (II) as the active unit, its connection with the is very particularly preferred Polymer enlargement via the free hydroxyl group. The starting material for this - hydroxyproline - is commercially available enantiomerically enriched and can thus be easily synthesized to the polymer enlargement via an ether or ester bond.

In a next embodiment, the invention is directed to the use of the catalyst according to the invention for the enantioselective aldol or Mannich reaction, in particular in a homogeneous phase. For this purpose, the regulations available in the literature are applied (e.g. List et. Al, JACS, 2000, 9336 and List et. Al., JACS, 2000, 2395). In order to achieve a short reaction time (<5 h; a reaction time of 1 h is preferred in order to achieve quantitative conversion at high ee), a catalyst requirement of up to 20 equivalents should be used.

The reaction according to the invention is therefore preferably carried out in a membrane reactor. The continuous mode of operation which is possible in this apparatus in addition to the batch and semi-continuous mode of operation can be carried out as desired in the cross-flow filtration mode (FIG. 2) or as dead-end filtration (FIG. 1). Both processes lead to in-situ recycling of the catalyst, so that an economical driving style is made possible despite the high catalyst requirement.

Both process variants are described in principle in the prior art (Engineering Processes for Bioseparations, Ed.: L.R. Weatherley, Heinemann, 1994, 135-165; Wandrey et al., Tetrahedron Asymmetry 1999, 10, 923-928).

The catalyst is particularly preferably used to produce bioactive substances. Descriptions of the drawings:

1 shows a membrane reactor with dead-end filtration. The substrate 1 is transferred via a pump 2 into the reactor space 3, which has a membrane 5. In the stirrer-operated reactor room are located next to the

Solvent catalyst 4, product 6 and unreacted substrate 1. Mainly low molecular weight 6 is filtered off through membrane 5.

Fig. 2 shows a membrane reactor with cross-flow filtration. The substrate 7 is transferred here via the pump 8 into the stirred reactor space, in which the solvent, catalyst 9 and product 14 are also located. A solvent flow is set via the pump 16, which leads into the cross-flow filtration cell 15 via a heat exchanger 12 which may be present. Here the low molecular weight product 14 is separated off via the membrane 13. High molecular weight catalyst 9 is then passed back into the reactor 10 with the solvent flow, if necessary again via a heat exchanger 12 and possibly via the valve 11.

In the context of the invention, mixtures of polymer-enlarged polymers are understood to mean the fact that individual polymers of different provenance are polymerized together to form block polymers. Statistical mixtures of the monomers in the polymer are also possible.

In the context of the invention, polymer enlargement is understood to mean the fact that one or more active units which are responsible for the chiral induction are copolymerized in a suitable form with further monomers, or that these units are coupled to an already existing polymer by methods known to the person skilled in the art. to

Forms of units suitable for copolymerization are well known to the person skilled in the art and can be freely selected by him. Preferably, the procedure is such that the molecule under consideration, depending on the type of copolymerization Groups capable of copolymerization derivatize, for example, in the case of copolymerization with (meth) acrylates by coupling to acrylate molecules.

The (Ci-Cs) -alkyl can be regarded as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl together with all binding isomers.

A (Cβ-cis) aryl radical is understood to mean an aromatic radical having 6 to 18 carbon atoms. In particular, these include compounds such as phenyl, naphthyl, anthryl,

Phenanthryl, biphenyl residues. These can be substituted one or more times with (-CC ₈ ) alkoxy, (-CC ₈ ) haloalkyl, OH, Cl, NH _{2 /} NO ₂ . In addition, the rest can have one or more heteroatoms such as N, 0, S.

(Ci-Cs) -alkoxy is a bonded via an oxygen atom to the molecule under consideration (-C-C ₈ ) alkyl radical.

A (C-Cι ₉₎ -aralkyl radical is a a _(Cι-C8) - bound to the molecule alkyl (C ₆ -Cι ₈₎ aryl.

In the context of the invention, the term acrylate is also understood to mean the term methacrylate.

(-C ~ C ₈ ) haloalkyl is a (C 1 -C ₈ ) alkyl radical substituted with one or more halogen atoms. Chlorine and fluorine are particularly suitable as halogen atoms.

A (C ₃ -C ₈ ) heteroaryl radical in the context of the invention denotes a five-, six- or seven-membered aromatic ring system of 3 to 18 carbon atoms, which heteroatoms such as, for. B. has nitrogen, oxygen or sulfur in the ring. Such heteroaromatics are in particular radicals, such as 1-, 2-, 3-furyl, such as 1-,

2-, 3-pyrrolyl, 1-, 2-, 3-thienyl, 2-, 3-, 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-indolyl, 3-, 4 -, 5-pyrazolyl, 2-, 4-, 5-imidazolyl, acridinyl, quinolinyl, phenanthridinyl, 2-, 4-, 5-, 6-pyrimidinyl. This can be substituted one or more times with (-CC ₈ ) alkoxy, (-CC ₈ ) haloalkyl, OH, halogen, NH ₂ , NO ₂ , SH, S- (-C ₈ ) -alkyl.

