Chemical Synthesis

catASium

Introduction

Advantages

Representative Applications


Introduction
Transition metal catalyzed enantioselective hydrogenation has been established as one of the most favorable strategies for the synthesis of optically active compounds in academic and industrial scale. In particular, chiral ligands bearing trivalent phosphorus as ligating atom for "soft" metals like rhodium(I), ruthenium(II), or iridium(I) play a pivotal role in this area. Among electron-rich chiral phosphines, chiral phospholanes have emerged as one of the most efficient classes of ligands in metal catalyzed enantioselective reactions. Prominent examples are bisphospholane ligands like DuPHOS and BPE. In general, these compounds are synthesized by a linear approach, where the phospholane is constructed by condensation of a primary phosphine with the sulfate or sulfonates derived from the appropriate chiral diols in the presence of strong bases. This tedious approach is restricted by low tolerance of the functional groups and, therefore, strongly limits the possible variations of the backbone.

EVONIK DEGUSSA GmbH has developed a modular synthesis of diverse arrays of chiral vicinal bisphospholanes in collaboration with the Leibniz-Institut of Organic Catalysis in Rostock. These ligands, which are now commercially available on a multi-kilogram scale under the trademark catASium® M, are characterized by varied "bite-angle" and electronic properties of the bridging unit. The new ligands can be advantageously employed in the fine-tuning of those enantioselective hydrogenations, where the results obtained with traditional bisphospholane ligands require optimization.



                       
672653 Structure 670693 Structure 669814 Structure 670030 Structure
catASium® D(R)
672653
catASium® M(R)
670693
catASium® MNXyl(R)
669814
catASium® MNXylF(R)
670030
 
670928 Structure 670804 Structure 670472 Structure 670588 Structure
catASium® M(R)RhNor
670928
catASium® M(R)Rh
670804
catASium® MQF(R)Rh
670472
catASium® MNN(R)Rh
670588
 
670251 Structure 669938 Structure 670472 Structure
catASium® MNAn(R)Rh
670251
catASium® MNXyl(R)Rh
669938
catASium® D(R)Rh
672777
 
670154 Structure 669598 Structure 670472 Structure
catASium® MNXylF(R)Rh
670154
catASium® MN(R)Rh
669598
catASium® MNBn(R)Rh
669709
 
670928 Structure 671029 Structure 671142 Structure 671258 Structure
catASium® MNF(R)Rh
670367
catASium® T1(R)
671029
catASium® T2(R)
671142
catASium® T3(R)
671258
 

References:

  1. Holz, J.; Monsees, A.; Jiao, H.; You, J.; Komarov, I. V.; Fischer, C.; Drauz, K.; Börner, A. J. Org. Chem. 2003, 68, 1701–1707.
  2. Holz, J.; Zayas, O.; Jiao, H.; Baumann, W.; Spannenberg, A.; Monsees, A.; Riermeier, T. H.; Almena, J.; Kadyrov, R.; Börner, A. Chem.—Eur. J. 2006, 12, 5001–5013.

 


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Advantages

  • Atom-economical catalytic method
  • High yields and synthetically useful levels of enantiocontrol
  • Unparallelled ability to prepare chiral building blocks from simple precursors

 


Representative Applications

Hydrogenation of Non-substituted and β-substituted Itaconic Acid Derivatives

A rhodium(I) catalyst based on the new chiral bisphospholane ligand proved to be one of the most effective catalytic systems for the hydrogenation of non-substituted and β-substituted itaconic acid derivatives known up to now. The selected results (Table 1) show that this ligands displays higher performance compared to the known systems. The excellent enantioselectivities (up to 99%) are combined with the high catalytic activity (TOF up to 40,000 h-1).

Table 1: Hydrogenation of β-substituted itaconic acid derivatives

Table 1 Structure

Catalyst R R' Solvent TON ee [%]b
catASium® M(R)Rh H Me CH2Cl2 10,000 99
catASium® M(R)Rh H H CH2Cl2 4,000 99
catASium® MN(R)Rh Ph H Acetone 500 98
catASium® MNBn(R)Rh i-Pr H CH3OH 500 98

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Hydrogenation of β-acylamido Acrylates

Exciting results were also observed in the hydrogenation of β-acylamido acrylates (Table 2). These are important intermediates in the synthesis of enantiopure β-amino acids. Particularly when the hydrogenation of the challenging Z-configured substrates bearing bulky substituents in the 3-position (for example i-Pr) were tested, a catASium® M(R)Rh-catalyst showed the highest enantioselectivities known for this substrates.

Table 2: Enantioselective hydrogenations of β-enamides using catASium® ligands

Table 2 Structure

Catalyst Configuration R R' Solvent ee [%]b
catASium® M(R)Rh E Me Bn CH2Cl2 99.5
catASium® M(R)Rh Z Me Bn CH3OH 89.9
catASium® M(R)Rh E i-Pr Et CH2Cl2 99.7
catASium® M(R)Rh Z i-Pr Et CH2Cl2 89.6
catASium® T2(R)/Rh E Me Me CH3OH 99.3
catASium® T2(R)/Rh Z Me Me CH2Cl2 94

Reference:
Almena, J.; Monsees, A.; Kadyrov, R.; Riermeier, T. H.; Gotov, B.; Holz, J.; Börner, A. Adv. Synth. Catal. 2004, 346,
1263–1266.

