Trost Ligands

By: William Sommer and Daniel Weibel, Aldrich ChemFiles 2008, 8.2, 82.

Palladium-catalyzed asymmetric allylic alkylation (AAA) has proven to be an exceptionally powerful method for the efficient construction of stereogenic centers. In sharp contrast to many other catalytic methods, AAA has the ability to form multiple types of bonds (C–C, C–O, C–S, C–N) with a single catalyst system.

The Trost group at Stanford University has pioneered the use of C-2 symmetric diaminocyclohexyl (DACH) ligands in AAA, allowing for the rapid synthesis of a diverse range of chiral products with a limited number of chemical transformations. Reactions are typically high-yielding, and excellent levels of enantioselectivity are observed.1

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Carbon Nucleophiles

In early examples of this methodology, Trost and co-workers demonstrated diesters are competent nucleophiles for the deracemization of cyclic allylic acetates, to afford chiral malonate derivatives. Since that time, soft carbon nucleophiles such as barbituric acid derivatives, β-keto esters, nitro compounds, and many others have been employed in AAA for assembly of tertiary and quaternary asymmetric centers.

Malonate Nucleophiles2

β-Keto Ester Nucleophiles 3

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Oxygen Nucleophiles

Carbon-oxygen bond-forming reactions using palladium-catalyzed asymmetric allylic alkylation have been well-demonstrated in numerous natural product syntheses. Alcohols, carboxylates, and hydrogencarbonates have all been employed as O-nucleophiles.

Alcohol Nucleophiles4

Carboxylate Nucleophiles5

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Nitrogen Nucleophiles

A formidable challenge in asymmetric synthesis is the stereocontrolled construction of carbon-nitrogen bonds. Nitrogen nucleophiles such as alkylamines, azides, amides, imides, and N-heterocycles have all been employed in asymmetric allylic alkylation reactions.

Alkylamines Nucleophiles6

Azide Nucleophiles7

Imide Nucleophiles8

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Molybdenum-Catalyzed Reactions

The mechanism of the molybdenum-catalyzed AAA reaction is presumed to be distinctly different from the analogous Pd-catalyzed reaction, and in some cases, the levels of regio-, enantio-, and diastereoselectivity are enhanced relative to the palladium-catalyzed reaction. Trost and Dogra report the total synthesis of (–)-Δ9-trans-tetrahydrocannabinol, a psychomimetic of marijuana, utilizing a molybdenum catalyst.9 An overall yield of 30% of enantiomerically pure (–)-Δ9-trans-tetrahydrocannabinol (Scheme 1).

Scheme 1

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References

  1. (a) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59. (b) Trost, B. M. et al. Acc. Chem. Res. 2006, 39, 747. (c) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (d) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (e) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (f) Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
  2. (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. (b) Ernst, M.; Helmchen, G. Synthesis 2002, 1953. (c) Ernst, M.; Helmchen, G. Angew. Chem., Int. Ed. 2002, 41, 4054.
  3. Trost, B. M. et al. J. Am. Chem. Soc. 1997, 119, 7879.
  4. (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090. (c) Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328. (d) Trost, B. M.; Crawley, M. L. Chem.-Eur. J. 2004, 10, 2237.
  5. Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 32, 1613.
  6. Trost, B. M. et al. J. Am. Chem. Soc. 1996, 118, 6297.
  7. (a) Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143. (b) Trost, B. M. et al. Chem.-Eur. J. 2001, 7, 1619.
  8. (a) Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444. (b) Trost, B. M. et al. J. Am. Chem. Soc. 1992, 114, 9327. (c) Trost, B. M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339.
  9. Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861.

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Materials

     
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