Asymmetric Allylic Alkylation

Introduction

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.

 

C-2 symmetric diaminocyclohexyl (DACH) ligands in AAA

 

The Trost group at Stanford University has pioneered the use of <i>C</i>-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.

 

DACH Table

 

References
  1. Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
  2. Trost, B. M. et al. Acc. Chem. Res. 2006, 39, 747.
  3. Trost, B. M. J. Org. Chem. 2004, 69, 5813.
  4. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
  5. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
  6. Trost, B. M. Acc. Chem. Res. 1996, 29, 355.

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Advantages

  • Atom-economical catalytic method
  • High yields and synthetically useful levels of enantiocontrol
  • Unparallelled ability to prepare chiral building blocks from simple precursors

Representative Applications

Pd-Catalyzed Asymmetric Allylic Alkylation: Carbon Nucleophiles


In early examples of this methodology, Trost and co-workers demonstrated that 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 Nucleophiles:

 

Malonate Nucleophiles 1

 

References
  1. Trost, B. M. Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.
  2. Ernst, M.; Helmchen, G. Synthesis 2002, 1953.
  3. Ernst, M.; Helmchen, G. Angew. Chem., Int. Ed. 2002, 41, 4054.

 

Malonate Nucleophiles 2

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 2005, 127, 14186.

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Malonate Nucleophiles:

 

Barbituric Acid Nucleophiles

 

References
  1. Trost, B. M.; Schroeder, G. M. J. Org. Chem. 2000, 65, 1569.

 

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β-Keto Ester Nucleophiles:

 

ß-Keto Ester Nucleophiles

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1997, 119, 7879.

 

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Nitrosulfonyl Nucleophiles:

 

Nitrosulfonyl Nucleophiles 1

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1998, 120, 1732.

 

Nitrosulfonyl Nucleophiles 1

 

References
  1. Trost, B. M. et al. Chem.—Eur. J. 2001, 7, 3768.

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Nitroalkane Nucleophiles:

 

Nitroalkane Nucleophiles 1

 

References
  1. Trost, B. M.; Surivet, J. P. Angew. Chem., Int. Ed. 2000, 39, 3122.

 

Nitroalkane Nucleophiles 2

 

References
  1. Trost, B. M.; Surivet, J. P. Angew. Chem., Int. Ed. 2000, 39, 3122.

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Other Carbon Nucleophiles:

 

Other Carbon Nucleophiles 1

 

References
  1. Trost, B. M.; Kallander, L. S. J. Org. Chem. 1999, 64, 5427.

 

Other Carbon Nucleophiles 2

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 2002, 124, 12420.

 

Other Carbon Nucleophiles 3

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 2005, 127, 2844.
  2. Trost, B. M. et al. J. Am. Chem. Soc. 2005, 127, 10259.
  3. Trost, B. M. et al. Chem.—Eur. J. 2005, 11, 951.

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Pd-Catalyzed Asymmetric Allylic Alkylation: 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 Nucleophiles:

 

Alcohol Nucleophiles Structure

 

References
  1. Lennon, I. C. et al. Chimica Oggi; Chemistry Today 2004, 11.

 

Alcohol Nucleophiles Structure

 

References
  1. Fox, M. E. et al. Tetrahedron Lett. 2007, 48, 945.

 

Alcohol Nucleophiles 1

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1998, 120, 12702.

 

Alcohol Nucleophiles 2

 

References
  1. Trost, B. M. et al. Chem.—Eur. J. 2003, 9, 4442.
  2. Trost, B. M. et al. Org. Lett. 2000, 2, 4013.
  3. Trost, B. M.; Anderson, N. G. J. Am. Chem. Soc. 2002, 124, 14320.
  4. Trost, B. M.; Tang, W. Org. Lett. 2001, 3, 3409.
  5. Trost, B. M.; Zhang, T. Org. Lett. 2006, 8, 6007 (synthesis of allyl vinyl ethers).

 

Alcohol Nucleophiles 3

 

References
  1. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543.
  2. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090.
  3. Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124, 9328.
  4. Trost, B. M.; Crawley, M. L. Chem.—Eur. J. 2004, 10, 2237.

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Carboxylate Nucleophiles:

 

Carboxylate Nucleophiles 1

 

References
  1. Trost, B. M.; Organ, M. G. J. Am. Chem. Soc. 1994, 116, 10320.

