Total synthesis of gambieric acid A, a potent antifungal polycyclic ether metabolite, has been accomplished for the first time, which firmly established the complete stereostructure of this natural product.

A convergent synthesis of the C1−C16 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved via a 2-fold application of palladium-catalyzed organostannane−thioester coupling.

A stereocontrolled synthesis of the GHIJ-ring fragment having a side chain of gambieric acids, which are potent antifungal polycyclic ether natural products, has been achieved. The synthesis features convergent assembly of the tetracyclic polyether skeleton by using aldol coupling and stereoselective construction of the J-ring side chain by a cerium chloride-promoted Julia–Kocienski reaction.

Stereoselective convergent synthesis of the C15−C36 segment of goniodomin A, an actin-targeting marine polyether macrolide natural product, has been achieved. The present synthesis features palladium(0)-catalyzed, copper(I)-mediated Liebeskind−Srogl cross-coupling as the fragment assembly process.

A highly stereocontrolled, convergent synthesis of the A/B-ring fragment of gambieric acids (GAs) has been developed on the basis of (i) a Suzuki−Miyaura coupling of the C1−C6 alkylborate and the C7−C17 vinyl iodide and (ii) a diastereoselective haloetherification for the construction of the A-ring tetrahydrofuran as key steps. Inspection of the 1H and 13C NMR chemical shifts of the synthesized A/B-ring model compounds led to a stereochemical reassignment of the absolute configuration of the polycyclic ether core of GAs. This structure revision was further supported by a synthesis of the A/BC-ring model compound of gambieric acid B and a comparison of its 1H and 13C NMR data with those of the natural product.

Covering: up to 2007

An intramolecular Heck/Diels–Alder cycloaddition cascade starting from acyclic α-phosphono enecarbamates has been developed to prepare nitrogen heterocycles viaindole-2,3-quinodimethanesand 2-(N-alkoxycarbonylamino)-1,3-dienes.

An efficient method for the synthesis of enol ethers and enecarbamates has been developed based on catalytic hydrosilane reduction of α-phosphonoxy enol ethers and α-phosphonoxy enecarbamates. This method has been applied to the total syntheses of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.

A strategy for the synthesis of 2,3-disubstituted indole derivatives based on an intramolecular carbopalladation–anion capture cascade has been developed, wherein construction of the pyrrole ring and functionalisation of the indole C2 and C3 positions were achieved by extensive use of palladium(0)-catalysed coupling reactions.

To enable studies to elucidate the detailed biological function of dysiherbaine and neodysiherbaine A, potent and subunit-selective agonists for ionotropic glutamate receptors, the derivative with a hydroxymethyl substituent at the C10 position has been developed. Preliminary biological evaluation of the analogue showed that a C10 hydroxymethyl substituent produced significant alterations in binding affinities for the ionotropic glutamate receptor subtypes.The total synthesis and biological evaluation of neodysiherbaine A analogue are described.

Dysiherbaine (DH) and neodysiherbaine A (NDH) selectively bind and activate two kainate-type ionotropic glutamate receptors, GluK1 and GluK2. The ligand-binding domains of human GluK1 and GluK2 were crystallized as bound forms with a series of DH analogues including DH, NDH, 8-deoxy-NDH, 9-deoxy-NDH and 8,9-dideoxy-NDH (MSVIII-19), isolated from natural sources or prepared by total synthesis. Since the DH analogues exhibit a wide range of binding affinities and agonist efficacies, it follows that the detailed analysis of crystal structure would provide us with a significant opportunity to elucidate structural factors responsible for selective binding and some aspects of gating efficacy. We found that differences in three amino acids (Thr503, Ser706 and Ser726 in GluK1 and Ala487, Asn690 and Thr710 in GluK2) in the ligand-binding pocket generate differences in the binding modes of NDH to GluK1 and GluK2. Furthermore, deletion of the C9 hydroxy group in NDH alters the ligand conformation such that it is no longer suited for binding to the GluK1 ligand-binding pocket. In GluK2, NDH pushes and rotates the side chain of Asn690 (substituted for Ser706 in GluK1) and disrupts an interdomain hydrogen bond with Glu409. The present data support the idea that receptor selectivities of DH analogues resulted from the differences in the binding modes of the ligands in GluK1/GluK2 and the steric repulsion of Asn690 in GluK2. All ligands, regardless of agonist efficacy, induced full domain closure. Consequently, ligand efficacy and domain closure did not directly coincide with DH analogues and the kainate receptors.Download high-res image (165KB)Download full-size imageHighlights► Determined the structures of GluK1 in complex with a series of DH analogues. ► All ligands induced full domain closure of the binding core. ► Determined the structure of the GluK2–NDH complex. ► NDHs bound to the two receptors in a slightly different manner. ► Binding mode differences were attributed to differences in just three residues.

A strategy for the synthesis of 2,3-disubstituted indole derivatives based on an intramolecular carbopalladation–anion capture cascade has been developed, wherein construction of the pyrrole ring and functionalisation of the indole C2 and C3 positions were achieved by extensive use of palladium(0)-catalysed coupling reactions.

An efficient method for the synthesis of enol ethers and enecarbamates has been developed based on catalytic hydrosilane reduction of α-phosphonoxy enol ethers and α-phosphonoxy enecarbamates. This method has been applied to the total syntheses of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.

An intramolecular Heck/Diels–Alder cycloaddition cascade starting from acyclic α-phosphono enecarbamates has been developed to prepare nitrogen heterocycles viaindole-2,3-quinodimethanesand 2-(N-alkoxycarbonylamino)-1,3-dienes.