Trost Ligands for Allylic Alkylation

The Tsuji Trost cycle is a synthetic methodology used in organic chemistry for the construction of complex molecules. It involves the use of a palladium-catalyzed reaction to facilitate the formation of carbon-carbon bonds through the coupling of allylic alcohols with nucleophiles. Palladium-catalyzed asymmetric allylic alkylation (AAA) is a powerful method for the efficient construction of stereogenic centers. In 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.

Section Overview

• Carbon Nucleophiles
• Oxygen Nucleophiles
• Nitrogen Nucleophiles
• Molybdenum-Catalyzed Reactions
• Related Materials

Figure 1. Nucleophilic Addition

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

Figure 2. Trost Ligands

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.

Figure 3. Malonate Nucleophiles

Figure 4. β-Keto Ester Nucleophiles

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.

Figure 5. Alcohol Nucleophiles

Figure 6. Carboxylate Nucleophiles

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.

Figure 7. Alkylamines Nucleophiles

Figure 8. Azide Nucleophiles

Figure 9. Imide Nucleophiles

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 (Figure 10).

Figure 10. Molybdenum-Catalyzed Reactions

References

1. Trost BM, Fandrick D. 2007. The growing impact of asymmetric catalysis. Aldrichimica Acta. 40(59):

2. Trost BM, Machacek MR, Aponick A. 2006. Predicting the Stereochemistry of Diphenylphosphino Benzoic Acid (DPPBA)-Based Palladium-Catalyzed Asymmetric Allylic Alkylation Reactions:  A Working Model. Acc. Chem. Res.. 39(10):747-760. https://doi.org/10.1021/ar040063c

3. Trost BM. 2004. Asymmetric Allylic Alkylation, an Enabling Methodology. J. Org. Chem.. 69(18):5813-5837. https://doi.org/10.1021/jo0491004

4. Trost BM, Crawley ML. 2003. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations:  Applications in Total Synthesis. Chem. Rev.. 103(8):2921-2944. https://doi.org/10.1021/cr020027w

5. Trost BM, Van Vranken DL. 1996. Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem. Rev.. 96(1):395-422. https://doi.org/10.1021/cr9409804

6. Trost BM. 1996. Designing a Receptor for Molecular Recognition in a Catalytic Synthetic Reaction:  Allylic Alkylation. Acc. Chem. Res.. 29(8):355-364. https://doi.org/10.1021/ar9501129

7. Trost BM, Bunt RC. 1994. Asymmetric induction in allylic alkylations of 3-(acyloxy)cycloalkenes. J. Am. Chem. Soc.. 116(9):4089-4090. https://doi.org/10.1021/ja00088a059

8. Helmchen G, Ernst M. A Novel Route to Iridoids: Enantioselective Syntheses of Isoiridomyrmecin and ?-Skytanthine. Synthesis. 2002(14 Special Issue): https://doi.org/10.1055/s-2002-34382

9. Helmchen G, Ernst M. A Novel Route to Iridoids: Enantioselective Syntheses of Isoiridomyrmecin and ?-Skytanthine. Synthesis. 2002(41):4054-4056.

10. Trost BM, Radinov R, Grenzer EM. 1997. Asymmetric Alkylation of ?-Ketoesters. J. Am. Chem. Soc.. 119(33):7879-7880. https://doi.org/10.1021/ja971523i

11. Trost BM, Toste FD. 1999. Palladium-Catalyzed Kinetic and Dynamic Kinetic Asymmetric Transformation of 5-Acyloxy-2-(5H)-furanone. Enantioselective Synthesis of (?)-Aflatoxin B Lactone. J. Am. Chem. Soc.. 121(14):3543-3544. https://doi.org/10.1021/ja9844229

12. Trost BM, Toste FD. 2003. Palladium Catalyzed Kinetic and Dynamic Kinetic Asymmetric Transformations of ?-Acyloxybutenolides. Enantioselective Total Synthesis of (+)-Aflatoxin B1and B2a. J. Am. Chem. Soc.. 125(10):3090-3100. https://doi.org/10.1021/ja020988s

13. Trost BM, Crawley ML. 2002. 4-Aryloxybutenolides As ?Chiral Aldehyde? Equivalents:  An Efficient Enantioselective Synthesis of (+)-Brefeldin A. J. Am. Chem. Soc.. 124(32):9328-9329. https://doi.org/10.1021/ja026438b

14. Trost BM, Crawley ML. 2004. A?Chiral Aldehyde? Equivalent as a Building Block Towards Biologically Active Targets. Chem. Eur. J.. 10(9):2237-2252. https://doi.org/10.1002/chem.200305634

15. Trost BM, Kondo Y. 1991. An asymmetric synthesis of (+)-phyllanthocin. Tetrahedron Letters. 32(13):1613-1616. https://doi.org/10.1016/s0040-4039(00)74285-7

16. Trost BM, Krische MJ, Radinov R, Zanoni G. 1996. On Asymmetric Induction in Allylic Alkylation via Enantiotopic Facial Discrimination. J. Am. Chem. Soc.. 118(26):6297-6298. https://doi.org/10.1021/ja960649x

17. Trost BM, Pulley SR. 1995. Asymmetric Total Synthesis of (+)-Pancratistatin. J. Am. Chem. Soc.. 117(40):10143-10144. https://doi.org/10.1021/ja00145a038

18. Trost BM, Joseph D, Hembre EJ. 2001. Asymmetric Induction of Conduritols via AAA Reactions: Synthesis of the Aminocyclohexitol of Hygromycin A. Chem.-Eur. J..(7):1619-1629.

19. Trost BM, Van Vranken DL. 1993. A general synthetic strategy toward aminocyclopentitol glycosidase inhibitors. Application of palladium catalysis to the synthesis of allosamizoline and mannostatin A. J. Am. Chem. Soc.. 115(2):444-458. https://doi.org/10.1021/ja00055a013

20. Trost BM, Van Vranken DL, Bingel C. 1992. A modular approach for ligand design for asymmetric allylic alkylations via enantioselective palladium-catalyzed ionizations. J. Am. Chem. Soc.. 114(24):9327-9343. https://doi.org/10.1021/ja00050a013

21. Trost BM, Patterson DE. 1998. Enhanced Enantioselectivity in the Desymmetrization of Meso-Biscarbamates. J. Org. Chem.. 63(4):1339-1341. https://doi.org/10.1021/jo971746r

22. Trost BM, Dogra K. 2007. Synthesis of (-)-?9-trans-Tetrahydrocannabinol:  Stereocontrol via Mo-Catalyzed Asymmetric Allylic Alkylation Reaction. Org. Lett.. 9(5):861-863. https://doi.org/10.1021/ol063022k