Cyclopropenium Ions in Catalysis.

Cyclopropenium ions are the smallest class of aromatic compounds, satisfying Hückel's rules of aromaticity with two π electrons within a three-membered ring. First prepared by Breslow in 1957, cyclopropenium ions have been found to possess extraordinary stability despite being both cationic and highly strained. In the 65 years since their first preparation, cyclopropenium ions have been the subject of innumerable studies concerning their synthesis, physical properties, and reactivity.

The Role of Ligand Steric Bulk in New Monovalent Aluminum Compounds.

The tetrameric Al(I) cyclopentadienyl compound AlCp* (Cp* = CMe) is a prototypical low-valence Al compound, with delocalized bonding between four Al(I) atoms and η ligands bound to the cluster exterior. The synthesis of new [AlR] (R = CMePr, CMeiPr) tetramers is presented. Though these systems failed to crystallize, comparison of variable-temperature Al NMR data with density functional theory (DFT) calculations indicate that these are AlR tetramers analogous to AlCp* but with increased ligand steric bulk.

A vision for vaccines built from fully synthetic tumor-associated antigens: from the laboratory to the clinic.

Cancer cells may be distinguished from normal cells by cell surface displays of aberrant levels and types of carbohydrate domains. Accordingly, these tumor-associated carbohydrate antigens (TACAs) represent promising target structures for the design of anticancer vaccines. Over the past 20 years, our laboratory has sought to use the tools of chemical synthesis to develop TACA-based anticancer vaccine candidates.

Pattern recognition analysis in complex molecule synthesis and the preparation of iso-Diels-Alder motifs.

The identification of synthesizable substructural domains within more complex structural targets is of significant value in designing a workable plan of synthesis. We term this process "pattern recognition analysis" (PRA). In this paper we continued to build on the theme of PRA as a potential resource in retrosynthetic blueprints to reach highly challenging targets.

The winding pathway to erythropoietin along the chemistry-biology frontier: a success at last.

The total synthesis of a homogeneous erythropoietin (EPO), possessing the native amino acid sequence and chitobiose glycans at each of the three wild-type sites of N glycosylation, has been accomplished in our laboratory. We provide herein an account of our decade-long research effort en route to this formidable target compound. The optimization of the synergy of the two bedrock sciences we now call biology and chemistry was central to the success of the synthesis of EPO.

A fascinating journey into history: exploration of the world of isonitriles en route to complex amides.

We describe herein our recent explorations in the field of isonitrile chemistry. An array of broadly useful coupling methodologies has been developed for the formation of peptidyl and glycopeptidyl amide bonds. We further describe the application of these methods to the syntheses of complex systems, including the cyclic peptide cyclosporine A, constrained peptide systems, and heterocycles.

Multifaceted cytoprotection by synthetic polyacetylenes inspired by the ginseng-derived natural product, panaxytriol.

We describe herein the discovery of a series of panaxytriol (PXT)-derived polyacetylene small molecules with promising cytoprotective activity. In mouse xenograft models, we have demonstrated the capacity of our synthetic analogs to mitigate a range of cancer therapeutic agent-induced toxicities, including body weight loss, lethality, neurotoxicity, and hematotoxicity. Our PXT analogs have also been found to reduce radiation-induced body weight loss and lethality in mouse models.

On the reach of chemical synthesis: creation of a mini-pipeline from an academic laboratory.

In this retrospective, we recall some select cases of synergy between very challenging chemical synthesis and the identification of promising new candidates for pharmaceutics development. The progression from targets, often referred to as small molecules, to those of a size commonly associated with biologics (including glycoproteins) is also charted.

Toward fully synthetic, homogeneous glycoproteins: advances in chemical ligation.

Traditionally, in the pharma sciences, there has been an unstated but operative bifurcation into small molecules and biologics. Small molecules were seen to be, at the discovery level, in the province of chemistry, based on targets provided through biology. By contrast, "biologics" were seen to arise solely from the province of biology exploiting its accessible replicative mechanisms.

