Development of the Synthesis of Desepoxy-Tedanolide C.

We are presenting the development of our route for the total synthesis of desepoxy-tedanolide C. Through the obtained analytical data, the proposed structure of tedanolide C is questioned and a different configuration for this natural product is proposed. Key steps of the synthesis are a Kiyooka aldol reaction that builds up the tertiary alcohol flanked by three oxygenated carbon atoms and two aldol reactions used for fragment couplings.

Total Synthesis of Acanthodoral Using a Rearrangement Strategy.

We present the second total synthesis of (±)-acanthodoral, a sesquiterpenoid derived from the marine nudibranch . Our approach involves a concise three-step transformation from a previously reported compound, resulting in the formation of a less strained precursor of the bicyclo[3.1.

Stereoselective Construction of β-chiral Homoallyl Functionalities by Substrate- and Reagent-Controlled Iterative 1,2-Metallate Rearrangements.

Homoallylic alcohols possessing chiral β-centers are considered highly valuable in the synthesis of polyketide-based natural products. Therefore, there is a significant demand for new methods that allow for their stereoselective access. In pursuit of this objective, we have successfully combined our substrate-controlled protocol of Hoppe-Matteson-Aggarwal chemistry with iterative 1,2-metallate rearrangements.

Stereoselective Synthesis of Allylic Alcohols via Substrate Control on Asymmetric Lithiation.

Allylic alcohols are a privileged motif in natural product synthesis and new methods that access them in a stereoselective fashion are highly sought after. Toward this goal, we found that chiral acetonide-protected polyketide fragments performing the Hoppe-Matteson-Aggarwal rearrangement in the absence of sparteine with high yields and diastereoselectivities rendering this protocol a highly valuable alternative to the Nozaki-Hiyama-Takai-Kishi reaction. Various stereodyads and -triads were investigated to determine their substrate induction.

1,2-Metallate Rearrangement as a Toolbox for the Synthesis of Allylic Alcohols.

The development of new methods and protocols for the synthesis of biologically active substances remains one of the most important pillars in organic chemistry, and one of these privileged structural motifs are allylic alcohols. The method of choice to date for the synthesis of these is the Nozaki-Hiyama-Takai-Kishi reaction. We describe here a valuable alternative to the synthesis of allylic alcohols via 1,2-metallate rearrangement.

Sparteine-Free, Highly Stereoselective Construction of Complex Allylic Alcohols Using 1,2-Metallate Rearrangements.

Stereotriads bearing allylic alcohols are privileged structures in natural products, and new methods accessing these in a stereoselective fashion are highly sought after. Toward this goal, we found that the use of chiral polyketide fragments allows for performing the Hoppe-Matteson-Aggarwal rearrangement in the absence of sparteine with high yields and diastereoselectivities, rendering this protocol a highly valuable alternative to the Nozaki-Hiyama-Takai-Kishi reaction. The switch of directing groups in most cases resulted in the reversed stereochemical outcome, which could be explained by conformational analysis on density functional theory level and a Felkin-like model.

Asymmetric Total Synthesis of Illisimonin A.

The discovery of illisimonin A in 2017 extended the structural repertoire of the sesquiterpenoids─a class of natural products known for their high oxidation levels and neurotrophic properties─with a new carbon backbone combining the strained -pentalene and norbornane substructures. We report an asymmetric total synthesis of (-)-illisimonin A that traces its tricyclic carbon framework back to a spirocyclic precursor, generated by a tandem-Nazarov/ene cyclization. As crucial link between the spirocyclic key intermediate and illisimonin A, a novel approach for the synthesis of tricyclo[5.

Moonlighting chaperone activity of the enzyme PqsE contributes to RhlR-controlled virulence of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a major cause of nosocomial infections and also leads to severe exacerbations in cystic fibrosis or chronic obstructive pulmonary disease. Three intertwined quorum sensing systems control virulence of P. aeruginosa, with the rhl circuit playing the leading role in late and chronic infections.

Total Synthesis of (-)-Antroalbocin A Enabled by a Strain Release-Controlled Photochemical 1,3-Acyl Shift.

The first bioinspired, enantioselective, and protecting group free total synthesis of the antibacterial sesquiterpenoid (-)-antroalbocin A () has been achieved in 12 steps (5.4% overall yield) from dimedone. An organocatalytic Robinson annulation gave rapid access to the tricyclic enone () as starting material for the photochemical domino process of deconjugation and sigmatropic 1,3-acyl shift.

Oxazaborolidinone-Mediated Asymmetric Bisvinylogous Mukaiyama Aldol Reaction.

A bisvinylogous Mukaiyama aldol reaction using oxazaborolidinones as a source of chirality was developed. This methodology allows the fast assembly of conjugated dienols by expanding the vinylogy principle by two additional carbons, and can be conducted using a readily available Lewis acid at reasonable reaction times. A broad range of aromatic and aliphatic aldehydes can be used providing access to complex building blocks for polyketide synthesis.

A Nazarov-Ene Tandem Reaction for the Stereoselective Construction of Spiro Compounds.