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Hydrogenation of (Z)-and (E)-methyl 3-acetylamino-but-2-enoates

A new class of atropisomeric ligands based on camphor catASium® T were developed in close collaboration with Russian researchers. The new ligand system combines the features of central chirality derived from a natural product with axial chirality like in the biaryl type ligands. In addition to this, the two phosphorous groups are introduced sequentially leading to a large variety of tuneable ligands.

The selected results of hydrogenation of (Z)-and (E)-methyl 3-acetylamino-but-2-enoates are summarized in Table 2. Excellent enantiomeric excesses of >99 % were reached by hydrogenation of the E-isomer. Noteworthy 94% ee was achieved using catASium® T2 catalyst in the hydrogenation of the Z-isomer. It is one of the best optical inductions achieved in the hydrogenation of the Z-β-enamides. These ligands show also interesting properties in the hydrogenation of challenging simple α-enamides (Table 3).

Table 3: Enantioselective hydrogenation of enamides using Rh(I)-complexes of catASium® T

Table 3 Structure

R ligand Solvent ee [%]
t-Bu catASium® T1 CH2Cl2 87
Ph catASium® T2 MeOH 92
3-NO2C6H4 catASium® T2 toluene 99.7
2-naphthyl catASium® T2 toluene 98

Reference:
Kadyrov, R.; Ilaldinov, I. Z.; Almena, J.; Monsees, A.; Riermeier, T. H. Tetrahedron Lett. 2005, 46, 7395–7400.

Whereas applying catalysts based on catASium® T ligands to electron rich substrates induce only moderate enantiomeric excesses the hydrogenation of the substrate with electron-withdrawing groups surprisingly leads to near complete enantioselectivity.

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Enantioselective Reductive Amination of Keto Acids

Cationic catalyst catASium® DRh with ligand well known under the old name Deguphos was successfully utilized in the first highly enantioselective reductive amination of keto acids, where several chiral α-amino acids were produced in good yield and very high ee’s (up to 98%) (Table 4).

Table 4: Yields and enantioselectivities of the reductive amination of α-keto acids with benzylamine using catASium® D(R)Rh

Table 4 Structure

R Product Isolated yield ee [%]
Me N-Bn-Ala 43 78
PhCH2 N-Bn-Phe 99 98
PhCh2CH2 N-Bn-Bn-Ala 79 81
Me2CHCH2 N-Bn-Leu 99 90
Me3CCH2 N-Bn-t-Bu-Ala 94 86

Reference:
Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Börner, A. J. Org. Chem. 2003, 68, 4067–4070.

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Product Information

Product # Product Name Structure Add to Cart
672653 catASium® D(R) catASium® D(R) Structure Image Shopping Cart
672777 catASium® D(R)Rh catASium® D(R)Rh Structure Image Shopping Cart
670693 catASium® M(R) catASium® M(R) Structure Image Shopping Cart
669814 catASium® MNXyl(R) catASium® MNXyl(R) Structure Image Shopping Cart
670030 catASium® MNXylF(R) catASium® MNXylF(R) Structure Image Shopping Cart
670804 catASium® M(R)Rh catASium® M(R)Rh Structure Image Shopping Cart
670928 catASium® M(R)RhNor catASium® M(R)RhNor Structure Image Shopping Cart
669598 catASium® MN(R)Rh catASium® MN(R)Rh Structure Image Shopping Cart
670588 catASium® MNN(R)Rh catASium® MNN(R)Rh Structure Image Shopping Cart
670251 catASium® MNAn(R)Rh catASium® MNAn(R)Rh Structure Image Shopping Cart
670367 catASium® MNF(R)Rh catASium® MNF(R)Rh Structure Image Shopping Cart
669709 catASium® MNBn(R)Rh catASium® MNBn(R)Rh Structure Image Shopping Cart
669938 catASium® MNXyl(R)Rh catASium® MNXyl(R)Rh Structure Image Shopping Cart
670154 catASium® MNXylF(R)Rh catASium® MNXylF(R)Rh Structure Image Shopping Cart
670472 catASium® MQF(R)Rh catASium® MQF(R)Rh Structure Image Shopping Cart
671029 catASium® T1(R) catASium® T1(R) Structure Image Shopping Cart
671142 catASium® T2(R) catASium® T2(R) Structure Image Shopping Cart
671258 catASium® T3(R) catASium® T3(R) Structure Image Shopping Cart
672556 Evonik Ligand Kit for Asymmetric Hydrogenation Evonik Ligand Kit for Asymmetric Hydrogenation Image Shopping Cart

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