Cascade syntheses routes to the centrocountins.

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one-pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3-formylchromones as starting materials provided evidence that this one-pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis.

Natural product-inspired cascade synthesis yields modulators of centrosome integrity.

In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.

Lewis base catalyzed [4+2] annulation of electron-deficient chromone-derived heterodienes and acetylenes.

Lewis base catalyzed [4+2] annulation reactions between electron-deficient chromone oxa- and azadienes and acetylene carboxylates provide tricyclic benzopyrones inspired by natural products. An asymmetric synthesis of the tricyclic benzopyrones was developed by using modified cinchona alkaloids as enantiodifferentiating Lewis base catalysts.

A dramatic effect of aryloxo ligands on the titanium-catalyzed hydroamination of alkynes.

The aryloxotitanium complex 1 is a highly chemo- and regioselective catalyst for intermolecular hydroamination of terminal alkynes. Branched imines are obtained in good to excellent yield (up to 99%) with various primary aromatic and aliphatic amines. [reaction: see text]

Stereoselective cascade double-annulations provide diversely ring-fused tetracyclic benzopyrones.

A cascade double-annulation strategy employing diverse pairs of zwitterions with 3-formylchromones is presented that provides stereoselective access to complex tetracyclic benzopyrones. Different zwitterions incorporated different rings that include aza-, oxa-, and carbocycles fused to a common benzopyrone scaffold and in the process created three contiguous chiral centers including an all-carbon-quaternary center with high efficiency and excellent stereoselectivity.

Synthesis of 3-(2-N,N-diethylaminoethoxy)indoles as potential 5-HT6 receptor ligands.

The synthesis of new pharmaceutically interesting 3-(2-N,N-diethylaminoethoxy)indole derivatives is described. Starting from 3-silyloxy-2-methylindoles, deprotection and in situ aminoalkylation provided 3-(2-N,N-diethylaminoethoxy)indoles in good yield. Further sulfonylation of these novel indoles gave access to potential 5-HT(6) receptor ligands.