Silver(i) Perfluoroalcoholates: Synthesis, Structure, and their Use as Transfer Reagents.

Herein we report a general access to silver(i) perfluoroalcoholates, their structure in the solid state and in solution, and their use as transfer reagents. The silver(i) perfluoroalcoholates are prepared by the reaction of AgF with the corresponding perfluorinated carbonyl compounds in acetonitrile and are stable for a prolonged time at -18 °C. X-ray analysis of single crystals of perfluoroalcoholate species showed that two Ag(i) centers are bridged by the alcoholate ligands. In acetonitrile solution, Ag[OCF3] forms different structures as indicated by IR spectroscopy. Furthermore, the silver(i) perfluoroalcoholates can be used as easy-to-handle transfer reagents for the synthesis of Cu[OCF3], Cu[OC2F5], [PPh4][Au(CF3)3(OCF3)], and fluorinated alkyl ethers.

Unified Synthesis of Polycyclic Alkaloids by Complementary Carbonyl Activation*.

A complementary dual carbonyl activation strategy for the synthesis of polycyclic alkaloids has been developed. Successful applications include the synthesis of tetracyclic alkaloids harmalanine and harmalacinine, pentacyclic indoloquinolizidine alkaloid nortetoyobyrine, and octacyclic ß-carboline alkaloid peganumine A. The latter synthesis features a protecting-group-free assembly and an asymmetric disulfonimide-catalyzed cyclization. Furthermore, formal syntheses of hirsutine, deplancheine, 10-desbromoarborescidine A, and oxindole alkaloids rhynchophylline and isorhynchophylline have been achieved. Finally, a concise synthesis of berberine alkaloid ilicifoline B was completed.

Semisynthesis of Plant-Derived Englerin A Enabled by Microbe Engineering of Guaia-6,10(14)-diene as Building Block.

Herein, we report a short semisynthesis of the potent transient receptor potential canonical (TRPC) channel agonist englerin A (EA) and the related guaianes oxyphyllol and orientalol E. The guaia-6,10(14)-diene starting material was systematically engineered in Escherichia coli and Saccharomyces cerevisiae using the CRISPR/Cas9 system and was produced with high titers. The potentially scalable approach combines the advantages of synthetic biology and chemical synthesis providing an efficient and economical method for producing EA and analogues.

N-Hydroxysuccinimide-Modified Ethynylphosphonamidates Enable the Synthesis of Configurationally Defined Protein Conjugates.

Herein, the application of N-hydroxysuccinimide-modified phosphonamidate building blocks for the incorporation of cysteine-selective ethynylphosphonamidates into lysine residues of proteins, followed by thiol addition with small molecules and proteins, is reported. It is demonstrated that the building blocks significantly lower undesired homo-crosslinking side products that can occur with commonly applied succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) under physiological pH. The previously demonstrated stability of the phosphonamidate moiety additionally solves the problem of premature maleimide hydrolysis, which can hamper the efficiency of subsequent thiol addition. Furthermore, a method to separate the phosphonamidate enantiomers to be able to synthesize protein conjugates in a defined configuration has been developed. Finally, the building blocks are applied to the construction of functional antibody-drug conjugates, analogously to FDA-approved, SMCC-linked Kadcyla, and to the synthesis of a functional antibody-protein conjugate.

In Situ Synthesis and Applications for Polyinterhalides Based on BrCl.

The use of neat BrCl in organic and inorganic chemistry is limited due to its gaseous aggregate state and especially its decomposition into Cl2 and Br2 . The stabilization of BrCl in form of reactive ionic liquids via a novel in situ synthesis route shifts this equilibrium drastically to the BrCl side, which leads to safer and easier-to-handle interhalogenation reagents. Furthermore, the crystalline derivatives of the hitherto unknown [Cl(BrCl)2 ]- and [Cl(BrCl)4 ]- anions were synthesized and characterized by single-crystal X-ray diffraction (XRD), Raman and IR spectroscopy, as well as quantum chemical calculations.

Enabling strategies for step efficient syntheses.

The field of natural product total synthesis has reached the point where synthetic efficiency has become more important than merely defining a viable (yet less ideal) route to the target molecule. Synthetic efficiency is best represented by the number of steps it takes to finish the target molecule from readily available starting materials, as by reducing the number of steps, all other factors of synthetic efficiency are influenced positively. By comparing several total syntheses from the recent years, the most successful strategies for step efficient syntheses will be highlighted. Each synthesis will be presented using a color-coded synthetic flowchart, in which each step is categorized by a colored box. Five categories of transformations are defined and rated according to their synthetic value. Each class will be signified by different colors so that the reader can quickly see which parts of the synthesis are productive and those that are not.

Synthesis of (+)-Darwinolide, a Biofilm-Penetrating Anti-MRSA Agent.

Darwinolide, a recently identified marine natural product from the Antarctic sponge Dendrilla membranosa, was previously shown to exhibit promising activity against the biofilm phase of methicillin-resistant Staphylococcus aureus. Its challenging tetracyclic rearranged spongian diterpenoid structure links a trimethylcyclohexyl subunit to a seven-membered core with two fused tetrahydrofuran units. Herein, we describe the first synthesis of (+)-darwinolide, which features a convergent aldol fragment coupling, an Ireland-Claisen rearrangement, and an organocatalytic desymmetrization as the key steps. Our results provide a foundation for the development of novel antibiofilm-specific antibiotics.

Dienamine-Induced Divinylcyclopropane-Cycloheptadiene Rearrangements.

