Convenient Synthesis of 6,6-Bicyclic Malonamides:  A New Class of Conformationally Preorganized Ligands for f-Block Ion Binding

Abstract

A general synthetic approach was developed for the preparation of a series of 6,6-bicyclic malonamides, a class of ligands that provide a preorganized binding site for f-block ions (particularly trivalent lanthanides). The approach described is convenient to introduce a variety of functional groups at the amide nitrogens to tune the properties of the ligand without altering the preorganized binding. Each of the ten derivatives (that represent a range of functionality, including R = alkyl, hydroxy, phenyl, ester, perfluorocarbon) reported here derives from a single, readily prepared dialdehyde intermediate. This intermediate is converted to the final products via reductive amination with an appropriately functionalized benzylamine, followed by hydrogenolysis and lactam formation. Because derivatization occurs late in the synthesis, the approach is general, requiring only modification of the purification procedures for each new derivative. To aid in the purification of the bicyclic malonamides, we report a novel complexation-based purification method that takes advantage of the high affinity of the ligand for f-block metals.

Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau

“…Anomaly in the dialdehyde series of analogs was observed for the saturated dialdehyde 23, lacking the olefin. However, during the course of experiments, we discovered that 23, like many saturated 1, 5-dialdehydes (Parks et al 2006), decomposes under the assay conditions after 6 h. We next examined a series of monoaldehyde analogs, 20, 24, and 25. When either of the aldehyde carbonyls was reduced, a significant loss in activity was observed.…”

Lanthanum(III)-Catalyzed Three-Component Reaction of Coumarin-3-carboxylates for the Synthesis of Indolylmalonamides and Analysis of Their Photophysical Properties

“…Here we describe the development of a Sc­(III)-catalyzed addition of nucleophiles to coumarin-3-carboxylates where we recognized the opportunity to design a La­(III)-catalyzed three-component reaction (3CR) involving indoles, amines, and coumarin-3-carboxylates for the synthesis of indolylmalonamides (Figure A). Many traditional MCRs utilize imine or isocyanide substrates; however, MCRs incorporating indoles are desirable because these important heterocycles are found in many natural products and medicinally relevant compounds. − Furthermore, the malonamide motif is useful for various applications in medicinal and industrial chemistry (Figure B), including ligands for copper and lanthanides, − actinide chelators for nuclear waste sequestration, − and medicinal compounds such as opioid κ agonists and 1,5-benzodiazepinedione derivatives. , In addition to these applications, our results presented here also demonstrate the fluorescence properties of indolylmalonamides.…”

Application of Stereoselective Ether Transfer to the Synthesis of Isotactic Polyethers

“…Alternatively, 5 can also be efficiently made by a simple sequence through asymmetric resolution . Commercially available hepta-1,6-dien-4-ol ( 10 ) was desymmetrized using iodine-induced carbonate cyclization , to produce iodocarbonate rac -11 with excellent diastereoselectivity (dr 15:1 by 1 H NMR). Solvolysis of the carbonate led to the corresponding epoxide.…”