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.
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.The direct addition of N-H bonds to alkenes and alkynes (hydroamination reaction) is a straightforward approach toward the synthesis of substituted nitrogen-containing products. 1 As a result of the 100%-atom economy of the reaction, no byproducts such as salts or water are produced. Apart from being environmentally benign, in the case of alkynes this method opens up interesting possibilities for new domino or one-pot reactions, e.g., a hydroamination coupled with direct nucleophilic addition of organometallic reagents. 2 Originally, the catalytic intermolecular hydroamination of alkynes was carried out in the presence of Hg and Tl salts. 3 Later, alkali metals, 4 complexes of early-transition 5 and latetransition metals, 6 lanthanides, 7 and actinides 8 have been developed to promote these reactions.Among the different catalysts for alkyne aminations, titanium compounds have found widespread interest due to their general reactivity and cheap and ubiquitous availability as compared to toxic metals (Hg, Tl, U, and Th) or more expensive metal complexes (Ru, Pd, and Rh). Important progress in the intermolecular hydroamination of alkynes with titanium complexes has been reported by Bergman 9 and Doye. 10 In addition to synthetic applications, they also performed kinetic measurements 5e,10a and established a general mechanism using dimethyltitanocene as catalyst. Inspired
Going back to nature: Electron‐deficient oxadienes and electron‐poor acetylene carboxylates react in the presence of an organocatalyst to give natural product inspired tricyclic benzopyrones efficiently (up to 99 % yield) and stereoselectively (up to 87 % ee; see scheme). This efficient and operationally simple asymmetric annulation involves the generation of zwitterions from acetylene carboxylates.
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