catASium®—Essential Elements for Asymmetric Hydrogenations

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.

catASium® D(R) 672653 catASium® M(R) 670693 catASium® MNXyl(R) 669814 catASium® MNXylF(R) 670030   catASium® M(R)RhNor 670928 catASium® M(R)Rh 670804 catASium® MQF(R)Rh 670472 catASium® MNN(R)Rh 670588   catASium® MNAn(R)Rh 670251 catASium® MNXyl(R)Rh 669938 catASium® D(R)Rh 672777   catASium® MNXylF(R)Rh 670154 catASium® MN(R)Rh 669598 catASium® MNBn(R)Rh 669709   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.

Back to Top

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

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

Back to Top

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

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.

Back to Top

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

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.

Back to Top

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

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-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.

Back to Top