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. However, prior to our work, the reactivity of these unique carbocations had not been exploited for reaction promotion or catalysis.Over the past 13 years, we have been exploring aromatic ions as unique and versatile building blocks for the development of catalysts for organic chemistry. A major portion of this work has been focused on leveraging the remarkable properties of the smallest of the aromatic ions─cyclopropeniums─as a design element in the invention of highly reactive catalysts. Indeed, because of its unique profile of hydrolytic stability, compact geometry, and relatively easy oxidizability, the cyclopropenium ring has proven to be a highly advantageous construction module for catalyst invention.In this Account, we describe some of our work using cyclopropenium ions as a key element in the design of novel catalysts. First, we discuss our early work aimed at promoting dehydrative reactions, starting with Appel-type chlorodehydrations of alcohols and carboxylic acids, cyclic ether formations, and Beckmann rearrangements and culminating in the realization of catalytic chlorodehydrations of alcohols and a catalytic Mitsunobu-type reaction. Next, we describe the development of cyclopropenimines as strong, neutral organic Brønsted bases and, in particular, the use of chiral cyclopropenimines for enantioselective Brønsted catalysis. We also describe the development of higher-order cyclopropenimine superbases. The use of tris(amino)cyclopropenium (TAC) ions as a novel class of phase-transfer catalysts is discussed for the reaction of epoxides with carbon dioxide. Next, we describe the formation of a cyclopropenone radical cation that has a portion of its spin density on the oxygen atom, leading to some peculiar metal ligand behavior. Finally, we discuss recent work that employs TAC electrophotocatalysts for oxidation reactions. The key intermediate for this chemistry is a TAC radical dication, which as an open-shell photocatalyst has remarkably strong excited-state oxidizing power. We describe the application of this strategy to transformations ranging from the oxidative functionalization of unactivated arenes to the regioselective derivatization of ethers, C-H aminations, vicinal C-H diaminations, and finally aryl olefin dioxygenations. Collectively, these catalytic platforms demonstrate the utility of charged aromatic rings, and cyclopropenium ions in particular, to enable unique advances in catalysis.

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

The tetrameric Al(I) cyclopentadienyl compound Al4Cp*4 (Cp* = C5Me5) is a prototypical low-valence Al compound, with delocalized bonding between four Al(I) atoms and η5 ligands bound to the cluster exterior. The synthesis of new [AlR]4 (R = C5Me4Pr, C5Me4iPr) tetramers is presented. Though these systems failed to crystallize, comparison of variable-temperature 27Al NMR data with density functional theory (DFT) calculations indicate that these are Al4R4 tetramers analogous to Al4Cp*4 but with increased ligand steric bulk. NMR, DFT, and Atoms in Molecules analyses show that these clusters are enthalpically more stable as tetramers than the Cp* variant, due in part to noncovalent interactions across the bulkier ligand groups. Thermochemistry calculations for the low-valence metal interactions were found to be extremely sensitive to the DFT methodology used; the M06-2X functional with a cc-pVTZ basis set is shown to provide very accurate values for the enthalpy of tetramerization and 27Al NMR shifts. This computational method is then used to predict geometrical structures, noncovalent ligand interactions, and monomer/tetramer equilibrium in solution for a series of Al(I) cyclopentadienyl compounds of varying 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. We provide herein a personal accounting of our laboratory's progress toward the long-standing goal of developing clinically viable fully synthetic carbohydrate-based anticancer vaccines.

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 paper operates at two levels. First, there is provided a clear sense of definitions of categories by which patterns are related to hypothetical reaction types. Although the required reaction type may for the moment not exist, we believe that this method of analysis is likely to promote innovation that identifies unmet needs and opportunities to advance the cause of complex target synthesis. In addition, we describe reductions to practice in expanding the menu of achievable patterns. It is likely that the future value of PRA will be associated with its utility in leading the way to new and exploitable chemical innovation.

