Paul Anthony Worthington

Stereocontrolled Synthesis of Carbon Chains Bearing Contiguous Methyl Groups by Iterative Boronic Ester Homologations: Application to the Total Synthesis of (+)-Faranal†

Carbon chains bearing 1, 3, 5... n polymethyl groups are ubiquitous in natural products. Recently, effective solutions for a flexible, stereocontolled synthesis of such arrays have been achieved by the groups of Feringa-Minnaard, Breidt, and Negishi. Carbon chains bearing adjacent methyl groups, although less common, are also frequently encountered (Figure 1), but a general stereocontrolled solution to this problem has not been advanced. For example, in the previous syntheses of the insect pheromone (+ )-faranal (1), one or both methyl groups originate from a carboxylic ester to enable control of relative stereochemistry during C C bond formation (both utilize resolution to achieve absolute control). Introducing the methyl groups in the wrong oxidation state invariably leads to an increase in the total number of steps required. We recently reported a method to homologate carbon chains bearing boronic esters using Hoppe s lithiated carbamates. 8] Through appropriate choice of the diamine ligand employed in the lithiation of the carbamate [( )-sparteine or O Brien s (+)-sparteine surrogate] we showed that either enantiomer of either diastereomer of the homologated product could be easily obtained (Scheme 1). We now demonstrate the application of this methodology to a stereocontrolled synthesis of (+ )-faranal and furthermore, highlight a new one-pot multiple-homologation process.

The synthesis of substituted pyridylpyrimidine fungicides using palladium-catalysed cross-coupling reactions

Abstract Various substituted phenyl, pyridyl and benzyl zinc chlorides have been generated from the corresponding lithium or magnesium organometallic reagents. These have been cross-coupled with 2-(6-bromo-2-pyridyl)pyrimidines in the presence of tetra kis (triphenylphosphine)palladium(0) to produce a series of substituted pyridylpyrimidine fungicides in 32–99% yields.

The Diels–Alder route to drimane related sesquiterpenes; synthesis of cinnamolide, polygodial, isodrimeninol, drimenin and warburganal

The stereospecific preparation of various 1-vinyl-2,6,6-trimethylcyclohex-1-enes (6) as potential diene precursors in the Diels–Alder reaction with dimethyl acetylenedicarboxylate have been investigated. The reaction of the parent diene (6a) with dimethyl acetylenedicarboxylate affords an adduct (18) in 94% yield. This species was reductively isomerised using 10% Pd/C/H2 and a mineral acid to give a trans-fused decalin diester (19). Reduction of (19) with lithium aluminium hydride afforded 1,4,4a,5,6,8,8a-octahydro-5,8,8a-trimethyl-1 β,4a α,8aβ-naphthalene-1,2-dimethanol (24) a key starting material for the highly efficient syntheses of five drimane sesquiterpene natural products, cinnamolide (1), polygodial (2), isodrimeninol (3), drimenin (4), and warburganal (5). Microbial oxidation reactions using C. elegans or A. niger of (2), (24), and (1) gave good yields of the corresponding 3β-hydroxy derivatives, (30), (31), and (32). Several other unusually substituted drimane derivatives are reported.

Synthesis of Some Arylsulfur Pentafluoride Pesticides and Their Relative Activities Compared to the Trifluoromethyl Analogues

Examples of pesticides containing an arylsulfur pentafluoride group were made and their biological activities compared to the corresponding trifluoromethyl analogues. A phenylsulfur pentafluoride analogue of the insecticide fipronil, screened against a resistant strain of Musca domestica, showed higher activity than the corresponding trifluoromethyl analogue.

Spiroindolines identify the vesicular acetylcholine transporter as a novel target for insecticide action.

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family.

