Professor Chris Willis – Research Summary
Natural products isolated from bacteria, fungi and plants from both marine and terrestrial environments are a rich source of compounds of medicinal and agrochemical importance. We have published >100 papers which centre upon:-
§ Structure elucidation and total synthesis of natural products
§ Design and synthesis of probes to elucidate biosynthetic pathways and enzyme mechanisms
§ Enantioselective synthesis of amino acids and heterocycles
§ Isotopic labelling, biotransformations and reaction mechanisms
Research programmes
Total syntheses of a number of natural products have been completed (for example those shown below) and new targets being pursued include those with anticancer and antibiotic properties.
Prins cyclisations: Mechanism and applications in natural product synthesis
The stereocontrolled synthesis of oxygen heterocycles is an important goal and our interest in this area stems from the wealth of structural diversity of marine natural products assembled on a tetrahydropyran core. Prins-type cyclisations have the potential to give versatile and efficient approaches to the synthesis of substituted tetrahydropyrans. In collaboration with Professor Roger Alder we are investigating the mechanism of Prins cyclisations and applying the chemistry in natural product synthesis. Studies in this area are ongoing and recent results have revealed that:-
§ The mechanism of Prins cyclisations is not simple and can involve fragmentations, allyl transfer processes and 2-oxonia Cope rearrangements.
§ By varying the reaction conditions halogen, oxygen and nitrogen nucleophiles may be introduced at C-4 of the tetrahydropyrans.
§ A deeper understanding of the reaction mechanism has facilitated the first total synthesis of 2 catechol natural products isolated from Plectranthus sylvestris (labiatae).
§ Reaction of aldehydes with homoallylic alcohols can give tetrahydropyrans in excellent yields and with the creation of 3 new asymmetric centres with complete stereocontrol in a single step. The chemistry has been applied to the total synthesis of the 16-membered ring dilactone, clavosolide A isolated from a marine sponge which revealed that the original structure proposed in the literature was a diastereomer of the natural product.
Selected publications:
Total synthesis of a diastereomer of the marine natural product clavosolide A, Chem. Comm., 2005, 5097.
Stereoselective synthesis of the tetrahydropyran core of polycavernoside A, Org. Lett., 2005, 7, 2683.
Probing the mechanism of Prins cyclisations and application to the synthesis of 4-hydroxytetra-hydropyrans, Chem. Comm., 2005, 3727.
Stereoselective synthesis of 4-hydroxy-2,3,6-trisubstituted tetrahydropyrans, Org. Lett., 2003, 5, 2429.
Prins cyclisations: labelling studies and applications to natural product synthesis, Org. Lett., 2002, 4, 3407.
Oxonia-Cope rearrangement and side-chain exchange in the Prins cyclisation, Org. Lett, 2002, 4, 577.
Stereocontrolled synthesis of 2,4,5-trisubstituted tetrahydropyrans, Chem. Commun., 2001, 835.
Chlorinated marine natural products
The marine environment is proving to be a treasure trove of biologically active molecules and some of these secondary metabolites are emerging as lead compounds in drug discovery. A fascinating structural feature of many marine natural products is the covalent inclusion of halides. In collaboration with Professor Bill Gerwick, USA, we are exploring the biosynthesis of barbamide (containing an unusual trichloromethyl group) isolated from Lyngbya majuscula. In addition methods are being developed for the synthesis of a series of natural products incorporating dichloromethyl and trichloromethyl groups e.g the dysamides. Our studies have led to:-
§ The first total synthesis of barbamide.
§ Synthesis and incubation studies with novel amino acids selectively labelled with carbon-13 have revealed that selective chlorination of the unactivated pro-R methyl group of leucine occurs. With no apparent activation we propose that a novel biochemical stepwise mechanism of chlorination operates, possibly involving radicals.
§ The gene cluster responsible for the biosynthesis of barbamide has been cloned and characterised.
Selected publications:
[6-13C]-(2S,4S)-5-Chloroleucine: Synthesis and incubation studies with cultures of the cyanobacterium, Lynbya majuscula, Tetrahedron Lett., 2003, 44, 285.
The barbamide biosynthetic gene cluster: a novel marine cyanobacterial system of mixed polyketide (PKS)-non-ribosomal peptide synthase (NRPS) origin involving an unusual trichloromethyl starter unit, Gene, 2002, 296, 235.
Barbamide and dechlorobarbamide, molluscicidal agents from the marine cyanobacterium, Lyngbya majuscula: Biosynthetic pathway and origin of the chlorinated methyl group, Tetrahedron, 2000, 56, 9103.
Total synthesis of the marine natural product barbamide, Chem. Commun., 2001, 1934.
Biosynthesis of the marine cyanobacterial metabolite barbamide. 1. Origin of the trichloromethyl group, J. Am. Chem. Soc., 1998, 120, 7131.