Under a (C-Cιg) heteroaralkyl is a

(C ₇ -C ₉ ) aralkyl radical corresponding heteroaromatic system understood.

The term (-C ₈ ) alkylene chain is to be understood as a (-C ₈ ) alkyl radical which is bonded to the molecule in question via two different C atoms. This can be substituted one or more times with (-CC ₈ ) alkoxy, (Cχ-C ₈ ) haloalkyl, OH, halogen, NH ₂ , NO ₂ , SH, S- (Cχ-C ₈ ) alkyl.

(C ₃ -C ₈ ) Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl or cyclooctyl radicals.

Halogen is fluorine, chlorine, bromine, iodine.

In the context of the invention, membrane reactor is understood to mean any reaction vessel in which the catalyst is enclosed in a reactor while low-molecular substances are fed to the reactor or can leave it. The membrane can be integrated directly into the reaction space or installed outside in a separate filtration module, in which the reaction solution flows continuously or intermittently through the filtration module and the retentate is returned to the reactor. Suitable embodiments are inter alia in W098 / 22415 and in Wandrey et al. in yearbook 1998, process engineering and chemical engineering, VDI p. 151ff .; Wandrey et al. in Applied Ho ogeneous Catalysis with Organometallic Compounds, Vol. 2, VCH 1996, p.832 ff .; Kragl et al. , Appl. Chem. 1996, 6, 684f. described. The chemical structures shown relate to all possible stereoisomers that can be achieved by changing the configuration of the individual chiral centers, axes or planes, i.e. all possible diastereomers, as well as all optical isomers (enantiomers) that fall under them. However, it should be clarified that all active units present according to the invention should be of the same chirality within a polymer-enlarged catalyst.

Claims

Claims:

1. Polymer-enlarged catalysts comprising one or more of the structures of the general formula (I) as the active unit which causes chiral induction

where m, n independently of one another are 0.1, 2, 3.4 X is CH ₂ , 0, N, S, CHO-, CHNH-, CHSH-, RH, (Cx-Cs) -alkyl, (C ₃ - C ₈ ) -cycloalkyl, (C ₆ -C ₈ ) aryl, (C ₇ -C ₉ ) aralkyl means.

2. Catalyst according to claim 1, characterized in that it acts as the active chiral induction unit or one or more of the structures of the general formula (II)

3. Catalyst according to claim 1 and / or 2, characterized in that the polymer enlargement by polyacrylates, polyacrylamides, polyvinylpyrrolidinones, polysiloxanes, Polybutadienes, polyisoprenes, polyalkanes, polystyrenes, polyoxazolines or polyethers or mixtures thereof is formed.

4. Catalyst according to one or more of the preceding claims, characterized in that the active chiral induction unit selected via a linker selected from the group a) -Si (R ₂ ) - b) - (SiR ₂ -0) _n - n = l-10000 c) - (CHR-CHR-0) _n - n = l-10000 d) - (X) n- n = l-20 e) Z- (X) _n - n = 0-20 f) - (X) _n -W n = 0-20 g) Z- (X) _n -W n = 0-20 where

R means H, (-C ₈ -C) alkyl, (C ₆ -C ₈ ) aryl, (C ₇ -C ₉ ) aralkyl, ((-C ₈ ) alkyl) _! - ₃ - (C ₆ -C ₈ ) aryl, X means (C ₆ -C ₈ ) arylene, (C ₈ -C ₈ ) alkylene, (C ₈ C) alkenylene, ((-C ₈ ) Alkyl) ₃ - (C ₆ -C ₈ ) arylene, (C ₇ -C ₉ ) aralkylene,

Z, W independently of one another mean -C (= 0) 0-, -C (= 0) NH-, -C (= 0) -, NR, 0, CHR, CH ₂ , C = S, S, PR the polymer is bound.

5. Catalyst according to one or more of the preceding claims, characterized in that it is a homogeneously soluble catalyst.

6. Catalyst according to one or more of the preceding claims, characterized in that the average molecular weight of the catalyst is in the range of 5,000-300,000 g / mol.

7. A process for the preparation of catalysts according to claim 1, characterized in that a) the active chiral induction-causing unit with linked linker or directly to a monomer and this is copolymerized with other unmodified monomers, b) the active chiral induction conditional unit binds via a linker or directly to the finished polymer, or c) polymers prepared according to a) or b) and block copolymerized with other polymers which also have the active units which determine chiral induction or which do not have them.

8. Use of the catalyst according to claim 1 for the enantioselective aldol or Mannich reaction, in particular in a homogeneous phase.

9. Use according to claim 8, characterized in that one carries out the reaction in a membrane reactor.

10. Use of the catalyst according to claim 1 for the synthesis of bioactive substances.