Quaternary-centre-guided synthesis of complex polycyclic terpenes.

The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability1. Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability2. When present in chiral ligands3, catalysts4 and auxiliaries5, quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations6,7. For particularly challenging cases-for example, the vicinal all-carbon8, oxa- and aza-quaternary centres9 in molecules such as azadirachtin10,11, scopadulcic acid A12,13 and acutumine14-the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.

Discovery of Thioether-Cyclized Macrocyclic Covalent Inhibitors by mRNA Display.

Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalization─installation of a covalent warhead─with mRNA display and showcases its application in targeted covalent ligand discovery.

Enhancing the Equilibrium of Dynamic Thia-Michael Reactions through Heterocyclic Design.

Although the catalyst-free dynamic thia-Michael (tM) reaction has been leveraged for a range of significant applications in materials science and pharmaceutical development, exploiting its full potential has been limited by relatively low equilibrium constants. To address this shortcoming, a new series of catalyst-free, room-temperature dynamic thia-Michael acceptors bearing an isoxazolone motif were developed and utilized to access both dynamic covalent networks and linear polymers. By leveraging the generation of aromaticity upon thiol addition and tuning the electronic-withdrawing/donating nature of the acceptor at two different sites, a wide range of equilibrium constants (Keq ∼1000 to ∼100,000 M-1) were obtained, constituting a 2 orders of magnitude increase compared to their noncyclic benzalcyanoacetate analogues. Integration into a ditopic isoxazolone-based Michael acceptor allowed access to both bulk dynamic networks and linear polymers; these materials not only exhibited tailorable thermomechanical properties based on thia-Michael acceptor composition, but the higher Keq tM bonds resulted in more mechanically robust materials relative to past designs. Furthermore, solution-state formation of linear polymers was achieved thanks to the increased Keq of the isoxazolone-based acceptors.

Exchange-Mediated Transport in Battery Electrolytes: Ultrafast or Ultraslow?

Understanding the mechanisms of charge transport in batteries is important for the rational design of new electrolyte formulations. Persistent questions about ion transport mechanisms in battery electrolytes are often framed in terms of vehicular diffusion by persistent ion-solvent complexes versus structural diffusion through the breaking and reformation of ion-solvent contacts, i.e., solvent exchange events. Ultrafast two-dimensional (2D) IR spectroscopy can probe exchange processes directly via the evolution of the cross-peaks on picosecond time scales. However, vibrational energy transfer in the absence of solvent exchange gives rise to the same spectral signatures, hiding the desired processes. We employ 2D IR on solvent resonances of a mixture of acetonitrile isotopologues to differentiate chemical exchange and energy-transfer dynamics in a comprehensive series of Li+, Mg2+, Zn2+, Ca2+, and Ba2+ bis(trifluoromethylsulfonyl)imide electrolytes from the dilute to the superconcentrated regime. No exchange phenomena occur within at least 100 ps, regardless of the ion identity, salt concentration, and presence of water. All of the observed spectral dynamics originate from the intermolecular energy transfer. These results place the lower experimental boundary on the ion-solvent residence times to several hundred picoseconds, much slower than previously suggested. With the help of MD simulations and conductivity measurements on the Li+ and Zn2+ systems, we discuss these results as a continuum of vehicular and structural modalities that vary with concentration and emphasize the importance of collective electrolyte motions to ion transport. These results hold broadly applicable to many battery-relevant ions and solvents.

The Development of Reaction Cascades to Synthesize Dimeric Coccinellid Alkaloids.

Over the course of the past decade, our group has been intensely interested in achieving the laboratory synthesis of varied members of the coccinellid alkaloid family of natural products. These compounds, produced by varied species of ladybugs throughout the world as defensive agents, include several polycyclic members that can formally be considered as either monomeric or dimeric with architectures that contain between 3 and 7 ring systems along with an array of stereocenters. As a result of their fascinating structures, many groups have achieved syntheses of varied monomeric members using a variety of synthetic strategies and tactics. However, no efforts to synthesize any of the dimeric structures had been reported at the time we began our studies, and only a modest amount of study had been performed as relates to their biosynthesis, with little knowledge of how the larger structures might actually arise in Nature. In this Account, we provide an overview of our general synthetic considerations to achieve a global synthesis of the collection, efforts that have led to date to the formal and total synthesis of 12 different members, 4 at the dimer level. Critical was (1) the identification of a key, common intermediate to enable access to a large number of monomeric substructures in short order, (2) careful thinking as to how the larger structures might arise biosynthetically to fuel building block design, and (3) the development of several reaction cascades that rapidly assembled the majority of their molecular complexity in single-pot operations. Key discoveries in the program include the finding that when efforts to achieve intermolecular dimerizations fail with advanced intermediates, attempts to couple more functionalized fragments earlier and then fold them into the desired structure can be an effective strategy. We also highlight suggestive evidence that a non-natural isomer we originally prepared from one of those cascades may, in fact, be a natural product. And, in particular, we will focus on how two key cascades were developed, as a result of synthetic challenges at varied points in our explorations, which proved capable of forging multiple bonds, rings, and stereocenters in the target structures. One of these includes a designed event that combined 9 different chemical reactions in a single pot and may prove useful for the synthesis of other targets.

Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E.

The annotinolides are one of the most recent additions to the Lycopodium family of alkaloids, with its members possessing challenging, caged structures that include a [3.2.1]-bicyclic core bearing six contiguous stereocenters, including four that are fully substituted. Herein, we document a concise and stereoselective route that achieves the first total syntheses of three of its members: annotinolides C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene reaction that fashions much of the main core in a single operation, as well as a number of other challenging and chemoselective transformations to generate the remaining elements. Moreover, efforts utilizing the natural products themselves, seeking adjustments in their oxidation states and the rearrangement of individual ring systems, shed light on their potential biogenesis with some outcomes counter to those originally proposed. Finally, formal enantioenriched syntheses of the target molecules are also presented.

Highly Selective Hydrogenation of C═C Bonds Catalyzed by a Rhodium Hydride.

Under mild conditions (room temperature, 80 psi of H2) Cp*Rh(2-(2-pyridyl)phenyl)H catalyzes the selective hydrogenation of the C═C bond in α,ß-unsaturated carbonyl compounds, including natural product precursors with bulky substituents in the ß position and substrates possessing an array of additional functional groups. It also catalyzes the hydrogenation of many isolated double bonds. Mechanistic studies reveal that no radical intermediates are involved, and the catalyst appears to be homogeneous, thereby affording important complementarity to existing protocols for similar hydrogenation processes.

Resveratrol trimer enhances gene delivery to hematopoietic stem cells by reducing antiviral restriction at endosomes.

Therapeutic gene delivery to hematopoietic stem cells (HSCs) holds great potential as a life-saving treatment of monogenic, oncologic, and infectious diseases. However, clinical gene therapy is severely limited by intrinsic HSC resistance to modification with lentiviral vectors (LVs), thus requiring high doses or repeat LV administration to achieve therapeutic gene correction. Here we show that temporary coapplication of the cyclic resveratrol trimer caraphenol A enhances LV gene delivery efficiency to human and nonhuman primate hematopoietic stem and progenitor cells with integrating and nonintegrating LVs. Although significant ex vivo, this effect was most dramatically observed in human lineages derived from HSCs transplanted into immunodeficient mice. We further show that caraphenol A relieves restriction of LV transduction by altering the levels of interferon-induced transmembrane (IFITM) proteins IFITM2 and IFITM3 and their association with late endosomes, thus augmenting LV core endosomal escape. Caraphenol A-mediated IFITM downregulation did not alter the LV integration pattern or bias lineage differentiation. Taken together, these findings compellingly demonstrate that the pharmacologic modification of intrinsic immune restriction factors is a promising and nontoxic approach for improving LV-mediated gene therapy.

Total Synthesis of the Meroterpenoid Manginoid†A as Fueled by a Challenging Pinacol Coupling and Bicycle-forming Etherification.

The manginoids are a unique collection of bioactive natural products whose structures fuse an oxa-bridged spirocyclohexanedione with a heavily substituted trans-hydrindane framework. Herein, we show that such architectures can be accessed through a strategy combining a challenging pinacol coupling and bicycle-forming etherification with several additional chemo- and regioselective reactions. The success of these key events proved to be highly substrate and condition specific, affording insights for their application to other targets. As a result, not only has a 19-step total synthesis of manginoid A been achieved, but a potential roadmap to access other members of the family and related natural products has also been identified.

Generation of α-Boryl Radicals by H. Transfer and their Use in Cycloisomerizations.

Carbon-centered radicals can be stabilized by delocalization of their spin density into the vacant p orbital of a boron substituent. α-Vinyl boronates, in particular pinacol (Bpin) derivatives, are excellent hydrogen atom acceptors. Under H2 , in the presence of a cobaloxime catalyst, they generate α-boryl radicals; these species can undergo 5-exo radical cyclizations if appropriate double bond acceptors are present, leading to densely functionalized heterocycles with tertiary substituents on Bpin. The reaction shows good functional group tolerance with wide scope, and the resulting boronate products can be converted into other useful functionalities.

