The first enantioselective total synthesis of the cytotoxic natural product (+)-psiguadial B is reported. Key features of the synthesis include (1) the enantioselective preparation of a key cyclobutane intermediate by a tandem Wolff rearrangement/asymmetric ketene addition, (2) a directed C(sp 3 )−H alkenylation reaction to strategically forge the C1−C2 bond, and (3) a ring-closing metathesis to build the bridging bicyclo[4.3.1]decane terpene framework.
Into the groove: The introduction of a C2‐symmetric N‐heterocyclic carbene ligand with appropriately substituted naphthyl side chains enables the efficient Suzuki–Miyaura coupling to form bulky tetra‐ortho‐substituted biaryls from aryl bromides and chlorides at room temperature. DFT calculations uncover the subtle steric phenomena at play that lead to the superior catalytic performance. Cyoct=cyclooctyl.
Monodentate N-heterocyclic carbene (NHC) ligands have become ubiquitous in organometallic chemistry and catalysis. [1] Conversely, development of chiral monodentate NHC ligands that induce high selectivity in asymmetric metal catalysis is still at an early stage with relatively few reports detailing enantioselectivities of 90 % ee and higher. [2][3][4][5][6] The main difficulties in designing efficient ligands of this type reside in placing stereocontrol elements at positions near the metal center without affecting the overall reactivity of the catalysts. Scheme 1 shows some of the most promising ligand designs to date and highlights the fact that the inherent flexibility of the N substituents has to be restricted to afford ligands that efficiently transfer their chiral information. This restriction can be done by fusing these wingtips onto the N heterocycle, a design motif pioneered by Glorius et al., [2] and more recently developed further by Murakami et al. [3] Decreasing the rotation of the N substituents is also key in the successful C 2 -symmetric ligands reported by Kündig et al., [4] who have been able to show that such ligands can be used very effectively in palladium chemistry. [5] Probably the most versatile ligand system developed so far was first reported by Grubbs et al., [6,7] and they rely on transferring chirality from a chiral N-heterocyclic backbone onto unsymmetrically substituted aryl side chains and ultimately onto the metal coordination sphere. While the design permits easy access to the precursor imidazolinium salts, such side chains will in principle create three diastereomers which would have to be separated for optimal use in catalysis. Our own efforts, [8] have indeed highlighted the pivotal role the respective orientation of naphthyl wingtips can have on enantioselectivity and, contrary to what other groups have proposed or found, the best ligands with 2-alkyl-substituted naphthyl side chains position their alkyl substituents directly below the corresponding phenyl group of the backbone [(Ra,Ra)-isomer].Encouraged by our first results, we became interested in ways of exclusively accessing this particular diastereomer, as it would undoubtedly allow a more straightforward synthesis and use of these ligands. After testing several substitution patterns, we were pleased to find that placing a relatively rigid cyclooctyl group at the 2-position of the naphthyl moieties and ring-closing the corresponding chiral diamine A at 120 8C for 2 hours (Scheme 2) generated the virtually pure NHC salt (Ra,Ra)-B. The salt showed one set of signals and a diagnostic single peak for the C2 proton of the imidazolinium ring in the 1 H NMR spectrum.This salt was then used to synthesize the palladium cinnamyl complex (Ra,Ra)-C in high yield, the structure of which was unambiguously confirmed by single-crystal X-ray crystallography. [9,10] Qualitative assessment of the structure shows both the relative bulk and the C 2 symmetry of the ligand. The overall steric demand of the ligand was then quantified by it...
A new NHC x Pd-catalyzed asymmetric alpha-arylation of amides is reported that gives direct access to synthetically valuable, allylated oxindoles with quaternary carbon centers. The reaction is made possible by the introduction of a new chiral NHC ligand. The palladium complexes derived therefrom combine excellent reactivity with high chemo- and enantioselectivity for the title transformation.
We present the first productive ring-closing metathesis reaction that leads to the construction of cyclic alkenyl bromides. Efficient catalysis employing commercially available Grubbs II catalyst is possible through appropriate modification of the starting bromoalkene moiety.
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