Richard J. Whitby

A zirconium catalysed synthesis of 1,4-dimagnesium reagents.

Abstract The zirconium catalysed addition of diethylmagnesium to a variety of unactivated alkenes affords either the simple carbometallation product, or, 1,4-dimagnesium reagents depending on the conditions and substrate. The products can be successfully functionalised with a variety of electrophiles.

Palladium-catalysed synthesis of imidates, thioimidates and amidines from aryl halides

Abstract Palladium-catalysed coupling between aryl- or heteroaryl-bromides, alkoxides, aryloxides or thioalkoxides, and isocyanides gives aryl-imidates and -thioimidates in high yield. Amidines can be synthesised in a one-pot procedure via imidates.

The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells

Estrogen receptor-α (ER) is expressed in the great majority of breast cancers, and the inhibition of ER action is a key part of breast cancer treatment. The inhibition of ER action is achieved using anti-estrogens, primarily tamoxifen, and with aromatase inhibitors that inhibit estrogen biosynthesis, thereby preventing ER activation. However, resistance to these therapies is common. With the aim of identifying new molecular targets for breast cancer therapy, we have identified the liver receptor homolog-1 (LRH-1) as an estrogen-regulated gene. RNA interference and over-expression studies were used to investigate the role of the LRH-1 in regulating breast cancer growth and to identify the targets of an LRH-1 action. Promoter recruitment was determined using reporter gene and chromatin immunoprecipitation (ChIP) assays. We show that LRH-1 regulates breast cancer cell growth by regulating the ER expression. Reporter gene and in vitro DNA-binding assays identified an LRH-1-binding site in the ER gene promoter, and ChIP assays have demonstrated in vivo binding at this site. We also provide evidence for new LRH-1 variants in breast cancer cells arising from the use of alternative promoters. Previous studies have shown that LRH-1 functions in estrogen biosynthesis by regulating aromatase expression. Our findings extend this by highlighting LRH-1 as a key regulator of the estrogen response in breast cancer cells through the regulation of ER expression. Hence, inhibition of LRH-1 could provide a powerful new approach for the treatment of endocrine-resistant breast cancer.

Formation of zirconocene η2-imine complexes by rearrangement of cyclic iminoacyl complexes

Abstract Insertion of phenylisocyanide into bicyclic zirconacyclopentanes, obtained from a 1,7-octa- or 1,6-hepta-diene by reaction with dibutylzirconocene, affords initially an iminoacyl complex that rearranges on warming to form a zirconocene η 2 -imine complex which inserts unactivated alkenes and alkynes.

The dipolar endofullerene HF@C60

The cavity inside fullerenes provides a unique environment for the study of isolated atoms and molecules. We report the encapsulation of hydrogen fluoride inside C60 using molecular surgery to give the endohedral fullerene HF@C60. The key synthetic step is the closure of the open fullerene cage with the escape of HF minimized. The encapsulated HF molecule moves freely inside the cage and exhibits quantization of its translational and rotational degrees of freedom, as revealed by inelastic neutron scattering and infrared spectroscopy. The rotational and vibrational constants of the encapsulated HF molecules were found to be redshifted relative to free HF. The NMR spectra display a large (1)H-(19)F J coupling typical of an isolated species. The dipole moment of HF@C60 was estimated from the temperature dependence of the dielectric constant at cryogenic temperatures and showed that the cage shields around 75% of the HF dipole.

Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2).

The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

The mechanism of the zirconium catalysed ethyl- and 2-magnesioethyl-magnesiation of unactivated alkenes

Abstract Deuterium labelling experiments prove that the zirconocene dichloride catalysed ethylmagnesiation of alkenes occurs via a zirconocene η2-ethylene complex and allow a deuterium isotope effect for a key β-hydride transfer to be estimated ( k H k D = 2.5 ). Transmetallation from zirconium to magnesium to form 1,4-dimagnesiated reagents is shown to be an intramolecular process. Kinetic studies show that the reaction between η2-ethylene zirconocene and the alkene is rate limiting and that Lewis bases inhibit the reaction by decreasing the amount of η2-ethylene zirconocene in equilibrium with the ‘ate’ complex [Cp2Zr(CH2=CH2)Et]−.[MgX.Base]+.

Catalytic asymmetric carbomagnesiation of unactivated alkenes. A new, effective, active, cheap and recoverable chiral zirconocene

Abstract The ethylmagnesiation of terminal alkenes catalysed by ( R , R )-ethylene-1,2-bis(η 5 -4,5,6,7-tetrahydro-1-indenyl)zirconium( R )-1,1′-binaphth-2,2′-diolate gave low turnovers and enantioexcesses. A novel C i symmetric zirconocene dichloride CpCp′ZrCl 2 (Cp = C 5 H 5 , Cp′ = 1-neomenthyl-4,5,6,7-tetrahydroindenyl) was prepared which gave better enantioselectivity, is cheaper to make, catalytically more active, and recoverable.

An Efficient Flow‐Photochemical Synthesis of 5H‐Furanones Leads to an Understanding of Torquoselectivity in Cyclobutenone Rearrangements

Go with the flow: 4-Hydroxycyclobutenones were efficiently transformed into 5H-furanones using an inexpensive flow-photochemical setup. The results challenge the notion that this and the related thermochemical rearrangement display torquoselectivity in their electrocyclic opening to a vinylketene intermediate. Selectivity in the photochemical rearrangement is due a dichotomous reactivity of the (E)- and (Z)-vinylketene intermediates.

Elaboration of zirconacyclopentanes by sequential insertion of lithium chloroallylide and ketones or aldehydes

Abstract Insertion of lithium chloropropargylide or lithium chloroallylide into bicycliczirconacyclopentanes gives 1-zirconacyclooct-3-ynes or -3-enes respectively. The former give allenes on protonolysis. The latter react further with ketones or aldehydes to afford 1-zircona-2-oxa-5-decenes which give (E)-homoallyic alcohols on aqueous work-up. With aldehydes moderate 1,6-diastereocontrol is observed.