A mild, chemoselective reduction of aromatic ketones was discovered and investigated. The combination of photoredox and Lewis acid catalysis with an organic hydrogen source reduced aromatic ketones in good to high yield. Optimization found 2-phenylbenzothiazoline to be a sufficiently strong source of hydrogen in combination with an iridium photosensitizer and lanthanum triflate. Effective photomediated reduction of some substrates was also observed in the absence of photocatalyst and Lewis acid or with photocatalyst only. While yields were typically higher under catalytic conditions, some acid-sensitive substrates were more effectively reduced in the absence of Lewis acid. The reaction was generally high yielding, and chemoselecte, while tolerant of complex and functionally rich molecules.

The total synthesis of (±)-3-thiaglutamate is reported. Central to our strategy is an thiol addition to an imine to form the thioaminal of the natural product. The resulting thioaminal product is then subjected to triflic acid global deprotection to produce 3-thiaglutamate as a triflate salt. This work constitutes the first total synthesis of 3-thiaglutamate and demonstrates that the hemithioaminal group in 3-thiaglutamate can be stabilized under acidic conditions.

Neutral dual hydrogen bond donors (HBDs) are effective catalysts that enhance the electrophilicity of substrates or the Lewis/Brønsted acidity of reagents through an anion-binding mechanism. Despite their success in various enantioselective organocatalytic reactions, their application to transition metal catalysis remains rare. Herein, we report the activation of gold(I) precatalysts by chiral ureas, leading to enantioselective hydroarylation of allenes with indoles. Experimental and computational studies support an anion-binding mechanism for gold(I) precatalyst activation. Noncovalent interactions were identified as the source of enantiodifferentiation, providing insights into the cooperativity between achiral phosphine ligands and chiral ureas.

Herein, we report a mild palladium-catalyzed decarboxylative allylic alkylation of allyl ester-substituted isoindolinone substrates to afford a variety of 3,3-disubstituted isoindolinone derivatives. The decarboxylative coupling reaction tolerates a range of functional groups, including ketones and alkenyl halides, and does not require protection of the isoindolinone nitrogen. Additionally, the reaction was found to proceed in near-quantitative yield for most substrates evaluated. Based on the isolation of competing cyclopropane and protonation products, a reaction mechanism is proposed.

The rational design of atropisomeric small molecules is becoming increasingly common in chemical synthesis as a result of the unique advantages this property provides in drug discovery, asymmetric catalysis, and chiroptical activity. In this study, we designed a synthesis of a configurationally stable β-carboline in six steps. Our synthesis made use of an innovative Grignard addition/elimination reaction that formed an yne-ynamide precursor that then reacted with ethyl cyanoformate in a rhodium(I)-catalyzed [2+2+2] cyclotrimerization reaction to give the atropisomeric β-carboline in excellent yield, good enantioselectivity, and excellent regioselectivity. Extensive optimization of this transformation is described. Racemization kinetics experiments were also conducted on the individual atropisomers and their absolute configurations were determined by circular dichroism.

Thienamycin is a carbapenem antibiotic with potent activity against gram-negative and gram-positive bacteria. Due to its promising activity but lack of chemical stability, thienamycin serves as inspiration for new synthetic antibiotic scaffolds. In this study, we report a nine-step enantioselective formal synthesis of thienamycin. Our route utilizes an asymmetric reduction, enabled by NaBH and D-tartaric acid, followed by a series of diastereoselective reactions to access the key azetidinone precursor to thienamycin. This azetidinone precursor could be used as an intermediate to further develop and expand the scope of next-generation beta-lactam antibiotic scaffolds.

The synthesis of a new homogeneous reductant based on 4,4'-Bu-2,2'-bipyridine, Bu-OED, is reported. Bu-OED was prepared on a multigram scale in two steps from inexpensive and commercially available starting materials, with no chromatography required for purification. Bu-OED has a reduction potential of -1.33 V (vs Ferrocenium/Ferrocene) and is soluble in a range of common organic solvents. We demonstrate that Bu-OED can facilitate Ni/Co dual-catalyzed C(sp)-C(sp) cross-electrophile coupling reactions and is highly functional group tolerant. Bu-OED is expected to be a valuable addition to the set of homogeneous reductants available for organic transformations.

