Various optically active phosphine ligands incorporating a chiral center at phosphorus display exceptional enantiosectivities in metal-catalyzed asymmetric synthesis.1 For instance, known classes 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 invention of QuinoxP*, which contains an electron-withdrawing quinoxaline architecture.3 In collaboration with Nippon Chemical, we are pleased to offer R,R-QuinoxP* for the research market.

Advantages of the QuinoxP* Ligands:

  • QuinoxP* is not oxidized nor epimerized at ambient conditions in air
  • Enantioselectivities are outstanding for various reaction paradigms
  • Hydrogenations proceed under mild reaction conditions
  • Low catalyst loadings yield high TONs

Representative Applications:
The reactivity profile of these innovative, chiral ligands is covered below and highlights the impressive breadth of valuable transformations mediated by QuinoxP*. These powerful 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.

Highly Asymmetric Rhodium-Catalyzed Hydrogenation
Imamoto has 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). The authors carried out these experiments at room temperature in methanol under low hydrogen pressures (3 atm). Note that 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

Scheme 1

Table 1.The reaction was completed within 1h.

Asymmetric 1,4-additions of Arylboronic Acids

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

Scheme 2

Scheme 2

Asymmetric Pd-catalyzed Ring Opening

Imamoto and co-workers have also 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 entails 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 useful for a broad variety of asymmetric metal-catalyzed transformations.

Scheme 3

Scheme 3

Table 2.
Product Information


Vineyard BD, Knowles WS, Sabacky MJ, Bachman GL, Weinkauff DJ. 1977. Asymmetric hydrogenation. Rhodium chiral bisphosphine catalyst. J. Am. Chem. Soc.. 99(18):5946-5952.
Robin F, Mercier F, Ricard L, Mathey F, Spagnol M. 1997. BIPNOR: A New, Efficient Bisphosphine Having Two Chiral, Nonracemizable, Bridgehead Phosphorus Centers for Use in Asymmetric Catalysis. Chem. Eur. J.. 3(8):1365-1369.
Hamada Y, Matsuura F, Oku M, Hatano K, Shioiri T. 1997. Synthesis and application of new chiral bidentate phosphine, 2,7-di-tert-butyl-9,9-dimethyl-4,5-bis(methylphenylphosphino)xanthene. Tetrahedron Letters. 38(52):8961-8964.
Kurth V. 1998. Eur. J. Inorg. Chem.. 597.
Stoop RM, Mezzetti A, Spindler F. 1998. Diphosphines Containing Stereogenic P Atoms:  Synthesis of (S,S)-C,C?-Tetramethylsilanebis- (1-naphthylphenylphosphine) and Applications in Enantioselective Catalysis. Organometallics. 17(4):668-675.
Imamoto T, Watanabe J, Wada Y, Masuda H, Yamada H, Tsuruta H, Matsukawa S, Yamaguchi K. 1998. P-Chiral Bis(trialkylphosphine) Ligands and Their Use in Highly Enantioselective Hydrogenation Reactions. J. Am. Chem. Soc.. 120(7):1635-1636.
Maienza F, Wörle M, Steffanut P, Mezzetti A, Spindler F. 1999. Ferrocenyl Diphosphines Containing Stereogenic Phosphorus Atoms. Synthesis and Application in the Rhodium-Catalyzed Asymmetric Hydrogenation. Organometallics. 18(6):1041-1049.
Yamanoi Y, Imamoto T. 1999. Methylene-Bridged P-Chiral Diphosphines in Highly Enantioselective Reactions. J. Org. Chem.. 64(9):2988-2989.
Tsuruta H, Imamoto T. 1999. A new P-chiral bisphosphine, 1,1?-bis[(t-butyl)methyl-phosphino]ferrocene, as an effective ligand in catalytic asymmetric hydrosilylation of simple ketones. Tetrahedron: Asymmetry. 10(5):877-882.
Nettekoven U, Kamer PCJ, van Leeuwen PWNM, Widhalm M, Spek AL, Lutz M. 1999. Phosphorus-Chiral Analogues of 1,1?-Bis(diphenylphosphino)ferrocene:  Asymmetric Synthesis and Application in Highly Enantioselective Rhodium-Catalyzed Hydrogenation Reactions. J. Org. Chem.. 64(11):3996-4004.
Zhang Z, Qian H, Longmire J, Zhang X. 2000. Synthesis of Chiral Bisphosphines with Tunable Bite Angles and Their Applications in Asymmetric Hydrogenation of ?-Ketoesters. J. Org. Chem.. 65(19):6223-6226.
Tang W, Wu S, Zhang X. 2003. Enantioselective Hydrogenation of Tetrasubstituted Olefins of Cyclic ?-(Acylamino)acrylates. J. Am. Chem. Soc.. 125(32):9570-9571.
Lei A, Wu S, He M, Zhang X. 2004. Highly Enantioselective Asymmetric Hydrogenation of ?-Phthalimide Ketone:  An Efficient Entry to Enantiomerically Pure Amino Alcohols. J. Am. Chem. Soc.. 126(6):1626-1627.

Tang W, Zhang X. 2002. A Chiral 1, 2‐Bisphospholane Ligand with a Novel Structural Motif: Applications in Highly Enantioselective Rh‐Catalyzed Hydrogenations.. Angewandte Chemie International Edition.. 41(9):1612-4.
Tang W, Zhang X. 2002. Highly Efficient Synthesis of Chiral ?-Amino Acid Derivatives via Asymmetric Hydrogenation. Org. Lett.. 4(23):4159-4161.
Tang W, Liu D, Zhang X. 2003. Asymmetric Hydrogenation of Itaconic Acid and Enol Acetate Derivatives with the Rh-TangPhos Catalyst. Org. Lett.. 5(2):205-207.
Tang W, Wang W, Chi Y, Zhang X. 2003. Angew. Chem.. 115(30):3633-3635.
Xiao D, Zhang Z, Zhang X. 1999. Synthesis of a Novel Chiral Binaphthyl Phospholane and Its Application in the Highly Enantioselective Hydrogenation of Enamides. Org. Lett.. 1(10):1679-1681.
Liu D, Zhang X. 2005. Practical P-Chiral Phosphane Ligand for Rh-Catalyzed Asymmetric Hydrogenation. Eur. J. Org. Chem.. 2005(4):646-649.
Imamoto T, Sugita K, Yoshida K. 2005. An Air-Stable P-Chiral Phosphine Ligand for Highly Enantioselective Transition-Metal-Catalyzed Reactions. J. Am. Chem. Soc.. 127(34):11934-11935.
Gridnev ID, Higashi N, Imamoto T. 2000. On the Origin of Opposite Stereoselection in the Asymmetric Hydrogenation of Phenyl- andtert-Butyl-Substituted Enamides. J. Am. Chem. Soc.. 122(42):10486-10487.
Gridnev ID, Yasutake M, Higashi N, Imamoto T. 2001. Asymmetric Hydrogenation of Enamides with Rh-BisP* and Rh-MiniPHOS Catalysts. Scope, Limitations, and Mechanism. J. Am. Chem. Soc.. 123(22):5268-5276.
Takaya Y, Ogasawara M, Hayashi T, Sakai M, Miyaura N. 1998. Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryl- and Alkenylboronic Acids to Enones. J. Am. Chem. Soc.. 120(22):5579-5580.
Takaya Y, Ogasawara M, Hayashi T. 1999. Rhodium-catalyzed asymmetric 1,4-addition of arylboron compounds generated in situ from aryl bromides. Tetrahedron Letters. 40(38):6957-6961.
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