 

Carboxylate Nucleophiles 2

 

References
  1. Trost, B. M.; Kondo, Y. Tetrahedron Lett. 1991, 32, 1613.

 

Carboxylate Nucleophiles 3

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1999, 121, 10834.
  2. Trost, B. M. et al. Chem.—Eur. J. 2001, 7, 1619.

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Hydrogencarbonate Nucleophiles:

 

Hydrogencarbonate Nucleophiles 1

 

References
  1. Lüssem, B. J.; Gais, H.-J. J. Am. Chem. Soc. 2003, 125, 6066.
  2. Gais, H.-J. et al. Tetrahedron Lett. 2005, 46, 6279.

 

Hydrogencarbonate Nucleophiles 2

 

References
  1. Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999, 121, 8649.

 

Hydrogencarbonate Nucleophiles 3

 

References
  1. Gais, H.-J. et al. Tetrahedron Lett. 2005, 46, 6279.
  2. Dong, Y. et al. Tetrahedron Lett. 2005, 46, 353.

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Pd-Catalyzed Asymmetric Allylic Alkylation: 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 Nucleophiles:

 

Alkylamines Nucleophiles

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1996, 118, 6297.

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Azide Nucleophiles:

 

Azide Nucleophiles 1

 

References
  1. Trost, B. M.; Pulley, S. R. J. Am. Chem. Soc. 1995, 117, 10143.
  2. Trost, B. M. et al. Chem.—Eur. J. 2001, 7, 1619.

 

Azide Nucleophiles 2

 

References
  1. Trost, B. M.; Cook, G. C. Tetrahedron Lett. 1996, 37, 7485.

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Sulfonamide Nucleophiles:

 

Sulfonamide Nucleophiles 1

 

References
  1. Ovaa, H. et al. Chem. Commun. 2000, 1501.
  2. Trost, B. M.; Sorum, M. T. Org. Process Res. Dev. 2003, 7, 432.

 

Sulfonamide Nucleophiles 2

 

References
  1. Stragies, R.; Blechert, S. J. Am. Chem. Soc. 2000, 122, 9584.

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Imide Nucleophiles:

 

Imide Nucleophiles 1

 

References
  1. Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444.
  2. Trost, B. M. et al. J. Am. Chem. Soc. 1992, 114, 9327.
  3. Trost, B. M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339.

 

Imide Nucleophiles 2

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1996, 118, 6520.

 

Imide Nucleophiles 3

 

References
  1. Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.

 

Imide Nucleophiles 4

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 2000, 122, 5968.
  2. Trost, B. M.; Lemoine, R. C. Tetrahedron Lett. 1996, 37, 9161.
  3. Trost, B. M. et al. Angew. Chem., Int. Ed. 2003, 42, 5987.
  4. Trost, B. M. et al. Chem.—Eur. J. 2006, 12, 6607.

 

Imide Nucleophiles 5

 

References
  1. Trost, B. M.; Aponick, A. J. Am. Chem. Soc. 2006, 128, 3931.

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Pd-Catalyzed Asymmetric Allylic Alkylation: Sulfur Nucleophiles


While not as extensively explored, certain sulfur nucleophiles are competent in the allylation reaction. In particular, sodium benzenesulfinate under goes alkylation to afford synthetically useful chiral sulfones.

 

Alkylamines Nucleophiles:

 

Sulfur Nucleophiles 1

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 1995, 117, 9662.

 

Sulfur Nucleophiles 2

 

References
  1. Trost, B. M. et al. J. Am. Chem. Soc. 2000, 122, 6120.

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Asymmetric Allylic Alkylation: Molybdenum-catalyzed Reactions


The mechanism of molybdenum-catalyzed AAA reaction is presumed to be distinctly different from the analogous Pd-catalyzed reaction, and in some cases, levels regio-, enantio- and diastereoselectivity enhanced relative to the palladium-catalyzed reaction.

 

Asymmetric Allylic Alkylation: Molybdenum-catalyzed Reactions 1

 

References
  1. Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.

 

Asymmetric Allylic Alkylation: Molybdenum-catalyzed Reactions 2

 

References
  1. Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861.

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Materials List

     
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