Asymmetric Hydrogenation

By: William Sommer, Aldrich ChemFiles 2008, 8.6, 3.

Asymmetric hydrogenation plays an important role in today’s synthesis world. Knowles and Noyori pioneered this field and were rewarded with the Nobel Prize in 2001 for their work. It allows the generation of chiral centers selectively, with good yields. Furthermore, it gives access to a new pool of molecules with specific properties used in the pharmaceutical, flavors and fragrances, and agrochemical industries. However, the metal complex commonly used for these transformations is usually based on rhodium or ruthenium. The high cost and scarcity of these metal complexes make the technology prohibitive for use in large-scale synthesis. Based on the preliminary work of Stryker with copper catalysts, Shimizu et al. developed a new methodology for the hydrogenation of aryl ketones using copper complexes.1 To achieve high enantioselectivities, (S,S)-BDPP ligand is necessary. Using a copper complex with (S,S)-BDPP, and tri(3,5-xylyl)-phosphine, a variety of aryl ketones were reduced to secondary alcohols in good to excellent yields with overall good ee’s (Scheme 1).

 



Scheme 1.

The versatility of (S,S)-BDPP was demonstrated in the work done by Lu and Alper.2 In their quest to synthesize chiral heterocycles, they investigated a number of catalysts and ligands for the asymmetric hydrogenation of terminal alkenes. Common ruthenium and iridium complexes were used with limited success. Furthermore, several chiral bidentate ligands such as BINAP, Monophos, DIOP, Duphos or Josiphos were tested in the transformation with little success. The best catalytic system was found to be (S,S)-BDPP with Rh(cod)2BF4. A variety of tricyclic lactams were synthesized with excellent enantioselectivity. The procedure typically involves the use of 1 mol% of rhodium complex and ligand in methanol at 0 ºC under 20 psi of H2. It is important to note that these heterocyclic motifs are encountered in many biologically active natural products as well as drug candidates.

 


Scheme 2.

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Materials

     

References

  1. Shimizu, H. et al. Org. Lett. 2007, 9, 1655.
  2. Lu, S. -M. et al. J. Am. Chem. Soc. 2008, 130, 6451.

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