A "Motif-Oriented" Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues.

The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1α (EF-1α). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be "motif-oriented": specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited.

Enantioselective Rhodium-catalyzed C-C Bond Activation of Cyclobutanones.

The activation of carbon-carbon bonds has attracted much attention in the past decade. Despite important progress, the development of asymmetric reactions lags behind. For the first time, asymmetric rhodium(I)-catalyzed direct oxidative additions into enantiotopic C-C bonds of cyclobutanones could be realized. Subsequent carboacylation of tethered olefins and carbonyl groups of the generated rhoda(III)cyclopentanone give an efficient access to complex polycyclic scaffolds in high yields. Despite operating at high reaction temperatures, the processes are characterized by outstanding enantioselectivities of generally greater than 99.5:0.5 er.

Regiodivergent cyclobutanone cleavage: switching selectivity with different Lewis acids.

The exploitation of strain release in small rings as driving force to enable complex transformations is a powerful synthetic tool. Among them, cyclobutanones are particularly versatile substrates that can be elaborated in a wide variety of structurally diverse building blocks. Herein, Lewis acid catalyzed rearrangement reactions are presented that provide selective access to two structurally distinct polycyclic scaffolds, that is, indenylacetic acid derivatives and benzoxabicyclo[3.2.1]octan-3-ones. The choice of the Lewis acid fully controls the reaction pathway and the regioselectivity of the cyclobutanone CC bond cleavage site.

Highly enantioselective rhodium(I)-catalyzed carbonyl carboacylations initiated by C-C bond activation.

The lactone motif is ubiquitous in natural products and pharmaceuticals. The Tishchenko disproportionation of two aldehydes, a carbonyl hydroacylation, is an efficient and atom-economic access to lactones. However, these reaction types are limited to the transfer of a hydride to the accepting carbonyl group. The transfer of alkyl groups enabling the formation of CC bonds during the ester formation would be of significant interest. Reported herein is such asymmetric carbonyl carboacylation of aldehydes and ketones, thus affording complex bicyclic lactones in excellent enantioselectivities. The rhodium(I)-catalyzed transformation is induced by an enantiotopic CC bond activation of a cyclobutanone and the formed rhodacyclic intermediate reacts with aldehyde or ketone groups to give highly functionalized lactones.

Highly enantioselective rhodium(I)-catalyzed activation of enantiotopic cyclobutanone C-C bonds.

The selective functionalization of carbon-carbon σ bonds is a synthetic strategy that offers uncommon retrosynthetic disconnections. Despite progress in C-C activation and its great importance, the development of asymmetric reactions lags behind. Rhodium(I)-catalyzed selective oxidative additions into enantiotopic C-C bonds in cyclobutanones are reported. Even operating at a reaction temperature of 130 °C, the process is characterized by outstanding enantioselectivity with the e.r. generally greater than 99.5:0.5. The intermediate rhodacycle is shown to react with a wide variety of tethered olefins to deliver complex bicyclic ketones in high yields.

Asymmetric transformations via C-C bond cleavage.

Catalytic asymmetric transformations operating by carbon-carbon (C-C) bonds cleavages have emerged as intriguing strategies to access transient organometallic species from different reaction pathways. The reactions and the applicable substrate range have expanded considerably over the last decade. This overview covers the main developments in this field. A major focus is placed on ß-carbon eliminations of strained tert-alcohols and related processes which have been shown to be particularly versatile in a broad range of transformations. Furthermore, exciting developments of asymmetric processes based on direct oxidative C-C bond insertion reactions, for instance into the acyl C-C bond of ketones or the C-CN bond of nitriles, are discussed.