The different reactivity of trienones under Lewis and Brønsted acids catalysis was investigated, resulting in distinct cyclization products and carbon backbones that originated either from a conjugate Prins cyclization or an interrupted Nazarov cyclization. In particular, an unprecedented Nazarov cyclization tandem reaction is presented, terminating the oxyallyl cation by an ene-type reaction, and leading stereoselectively to bicyclic spiro compounds. The terminal olefin of this motif represents a useful handle for further functionalization, making it a strategic intermediate in total syntheses.

Synthesis of Desepoxy-Tedanolide C.

The synthesis of desepoxy-tedanolide C was accomplished and provided experimental evidence on the configuration of tedanolide C. The reported chemical shifts and coupling constants point to a configuration different from the published structure and analogous to the structures of the other members of this family of natural products. The key step is a Kiyooka aldol protocol for the stereoselective synthesis of the tertiary alcohol flanked by three additional oxygenated carbon atoms.

The Total Synthesis of Chondrochloren A.

The first total synthesis of chondrochloren A is accomplished using a 1,2-metallate rearrangement addition as an alternative for the Nozaki-Hiyama-Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z-enamide is accomplished using a Z-selective cross coupling of the corresponding amide to a Z-vinyl bromide.

Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis.

While antibiotics are intended to specifically target bacteria, most are known to affect host cell physiology. In addition, some antibiotic classes are reported as immunosuppressive for reasons that remain unclear. Here, we show that Linezolid, a ribosomal-targeting antibiotic (RAbo), effectively blocked the course of a T cell-mediated autoimmune disease.

Total Synthesis and Structure Revision of Halioxepine.

The first total synthesis of halioxepine is accomplished using a 1,4-addition for constructing the quaternary center at C10 and a halo etherification for the generation of the tertiary ether at C7. The correct structure of halioxepine was determined by assembling different enantiomeric building blocks and by changing the relative configuration between C10 and C15.

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain-A new treatment strategy for neonatal seizures?

Objectives: The loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ-aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N-dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents.

Contiguous Quaternary Carbons: A Selection of Total Syntheses.

Contiguous quaternary carbons in terpene natural products remain a major challenge in total synthesis. Synthetic strategies to overcome this challenge will be a pivotal prerequisite to the medicinal application of natural products and their analogs or derivatives. In this review, we cover syntheses of natural products that exhibit a dense assembly of quaternary carbons and whose syntheses were uncompleted until recently.

Towards the total synthesis of chondrochloren A: synthesis of the ()-enamide fragment.

The stereoselective synthesis of the ()-enamide fragment of chondrochloren () is described. A Buchwald-type coupling between amide and ()-bromide was used to generate the required fragment. The employed amide comprising three chiral centers was obtained through a seven-step sequence starting from ᴅ-ribonic acid-1,4-lactone.

Haprolid Inhibits Tumor Growth of Hepatocellular Carcinoma through Rb/E2F and Akt/mTOR Inhibition.

Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria.

Hydrazine clubbed 1,3-thiazoles as potent urease inhibitors: design, synthesis and molecular docking studies.

Synthesis of a novel series of hydrazine clubbed 1,3-thiazoles (5a-m) has been described by reacting hydrazine-1-carbothioamides (3a-k) with α-chloro- or bromo-acetophenones (4a-d) in refluxing ethanol in good to excellent yields (65-86%). Structural confirmation was based upon spectroscopic techniques such as H-NMR, C-NMR, FT-IR and mass spectrometry. The biological application of these motifs has been demonstrated in terms of their strong urease inhibition activity.

Desymmetrization of C -Symmetric Bis(Boronic Esters) by Zweifel Olefinations.

anti-Configured 1,3-dimethyl deoxypropionate motifs are important sub structures in natural products. Herein, we describe a bidirectional approach for the rapid construction of natural products featuring such motifs by using C -symmetrical 1,3-bis(boronic esters). As for its application in convergent syntheses it was important to establish a selective mono-Zweifel olefination we describe the scope and limitations by using different 1,3-bis(boronic esters) and nucleophiles.

Very Recent Advances in Vinylogous Mukaiyama Aldol Reactions and Their Applications to Synthesis.

It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a β-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C-C bonds but also establishes stereogenic centers.

Polyoxygenated Tertiary Alcohols: A Kiyooka Approach.

A Kiyooka aldol approach for the stereoselective synthesis of tertiary alcohols is presented. This approach allows for the incorporation of different substituents at all three remaining positions at the chiral center bearing the tertiary alcohol. To demonstrate the validity of this approach different chiral alcohols were depicted and the relationship of double bond geometry of the ketene acetal and the diastereoselectivity was established.

Synthesis of sulfonamide, amide and amine hybrid pharmacophore, an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis.

Selective inhibition of carbonic anhydrase (CA) enzyme is an active area of research for medicinal chemists. In the current account, a hybrid pharmacophore approach was employed to design sulfonamide, amide and amine containing new series of potent carbonic anhydrase II inhibitors. The aromatic fragment associated with pharmacophore was altered suitably in order to find effective inhibitors of CA-II.