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DuPhos and BPE Phospholane Ligands and Complexes

By: William Sommer and Daniel Weibel, Aldrich ChemFiles 2008, 8.2, 34.

Aldrich ChemFiles 2008, 8.2, 34.

In the early 1990s, Burk and coworkers developed new electron-rich C2 symmetric bis(phospholane) ligands. The modular nature of these ligands allowed for variation of both phosphane substituent and backbone structures, leading to an extensive library of ligands for enantioselective catalytic reactions. The large-scale capacity of these robust catalysts is observed in the efficiency (substrate-to-catalyst (s/c) ratios up to 50,000) and the high activities (TOF >5,000 h-1) in a myriad of enamide and ketone reductions. Under optimized conditions, (R,R)-Me-BPE-Rh reduced N-acetyl α-arylenamides in >95% ee to yield valuable α-1‑arylethylamines (Scheme 1).1

Scheme 1

Scheme 1

It should be noted that Me-DuPhos-Rh complexes were equally effective in asymmetric reductions of prochiral enamides. The general utility of these phospholane ligands is illustrated in the incredible diversity-oriented production of a vast array of amino acid derivatives (Scheme 2).2

Scheme 2

Scheme 2

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Asymmetric Hydrogenation of the C=N Group

Burk and co-workers exploited the high activity of the Ethyl-DuPhos ligand via a powerful catalytic reductive amination process.3 The procedure exhibits general applicability in the reduction of a wide variety of N-aroylhydrazones, yielding enantioselectivies for most substrates >90% (Scheme 3). Additionally this (Et-DuPhos)-Rh catalyst system displays exceptionally high chemoselectivies, yielding little or no reduction of unfunctionalized alkenes, alkynes, ketones, aldehydes, and imines in competition experiments. The synthetic utility of these asymmetric hydrazone reductions is enhanced by their facile reaction at ambient temperature with samarium diiodide, which proceed with no observable loss of optical purity.

Scheme 3

Scheme 3

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Catalytic Hydrogenation of Enamides

Burk has also pioneered the asymmetric hydrogenation of various enamido olefins affording highly enantiopure unsaturated amino acid products.4The ((S,S)-Et-DuPhos)-Rh) catalyst system controls the reactivity of conjugated substrates with high regioselectivies as well. Under the standard hydrogenation conditions (s/c =500, H2 pressures ranging from 60 to 90 psi, and 0.5−3 h), this catalyst gave less than 2% overreduction, with all products isolated in better than 95% yield. The authors elaborated upon this outstanding catalyst reactivity by demonstrating a concise and highly selective synthesis of the natural product (−)-bulgecinine, preceeded by formation of the key chiral intermediate in 99% yield with 99.3% ee (Scheme 4).

Scheme 4

Scheme 4

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Preparation of Chiral Organics with C–O Stereogenic Centers

Neil Boaz has also utilized rhodium(I)-((R,R)-Me-DuPhos) catalyst 1 to produce chiral alcohols via the asymmetric hydrogenation of enol esters (Scheme 5). Allylic alcohol derivatives are desirable organic building blocks in diversity-oriented synthesis, because the olefin can be further functionalized after the stereochemistry has been set in the hydrogenation.5 Under asymmetric hydrogenation conditions, the initially formed propargylic acetate was subsequently reduced to yield the Z-allylic acetate. Impressively, the enantioselectivity observed in this reaction was very high among the general substrate class 2a-c.

Scheme 5

Scheme 5

Burk and co-workers have also designed highly effective catalysts for the asymmetric reduction of C=O bonds under hydrogenation conditions.6 In this case, the methodology proceeded via use of a chiral Ru(II)Br2-(i-Pr- BPE) complex, which was prepared by reacting [(COD)Ru(2‑methylallyl)2] with the BPE ligand followed by treatment with methanolic HBr. A variety of ketoesters were rapidly hydrogenated as mediated by this catalyst to the hydroxyl esters with very high enantioselectivities >98% ee for the alkyl-substituted substrates (Scheme 6).

Scheme 6

Scheme 6

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Enantioselective Hydrogenation of Alkenes and Imines

The use of gold complexes to effect catalytic transformations is on the rise, with numerous reports of catalytically active gold species.7 Sanchez and co-workers have now reported the first example of a gold hydrogenation catalyst utilized in asymmetric transformations.8 The authors found that the bulkiest substrate, which incorporates a diethyl 2‑naphthylidenesuccinate group, proceeds under the reaction conditions to afford the highest enantioselectivities due to reactant control (Scheme 7). Future plans in gold-mediated asymmetric hydrogenation involve substantial modifications to the ligand structure to provide higher levels of enantiocontrol in this reaction paradigm.

Scheme 7

Scheme 7

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Enantioselective Allylboration of Ketones

The Shibasaki research group has also championed the use of the DuPhos ligand system for asymmetric catalysis.9 They have now reported the first general catalytic, enantioselective allylation reaction with ketones, which employs copper salts and a rare-earth lanthanide additive. Impressively, a diverse array of aromatic, heteroaromatic, α,β-unsaturated, and aliphatic ketones are rapidly allylated at ambient temperature and under low catalyst loadings (Scheme 8). The enantioselectivities range from 67 to 92%; however, the reaction appears to be quite general for both the allylation and crotylboration reaction paradigms.

Scheme 8

Scheme 8

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Enantioselective Addition of Dialkylzinc to β-Nitroalkenes

The use of chiral bis(phosphine) monoxide ligand has found widespread applications in catalysis. Côté et al. reported the use of Me-DuPhos monoxide in the addition of dialkyzinc to nitroalkenes. Various chiral nitroalkanes were synthesized with excellent yields and selectivities (Scheme 9).10

Scheme 9

Scheme 9

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Materials

     

References

  1. Burk, M. J. et al. J. Am. Chem. Soc. 1996, 118, 5142.
  2. (a) Burk, M. J. Acc. Chem. Res. 2000, 33, 363. (b) Burk, M. J. et al. J. Org. Chem. 2003, 68, 5731.
  3. Burk, M. J. et al. J. Am. Chem. Soc. 1992, 114, 6266.
  4. Burk, M. J. et al. J. Am. Chem. Soc. 1998, 120, 657.
  5. Burk, M. J. et al. J. Am. Chem. Soc. 1995, 117, 4423.
  6. Burk, M. J. et al. J. Org. Chem. 1999, 64, 3290.
  7. Dyker, G. Angew. Chem., Int. Ed. 2000, 39, 4237.
  8. Sanchez, F. et al. Chem. Commun. 2005, 3451.
  9. Shibasaki, M. et al. J. Am. Chem. Soc. 2004, 126, 8910.
  10. Côté, A. et al. Org. Lett. 2007, 9, 85.

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