Stereoselective Synthesis of the C1-C9 and C11-C25 Fragments of Amphidinolides C, C2, C3, and F.

An efficient synthesis of the C1-C9 and the C11-C25 fragments of amphidinolides C, C2, C3, and F from a common intermediate is reported. The construction of the C1-C9 fragment involves an intramolecular hetero-Michael cyclization to form the 3,5-disubstituted trans-tetrahydrofuran moiety. The approach to prepare the C11-C25 fragment utilizes a highly stereoselective aerobic cobalt-catalyzed alkenol cyclization and a chelated Mukaiyama aldol reaction to form the C13-C14 bond and to concomitantly install the C13 hydroxyl group.

Ligand Design for Isomer-Selective Oxorhenium(V) Complex Synthesis.

Recently, N,N-trans Re(O)(LN-O)2X (LN-O = monoanionic N-O chelates; X = Cl or Br prior to being replaced by solvents or alkoxides) complexes have been found to be superior to the corresponding N,N-cis isomers in the catalytic reduction of perchlorate via oxygen atom transfer. However, reported methods for Re(O)(LN-O)2X synthesis often yield only the N,N-cis complex or a mixture of trans and cis isomers. This study reports a geometry-inspired ligand design rationale that selectively yields N,N-trans Re(O)(LN-O)2Cl complexes. Analysis of the crystal structures revealed that the dihedral angles (DAs) between the two LN-O ligands of N,N-cis Re(O)(LN-O)2Cl complexes are less than 90°, whereas the DAs in most N,N-trans complexes are greater than 90°. Variably sized alkyl groups (-Me, -CH2Ph, and -CH2Cy) were then introduced to the 2-(2'-hydroxyphenyl)-2-oxazoline (Hhoz) ligand to increase steric hindrance in the N,N-cis structure, and it was found that substituents as small as -Me completely eliminate the formation of N,N-cis isomers. The generality of the relationship between N,N-trans/cis isomerism and DAs is further established from a literature survey of 56 crystal structures of Re(O)(LN-O)2X, Re(O)(LO-N-N-O)X, and Tc(O)(LN-O)2X congeners. Density functional theory calculations support the general strategy of introducing ligand steric hindrance to favor synthesis of N,N-trans Re(O)(LN-O)2X and Tc(O)(LN-O)2X complexes. This study demonstrates the promise of applying rational ligand design for isomeric control of metal complex structures, providing a path forward for innovations in a number of catalytic, environmental, and biomedical applications.

A New Bioinspired Perchlorate Reduction Catalyst with Significantly Enhanced Stability via Rational Tuning of Rhenium Coordination Chemistry and Heterogeneous Reaction Pathway.

Rapid reduction of aqueous ClO4(-) to Cl(-) by H2 has been realized by a heterogeneous Re(hoz)2-Pd/C catalyst integrating Re(O)(hoz)2Cl complex (hoz = oxazolinyl-phenolato bidentate ligand) and Pd nanoparticles on carbon support, but ClOx(-) intermediates formed during reactions with concentrated ClO4(-) promote irreversible Re complex decomposition and catalyst deactivation. The original catalyst design mimics the microbial ClO4(-) reductase, which integrates Mo(MGD)2 complex (MGD = molybdopterin guanine dinucleotide) for oxygen atom transfer (OAT). Perchlorate-reducing microorganisms employ a separate enzyme, chlorite dismutase, to prevent accumulation of the destructive ClO2(-) intermediate. The structural intricacy of MGD ligand and the two-enzyme mechanism for microbial ClO4(-) reduction inspired us to improve catalyst stability by rationally tuning Re ligand structure and adding a ClOx(-) scavenger. Two new Re complexes, Re(O)(htz)2Cl and Re(O)(hoz)(htz)Cl (htz = thiazolinyl-phenolato bidentate ligand), significantly mitigate Re complex decomposition by slightly lowering the OAT activity when immobilized in Pd/C. Further stability enhancement is then obtained by switching the nanoparticles from Pd to Rh, which exhibits high reactivity with ClOx(-) intermediates and thus prevents their deactivating reaction with the Re complex. Compared to Re(hoz)2-Pd/C, the new Re(hoz)(htz)-Rh/C catalyst exhibits similar ClO4(-) reduction activity but superior stability, evidenced by a decrease of Re leaching from 37% to 0.25% and stability of surface Re speciation following the treatment of a concentrated "challenge" solution containing 1000 ppm of ClO4(-). This work demonstrates the pivotal roles of coordination chemistry control and tuning of individual catalyst components for achieving both high activity and stability in environmental catalyst applications.

