Second-Generation Synthesis of the Northern Fragment of Mandelalide A: Role of π-Stacking on Sharpless Dihydroxylation of cis-Enynes.

The development of a π-stacking-based approach for increased stereoselectivity in Sharpless asymmetric and diastereomeric dihydroxylation of cis-enynes is disclosed. The use of neighboring, electron-rich benzoate esters proved key to the success of this process. Density functional theory study suggests that the substrate benzoate ester group rigidifies the dihydroxylation transition states by forming a favorable π-stacking interaction in both Major-TS and Minor-TS. The energetic preference for the Major-TS was found in part because of the favorable eclipsing conformation of the alkene substituent as opposed to the disfavored bisecting conformation found in the Minor-TS. The application to a second-generation synthesis of the C15-C24 northern portion of mandelalide A is demonstrated.

Recent Syntheses and Strategies toward Polycyclic Gelsemium Alkaloids.

This Minireview is focused on an in-depth discussion of comparative strategies to construct the gelsemine and gelsedine classes of the gelsemium alkaloids. This document highlights the diversity of strategies used to access specific motifs found within these targets: a) the fused "[3.2.1]bicycle" (in gelsemine) and "oxabicycle" (in gelsedine class); b) the "piroxindole" moiety with C7 quaternary center; c) the "N-heterocycles" and d) the "THP" moiety with C20 quaternary center (in gelsemine).

Enantioselective Synthesis of (-)-Halenaquinone.

The efficient, 12-14 step (LLS) total synthesis of (-)-halenaquinone has been achieved. Key steps in the synthetic sequence include: (a) proline sulfonamide-catalyzed, Yamada-Otani reaction to establish the C6 all-carbon quaternary stereocenter, (b) multiple, novel palladium-mediated oxidative cyclizations to introduce the furan moiety, and (c) oxidative Bergman cyclization to form the final quinone ring.

Mg-Ion Battery Electrode: An Organic Solid's Herringbone Structure Squeezed upon Mg-Ion Insertion.

We report that crystalline 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA), an organic solid, is highly amenable to host divalent metal ions, i.e., Mg2+ and Ca2+, in aqueous electrolytes, where the van der Waals structure is intrinsically superior in hosting charge-dense ions. We observe that the divalent nature of Mg2+ causes unique squeezing deformation of the electrode structure, where it contracts and expands in different crystallographic directions when hosting the inserted Mg-ions. This phenomenon is revealed experimentally by ex situ X-ray diffraction and transmission electron microscopy, and is investigated theoretically by first-principles calculations. Interestingly, hosting one Mg2+ ion requires the coordination from three PTCDA molecules in adjacent columns of stacked molecules, which rotates the columns, thus reducing the (011) spacing but increasing the (021) spacing. We demonstrate that a PTCDA Mg-ion electrode delivers a reversible capacity of 125 mA h g-1, which may include a minor contribution of hydronium storage, a good rate capability by retaining 75 mA h g-1 at 500 mA g-1 (or 3.7 C), and a stable cycle life. We also report Ca2+ storage in PTCDA, where a reversible capacity of over 80 mA h g-1 is delivered.

Schinortriterpenoids: A Case Study in Synthetic Design.

Since the pioneering days of total synthesis and retrosynthetic analysis, the community has embraced guiding principles for planning synthetic approaches towards complex natural products. These guideposts have enabled the community to synthesize ever more complex compounds by applying prior knowledge gained in new settings. The recently isolated schinortriterpenoid family of natural products has attracted considerable synthetic attention and provided a rich opportunity to evaluate the lessons learned in the construction of complex, polycyclic scaffolds. In this Minireview, a detailed discussion of the synthetic work within this family is provided, including the six reported total syntheses, as well as a comparative analysis of the approaches utilized in their construction.

Enantioselective Total Synthesis of Mandelalide A and Isomandelalide A: Discovery of a Cytotoxic Ring-Expanded Isomer.

The total synthesis of mandelalide A and its ring-expanded macrolide isomer isomandelalide A has been achieved. Unexpected high levels of cytotoxicity were observed with the ring-expanded isomandelalide A with a rank order of potency: mandelalide A > isomandelalide A > mandelalide B. Key aspects of the synthesis include Ag-catalyzed cyclizations (AgCC's) to construct both the THF and THP rings present in the macrocycle, diastereoselective Sharpless dihydroylation of a cis-enyne, and lithium acetylide coupling with a chiral epoxide.

Unified Synthesis of 10-Oxygenated Lycopodium Alkaloids: Impact of C10-Stereochemistry on Reactivity.

The pronounced impact of the C10 stereochemistry on the successful construction of a polycyclic Lycopodium alkaloid scaffold has been explored. A wide range of reaction conditions and functionality were investigated to control a keto sulfone Michael addition to construct the C7-C12 linkage. An unexpected, overriding impact of the C10 stereochemistry in stereoselectivity and reaction rate in the Michael addition was observed. Furthermore, divergent reactivity of a conformationally accelerated, intramolecular Mannich cyclization based on the C10 stereochemistry was discovered. The successful execution of this synthetic route resulted in the total synthesis of all three known 10-oxygenated Lycopodium alkaloids: 10-hydroxylycopodine, paniculine, and deacetylpaniculine.

