It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue.
The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late-stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3 Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate.
International audienceSynthetic applications of cyclobutanones other than ring expansion and fragmentation reactions are rare. Herein, highly efficient diastereo- and enantioselective organocatalytic Michael additions of 2-substituted cyclobutanone derivatives to nitroalkenes are reported allowing the stereocontrolled creation of " all-carbon " quaternary centers. The approach relies on both the use of Brønsted base/hydrogen-bond donor bifunctional organocatalysts, and importantly, the specific stabilization and activation of cyclobutanone with a secondary amide moiety. The reaction was found to nicely accommodate a broad scope of substrates, allowing the control of up to three contiguous stereogenic centers. This work has opened new synthetic opportunities
Re‐investigation of the l‐proline catalyzed double aldol cascade dimerization of succinaldehyde for the synthesis of a key bicyclic enal intermediate, pertinent in the field of stereoselective prostaglandin synthesis, is reported. The yield of this process has been more than doubled, from 14 % to a 29 % isolated yield on a multi‐gram scale (32 % NMR yield), through conducting a detailed study of the reaction solvent, temperature, and concentration, as well as a catalyst screen. The synthetic utility of this enal intermediate has been further demonstrated through the total synthesis of Δ12‐prostaglandin J3, a compound with known anti‐leukemic properties.
The first organocatalytic general, efficient and highly enantioselective α‐hydroxyamination reactions of β‐ketoamides with nitrosobenzene are described using a thiourea/tertiary amine bifunctional catalyst. Significantly, the products were obtained in high enantiomeric purity using a low catalyst loading, and in the context of sustainable development, the full reaction mixture, including solvent, catalyst and excess substrate, can be recycled without significant erosion in the efficiency and enantioselectivity of the reaction. The described catalytic transformations secure a practical synthetic access to stereodefined and conformationally constrained α‐amino acid derivatives exhibiting a quaternary chiral center at the α position.
Fast, efficient and green! Highly regioselective and efficient catalyst- and halogen-free Friedel-Crafts α-ketoacylation reactions leading to heterocycles functionalized with a very versatile 1,3-diketone moiety are described. The reactions rely on microwave-assisted domino Wolff rearrangement/Friedel-Crafts sequences from 2-diazo-1,3-diketones via transient, highly reactive α-keto ketene intermediates.
A practical protocol for the large-scale preparation of 2-diazo-1,3-dicarbonyl compounds is described by diazo-transfer reactions with tosyl azide followed by efficient chromatographic purifications on silica gel and/or alumina.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.