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. Moreover, several PXT analogs appear to exhibit moderate in vivo antiinflammatory activity as well as in vitro immunoenhancing capabilities. These compounds appear to derive their activity through induction of cancer preventive phase 2 enzymes. The studies described herein suggest that coadministration of a PXT-derived agent with cancer chemotherapeutics or radiation therapy may serve to mitigate a range of therapy-associated toxicities.

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. Our laboratory has been dedicated to the proposition that explosive advances in chemical synthesis have been such as to render so called "biologics" as being accessible to chemical synthesis. In this article, we focus particularly on the area of glycopeptides. Chemical synthesis, in principle, offers an advantage, in that it can lead to homogeneous glycopeptides characterized by a single glycoform of the glycosidic domain mounted at a particular amino acid in the polypeptide domain. In support of this defining goal, a variety of new methods have been developed. The key problem addressed is that of ligation. In this article, we review how insights available from mechanistic organic chemistry have been used to create an imposing framework for the synthesis of structures which would, in an earlier day, have been seen to be strictly in the realm of chemically inaccessible "biologics".

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. We report herein the results of biological investigations directed at two epothilone congeners: iso-fludelone and iso-dehydelone. Iso-fludelone, in particular, exhibits a number of properties that render it an excellent candidate for preclinical development, including biological stability, excellent solubility in water, and remarkable potency relative to other epothilones. In nude mouse xenograft settings, iso-fludelone was able to achieve therapeutic cures against a number of human cancer cell lines, including mammarian-MX-1, ovarian-SK-OV-3, and the fast-growing, refractory, subcutaneous neuroblastoma-SK-NAS. Strong therapeutic effect was observed against drug-resistant lung-A549/taxol and mammary-MCF-7/Adr xenografts. In addition, iso-fludelone was shown to exhibit a significant therapeutic effect against an intracranially implanted SK-NAS tumor.

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. As a consequence of the enormous increase in the power of multistep chemical synthesis, one can now approach structures of previously impractical complexity. In constructing a plan for a multistep synthesis, two complementary thought styles are often encountered. One is the traditional and extremely powerful concept of prioritized strategic bond disconnections. The other, which we term "pattern recognition," involves the identification of moieties within the target, which are associated with reliable chemistry, and can serve to facilitate progress to the target. Recognition of such targets may require substantial recasting of the target structure to connect it to well-established types of transformations. Some of our older ventures, where ideas about pattern recognition were first being fashioned and used productively, are revisited. In addition, we provide snapshots of recently achieved total syntheses of SMNPs of novel biological potential. These vignettes serve to harmonize insights occasioned by pattern recognition, in concert with transformations enabled by the enormous growth in the power of synthesis.

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. As a consequence of major innovations in the subscience of synthetic methodology, the capacity of synthesis to deal with molecules of considerable complexity has increased dramatically. In this paper, we show by example some total syntheses which draw from strategy-enabling advances in methodology. Moreover, we show how these capabilities can be used to discover and develop new agents of potential pharmaceutical value without recourse to the natural product itself.

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.e., GM2) as one of the carbohydrate antigens. Details of the vaccine synthesis as well as the results of preliminary immunological investigations are described herein.

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. As will be seen, remarkable advances in carbohydrate and glycopeptide assembly techniques have allowed for the preparation of synthetic constructs of progressively increasing structural complexity. The authors describe the evolution of their synthetic carbohydrate program from first-generation constructs, which were monovalent in nature, to highly complex unimolecular multivalent vaccines, in which multiple carbohydrate antigens are displayed in the context of a single polypeptide backbone. It is the hope that each generation of vaccines represents a move closer to achieving the ultimate objective of developing broadly useful, robust anticancer vaccines.

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 [4.4.0] and [4.3.0] ring systems. Application of this methodology to the highly efficient asymmetric synthesis of the marine metabolite solanpyrone D has also been accomplished. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic transformation. Importantly, this technology has been utilized to execute the first enantioselective, catalytic Type II IMDA reaction.