Prof Jim Anderson

Research Overview

Research in my laboratory covers a broad portfolio of projects that combine contemporary synthetic organic chemistry methodology with highly adventurous, blue sky research. The basic theme in all of these projects is inventing fundamentally different ways of creating new organic structures in a stereocontrolled and, if applicable, catalytic fashion. This has encompassed the development of new reaction methodology which has been showcased in the synthesis of biologically active natural products, the details of which appear below.

The nitro Mannich reaction for the asymmetric synthesis of 1,2-diamines.

A main part of our research programme has been the development of the nitro-Mannich reaction for the synthesis of 1,2-diamines in stereochemically pure form. Although the nitro-Mannich reaction had been known since 1896, the yield of the reaction and the control of relative stereochemistry had not been generally developed. In 1998 we published a key paper detailing the diastereoselective nitro-Mannich reaction and its application to the synthesis of 1,2-diamines. This stimulated a rapid rise in research from many other research groups. During the whole of the 20th century, the reaction had remained a little understood bond construction that had only been used periodically and was not generally efficient. The reaction belongs to a formidable suite of carbon-carbon bond forming reactions that are well understood and used routinely in molecular construction (Fig. 1). 

The Aldol, Mannich, Henry Family of key C-C bond forming reactions

The aldol, Mannich and Henry reactions are all linked by the common addition of a stabilised anion to a carbonyl derivative. It seems peculiar that the missing permutation of this set of reactions, the addition of a nitronate anion to an imine (nitro-Mannich reaction), remained so elusive during the 20th century. The likely explanation is due to the β-nitro amine products from the nitro-Mannich reaction being prone to retro-addition, which complicates isolation, purification and other transformations.

The majority of the publications since 1998 have concentrated on showcasing asymmetric catalysis with standard, commercially available nitroalkanes and a limited range of aldimines in a generic nitro-Mannich reaction. In addition very few groups have reported any further transformations of the β-nitro amine products. In our research we have addressed key issues that have limited the wider use of the nitro Mannich reaction. We have shown that the reduction of the sensitive β-nitro amines can be achieved by using SmI2 or with Al/Hg amalgam followed by LiAlH4 or hydrogenolysis. We found that the amino group of the β-nitroamines was resistant to derivatisation, but fortunately the trifluoroacetamide derivatives are stable, often crystalline solids, amenable to chromatography and enable the reduction of the nitro function with simple Zn/acid (along with N-migration of the trifluoroacetyl group). More recently we have been addressing the complexity of the nitroalkane partner in the nitro-Mannich reaction. More complex nitroalkanes are most easily synthesised from the Henry reaction of nitromethane with an aldehyde, followed by reduction. We have developed conjugate addition / nitro Mannich reactions whereby the intermediate nitronate anion formed from conjugate addition of a nucleophile is trapped with an in situ nitro-Mannich reaction. These more structurally complex β-nitroamines can be manipulated to produce a range of useful molecular structures. We have shown this concept to work well for hydride nucleophiles (reductive nitro-Mannich reaction, Eq. 1) for 33 examples. The addition of a carbon nucleophile using dialkyl zincs creates a stereogenic centre and we developed a flexible asymmetric catalytic protocol to give either of two diastereoisomers in enantiomerically pure form (Eq. 2). This work was selected as a Feature Article in the ACS Journal of Organic Chemistry and appeared on the front cover.

nitro-Mannich reaction

The products can be useful for forming heterocycles. Conjugate addition of dialkyl zincs to ethyl nitroacrylate leads to a spontaneous cyclisation to form densely functionalised pyrrolidinones as single diastereoisomers in high yield (Eq. 3). 

Single Diastereoisomers in high yield

Incorporation of a coupling handle (Br) to one of the aromatic substituents of the stereochemically pure β-nitroamines allows an intramolecular palladium catalysed cyclisation of either nitrogen atom (after reduction of the nitro function) to give tetrahydroquinolines or indolines in high overall yield and diastereoselectivity (Eq. 4). This latter work was also selected as a Feature Article in the Journal of Organic Chemistry.

high yield and diastereoselectivity

Other permutations of this particular conjugate addition / nitro-Mannich strategy have enabled us to demonstrate the wider use of this reaction for the synthesis of heterocyclic ring structures which are extremely important for the drug discovery industry (Fig. 4, unpublished). 

Figure 2

We are currently developing other multicomponent startegies around this reaction and investigating the sunthesis of target molecules using these chiral building blocks.

The development of metal oxo chemistry.

In more fundamental work we have been trying to engineer a new synthesis of alkenes involving a carbonyl compound and a metal alkylidene, itself derived from the combination of a metal oxo species with a ketene. We have managed to characterize this process stoichiometrically, but a catalytic variant eludes us at present.