The norcembranoid and cembranoid diterpenoids represent an intriguing class of natural products isolated from marine sources. Their chemical synthesis has been a challenging and exciting field of research over the past two decades, owing largely to their structural complexity. We recently disclosed a total synthesis of a member of this class, ineleganolide, in a 23 step longest linear sequence. In search of a shorter, more efficient route, we have devised a new strategy for the synthesis of a key bicyclic enone. Disclosed herein is our improved synthesis of this strained intermediate, completing the formal synthesis of ineleganolide in only 14 steps, thereby shortening our previous synthesis by 9 steps. Dedicated to Prof. Thomas Maimone on his receipt of the Tetrahedron Young Investigator Award 2024.

We report that squaric esters can serve as bifunctional reagents for selective peptide stapling reactions. Formation of the squaric amide staple occurs under mild conditions with amine-containing side chains. We show that short resin-bound peptides are readily stapled on solid phase and that stapling can occur at various relative positions along the peptide and with various amine tether lengths (e.g. Lysine, ornithine, etc). The squaric amide staples are stable to strong acid conditions used to cleave the stapled peptide from the resin and the stapled peptides show an increase in helicity as analyzed through circular dichroism.

A 9-step synthetic route to a protected form of the C3-epimer of virenose from -fucose is described. C3--virenose is the carbohydrate unit of the bioactive polyketide elsamicin B and part of the carbohydrate unit of elsamicin A. The developed route enabled preparation of anomerically activated forms of this unique C6-deoxy sugar, including derivatives with 1-acetyl, 1-acetylthio, 1-trichloroacetimidate, 1-bromo, and 1-fluoro substituents.

We describe a stereoselective synthesis of an optically active (1, 3aS, 5, 6, 7)-octahydro-1,6-epoxy-isobenzo-furan-5-ol derivative. This stereochemically defined heterocycle serves as a high-affinity ligand for a variety of HIV-1 protease inhibitors. The key synthetic steps involve a highly enantioselective enzymatic desymmetrization of -1,2(dihydroxymethyl)cyclohex-4-ene and conversion of the resulting optically active alcohol to a methoxy hexahydroisobenzofuran derivative. A substrate controlled stereoselective dihydroxylation afforded -1,2-diols. Oxidation of diol provided the substituted 1,2-diketone and L-Selectride reduction provided the corresponding inverted -1,2-diols. Acid catalyzed cyclization furnished the ligand alcohol in optically active form.

In this manuscript, an oxidative carbon-carbon bond forming reaction to construct the framework of alkaloids such as scholarinine A is explored using a constrained substrate. Instead of the desired carbon-carbon bond formation between an indole C3 position and a malonate group, a competing carbon-nitrogen bond between the malonate and indole C3 position was observed to form. This work adds to the growing body of substrates for oxidative carbon-carbon bond formation and importantly, demonstrates that these reactions are challenging for some conformationally constrained substrates.

Diepoxin-η () is a cytotoxic fungal metabolite belonging to the spirobisnaphthalene structural class. In this study, four mono fluorinated analogues (-) of diepoxin-η () were semisynthesized in a single-step by selectively fluorinating the naphthalene moiety with Selectfluor. The structures of were elucidated using a set of spectroscopic and spectrometric techniques and were further confirmed by means of TDDFT-ECD and isotropic shielding tensors calculations. Compounds showed equipotent cytotoxic activity to when tested against OVCAR3 (ovarian) and MDA-MB-435 (melanoma) cancer cell lines with IC values that range from 5.7-8.2 M.

Isomorphic nucleosides are powerful tool compounds for interrogating a variety of biological processes involving nucleosides and nucleic acids. We previously reported a fluorescent isomorphic indole nucleoside called . A distinguishing molecular feature of is the presence of a 4-cyano moiety on the indole that functions as the nucleobase. Given the known chemical reactivity of isonitriles with tetrazines through [4+1]-cycloaddition chemistry, we investigated whether conversion of to the corresponding isonitrile would confer a useful chemical probe. Here we report the synthesis of 4-isocyanoindole-2'-deoxyribonucleoside () and the propensity of to undergo inverse electron demand Diels-Alder cycloaddition with a model tetrazine.

We combine the effects of spirocyclization and hyperconjugation to increase the Diels-Alder reactivity of the 4-pyrazole scaffold. A density functional theory (DFT) investigation predicts that 4-pyrazoles containing an oxetane functionality at the saturated center are extremely reactive despite having a relatively high-lying lowest unoccupied molecular orbital (LUMO) energy.

