The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact.

An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.

The poor reactivity of unactivated alkynes as dienophiles has for a long time limited their use in Diels-Alder reactions. [1] Only after the discovery of the remarkable catalytic effect of various transition-metal complexes could the synthetic potential of this transformation be exploited.[2-4] Such cycloadditions of dienynes A are assumed to proceed via metallacyclic intermediates of type B and C, which are formed by oxidative cyclization, and subsequent insertion of the alkyne (Scheme 1).[3] We speculated, however, that entirely different scenarios might also result in a net [4+2] cycloaddition, and present herein preliminary data to support this view.Activation of the triple bond of A followed by attack of the dienes proximal alkene moiety should generate an electrophilic metal carbene F with a pendant vinyl group on its cyclopropyl ring.[5] This species might undergo a "metallaCope" rearrangement with formation of C and proceed from there on; alternatively, one may envisage formation of cation G that releases cycloadduct D and regenerates the catalyst. The excellent performance of cationic gold complexes as carbophilic Lewis acids [5] prompted us to probe this concept by exposing various dienynes to [(Ph 3 P)Au]SbF 6 generated in situ (Table 1). Whereas the parent compounds 1 decomposed (Table 1, entry 1), substrates with a nonterminal alkyne were converted into the corresponding 1,4-cyclohexadiene products in respectable yields. As silyl end groups on the alkyne are lost upon work-up, [6] access to the unfunctionalized cycloadducts is secured (Table 1, entries 2-6).The proposed mechanism, which proceeds via an intermediate of type F, is consistent with the results shown in Scheme 2. Thus, compound 10 furnished cycloadduct 12 (68 %) and tetrahydrofuran 13 (15 %), which derives from the putative electrophilic carbene 11 by reaction with the tethered alcohol; such vinylogous alkoxycyclizations have ample precedence in gold and platinum catalysis.[7] Even more instructive is the conversion of substrate 14 into 16 and 18, both of which again likely originate from the same intermediate 15. Whereas evolution of this species along the pathway depicted in Scheme 1 affords cycloadduct 16, competing attack of the phenyl ring onto the electrophilic carbene provides the companion product 18. The latter course corroborates the view that gold cyclopropyl "carbenes" [c] The product is partly aromatized in air (ca. 10 %). Ts = toluene-4-sulfonyl.

Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.