Alkene synthesis reaction scheme involving a carbonyl compound and a metal alkylidene, derived from the combination of a metal oxo species with a ketene.

A spin off from this research has been the investigation of some molybdenum oxo-imido aryloxide complexes which are oxo analogues of olefin metathesis catalysts. These complexes are very efficient for the epoxidation of a range of alkenes and are very sensitive to the steric and electronic environment of the alkene allowing regiospecific epoxidation of non conjugated polyenes. We are investigating asymmetric variants of these novel complexes.

Reaction schemes involving molybdenum oxo-imido aryloxide complexes

Enabling fundamental reactions of CO2.

Most starting materials for the synthesis of fine chemicals are ultimately derived from petroleum. Carbon dioxide is also an important natural carbon resource and has many advantages over petroleum; it is non-toxic, nonflamable and abundant. There is also the possibility of recycling CO2 (an environmental pollutant) from industrial emissions. The possibility of using CO2 as the starting material for the synthesis of fine chemicals would be very valuable and is a chemical problem that has yet to be solved. Using our knowledge of metal oxo chemistry we have proposed a new catalytic cycle to make urethanes, which are very valuable to the chemical industry. This represents an extremely atom efficient and green synthesis of these high value compounds.

Reaction scheme using a metal oxo catalyst to synthesise urethanes

The development of near Infra Red luciferin chemiluminescent probes

Molecular imaging of living animals is crucial to allow understanding of complex biological processes, such as ageing, diseases and studying how therapies work for lifelong health. Bioluminescence imaging (BLI) exploits the remarkable properties of a firefly enzyme (Luciferase) to emit light whilst catalysing a substrate (Luciferase) to optically image biological events in living animals. BLI would be greatly enhanced if we could increase the wavelength of light emitted to infra red light, as mammalian tissues are almost transparent at these wavelengths.

We synthesised an extended luciferin and found that it gave red shifted bioluminescence of λmax 662 nm with wild type luciferase, which is competitive with the most red shifted analogues to date. In collaboration with Drs Pule and Jathoul (UCL Cancer) we have used a mutated luciferase that gives a maximum emission wavelength of 706 nm. This is the furthest red shift of any true bioluminescence system ever observed!

Luciferin and Stretch-luciferin

Light emission within the nrIR range 700-850 nm can travel further in biological tissues due to the existence of a spectral window where absorption by haemoglobin, lipids and water, is low. This results in better signal fit, substantially increasing the ability to separate multiple emissions. These results illustrate the benefit of red-shifting emission for the possibility of multi-parametric BLI in animals.

We are currently synthesising a derivative for X-ray studies with the enzyme and using theroretical calculations to predict what further modificiations can be made. We are actively synthesising further unusual analogues to further red shift the emitted light and improve the quantum yield.

Selected Publications

  1. Enantioselective Conjugate Addition Nitro-Mannich Reactions: Solvent Controlled Synthesis of Acyclic anti- and syn-β-nitroamines with 3 Contiguous Stereocenters. Anderson, J.C.; Stepney, G.J.; Mills, M.R.; Horsfall, L.R.; Blake, A.J.; Lewis, W. J. Org. Chem. 2011, 76, 1961-71, Feature article and front cover.
  2. Stereoselective Synthesis of Densely Functionalised Pyrroloidin-2-ones by a Conjugate Addition/Nitro-Mannich/Lactamisation Reaction. Anderson, J.C.; Horsfall, L.R.; Kalogirou, A.S.; Mills, M.R.; Stepney, G.J.; Tizzard, G.J. J. Org. Chem. 2012, 77, 6186-98.
  3. The Reductive nitro-Mannich Route for the Synthesis of 1,2-Diamine Containing Indolines and Tetrahydroquinolines Anderson, J.C.; Noble, A.; Tocher, D.A. J. Org. Chem. 2012, 77, 6703-27. Feature article
  4. An Enantioselective Tandem Reduction/Nitro-Mannich Reaction of Nitroalkenes using a Simple Thiourea Organocatalyst. Anderson, J.C.; Koovits, P.J. Chem. Sci. 2013, 4, 2897-901
  5. Synthesis of Ureas from Titanium Imido Complexes using CO2 as a C-1 Reagent at Ambient Temperature and Pressure. Anderson, J.C.; Bou Moreno, R. Org. Biomol. Chem. 2012, 10, 1334-8. Inside front cover.
  6. The efficient synthesis of carbodiimides and ureas using a titanium imido complex. Anderson, J.C.; Bou Moreno, R. Tetrahedron 2010, 66, 9182-6.