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses.

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,ß-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity.

Towards theory driven structure elucidation of complex natural products: mandelalides and coibamide A.

The effectiveness of computational tools in determining relative configurations of complex molecules is investigated, using natural products mandelalides A-D and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical NMR chemical shift predictions, and DP4 analyses led to confirmation of the revised structures of mandelalides A-D and coibamide A. All chiral centers in the northern hemisphere of mandelalides A-D are inverted with respect to the originally proposed structures, in agreement with recent total syntheses of mandelalide A by Ye, Fürstner & Carter. In the case of coibamide A, it was found that Fang & Su's revision, in which both the macrocycle [MeAla(11)] and the side chain [HIV(2)] residues are inverted from l to d, was consistent with the authentic natural product and computations.

Novel nitro-PAH formation from heterogeneous reactions of PAHs with NO2, NO3/N2O5, and OH radicals: prediction, laboratory studies, and mutagenicity.

The heterogeneous reactions of benzo[a]pyrene-d12 (BaP-d12), benzo[k]fluoranthene-d12 (BkF-d12), benzo[ghi]perylene-d12 (BghiP-d12), dibenzo[a,i]pyrene-d14 (DaiP-d14), and dibenzo[a,l]pyrene (DalP) with NO2, NO3/N2O5, and OH radicals were investigated at room temperature and atmospheric pressure in an indoor Teflon chamber and novel mono-NO2-DaiP and mono-NO2-DalP products were identified. Quartz fiber filters (QFF) were used as a reaction surface and the filter extracts were analyzed by GC/MS for nitrated-PAHs (NPAHs) and tested in the Salmonella mutagenicity assay, using Salmonella typhimurium strain TA98 (with and without metabolic activation). In parallel to the laboratory experiments, a theoretical study was conducted to rationalize the formation of NPAH isomers based on the thermodynamic stability of OH-PAH intermediates, formed from OH-radical-initiated reactions. NO2 and NO3/N2O5 were effective oxidizing agents in transforming PAHs to NPAHs, with BaP-d12 being the most readily nitrated. Reaction of BaP-d12, BkF-d12, and BghiP-d12 with NO2 and NO3/N2O5 resulted in the formation of more than one mononitro isomer product, while the reaction of DaiP-d14 and DalP resulted in the formation of only one mononitro isomer product. The direct-acting mutagenicity increased the most after NO3/N2O5 exposure, particularly for BkF-d12 in which di-NO2-BkF-d10 isomers were measured. The deuterium isotope effect study suggested that substitution of deuterium for hydrogen lowered both the direct and indirect acting mutagenicity of NPAHs and may result in an underestimation of the mutagencity of the novel NPAHs identified in this study.

Exploiting hidden symmetry in natural products: total syntheses of amphidinolides C and F.

The total synthesis of amphidinolide C and a second-generation synthesis of amphidinolide F have been accomplished through the use of a common intermediate to access both the C1-C8 and the C18-C25 sections. The development of a Ag-catalyzed cyclization of a propargyl benzoate diol is described to access both trans-tetrahydrofuran rings. The evolution of a Felkin-controlled, 2-lithio-1,3-dienyl addition strategy to incorporate C9-C11 diene as well as C8 stereocenter is detailed. Key controlling aspects in the sulfone alkylation/oxidative desulfurization to join the major subunits, including the exploration of the optimum masking group for the C18 carbonyl motif, are discussed. A Trost asymmetric alkynylation and a stereoselective cuprate addition to an alkynoate have been developed for the rapid construction of the C26-C34 subunit. A Tamura/Vedejs olefination to introduce the C26 side arm of amphidnolides C and F is employed. The late-stage incorporation of the C15, C18 diketone motif proved critical to the successful competition of the total syntheses.

Amphidinolide B: total synthesis, structural investigation, and biological evaluation.

The total syntheses of amphidinolide B1 and the proposed structure of amphidinolide B2 have been accomplished. Key aspects of this work include the development of a practical, non-transition-metal-mediated method for the construction of the C13-C15 diene, the identification of α-chelation and dipole minimization models for diastereoselective methyl ketone aldol reactions, the discovery of a spontaneous Horner-Wadsworth-Emmons macrocyclization strategy, and the development of a novel late stage method for construction of an allylic epoxide moiety. The originally proposed structure for amphidinolide B2 and diastereomers thereof display potent antitumor activities with IC50 values ranging from 3.3 to 94.5 nM against human solid and blood tumor cells. Of the different stereoisomers, the proposed structure of amphidinolide B2 is over 12-fold more potent than the C8,9-epimer and C18-epimer in human DU145 prostate cancer cells. These data suggest that the epoxide stereochemistry is a significant factor for anticancer activity.