Rhodium catalyzed enantioselective cyclization of substituted imidazoles via C-H bond activation.

The enantioselective intramolecular alkylation of substituted imidazoles with enantiomeric excesses up to 98% has been accomplished by rhodium catalyzed C-H bond functionalization with (S,S',R,R')TangPhos as the chiral ligand.

Therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones.

The epothilones represent a promising class of natural product-based antitumor drug candidates. Although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. We have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself.

Applications of total synthesis toward the discovery of clinically useful anticancer agents.

This tutorial review provides a historical sampling of synthetic efforts undertaken in our laboratory, which have led to the total syntheses of a range of small molecule natural products of potential interest in oncology. It has become evident that natural products, and structures clearly derivable from natural products, have a remarkable record in the treatment of cancer at the clinical level. It is likely that, with the growing power of chemical synthesis, small molecule natural products will play a continuing role in providing lead anticancer compounds.

Pattern recognition in retrosynthetic analysis: snapshots in total synthesis.

In this Perspective, the value of small molecule natural products (SMNPs) in the discovery of active biological agents is discussed. The usefulness of the natural products-based method of potential pharma discovery is much augmented by the capacities of chemical synthesis. The great advances in synthetic methodology allow for major editing of the natural product in the hopes of optimizing potency and therapeutic index.

Small molecule natural products in the discovery of therapeutic agents: the synthesis connection.

Natural products have been a rich source of agents of value in medicine. They have also inspired, at various levels, the fashioning of nonnatural agents of pharmaceutical import. Hitherto, these nonnatural derivatives have been primarily synthesized by manipulating the natural product.

Applications of total synthesis to problems in neurodegeneration: Fascinating chemistry along the way.

The possibility for the application of organic synthesis to the discovery of new agents in combating neurodegenerative disorders is described. Our focus has been on agents derived from natural-product leads and natural products themselves prepared through total synthesis. Herein, we describe some of the chemistry as well as interesting observations made along the way.

Enantioselective synthesis of a PKC inhibitor via catalytic C-H bond activation.

[reaction: see text] The syntheses of two biologically active molecules possessing dihydropyrroloindole cores (1 and 2) were completed using rhodium-catalyzed imine-directed C-H bond functionalization, with the second of these molecules containing a stereocenter that can be set with 90% ee during cyclization using chiral nonracemic phosphoramidite ligands. Catalytic decarbonylation and direct indole/maleimide coupling provide efficient access to 2.

Preparation and evaluation of unimolecular pentavalent and hexavalent antigenic constructs targeting prostate and breast cancer: a synthetic route to anticancer vaccine candidates.

Several novel, fully synthetic, carbohydrate-based antitumor vaccines have been assembled. Each construct consists of multiple cancer-related antigens displayed on a single polypeptide backbone. Recent advances in synthetic methodology have allowed for the incorporation of a complex oligosaccharide terminating in a sialic acid residue (i.

Synthetic carbohydrate-based antitumor vaccines: challenges and opportunities.

The development of a clinically effective, carbohydrate-based antitumor vaccine is a longstanding ambition in the prevention and treatment of cancer. This review seeks to provide a discussion of some of the unique challenges facing this particular field of immunology. The authors present a historic account of their ongoing research program devoted to the development of fully synthetic, carbohydrate-based anticancer vaccines of clinical value.

Enantioselective organocatalytic intramolecular Diels-Alder reactions. The asymmetric synthesis of solanapyrone D.

The first direct enantioselective organocatalytic intramolecular Diels-Alder reaction has been accomplished. The use of iminium catalysis has provided a new catalytic strategy for the enantioselective [4 + 2] cycloisomerization of a wide variety of tethered diene-enal systems. The use of imidazolidinones 1 and 2 as the asymmetric catalysts has been found to mediate the enantioselective construction of [4.