Oxidative Transformations of Allenes (Part I) and Enyne Ring-Closing Metathesis (Part II)

Exploration of new reactivity of silyl-substituted allenes along with the corresponding alkyl-substituted allenes under conditions with various oxidants and/or enophiles to induce nitration, Alder ene reaction, copper-catalyzed oxidative dimerization, and iron-catalyzed oxidative transformations. More specifically, in nitration chemistry; nitration of silylallenes with nitrogen dioxide radical, generated from NaNO2 and AcOH, to form α-nitro-α,β-unsaturated silyl oximes and also using Fe(NO3)3·9H2O and FeCl3·6H2O, to form regioisomeric chloride-trapped products depending on the steric bulk of the silyl group. Another novel class of compound isooxazolidinones were obtained upon treating the initially formed α-nitro-α,β-unsaturated silyl oximes with TBAF. In dimerization chemistry; silylallenes with a catalytic system of copper(I) chloride and N-hydroxyphthalamide (N-Hpth) along with a stoichiometric amount of a terminal oxidant diacetoxyiodobenzene were favored mainly for the formation of dimer products with or without 1,3-enynes, and N-Hpth adducts. In Alder ene reaction, activation of allenic C(sp2)–H bond over an allylic C(sp3)–H bond was described. In this ene reaction linear silylallenes preferentially engage an allenic C(sp2)–H bond with high selectivity but cycloalkyl-substituted silylallenes showed low or reversed selectivity. On the other hand, non-silylated allenes engage allylic C(sp3)–H bonds favorably regardless of their structural feature. DFT calculations were provided for further insight into the selectivity trend. In iron-catalyzed oxidative transformations substituent and oxidant-dependent transformations of allenes are described using alkyl- and silyl-substituted allenes with DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone) and TBHP (tert-butyl hydroperoxide). The reactions of non-silylated allenes involve allylic cation intermediate via forming C–O bond at the sp-hybridized C2 carbon and the reactions of silylated allenes favor the formation of propargylic cation intermediates via transferring the allenic hydride to the oxidant, generating 1,3-enynes or propargylic TBHP ethers. In addition, structure and reactivity of sulfonamide-, acetate-, alcohol, and alkene-chelated ruthenium alkylidene complexes derived from enyne RCM were investigated. All 5-membered sulfonamide chelates, hydroxy/ether chelates and 6-membered acetate chelates have the chelated oxygen and the NHC ligand in cis relationship. On the other hand, alkene-chelated ruthenium alkylidenes have N-heterocyclic carbene and chelated alkene in trans relationship. These newly generated variety of chelated complexes were further tested their metathesis activity as well as in some cases their behavior in presence of carbon monoxide were described. Also, the unexpected thermal bicyclization of metathesis substrates ynamide tethered triynes to generate novel class of tetrahydropyranopyridines were explored. Where the ynamide tethered triynes smoothly underwent 6-exo-mode ring-closure reaction by heating at 85 oC. The reaction has been explored by varying anion- and cation-stabilizing groups, including the ether side chain, and the alkyne substituent to provide broad range of tetrahydropyranopyridines

Nitration of Silyl Allenes To Form Functionalized Nitroalkenes

An efficient nitration of silyl allenes with nitrogen dioxide radical, generated from NaNO₂ and AcOH, to form α-nitro-α,β-unsaturated silyl oximes has been developed. A similar nitration could be achieved by using Fe(NO₃)₃·9H₂O and FeCl₃·6H₂O, but different from the regioselective oxime formation, two regioisomeric chloride-trapped products were isolated with varying ratios depending on the steric bulk of the silyl group. A novel ring-closure reaction of α-nitro-α,β-unsaturated silyl oximes upon treating with TBAF to form isooxazolidinone derivatives was also developed

Oxidative Dimerization of Silylallenes via Activation of the Allenic C(<i>sp</i>²)–H Bond Catalyzed by Copper(I) Chloride and <i>N</i>‑Hydroxyphthalimide

Novel oxidative dimerization of silylallenes is described. Treatment of silylallenes with a catalytic amount of copper­(I) chloride, a substoichiometric amount of <i>N</i>-hydroxyphthalamide, and a stoichiometric amount of a terminal oxidant diacetoxyiodobenzene afforded head-to-head dimers as the main products. Silyallenes containing a small ring afforded only dimers, whereas as the ring size increased 1,3-enynes became more favorable products. For silylallenes containing an acyclic substituent, dimer formation is a norm with exceptions where <i>N</i>-hydroxyphthalimide reacts at the propargylic center to generate the corresponding aminoxy ethers

Subtle Electronic Effects in Metal-Free Rearrangement of Allenic Alcohols

A general and stereoselective rearrangement of allenic alcohols to (<i>E,E</i>)-1,3-dien-2-yl triflates and chlorides was developed under metal-free conditions. Subtle electronic effects of the alkyl and aryl substituents on the carbon bearing the hydroxyl group has a profound impact on the reaction rate and efficiency such that vinyl triflates were obtained from electron-deficient substrates and trimethylsilyl triflate whereas vinyl chlorides were generated with an electron-rich substrate and trimethylsilyl chloride

Bifunctional Small Molecules That Mediate the Degradation of Extracellular Proteins

