Trost Ligands for Asymmetric Allylic Alkylation (AAA)

Introduction

Advantages

Pd-Catalyzed Asymmetric Allylic Alkylation:    • Carbon Nucleophiles    • Oxygen Nucleophiles    • Nitrogen Nucleophiles    • Sulfur Nucleophiles

Asymmetric Allylic Alkylation:    • Molybdenum-catalyzed Reactions

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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.



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.

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References: For comprehensive reviews, see: Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59. Trost, B. M. et al. Acc. Chem. Res. 2006, 39, 747. Trost, B. M. J. Org. Chem. 2004, 69, 5813. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. Trost, B. M. Acc. Chem. Res. 1996, 29, 355.

Advantages

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

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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:

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

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

Barbituric Acid Nucleophiles:

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

β-Keto Ester Nucleophiles:

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

Nitrosulfonyl Nucleophiles:

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

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

Nitroalkane Nucleophiles:

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

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

Other Carbon Nucleophiles:

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

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

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

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:

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

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

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

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

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

Carboxylate Nucleophiles:

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

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

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

Hydrogencarbonate Nucleophiles:

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

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

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

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:

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

Azide Nucleophiles:

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

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

Sulfonamide Nucleophiles:

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

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

Imide Nucleophiles:

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

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

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

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

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

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.

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

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

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.

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

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

Product Information

Product #	Product Name	Structure	Add to Cart
692794	(S,S)-DACH-phenyl Trost Ligand
692808	(R,R)-DACH-phenyl Trost Ligand
692786	(S,S)-DACH-naphthyl Trost Ligand
692778	(R,R)-DACH-naphthyl Trost Ligand
692743	(S,S)-DACH-pyridyl Trost Ligand
692751	(R,R)-DACH-pyridyl Trost Ligand

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