Instrumentation and Spectra Formats. NMR: Spectra were recorded on a Bruker AC 200, AMX 300, DPX 300, AMX 400 or DMX 600 spectrometer in CDCl 3 unless stated otherwise. Chemical shifts (8) are given in ppm relative to TMS, coupling constants (J) in Hz. The multiplicity in the 1 3 C NMR spectra refers to the geminal protons (DEPT). IR: Nicolet FT-7199, wavenumbers in cm-1. MS: Finnigan MAT 8200 (70 eV); HR-MS: Finnigan MAT SSQ 7000 (70 eV). Elemental analyses: Dornis & Kolbe, MUlheim.

PtCl(2) constitutes an efficient and practical catalyst for a set of different atom economical rearrangement reactions of enynes. This includes (i) a formal enyne metathesis reaction delivering 1,3-dienes, (ii) the formation of polycyclic vinylcyclopropane derivatives, and (iii) an unprecedented O-->C allyl shift reaction if unsaturated ethers are employed. Although these transformations produce significantly different structural motifs, they share a common mechanism comprising a cationic manifold triggered by the pi-complexation of Pt(II) onto the alkyne unit of the substrates. Strong experimental support for the proposed mechanism comes from deuterium-labeling studies, a careful analysis of the product distribution pattern, and the fact that in some cases PtCl(2) can be replaced by simple Lewis or Brønsted acids as the catalysts.

Pioneering studies of Murai et al. have shown that PtCl 2 is a versatile catalyst for intramolecular skeletal rearrangements of enynes. 1 These substrates convert (i) into 1,3-dienes via a formal enyne metathesis, 1,2 (ii) into 1,4-dienes if the alkene group is part of an allylsilane (stannane) entity, 3 or (iii) into polycyclic arrays if dienynes are used as starting materials. 4

The activation of the transcription factor NF-E2-related factor 2 (Nrf2) maintains cellular homeostasis in response to oxidative stress by the regulation of multiple cytoprotective genes. Without stressors, the activity of Nrf2 is inhibited by its interaction with the Keap1 (kelch-like ECH-associated protein 1). Here, we describe (3S)-1-[4-[(2,3,5,6-tetramethylphenyl) sulfonylamino]-1-naphthyl]pyrrolidine-3-carboxylic acid (RA839), a small molecule that binds noncovalently to the Nrf2-interacting kelch domain of Keap1 with a K d of ϳ6 M, as demonstrated by x-ray co-crystallization and isothermal titration calorimetry. Whole genome DNA arrays showed that at 10 M RA839 significantly regulated 105 probe sets in bone marrow-derived macrophages. Canonical pathway mapping of these probe sets revealed an activation of pathways linked with Nrf2 signaling. These pathways were also activated after the activation of Nrf2 by the silencing of Keap1 expression. RA839 regulated only two genes in Nrf2 knock-out macrophages. Similar to the activation of Nrf2 by either silencing of Keap1 expression or by the reactive compound 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester (CDDO-Me), RA839 prevented the induction of both inducible nitric-oxide synthase expression and nitric oxide release in response to lipopolysaccharides in macrophages. In mice, RA839 acutely induced Nrf2 target gene expression in liver. RA839 is a selective inhibitor of the Keap1/Nrf2 interaction and a useful tool compound to study the biology of Nrf2.The transcription factor NF-E2-related factor 2 (Nrf2) 2 is a promising target for the treatment of oxidative and inflammatory stress-related disorders, such as neurodegenerative and microvascular diseases (1-5). Nrf2 regulates the expression of several cytoprotective anti-oxidative and anti-inflammatory proteins by binding to the cis-acting antioxidant response element (ARE) within gene promoters. Nrf2 itself is regulated by the kelch-like ECH-associated protein 1 (Keap1), which is a substrate recognition subunit for a cullin3-based ubiquitin E3 ligase and functions as a sensor for oxidative and electrophilic stress. Structural elements of the Keap1 protein include the C-terminal Nrf2-binding kelch domain, the intervening region, and the broad complex-Tramtrack-Bric-a-Brac domain. Keap1 binds as a dimer via its two Kelch domains to one molecule of Nrf2, specifically to the high affinity ETGE and the low affinity DLG motives at the N terminus of Nrf2. Without stressors, this leads to the ubiquitinylation and subsequent proteolytic degradation of the transcription factor. In the presence of oxidative or electrophilic stress, cysteine residues within the intervening region and broad complex-Tramtrack-Bric-a-Brac domain of Keap1 become modified. According to the hinge and latch model, this weakens the interaction between Keap1 and the DLG motif of Nrf2 but does not lead to a release of Nrf2 (6, 7). The conformation cycling model postulates a stabilization of the Keap1/Nrf2 interaction by the Keap1 modifica...

N-Cumyl-N-ethylferrocenecarboxamide 5 provides planar chiral carboxamides 6 in high yield and % ee via (À)-sparteine-mediated directed orthometalation. Mild decumylation affords secondary amides 7, which serve as intermediates for a convenient and general route to the venerable Ugi planar chiral ferrocenylamines 13 and as versatile precursors for the preparation of novel chiral ferrocenes 15 and 20. The chiral TMS-ferrocenyl derivative 7c is used to prepare the enantiomeric (S)-7f, circumventing the lack of availability of ()-sparteine.