Research Guides

Department of Chemistry University of Oxford

Professor Darren J. Dixon

The research interests of the Dixon group lie mainly in the field of Organic Synthesis. We focus projects at the intersection between the discovery of new reactions and reactivity, the development of this into powerful synthetic methodology and its application to the total synthesis of natural products and molecules of biological significance. Furthermore we aim to make our chemistry accessible to the majority of organic synthesis chemists by making the reactions technically simple to perform, efficient, scaleable, selective and broad in scope. Our research is supported by a number of pharmaceutical companies (Pfizer, AstraZeneca, GlaxoSmithKline, UCB) largely through the CASE scheme and provides an excellent in-depth training in all aspects of organic synthesis. ‘Hot’ project areas where we have enjoyed significant successes include: asymmetric catalysis (organocatalysis and transition metal ion catalysis), reaction cascade catalysis (promoted by single and mutually compatible multiple catalysts), stereoselective methodology development and complex natural product synthesis.

These areas are expanded upon below:

New catalytic asymmetric methodologies – Bifunctional organocatalysis

Enantiomerically pure organic catalysts with the capacity to simultaneously activate electrophilic substrates and pro-nucleophilic reagents towards one another through acid and base interactions, offer numerous opportunities for the discovery of powerful new asymmetric carbon-carbon and carbon-heteroatom bond forming reactions. When the catalyst has a well-defined chiral pocket attached to a fairly rigid scaffold, the templating of the two reagents via a ternary complex can lead to excellent levels of enantio- and diastereo-control in efficient reactions at low catalyst loadings and at reasonable reaction rates.

  

Our recent investigations into this field of Bifunctional Lewis Base / Brønsted acid organocatalysis have highlighted the synthetic power of a 9-amino(9-deoxy) epicinchona alkaloid derived bifunctional catalysts for the highly enantioselective Michael addition of malonate nucleophiles to nitro olefins, β-keto esters to N-Boc imines and dioxolan-4-ones to nitro olefins. Recent work has demonstrated that related bifunctional catalysts can promote a novel aryloxylation reaction, the Michael addition of β-keto esters to acrylic acid derivatives and a direct and enantioselective arylative oxidation reaction of indanone carbon acids.

 

As well as developing asymmetric acid and base bifunctional organocatalysts and their reactions our group has significant ongoing research activity in the areas of strong acid chiral catalysts and strong base chiral catalysts and Lewis base / Lewis acid bifunctional chiral catalysts.

Reaction cascade catalysis

A powerful way of rapidly building complexity and diversity into product molecules is to employ new reaction cascade technologies. Commencing with relatively simple starting materials, the ‘clever’ design of cascade sequences using single or mutually compatible combinations of catalysts (metal or metal free) can allow multiple bond forming reactions to occur in the reaction vessel leading to the target compound efficiently and without the usual waste associated with one reaction, one-vessel approaches. Our group is actively investigating a range of cascades for both natural product and library synthesis and have published extensively. We have found that the catalyzed Michael addition to nitroolefins may be coupled with a nitro-Mannich lactamization cascade leading to a one-pot synthesis of complex multicyclic piperidinone heterocycles in high enantio- and diastereoselectivity. In other work we extended the ‘site isolation concept’ to allow the simultaneous use of strong acid and strong base catalysts for the development of new cascade sequences allowing direct access to complex multicyclic heterocycles in one-pot, or in a continuous flow reactor, under mild conditions. By modifying the starting materials, azaspirocycles could also be accessed. This has allowed a formal synthesis of perhydrohistrionicotoxin using a simple-to-perform reaction cascade.

 

The exploitation of single catalyst entities, such as Au (I), for multi-step cascade sequences leading to complex heterocyclic compounds has also been reported by our group. In a recent study, organic catalysts and transition metal ion catalysts have been combined in a single vessel to exploit iminium, enamine and Lewis acid catalysis for a Michael initiated carbocyclization reaction constituting a new and efficient carboannulation to cyclopentenes. These papers demonstrate the efficiency with which complex molecules may be synthesised in a single reaction vessel under mild conditions. The design, development and application of other synthetically powerful reaction cascades is an active area of research in our laboratories.

 

Stereoselective methodology development

Our highly diastereoselective oxy-Michael reaction of ‘naked’ delta lactol anions to nitro olefins, alkylidene, arylidene and heteroarylidene malonate esters, α,β-unsaturated-α-sulphonyl acetates and β,γ-unsaturated-α-keto esters has been reported. The chemistry has been applied to the total synthesis of natural products and pharmaceutical targets such as (R)-salmeterol and (R)-tembamide. A recent computational study has allowed the exceptional stereocontrol in this reaction to be rationalized. The development of other synthetically powerful and highly stereoselective carbon-carbon and carbon-heteroatom bond forming reaction is a vibrant area of research in our group.

