An Enantioselective Decarboxylative Glycolate Aldol Reaction.

Herein, we report the application of a benzyloxy-functionalized malonic acid half thioester as an activated ester equivalent in a highly enantioselective decarboxylative glycolate aldol reaction. This robust method operates at ambient temperature, tolerates air and moisture, and generates CO as the only byproduct. The synthetic applicability of the method is demonstrated by the large-scale enantiodivergent synthesis of α-benzyloxy-β-hydroxybutyric acid thioester and its subsequent conversion to diverse polyoxygenated building blocks, deoxy-sugars, and (-)-angiopterlactone B.

A Dual Role for the -Perfluorobutanesulfinamide Auxiliary in an Asymmetric Decarboxylative Mannich Reaction.

Herein, we demonstrate that the enhanced electrophilicity of -perfluorobutanesulfinamide auxiliary-derived imines enables a highly selective decarboxylative Mannich reaction under mild conditions. The molecular sieves-mediated transformation tolerates a broad substrate scope and produces chiral β-amino thioesters in high yield. Additionally, we demonstrate that the -perfluoroalkyl sulfinyl group can function as a phase tag for fluorous purification, thus enabling the rapid isolation of the chiral amine products by solid-phase extraction.

-to- Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis.

The observation of thioester-mediated acyl transfer processes in nature has inspired the development of novel protein synthesis and functionalization methodologies. The chemoselective transfer of an acyl group from -to- is the basis of several powerful ligation strategies. In this work, we sought to apply the reverse process, the transfer of an acyl group from -to-, as a method to convert stable chiral amides into more reactive thioesters.

Structure Elucidation of Secondary Metabolites: Current Frontiers and Lingering Pitfalls.

Analytical methods allow for the structure determination of submilligram quantities of complex secondary metabolites. This has been driven in large part by advances in NMR spectroscopic capabilities, including access to high-field magnets equipped with cryogenic probes. Experimental NMR spectroscopy may now be complemented by remarkably accurate carbon-13 NMR calculations using state-of-the-art DFT software packages.

Sulfonyl Chlorides as Thiol Surrogates for Carbon-Sulfur Bond Formation: One-Pot Synthesis of Thioethers and Thioesters.

A method to synthesize thioethers and thioesters directly from readily available sulfonyl chlorides is reported. We demonstrate that a transient intermediate formed during phosphine-mediated deoxygenation of sulfonyl chlorides can be trapped by activated alcohols or carboxylic acids to effect carbon-sulfur bond formation. The method is operationally simple and tolerates a broad range of functional groups.

Structure elucidation of colibactin and its DNA cross-links.

Colibactin is a complex secondary metabolite produced by some genotoxic gut strains. The presence of colibactin-producing bacteria correlates with the frequency and severity of colorectal cancer in humans. However, because colibactin has not been isolated or structurally characterized, studying the physiological effects of colibactin-producing bacteria in the human gut has been difficult.

Model Colibactins Exhibit Human Cell Genotoxicity in the Absence of Host Bacteria.

Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) in human cell lines and are thought to promote the formation of colorectal tumors. Although key structural and functional features of colibactins have been elucidated, the full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model colibactins induce DSBs in human cell cultures and do not require delivery by host bacteria.

Publisher Correction: A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.

The original PDF version of this Article listed the authors as "Marcus J.G.W.

A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.

The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH).

ClbS Is a Cyclopropane Hydrolase That Confers Colibactin Resistance.

Certain commensal Escherichia coli contain the clb biosynthetic gene cluster that codes for small molecule prodrugs known as precolibactins. Precolibactins are converted to colibactins by N-deacylation; the latter are postulated to be genotoxic and to contribute to colorectal cancer formation. Though advances toward elucidating (pre)colibactin biosynthesis have been made, the functions and mechanisms of several clb gene products remain poorly understood.

Molecular Basis of Gut Microbiome-Associated Colorectal Cancer: A Synthetic Perspective.

A significant challenge toward studies of the human microbiota involves establishing causal links between bacterial metabolites and human health and disease states. Certain strains of commensal Escherichia coli harbor the 54-kb clb gene cluster which codes for small molecules named precolibactins and colibactins. Several studies suggest colibactins are genotoxins and support a role for clb metabolites in colorectal cancer formation.

Structure and Functional Analysis of ClbQ, an Unusual Intermediate-Releasing Thioesterase from the Colibactin Biosynthetic Pathway.

Colibactin is a genotoxic hybrid nonribosomal peptide/polyketide secondary metabolite produced by various pathogenic and probiotic bacteria residing in the human gut. The presence of colibactin metabolites has been correlated to colorectal cancer formation in several studies. The specific function of many gene products in the colibactin gene cluster can be predicted.

Domain-Targeted Metabolomics Delineates the Heterocycle Assembly Steps of Colibactin Biosynthesis.

Modular polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs) comprise giant multidomain enzymes responsible for the "assembly line" biosynthesis of many genetically encoded small molecules. Site-directed mutagenesis, protein biochemical, and structural studies have focused on elucidating the catalytic mechanisms of individual multidomain proteins and protein domains within these megasynthases. However, probing their functions at the cellular level typically has invoked the complete deletion (or overexpression) of multidomain-encoding genes or combinations of genes and comparing those mutants with a control pathway.

A Mechanistic Model for Colibactin-Induced Genotoxicity.

Precolibactins and colibactins represent a family of natural products that are encoded by the clb gene cluster and are produced by certain commensal, extraintestinal, and probiotic E. coli. clb E.

Stereochemical Assignment of the Protein-Protein Interaction Inhibitor JBIR-22 by Total Synthesis.

Recent reports have highlighted the biological activity associated with a subfamily of the tetramic acid class of natural products. Despite the fact that members of this subfamily act as protein-protein interaction inhibitors that are of relevance to proteasome assembly, no synthetic work has been reported. This may be due to the fact that this subfamily contains an unnatural 4,4-disubstitued glutamic acid, the synthesis of which provides a key challenge.

Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A.

The colibactins are hybrid polyketide-nonribosomal peptide natural products produced by certain strains of commensal and extraintestinal pathogenic Escherichia coli. The metabolites are encoded by the clb gene cluster as prodrugs termed precolibactins. clb(+) E.

Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin.

Developing approaches to discover protein-protein interactions (PPIs) remains a fundamental challenge. A chemical biology platform is applied here to identify novel PPIs for the AAA+ superfamily oncoprotein reptin. An screen coupled with chemical optimization provided Liddean, a nucleotide-mimetic which modulates reptin's oligomerization status, protein-binding activity and global conformation.

Stereochemical assignment of the protein-protein interaction inhibitor JBIR-22 by total synthesis.

Recent reports have highlighted the biological activity associated with a subfamily of the tetramic acid class of natural products. Despite the fact that members of this subfamily act as protein-protein interaction inhibitors that are of relevance to proteasome assembly, no synthetic work has been reported. This may be due to the fact that this subfamily contains an unnatural 4,4-disubstitued glutamic acid, the synthesis of which provides a key challenge.

Total synthesis and biological evaluation of the tetramic acid based natural product harzianic acid and its stereoisomers.

The bioactive natural product harzianic acid was prepared for the first time in just six steps (longest linear sequence) with an overall yield of 22%. The identification of conditions to telescope amide bond formation and a Lacey-Dieckmann reaction into one pot proved important. The three stereoisomers of harzianic acid were also prepared, providing material for comparison of their biological activity.