Targeted protein degradation (TPD) has emerged as a promising and exciting therapeutic strategy. The majority of existing TPD technologies rely on the ubiquitin-proteasome system, and are therefore limited to targeting intracellular proteins. To address this limitation, we developed a class of modularly designed, bifunctional synthetic molecules called MoDE-As (Molecular Degraders of Extracellular proteins through the Asialoglycoprotein receptor (ASGPR)), which are capable of mediating the degradation of extracellular proteins. MoDE-A molecules mediate the formation of a ternary complex between a target protein and the ASGPR, which is expressed primarily on hepatocytes. The target protein is then endocytosed and degraded by lysosomal proteases. We demonstrated the modularity of the MoDE-A technology by synthesizing bifunctional molecules that induce the degradation of both antibody and pro-inflammatory cytokine proteins. To our knowledge, these data represent the first experimental evidence that non-proteinogenic, synthetic molecules can be employed for the TPD of extracellular proteins both in vitro and in vivo. We believe that TPD mediated by the MoDE-A technology will have widespread applications for disease treatment.</p

Structural Relationships to Efficacy for Prazole-Derived Antivirals.

Here, an in vitro characterization of a family of prazole derivatives that covalently bind to the C73 site on Tsg101 and assay their ability to inhibit viral particle production is presented. Structurally, increased steric bulk on the 4-pyridyl of the prazole expands the prazole site on the UEV domain toward the β-hairpin in the Ub-binding site and is coupled to increased inhibition of virus-like particle production in HIV-1. Increased bulk also increased toxicity, which is alleviated by increasing flexibility. Further, the formation of a novel secondary Tsg101 adduct for several of the tested compounds and the commercial drug lansoprazole. The secondary adduct involved the loss of the 4-pyridyl substituent to form an irreversible species, with implications for increasing the half-life of the active species or its specificity toward Tsg101 UEV. It is also determined that sulfide derivatives display effective viral inhibition, presumably through cellular sulfoxidation, allowing for delayed conversion within the cellular environment, and identify SARS-COV-2 as a target of prazole inhibition. These results open multiple avenues for the design of prazole derivatives for antiviral applications

Pentosinane, a Post-Translational Modification of Human Proteins with Underappreciated Stability

Pentosinane is a structurally complex nonenzymatic post-translational modification of proteins believed to be present in all living things. It falls into the category of advanced glycation end products (AGEs) and is structurally related to the other AGEs pentosidine and glucosepane. Although pentosidine and glucosepane have been widely studied for their role in wide-ranging conditions (e.g., diabetes mellitus, Alzheimer’s disease, and human aging), relatively little is known about pentosinane. Interestingly, previous reports have suggested that pentosidine may derive from pentosinane. The (patho)­physiological significance of pentosinane in humans is largely unexplored. As a first step to address this knowledge gap, we report herein the first total synthesis of pentosinane. Our synthesis is high yielding (1.7% over seven steps), concise, and enantioselective, and it leverages a strategy for synthesizing 2,5-diaminoimidazoles previously developed by our lab. Access to synthetic pentosinane has allowed us to perform additional studies showing that its oxidation to pentosidine is both pH and oxygen dependent and is substantially slower under physiological conditions than previously believed. Additionally, pentosinane rapidly decomposes under harshly acidic conditions typically employed for pentosidine isolation. Taken together, these results suggest that pentosinane is likely to be more abundant in vivo than previously appreciated. We believe these results represent a critical step toward illuminating the role(s) of pentosinane in human biology

Rapid ¹³C Hyperpolarization of the TCA Cycle Intermediate α‑Ketoglutarate via SABRE-SHEATH

α-Ketoglutarate is a key biomolecule involved in a number of metabolic pathwaysmost notably the TCA cycle. Abnormal α-ketoglutarate metabolism has also been linked with cancer. Here, isotopic labeling was employed to synthesize [1-13C,5-12C,D4]α-ketoglutarate with the future goal of utilizing its [1-13C]-hyperpolarized state for real-time metabolic imaging of α-ketoglutarate analytes and its downstream metabolites in vivo. The signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH) hyperpolarization technique was used to create 9.7% [1-13C] polarization in 1 minute in this isotopologue. The efficient 13C hyperpolarization, which utilizes parahydrogen as the source of nuclear spin order, is also supported by favorable relaxation dynamics at 0.4 μT field (the optimal polarization transfer field): the exponential 13C polarization buildup constant Tb is 11.0 ± 0.4 s whereas the 13C polarization decay constant T1 is 18.5 ± 0.7 s. An even higher 13C polarization value of 17.3% was achieved using natural-abundance α-ketoglutarate disodium salt, with overall similar relaxation dynamics at 0.4 μT field, indicating that substrate deuteration leads only to a slight increase (∼1.2-fold) in the relaxation rates for 13C nuclei separated by three chemical bonds. Instead, the gain in polarization (natural abundance versus [1-13C]-labeled) is rationalized through the smaller heat capacity of the “spin bath” comprising available 13C spins that must be hyperpolarized by the same number of parahydrogen present in each sample, in line with previous 15N SABRE-SHEATH studies. Remarkably, the C-2 carbon was not hyperpolarized in both α-ketoglutarate isotopologues studied; this observation is in sharp contrast with previously reported SABRE-SHEATH pyruvate studies, indicating that the catalyst-binding dynamics of C-2 in α-ketoglutarate differ from that in pyruvate. We also demonstrate that 13C spectroscopic characterization of α-ketoglutarate and pyruvate analytes can be performed at natural 13C abundance with an estimated detection limit of 80 micromolar concentration × *%P13C. All in all, the fundamental studies reported here enable a wide range of research communities with a new hyperpolarized contrast agent potentially useful for metabolic imaging of brain function, cancer, and other metabolically challenging diseases