Configuration Control in the Synthesis of Homo- and Heteroleptic Bis(oxazolinylphenolato/thiazolinylphenolato) Chelate Ligand Complexes of Oxorhenium(V): Isomer Effect on Ancillary Ligand Exchange Dynamics and Implications for Perchlorate Reduction Catalysis.

This study develops synthetic strategies for N,N-trans and N,N-cis Re(O)(LO-N)2Cl complexes and investigates the effects of the coordination spheres and ligand structures on ancillary ligand exchange dynamics and catalytic perchlorate reduction activities of the corresponding [Re(O)(LO-N)2](+) cations. The 2-(2'-hydroxyphenyl)-2-oxazoline (Hhoz) and 2-(2'-hydroxyphenyl)-2-thiazoline (Hhtz) ligands are used to prepare homoleptic N,N-trans and N,N-cis isomers of both Re(O)(hoz)2Cl and Re(O)(htz)2Cl and one heteroleptic N,N-trans Re(O)(hoz)(htz)Cl. Selection of hoz/htz ligands determines the preferred isomeric coordination sphere, and the use of substituted pyridine bases with varying degrees of steric hindrance during complex synthesis controls the rate of isomer interconversion. The five corresponding [Re(O)(LO-N)2](+) cations exhibit a wide range of solvent exchange rates (1.4 to 24,000 s(-1) at 25 °C) and different LO-N movement patterns, as influenced by the coordination sphere of Re (trans/cis), the noncoordinating heteroatom on LO-N ligands (O/S), and the combination of the two LO-N ligands (homoleptic/heteroleptic). Ligand exchange dynamics also correlate with the activity of catalytic reduction of aqueous ClO4(-) by H2 when the Re(O)(LO-N)2Cl complexes are immobilized onto Pd/C. Findings from this study provide novel synthetic strategies and mechanistic insights for innovations in catalytic, environmental, and biomedical research.

Syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C.

Divergent syntheses of the C1-C14 and C15-C25 fragments of amphidinolide C have been achieved. The synthesis of the C15-C25 fragment featured cobalt-catalyzed modified Mukaiyama aerobic alkenol cyclization and sulfur-directed regiocontrolled Wacker oxidation of an internal alkene. The C1-C14 fragment was established by alkenyllithium addition to an aldehyde followed by a challenging olefination of a highly inert C9 ketone.

Total synthesis of phorboxazole A via de novo oxazole formation: convergent total synthesis.

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product's (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product's oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.

Total synthesis of phorboxazole A via de novo oxazole formation: strategy and component assembly.

The phorboxazole natural products are among the most potent inhibitors of cancer cell division, but they are essentially unavailable from natural sources at present. Laboratory syntheses based upon tri-component fragment coupling strategies have been developed that provide phorboxazole A and analogues in a reliable manner and with unprecedented efficiency. This has been orchestrated to occur via the sequential or simultaneous formation of both of the natural product's oxazole moieties from two serine-derived amides, involving oxidation-cyclodehydrations. The optimized preparation of three pre-assembled components, representing carbons 3-17, 18-30, and 31-46, has been developed. This article details the design and syntheses of these three essential building blocks. The convergent coupling approach is designed to facilitate the incorporation of structural changes within each component to generate unnatural analogues, targeting those with enhanced therapeutic potential and efficacy.

Design, synthesis, and antitumor activity of bile acid-polyamine-nucleoside conjugates.

A series of bile acid-polyamine amides conjugated with 3'-azido-3'-deoxythymidine (AZT) as potential antitumor prodrugs in the form of phosphoramidates were synthesized in good yields and their antitumor activities were assayed against two human cancer cells in vitro: cervix cancer HeLa cells and renal cancer 7860 cells. The improved antitumor activity probably derived from the enhanced delivery efficiency of AZT due to bile acid-polyamine conjugates.