Sigmatropic rearrangements constitute an important group of pericyclic reactions. In contrast to cycloaddition reactions, examples of catalytic variants of electrocyclic reactions and sigmatropic rearrangements are still scarce in the chemical literature. Herein, we report the first organocatalytic Cope rearrangement of in situ-generated divinylcyclopropanes. The reactive motif was generated by condensation of 4-(2-vinylcyclopropyl)but-2-enal derivatives with a secondary amine catalyst to form a transient dienamine. The cycloheptadiene products could be obtained in high yield and excellent diastereoselectivity. Importantly, the reaction was demonstrated to be stereospecific, proceeding under mild conditions, while exhibiting broad functional group tolerance.

Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels.

The concentration of free cytosolic Ca2+ and the voltage across the plasma membrane are major determinants of cell function. Ca2+-permeable non-selective cationic channels are known to regulate these parameters, but understanding of these channels remains inadequate. Here we focus on transient receptor potential canonical 4 and 5 proteins (TRPC4 and TRPC5), which assemble as homomers or heteromerize with TRPC1 to form Ca2+-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested, including in epilepsy, innate fear, pain, and cardiac remodeling, but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools that are high-quality, reliable, easy to use, and readily accessible for all investigators. Here, through chemical synthesis and studies of native and overexpressed channels by Ca2+ and patch-clamp assays, we describe compound 31, a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pm, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8, and store-operated Ca2+ entry mediated by Orai1. These findings suggest identification of an important experimental tool compound, which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145.

Synthesis of Enantioenriched Bromohydrins via Divergent Reactions of Racemic Intermediates from Anchimeric Oxygen Borrowing.

We report a chiral phosphoric acid catalyzed bromocyclization/regiodivergent reaction of racemic intermediates sequence, which is enabled by anchimeric oxygen borrowing. Different types of alkenes are applicable, and both enantiomers of the bromohydrin products were obtained in generally excellent yields and enantioselectivities. In addition, an example of enantioconvergent synthesis from the two isomeric products is presented.

A General One-Pot Synthesis of 2H-Indazoles Using an Organophosphorus-Silane System.

A simple and direct approach for the regioselective construction of the privileged 2H-indazole scaffold is described. The developed one-pot strategy involves phospholene-mediated N-N bond formation to access 2H-indazoles. The amount of organophosphorus reagent was minimized by recycling the phospholene oxide with organosilane reductants. Starting from functionalized 2-nitrobenzaldehydes and primary amines, a mild reductive cyclization, involving the use of commercially available phospholene oxide and silanes, delivered a wide variety of substituted 2H-indazoles in good to excellent yields.

Synthesis of (+)-Vitepyrroloid A and (+)-Vitepyrroloid B by Late-Stage Ni-Catalyzed C(sp2)-C(sp3) Cross-Electrophile Coupling.

A concise and scalable five-step synthesis of vitepyrroloids A and B, two cytotoxic labdane diterpenoid alkaloids from Vitex trifolia, is reported. The presented approach features a Ni-catalyzed cross-electrophile coupling between a (+)-sclareolide-derived alkyl iodide and 3-bromo-2-cyanopyrrole.

Synthesis and Structure Revision of Dichrocephones†A and B.

Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B.

Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates.

Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.

Organophosphorus-mediated N-N bond formation: facile access to 3-amino-2H-indazoles.

A convenient and efficient strategy has been devised to access 3-amino-2H-indazole derivatives in two steps from readily available starting materials. The conversion of 2-nitrobenzonitriles to substituted benzamidines followed by an organophosphorus-mediated reductive cyclization and a subsequent N-N bond formation afforded 3-amino-2H-indazoles in good to excellent yields.

Mechanistic Characterisation of Two Sesquiterpene Cyclases from the Plant Pathogenic Fungus Fusarium fujikuroi.

Two sesquiterpene cyclases from Fusarium fujikuroi were expressed in Escherichia coli and purified. The first enzyme was inactive because of a critical mutation, but activity was restored by sequence correction through site-directed mutagenesis. The mutated enzyme and two naturally functional homologues from other fusaria converted farnesyl diphosphate into guaia-6,10(14)-diene. The second enzyme produced eremophilene. The absolute configuration of guaia-6,10(14)-diene was elucidated by enantioselective synthesis, while that of eremophilene was evident from the sign of its optical rotation and is opposite to that in plants but the same as in Sorangium cellulosum. The mechanisms of both terpene cyclases were studied with various (13) C- and (2) H-labelled FPP isotopomers.

Enantiogroup-differentiating biocatalytic reductions of prochiral Cs -symmetrical dicarbonyl compounds to meso compounds.

The stereoselective reduction of symmetrical prochiral dicarbonyl compounds bearing enantiotopic carbonyl groups yields several stereogenic centers in one step. In a proof-of-concept study, a new approach is described for the enzymatic desymmetrization of 5-nitrononane-2,8-dione via sequential biocatalytic reduction steps utilizing ketoreductases to yield all possible diastereomers of 5-nitrononane-2,8-diol.

(-)-Englerin†A is a potent and selective activator of TRPC4 and TRPC5 calcium channels.

Current therapies for common types of cancer such as renal cell cancer are often ineffective and unspecific, and novel pharmacological targets and approaches are in high demand. Here we show the unexpected possibility for the rapid and selective killing of renal cancer cells through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (-)-englerin A. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels. TRPC4/5 activation through a high-affinity extracellular (-)-englerin A binding site may open up novel opportunities for drug discovery aimed at renal cancer.