Stereoretentive enantioconvergent reactions.

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.

Modular synthesis of functional libraries by accelerated SuFEx click chemistry.

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.

Protocol for producing phosphoramidate using phosphorus fluoride exchange click chemistry.

Phosphorus fluoride exchange (PFEx) is a catalytic click reaction that involves exchanging high oxidation state P-F bonds with alcohol and amine nucleophiles, reliably yielding P-O- and P-N-linked compounds. Here, we describe steps for preparing a phosphoramidic difluoride and performing two sequential PFEx reactions to yield a phosphoramidate through careful catalyst selection. We then detail procedures for handling and quenching potentially toxic P-F-containing compounds to ensure user safety when conducting PFEx reactions. For complete details on the use and execution of this protocol, please refer to Sun et al.1.

Inhibition of mitochondrial metabolism by (-)-jerantinine A: synthesis and biological studies in triple-negative breast cancer cells.

A concise semi-synthesis of the Aspidosperma alkaloids, (-)-jerantinine A and (-)-melodinine P, and derivatives thereof, is reported. The novel compounds were shown to have potent activity against MDA-MB-231 triple-negative breast cancer cells. Furthermore, unbiased metabolomics and live cell reporter assays reveal (-)-jerantinine A alters cellular redox metabolism and induces oxidative stress that coincides with cell cycle arrest.

Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.

Diversity oriented clicking delivers ß-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors.

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented ß-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Accelerated SuFEx Click Chemistry For Modular Synthesis.

SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S-O linkages upon exchange of S-F bonds with aryl silyl-ether substrates, and while near-perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs. We demonstrate Barton's hindered guanidine base (2-tert-butyl-1,1,3,3-tetramethylguanidine; BTMG) as a superb SuFEx catalyst that, when used in synergy with silicon additive hexamethyldisilazane (HMDS), yields stable S-O bond linkages in a single step; often within minutes. The powerful combination of BTMG and HMDS reagents allows for catalyst loadings as low as 1.0 mol % and, in congruence with click-principles, provides a scalable method that is safe, efficient, and practical for modular synthesis. ASSC expands the number of accessible SuFEx products and will find significant application in organic synthesis, medicinal chemistry, chemical biology, and materials science.

Enantioselective para-Claisen Rearrangement for the Synthesis of Illicium-Derived Prenylated Phenylpropanoids.

The development of the first enantioselective para-Claisen rearrangement has been achieved. Using a chiral aluminum Lewis acid, illicinole is rearranged to give (-)-illicinone A (er 87:13), which can then be converted into more complex Illicium-derived prenylated phenylpropanoids. The absolute configurations of the natural products (+)-cycloillicinone and (-)-illicarborene A have been determined, and our results cast doubt on the enantiopurity of the natural samples.

Biomimetic synthesis of the bisindole framework present in sciodole, an alkaloid from Tricholoma sciodes.

A synthesis of the unique bisindole framework present in the mushroom-derived alkaloid sciodole has been achieved, validating a biosynthesis proposal that the C-N bisindole bond present in the natural product is forged by amination of an azafulvenium.

Mushroom-Derived Indole Alkaloids.

Mushrooms are known to produce over 140 natural products bearing an indole heterocycle. In this review, the isolation of these mushroom-derived indole alkaloids is discussed, along with their associated biological activities.