Enantioselective approach to quinolizidines: total synthesis of cermizine D and formal syntheses of senepodine G and cermizine C.

The formal syntheses of C5-epi-senepodine G and C5-epi-cermizine C have been accomplished through a novel diastereoselective, intramolecular amide Michael addition process. The total synthesis of cermizine D has been achieved through use of an organocatalyzed, heteroatom Michael addition to access a common intermediate. Additional key steps of this sequence include a matched, diastereoselective alkylation with an iodomethylphenyl sulfide and sulfone-aldehyde coupling/reductive desulfurization sequence to combine the major subunits. The utility of a Hartwig-style C-N coupling has been explored on functionally dense coupling partners. Diastereoselective conjugate additions to α,ß-unsaturated sulfones have been investigated, which provided the key sulfone intermediate in just six steps from commercially available starting materials. The formal syntheses of senepodine G and cermizine C have been accomplished through an intramolecular cyclization process of a N-Boc-protected piperidine sulfone.

Correction: Innovation and Entrepreneurship in Promotion and Tenure in Biomedical Engineering.

[This corrects the article DOI: 10.1007/s12195-023-00767-x.].

Innovation and Entrepreneurship in Promotion and Tenure in Biomedical Engineering: Communication from the Biomedical Engineering Society Long Range Planning Committee.

Promotion and tenure (P&T) remain the central tenets of academia. The criteria for P&T both create and reflect the mission of an institution. The discipline of biomedical engineering is built upon the invention and translation of tools to address unmet clinical needs. 'Broadening the bar' for P&T to include efforts in innovation, entrepreneurship, and technology-based transfer (I/E/T) will require establishing the criteria and communication of methodology for their evaluation. We surveyed the department chairs across the fields of biomedical and bioengineering to understand the state-of-the-art in incorporation, evaluation, and definition of I/E/T as applied to the P&T process. The survey results reflected a commitment to increasing and respecting I/E/T activities as part of the P&T criteria. This was balanced by an equally strong desire for improving the education and policy for evaluating I/E/T internally as well as externally. The potential for 'broadening the bar' for P&T to include I/E/T activities in biomedical engineering may serve as an example for other fields in engineering and applied sciences, and a template for potential inclusion of additional efforts such as diversity, equity, and inclusion (DEI) into the pillars of scholarship, education, and service.

Mechanism and stereoselectivity of a dual amino-catalyzed robinson annulation: rare duumvirate stereocontrol.

Computational study of the mechanisms and stereoselectivities of a dual amino-catalyzed synthesis of cyclohexenones containing all-carbon γ-quaternary and ∂-tertiary stereocenters is reported. Extensive conformational search with density functional theory optimizations, the high-accuracy SCS-MP2/cc-pV∞Z energies, and PCM solvation corrections were used to characterize all intermediates and transition states. Six mechanisms were considered, all consistent with available experiments. The reaction proceeds via sequential Michael and Mannich conjugate additions whereby the primary amine activates the aldehyde and the catalyst activates the pentenone. We have discovered a rare duumvirate stereocontrol: the Michael reaction sets the enantioselectivity, but both the Michael and the Mannich reactions control the diastereoselectivity.

Synthesis and computational analysis of densely functionalized triazoles using o-nitrophenylalkynes.

Dipolar cylcoadditions with azides using a series of o-nitrophenylethynes and disubstituted alkynes were studied experimentally and computationally. Density functional theory computations reveal the steric and electronic parameters that control the regioselectivity of these cycloadditions. Several new substrates were predicted that would either give enhanced regiocontrol or invert the regiochemical preference. Experimentally, the alkynes were screened in the [3 + 2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally, the acetylenes containing halogen substitution directly on the alkyne provided the highest levels of regioselectivity. These haloalkynes were also shown to tolerate variation of the azide moiety with continued good levels of regioselectivity in most cases. Diverse functional groups can be incorporated through the cycloaddition process and their subsequent orthogonal modification was demonstrated.

Proline sulphonamide-catalysed Yamada-Otani condensation: reaction development, substrate scope and scaffold reactivity.

The development of a proline sulphonamide-catalysed method for enantioselective and diastereoselective construction of functionalized cyclohexenones is described. Impact of catalyst structure as well as solvent effects and additives are explored. A significant substrate scope is demonstrated by variation of both the aldehyde and the enone components. Diastereoselective derivatization of the cyclohexenone scaffold illustrates its utility as a building block for chemical synthesis.

Highly regioselective nitrile oxide dipolar cycloadditions with ortho-nitrophenyl alkynes.

The dipolar cycloadditions of ortho-nitrophenyl alkynes with aryl nitrile oxides has been demonstrated. A range of substituents are tolerated on the alkyne. These reactions proceed with excellent levels of regioselectivity. Subsequent functionalization of the isoxazole scaffold has been demonstrated.

Innovation, entrepreneurship, promotion, and tenure.

Academic incentives must reward broader societal impacts.