ChiralQuest Phosphine Ligands

Aldrich ChemFiles 2006, 6.8, 10.

Aldrich ChemFiles 2006, 6.8, 10.

Introduction

One of the most efficient methods for constructing chiral compounds is asymmetric hydrogenation. Catalytic asymmetric hydrogenations are among the most widely used industrial catalytic processes, due to their high turnover rates, atom economy, and inexpensive material costs. Transition metal complexes associated with chiral phosphine ligands are the dominant choice of catalysts for asymmetric hydrogenation, in large part due to the Nobel prize-winning, pioneering work of Noyori and Knowles. The requirement of an electron-rich chiral phosphine ligand is at the core of this transformation.

Professor Xumu Zhang at Penn State has made remarkable advances by creating a toolbox of chiral phosphines which can be used on a variety of substrates, some of which have been historically resistant to hydrogenation. Furthermore, an additional benefit in some reductions is reduced catalyst loading, due to increased turnover numbers (TON). Sigma-Aldrich is pleased to announce an agreement with ChiralQuest to distribute research quantities of a series of Zhang’s chiral phosphines for catalytic asymmetric hydrogenations.

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Representative Ligands and Applications

(S)-C3-TunePhos

C3-TunePhos, a member of the atropisomeric aryl bisphosphine ligand family with tunable dihedral angles, provides comparable or superior enantioselectivities and catalytic abilities to BINAP in Ru-catalyzed asymmetric hydrogenation of b-keto esters (Scheme 25),1 cyclic b-(acylamino) acrylates (Scheme 26),2 and a-phthalimide ketones (Scheme 27).3

Scheme 25


Scheme 26


Scheme 27


(1S,1S’,2R,2R’)-TangPhos

A highly electron-donating, low molecular weight, and rigid P-chiral bisphospholane ligand, TangPhos proves incredibly efficient in the rhodium-catalyzed hydrogenation of a variety of functionalized olefins such as a-dehydroamino acids (Scheme 28),4 a-arylenamides (Scheme 29),4 b-(acylamino)acrylates (Scheme 30),5 itaconic acids (Scheme 31),6 and enol acetates (Scheme 32).6

Scheme 28


Scheme 29


Scheme 30


Scheme 31


Scheme 32


This P-chiral phosphorus ligand represents a superior ligand for asymmetric catalysis including hydrogenation because of its ability to force the chiral environment to encompass the substrate in close proximity to the reactive metal center. TangPhos exhibits substantial conformational rigidity allowing for high enantioselectivities in the hydrogenation of a wide variety of densely functionalized prochiral olefins, with some reaction examples approaching 100% ee.

(S)-BINAPINE

BINAPINE, a highly electron-donating rigid ligand, demonstrates excellent enantioselectivity and reactivity, with TON up to 10,000 for the asymmetric hydrogenation of Z-b-aryl(b-acylamino) acrylates (Scheme 33).7 Interestingly, BINAPINE is a rare example of a bisbinaphthophosphepine ligand with P-chiral phosphine atoms. High enantioselectivities have been obtained with substrates that contain diverse substituents ranging from electronrich and electron-poor aryl groups to heteroaryl components. This catalyst system illustrates the incredible effects of rigidity on stereocontrol in the hydrogenation reaction.

Scheme 33


(R)-BINAPHANE

(R)-BINAPHANE shows excellent enantioselectivity (up to >99% ee) for hydrogenation of E/Z-isomeric mixtures of b-substituted arylenamides (Scheme 34).8 This ligand incorporates a bisphosphinite backbone that displays restricted orientation of the aromatic groups proximate to the phosphines. Zhang and co-workers can tune BINAPHANE by modifying the groups on the aromatic and/or the phosphine, thus creating a general catalytic system useful for obtaining high enantioselectivities in the asymmetric hydrogenation reaction.

Scheme 34


(1R,1’R,2S,2’S)-DuanPhos

DuanPhos is more rigid than the related TangPhos ligand, due to the fused phenyl rings on the phospholane architecture. This selfimposed conformational stability improves the enantioselectivity in the hydrogenations of a diverse array of functionalized olefins. Furthermore, Zhang and co-workers have successfully synthesized both enantiomers of this electron-rich ligand through a trivial resolution process. Even highly electron-rich prochiral olefins are readily hydrogenated with exceptional stereocontrol by this productive Rh-catalyst system (Scheme 35).

Scheme 35


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Materials

     

References

  1. Zhang, Z. et al. J. Org. Chem. 2000, 65, 6223.
  2. Tang, W. et al. J. Am. Chem. Soc. 2003, 125, 9570.
  3. Lei, A. et al. J. Am. Chem. Soc. 2004, 126, 1626.
  4. Tang, W.; Zhang, X. Angew. Chem. Int. Ed. Engl. 2002, 41, 1612.
  5. Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159.
  6. Tang, W. et al. Org. Lett. 2003, 5, 205.
  7. Tang, W. et al. Angew. Chem. Int. Ed. Engl. 2003, 42, 3509.
  8. Xiao, D. et al. Org. Lett. 1999, 1, 1679.

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