The Crocacins: Novel natural products as leads for agricultural fungicides

A short route to the synthesis of analogues of the antifungal but unstable natural product crocacin D was developed. A wide range of compounds were made in which the complex side chain was replaced by simple aromatic units, and many of them showed high activity in a mitochondrial beef heart respiration assay. Some of these compounds were active against plant pathogenic fungi of agricultural importance in glasshouse tests. In order to find compounds with greater stability than the natural crocacins, the photolabile (Z)-enamide was replaced with many different moieties, but none gave rise to useful fungicidal activity.

Acetoacetoxy ethyl methacrylate (AAEM) resin, a new scavenger for primary amines in the presence of secondary amines

Preliminary results on a new type of polymer scavenger, acetoacetoxy ethyl methacrylate (AAEM) resin, are reported. AAEM resin can selectively remove primary amines in the presence of secondary amines. Its application in a solution library synthesis is demonstrated.

Improving resins for solid phase synthesis: incorporation of 1- 2-(2-methoxyethoxy)ethoxy -4-vinyl-benzene

Abstract The preparation, characterisation and application of a series of non-grafted polystyrene (PS) resins containing a styrenic methoxypoly(ethylene glycol) (MPEG) derivative is presented. These novel PS-MPEG resins were designed to balance swelling and solvation with improved handling. The monomer, 1-[2-(2-methoxyethoxy)ethoxy]-4-vinyl-benzene, contained an inert phenyl ether linkage designed to provide broad chemical compatibility and stability, yet imparting all the favourable properties of the PEG group into the new resin, whilst maintaining a high loading capacity. The synthetic performance of the new resins compared very favourably to those of TentaGel™, ArgoGel™ and aminomethyl PS.

Highly Substituted Homoallylvinylcyclopropanes by Indium‐Mediated Reaction of α,β‐Unsaturated Ketones and Aldehydes with Allylic Halides

Allylindium reagents, prepared from excess allylic halide (Br or I) and indium metal, react with α,β-unsaturated ketones and aldehydes to give, after aerobic acidic workup, homoallyl-substituted vinylcyclopropanes. This process was explored and developed after a chance discovery arising from a side reaction in an attempted Pd-catalysed process. The structure of the cyclopropane arising from the reaction of bis(p-chlorobenzylidine)acetone was confirmed by X-ray crystallography. Whilst bis-α,β−unsaturated ketones give rise to a single homoallylcyclopropane species, α,β-unsaturated ketones and aldehydes give diastereomeric mixtures whose relative stereochemistry were assigned by NOE experiments. Crotylindium reagents react with good to perfect regioselectivity to afford tetrasubstituted cyclopropanes but prenylindium reagents fail to generate the analogous pentasubstituted rings.

Powerful Kinetic Diastereoselection in Ruthenium-Catalysed Ring-Closing Metathesis of (Homoallyl)vinylcyclopropanes

Homoallyl-substituted vinyl cyclopropanes 1a-c, which are readily prepared by reaction of allylindium reagents with α,β-unsaturated ketones and aldehydes, undergo Ru-catalysed RCM reactions with Grubbs catalyst to give [4.1.0]bicyclooct-2-ene (norcarene) type bicyclic products. Noncyclisable ‘trans’ homoallyl-substituted vinyl cyclopropanes 1b and 1c are separated from their ‘cis’ diastereomers by RCM to 5b and 5c - but only with moderate efficiency due to a competing homo-cross metathesis (‘dimerisation’) to give 7b and 7c, respectively. However, the four diastereomers of the (homoallyl)distyrylcyclopropane 14a obtained from indium-mediated reaction of dibenzylideneacetone and crotyl bromide undergo remarkable kinetic diastereoselection in their RCM reactions to give a 4,7-dimethyl[4.1.0]bicyclohept-2-ene-type product 15a. This process allows recovery of a single diastereomer (> 95%) of 14a without dimerisation being a significant side reaction. Furthermore, the RCM product 15a is obtained rich in one diastereomer (ca. 90%). The kinetic diastereoselection and lack of dimerisation can be rationalised by considering developing transannular interactions and a pseudo-A1,3 strain model.