 

Total synthesis of complex natural products

Much of our developed methodology has been, or is being applied in complex natural product synthesis to demonstrate the power of the methodology, to uncover unsolved synthetic problems and to further improve the training of the Part II, PhD or post-doctoral researcher on the project. Some completed targets from our group include tarchonanthuslactone, Equisetin and Rolipram. On going total synthesis programs are targeting presilphiperfol-1-ene, subincanadine, nakadomarin A, buphanamine, manzamine A and daphniyunnine B. All the major synthetic problems to presilphiperfol-1-ene, subincanadine, nakadomarin A and buphanamine have been overcome and it is anticipated that their syntheses will be completed shortly.


“Enantio- and Diastereoselective Catalytic Alkylation Reactions with Aziridines” T. A. Moss, D. R. Fenwick, D. J. Dixon, J. Am. Chem. Soc. 2008, 130, 10076-10077.

“Brønsted Base / Lewis Acid Cooperative Catalysis in the Enantioselective Conia-ene Reaction” T. Yang, A. Ferrali, F. Sladojevich, L. Campbell, D. J. Dixon, J. Am. Chem. Soc. 2009, 131, 9140-9141.

“Enantioselective Brønsted Acid Catalyzed N-Acyl Iminium Cyclization Cascades” M. E. Muratore, C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt, D. J. Dixon J. Am. Chem. Soc. 2009, 131, 10796-10797.

“Total Synthesis of (–)-Nakadomarin A” P. Jakubec, D. Cockfield and D. J. Dixon J. Am. Chem. Soc. 2009, 131, 16632-16633.

“Asymmetric Organocatalytic Relay Cascades: Catalyst Controlled Stereoisomer Selection in the Synthesis of Functionalized Cyclohexanes” Y. Wang, R.-G. Han, Y.-L. Zhao, S. Yang, P.-F. Xu and D. J. Dixon, Angew. Chem. Int. Ed. 2009, 48, 9834-9837.

“Catalytic Enantio- and Diastereoselective Alkylations with Cyclic Sulfamidates” T. Moss, B. Alonso, D. R. Fenwick, D. J. Dixon, Angew. Chem. Int. Ed. 2010, 49, 568-571.

“A New Family of Cinchona-Derived Amino Phosphine Precatalysts: Application to the Highly Enantio- and Diastereoselective Silver-Catalyzed Isocyanoacetate Aldol Reaction” F. Sladojevich, A. Trabocchi, A. Guarna and D. J. Dixon, J. Am. Chem. Soc. 2011, 133, 1710-1713.

“Synthesis of macrocyclic natural products by catalyst-controlled stereoselective ring-closing metathesis” M. Yu, C. Wang, A. F. Kyle, P. Jakubec, D. J. Dixon, R. R. Schrock and A. H. Hoveyda, Nature 2011, 479, 88-93.

“Total Synthesis of Manzamine A and Related Alkaloids” P. Jakubec, A. Hawkins, W. Felzmann and D. J. Dixon, J. Am. Chem. Soc. 2012, 134, 17482-17485.

“Gold and BINOL-Phosphoric Acid Catalyzed Enantioselective Hydroamination/N-Sulfonyliminium Cyclization Cascade” A. W. Gregory, P. Jakubec, P. Turner, D. J. Dixon, Org. Lett. 2013, 15, 4330-4333.

“Mechanistic investigations on the enantioselective Conia-ene reaction catalyzed by cinchona-derived amino urea pre-catalysts and Cu(I),” F. Sladojevich, Á. L. Fuentes de Arriba, T. Yang, A. Ferrali, I. Ortin, R. Paton and D. J. Dixon, Chem. Eur. J 2013, 19, 14286-14295.

“Enantioselective Michael Addition/Iminium Ion Cyclization Cascades of Tryptamine-Derived Ureas” I. Aillaud, D. M. Barber, A. L. Thompson, D. J. Dixon, Org. Lett. 2013, 15, 2946-2949.

“Bifunctional Iminophosphorane Organocatalysts for Enantioselective Synthesis: Application to the Ketimine Nitro-Mannich Reaction” M. G. Núñez, A. J. M. Farley, D. J. Dixon, J. Am. Chem. Soc. 2013, 135, 16348-16351.