Fluorogenic probes for imaging enable visualization and analysis of difficult-to-reach cells and organelles. However, there are limited efficient examples of tuning these fluorescent molecules to higher wavelengths. This is vital since different tissues are sensitive to varying wavelength emissions. To address this need, we report the discovery, tuning, structure-photophysical property relationships (SPPR), and time-dependent DFT (TD-DFT) computations of 400-700+ nm fluorescent pyrido[2',1':2,3]imidazo[4,5-c]isoquinolines and substituted imidazo[1,2-a]pyridin-3-amines. The syntheses involve the trimethylsilylcyanide (TMSCN) modified Groebke-Blackburn-Bienaymé (GBB) multicomponent reaction as well as the TMSCN modified GBB combined with subsequent condensation of an aldehyde, and Aza-Friedel-Crafts-Intramolecular Cyclization-Oxidation all in one pot. The SPPR reveals that electron-withdrawing strength in the -position of the aminopyridine starting material has direct control over the absorption and fluorescence emission wavelengths of these molecules. The TD-DFT computations show the changes in the natural transition orbitals (NTOs) with differing substitutions to the parent molecule that dictate the observed excitations, emissions, and fluorescence intensities. These findings give insights and directions for tuning the fluorescent properties of these motifs for various uses as probes and imaging agents.

A method to introduce allyl or cinnamyl groups to the picolyl positions of 2- or 4-alkylpyridines is described. Substituted N-allyl pyridinium salts are first treated with base (KOBu) followed by catalytic [(η-allyl)PdCl] and PPh to result in formal Pd-catalyzed transfer of N-allyl groups to the pyridine periphery. The reaction is believed to proceed through initial formation of nucleophilic alkylidene dihydropyridine intermediates that react with (π-allyl)Pd(II) electrophiles, thereby regenerating N-allyl pyridinium cations. Catalytic turnover and liberation of pyridine products is then achieved by oxidative addition of Pd(0) to these activated allyl groups.

A concise linear synthesis of hypoxia inducible factor-2 (HIF-2) inhibitor, belzutifan was achieved by reproducing key components of previous synthetic approaches to this molecule as described in several publications and patents. Belzutifan is an orally bioavailable small-molecule (HIF-2) inhibitor for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) that received FDA approval in 2021. Herein, we report a 13-step synthesis of PT2977 that proceeded in good overall yield with high diastereoselectivity. Separation of diastereomeric mixtures at two different stages of the synthesis proved advantageous in ease of separation. The X-ray structure of belzutifan was determined.

We present a sodium trifluoroacetate (CFCONa) mediated copper-catalyzed -Michael addition of aromatic amines with activated olefins under mild, aqueous reaction conditions. This simplistic protocol employs a copper catalyst (10 mol%) and water as solvent. This transformation occurs precisely with aromatic substituted amines containing both electron-donating (EDG) and electron-withdrawing (EWG) groups. A broad range of substrates were tested under the optimized conditions, which are producing good to moderate yields.

Catalytic alkene hydrogenation is a powerful method that has been widely used in the syntheses of valuable products ranging from commodity chemicals to pharmaceuticals. Hydrogenation has also been a key strategy for selectively introducing heavy hydrogen isotopes to small molecules, a key strategy for metabolism studies and even the synthesis of "heavy drugs," where the hydrogen isotope is a key element of the active pharmaceutical ingredient. Traditional hydrogenations with pressurized H gas are atom economic but often require complex reaction setups or expensive metal catalysts. Further, use of diatomic hydrogen necessarily limits the ability to incorporate different hydrogen isotopes at each alkene position, with H, D, and T each resulting in compete labeling of the alkene. In response to these challenges, a recent and growing movement has sought to develop transfer hydrogenation methods using non-H hydrogen sources and earth abundant element catalysts to simplify reaction operation. Excitingly, recent developments have delivered transfer hydrogenations that proceed using cooperative hydrogen donor reagents, permitting the controllable incorporation of different hydrogen isotopes at each position of the alkene via reagent control. In this Digest, we disclose recent advances in Earth-abundant metal-catalyzed cooperative transfer hydrogenation of alkenes with various combinations of two distinct transfer hydrogen reagents as non-H hydrogen sources.

Vinyl bisphosphonates can be readily prepared by condensation of an aromatic aldehyde with the tetraester of a methylenebisphosphonate, and reduction of the resulting olefin is an attractive strategy for the preparation of monoalkyl geminal bisphosphonates. Conjugate reduction through use of variations on the Stryker approach has proven to be an efficient method for that reduction, even in the presence of aromatic substituents that also could be reduced. Furthermore, remote olefins in an isoprenoid chain survive this conjugate reduction unaffected, allowing access to isoprenoid-substituted triazole bisphosphonates of interest as potential inhibitors of terpenoid biosynthesis.