catASium®—Essential Elements for Asymmetric Hydrogenations

By: William Sommer and Daniel Weibel, Aldrich ChemFiles 2008, 8.2, 40.

Aldrich ChemFiles 2008, 8.2, 40.

Renat Kadyrov, Jürgen Krauter 
Evonik Degussa GmbH, Rodenbacher Chaussee 4, D-63457 Hanau-Wolfgang, Germany

Transition metal catalyzed enantioselective hydrogenation has been established as one of the most favorable strategies for the synthesis of optically active compounds in academia and on the industrial scale. In particular, chiral ligands bearing trivalent phosphorus as the 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-Institute of Organic Catalysis in Rostock.1 These ligands, which are now commercially available on a multikilogram scale under the trademark catASium M, are characterized by varied “bite-angle” and electronic properties of the bridging unit.2 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.

A rhodium(I) catalyst based on the new chiral bisphospholane ligand is one of the most effective catalytic systems for the hydrogenation of non-substituted and β-substituted itaconic acid derivatives known.3 The selected results (Table 1) show that this ligand displays a higher performance as compared to the known systems. The excellent enantioselectivities (up to 99%) are combined with a high catalytic activity (TOF up to 40,000 h-1).

Table 1. Hydrogenation of β-substituted itaconic acid derivatives

Table 1. Hydrogenation of β-substituted itaconic acid derivatives

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 these substrates.

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

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

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 phosphorus groups are introduced sequentially leading to a large variety of tuneable ligands.4

The selected results of hydrogenation of (Z)- and (E)-methyl 3‑acetylamino-2‑butenoates are summarized in Table 2. Excellent enantiomeric excesses of >99% were reached by hydrogenation of the E-isomer. Noteworthy is the 94% ee 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 also show 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. Enantioselective hydrogenation of enamides using Rh(I)-complexes of catASium® T

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.

Cationic catalyst catASium DRh, with a 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).5

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

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

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Materials

     

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.
  3. Almena, J.; Monsees, A.; Kadyrov, R.; Riermeier, T. H.; Gotov, B.; Holz, J.; Börner, A. Adv. Synth. Catal. 2004, 346, 1263‑1266.
  4. Kadyrov, R.; Ilaldinov, I. Z.; Almena, J.; Monsees, A.; Riermeier, T. H. Tetrahedron Lett. 2005, 46, 7395‑7400.
  5. Kadyrov, R.; Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Börner, A. J. Org. Chem. 2003, 68, 4067‑4070.

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