Polyketide derived natural products
The study of polyketides remains an area of intense research interest worldwide. The scope of the biosynthetic pathways for exploitation to make new biologically active entities via emerging methods of combinatorial biosynthesis are virtually limitless. In collaboration with Professor Tom Simpson, Drs Russell Cox, John Crosby and Matt Crump in Bristol as well as Professor Chris Thomas and his group at the University of Birmingham, investigations (synthetic, biosynthetic and genetic) are targeted at a range of polyketide derived natural products including the pseudomonic acids, monocerin and the decarestrictines. Research in our laboratories has led to:-
§ The total synthesis of pseudomonic acid C (an antibiotic isolated from Pseudomonas fluorescens) by a versatile approach which may be readily adapted for the synthesis of advanced biosynthetic intermediates.
§ Use of spectroscopic methods for the elucidation of the structure of two unusual 13-membered ring macrolides isolated from Cytopsora and confirmation of the structure of bartanol through total synthesis.
§ Elucidation of the structure of a novel g-lactone metabolite, (S,S)-sapinofuranone, from Acremonium strictum and confirmation of the structure by total synthesis.
§ Through synthesis and feeding studies we have provided compelling evidence for the structure of the first enzyme-free intermediate on the biosynthetic pathway to monocerin. This work has paved the way for use of this intermediate in further studies to isolate and sequence the moncerin PKS gene.
§ Methods have been developed for the enantioselective synthesis of a range of putative biosynthetic intermediates to polyketides which have been used to gain a deeper understanding of the assembly of polyketides.
Selected publications:-
Assembly intermediates in polyketide biosynthesis: Enantioselective syntheses of b-hydroxycarbonyl compounds, Org. Biomol. Chem., 2005, 3, 1719.
Synthesis and incorporation of the first PKS-free intermediate in monocerin biosynthesis, Angew. Chem., Int. Ed, 2004, 727.
Two approaches to the synthesis of the macrodiolide colletotriene, Aust. J. Chem., 2004, 645.
A versatile approach to the total synthesis of the pseudomonic acids, Chem. Commun., 2000, 1109.
Structure elucidation and synthesis of (4S,5S,6Z,8E)-5-hydroxydeca-6,8-dien-4-olide (S,S, Sapinofuranone B) - a novel g-lactone metabolite of Acremonium strictum, J. Chem. Soc., Perkin Trans. 1, 2000, 2475.
Isotopic labelling and biotransformations
Biotransformations are of widespread value in asymmetric synthesis and we are developing new methods for the stereocontrolled synthesis of molecules of biological interest such as substituted piperidines, pyrrolidines and isotopically labelled amino acids using enzymes in key synthetic transformations. For example:-
§ Combining two biotransformations in a single pot process has given a clean and efficient method for the conversion of 2-oxo esters to enantiomerically pure a-amino acids and 2-hydroxy acids. The approaches have been adapted for the selective incorporation of isotopic labels and the products used to probe biochemical mechanisms and protein structure.
§ Genetic manipulation of oxidoreductases has given catalysts with exciting potential in organic synthesis not only due to their broad substrate specificity but also their high catalytic activity.
§ Oxidoreductases have been shown to catalyse a combined resolution-reduction which we are exploiting for use in organic synthesis as well as to further probe the active sites of these enzymes.
§ We have reported the first examples of the reduction of 2-oxo acids with nitrogen functionality in the side chain giving valuable intermediates for the enantioselective synthesis of a series of 5- and 6- membered ring nitrogen heterocycles.
§ Isotopic labelling studies on the Ugi four component reaction have led to a greater understanding of the mechanism and utility of the reaction in organic synthesis.
Selected publications:-
Three approaches to the synthesis of L-leucine selectively labelled with carbon-13 or deuterium in either diastereotopic methyl group, J. Chem. Soc., Perkin Trans. 1, 2000, 43.
Chemoenzymatic syntheses of cis- and trans-3-hydroxy-5-methylpiperidin-2-ones, Tetrahedron Lett., 2000, 41, 397.
Synthesis and enzyme-catalysed reductions of 2-oxo acids with oxygen containing side-chains, J. Chem Soc., Perkin Trans. 1, 2000, 901.
Syntheses of isotopically labelled L-amino acids with an asymmetric centre at C-3, J. Chem. Soc., Perkin Trans. 1, 2000, 3406.
Ugi four component condensations using aldehydes with an asymmetric centre at C-2, Tetrahedron Lett., 2000, 41, 8001.
Probes for the active sites of leucine dehydrogenase, Bioorg. Med. Chem. Lett., 1999, 9, 1941.
Chemoenzymatic synthesis of 4-amino-2-hydroxy acids: A comparison of mutant and wild-type oxidoreductases, J. Org. Chem., 1998, 63, 7764.