QuinoxP* Ligands

Aldrich ChemFiles 2006, 6.10, 3.

Aldrich ChemFiles 2006, 6.10, 3.

Various optically active phosphine ligands incorporating a chiral center at phosphorus display exceptional enantiosectivities in metal-catalyzed asymmetric synthesis.1 For instance, known classes of P-chiral phosphine ligands offer good to excellent enantiocontrol in Ru- and Rh-catalyzed hydrogenation reactions.2 The one limitation associated with these ligands is their sensitivity to air, which has impeded widespread applicability in bench-top chemistry. Imamoto and co-workers have addressed this deficiency through the development of QuinoxP*, which is based on an electron-withdrawing quinoxaline architecture.3

Sigma-Aldrich is pleased to offer both enantiomers of QuinoxP* for the research market.† The reactivity profile of these innovative, chiral ligands is covered below and highlights the impressive breadth of valuable transformations mediated by QuinoxP*. These powerfully efficient ligands exhibit high levels of enantiocontrol in synthetic transformations ranging from metal-catalyzed asymmetric 1,4-additions of arylboronic acids to enantioselective alkylative ring opening to asymmetric hydrogenations.3 It is worth noting that QuinoxP* is not oxidized at the stereogenic phosphorus center on standing at ambient temperature in air for more than 9 months.

Imamoto has also gone to great lengths to develop enantiomerically pure P-chiral ligands for industrially useful transformations such as asymmetric hydrogenation. Impressively, a diverse array of prochiral amino acid and amine substrates were hydrogenated with great efficiency to yield highly enantiopure amine derivatives (Scheme 1). These experiments were carried out at room temperature in methanol under low pressures of hydrogen (3 atm). All hydrogenation reactions were complete in 6 hours and with enantiomeric excesses ranging from 96 to 99.9%. Dramatic stereochemical reversal, consistent with the results observed with the related (S,S)-tert-Bu-BisP* ligands,4,5 was obtained when 1-acetylamino-1-adamantylethene was hydrogenated to afford the S-configuration amine with >96% enantioselectivity (Table 1).


Scheme 1


Table 1

Imamoto and co-workers have also exploited the high activity of the QuinoxP* ligand in rhodium-catalyzed enantioselective 1,4-additions of arylboronic acids to α,β-unsaturated carbonyl substrates.3 High yields of the addition products were obtained by running the reactions between 40 and 50 ºC (Scheme 2). The exceptional enantiocontrol exerted by this Rh(I)-catalyzed system is evident in the robust performance when compared to the use of BINAP as the chiral ligand.6


Scheme 2

Additionally, Imamoto and co-workers have succeeded in developing a Pd-catalyzed C–C bond-forming reaction, which displays high enantioselectivities with both dimethyl- and diethylzinc (Scheme 3, Table 2). This alkylative ring-opening methodology benefits from simply premixing PdCl2(cod) and QuinoxP* for 2 hours at room temperature, leading to a highly active catalyst. This catalyst system affords excellent yields of the ring-opened products and selectivities that rival the highest reported for this transformation. These results, when combined with the outstanding methodologies presented above, indicate that QuinoxP* is broadly useful for a variety of asymmetric metal-catalyzed transformations.3


Scheme 3


Table 2

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Materials

     

References

  1. (a) Weinkauff, D. J. et al. J. Am. Chem. Soc. 1977, 99, 5946.
    (b) Spagnol, M. et al. Chem. Eur. J. 1997, 3, 1365.
    (c) Hamada, Y. et al. Tetrahedron Lett. 1997, 38, 8961.
    (d) Kurth, V. et al. Eur. J. Inorg. Chem. 1998, 597.
    (e) Mezzetti, A. et al. Organometallics 1998, 17, 668.
    (f) Imamoto, T. et al. J. Am. Chem. Soc. 1998, 120, 1635.
    (g) Mezzetti, A. et al. Organometallics 1999, 18, 1041.
    (h) Imamoto, T. J. Org. Chem. 1999, 64, 2988.
    (i) Imamoto, T. et al. Tetrahedron: Asymmetry 1999, 10, 877.
    (j) van Leeuwen, P. W. N. M. et al. J. Org. Chem. 1999, 64, 3996.
  2. (a) Zhang, Z. et al. J. Org. Chem. 2000, 65, 6223.
    (b) Tang, W. et al. J. Am. Chem. Soc. 2003, 125, 9570.
    (c) Lei, A. et al. J. Am. Chem. Soc. 2004, 126, 1626.
    (d) Tang, W.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2002, 41, 1612.
    (e) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159.
    (f) Tang, W. et al. Org. Lett. 2003, 5, 205.
    (g) Tang, W. et al. Angew. Chem. Int. Ed. Engl. 2003, 42, 3509.
    (h) Xiao, D. et al. Org. Lett. 1999, 1, 1679.
    (i) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646.
  3. Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934.
  4. Imamoto, T. et al. J. Am. Chem. Soc. 2000, 122, 10486.
  5. Imamoto, T. et al. J. Am. Chem. Soc. 2001, 123, 5268.
  6. (a) Miyaura, N. et al. J. Am. Chem. Soc. 1998, 120, 5579.
    (b) Hayashi, T. et al. Tetrahedron Lett. 1999, 40, 6957.

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