A Concise, Enantiospecific Total Synthesis of Chilocorine C Fueled by a Reductive Cyclization/Mannich Reaction Cascade.

Among defensive alkaloids isolated from ladybugs, the heterodimeric member chilocorine C possesses an alluring monomeric unit that combines quinolizidine and indolizidine substructures. Indeed, the overall stereochemical disposition of its ring fusions is distinct from those of related natural products. Herein we show that a carefully orchestrated sequence with several chemoselective transformations, including a designed cascade that accomplishes nine distinct chemical reactions in one-pot, can smoothly forge that domain and ultimately enable a 15-step, 11-pot enantiospecific synthesis of the natural product. Mechanistic studies, density functional theory calculations, and the delineation of several other unsuccessful approaches highlight its unique elements.

Development and Elucidation of a Pd-Based Cyclization-Oxygenation Sequence for Natural Product Synthesis.

Pd-catalyzed sequences involving oxidative addition, cyclization, and termination through intermolecular nucleophile capture have tremendous utility. Indeed, they can generate a plethora of different polycyclic structures possessing a diverse range of functionality. However, one area of deficiency for Pd0 /PdII variants is the ability to conclude them with oxygen-based species. Inspired by the recent discovery of one such reaction in the course of a total synthesis program, we delineate herein that it has significant strength, both in terms of substrate scope as well as the terminating oxygen nucleophile. As a result, the reaction proved critical in achieving total syntheses of two oxygenated natural products, one of which was prone to over-oxidation. Finally, a mechanistic proposal that accounts for its success is provided.

A Concise Total Synthesis of (+)-Waihoensene Guided by Quaternary Center Analysis.

The four contiguous all-carbon quaternary centers of waihoensene, coupled with the absence of any traditional reactive functional groups other than a single alkene, render it a particularly challenging synthetic target among angular triquinane natural products. Here, we show that its polycyclic frame can be assembled concisely by using a strategically chosen quaternary center to guide the formation of the other three through judiciously selected C-C bond formation reactions. Those events, which included a unique Conia-ene cyclization and a challenging Pauson-Khand reaction, afforded a 17-step synthesis of the molecule in enantioenriched form.

General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion.

The Laurencia family of C15-acetogenins is Nature's largest collection of halogenated natural products, with many of its members possessing a brominated 8-membered cyclic ether among other distinct structural elements. Herein, we demonstrate that a bromonium-induced ring expansion, starting from a common tetrahydrofuran-containing bicyclic intermediate and using the highly reactive bromenium source BDSB (Et2SBr·SbCl5Br), can lead to concise asymmetric total syntheses of microcladallenes A and B, desepilaurallene, laurallene, and prelaureatin. Key advances in this work include (1) the first demonstration that the core bromonium-induced cyclization/ring-expansion can be initiated using an enyne with an internal ether oxygen nucleophile, (2) that reasonable levels of stereocontrol in such processes can be achieved both with and without appended ring systems and stereogenic centers, (3) that several other unique chemoselective transformations essential to building their polyfunctional cores can be achieved, and (4) that a single, common intermediate can lead to five different members of the class encompassing two distinct 8-membered cyclic ether ring collections. Considering this work along with past efforts leading to two other natural products in the collection, we believe the breadth of structures prepared to date affords strong evidence for Nature's potential use of similar processes in fashioning these unique molecules.

The Total Synthesis of Chalcitrin.

The first total synthesis of the yellow pigment chalcitrin, a structurally distinct pulvinic acid dimer obtained from Chalciporous piperatus, has been achieved in 17 linear steps from commercially available materials. Key elements of the design include the use of a Au(I)-catalyzed Conia ene reaction and an N-heterocyclic carbene-mediated acyloin addition to rapidly fashion its unique polycyclic core, with the two high oxidation state side chains introduced in a single step via a late-stage double Stille coupling. Of note, many alternate designs based on differential final couplings failed, likely because of the hindered nature of the core. In addition, significant challenges in final natural product characterization in terms of matching NMR spectra were experienced; our studies reveal that the originally characterized material was its carboxylate salt form not its free acid.

Total Synthesis of (+)-Arborisidine.

The first total synthesis of arborisidine, a unique Kopsia indole alkaloid possessing a fully substituted cyclohexanone ring system with two quaternary carbons, has been achieved in seven steps in racemic format from tryptamine and in nine steps in asymmetric format from d-tryptophan methyl ester. Key elements of the design include a carefully orchestrated decyanation protocol to finalize the asymmetric formation of an aza-quaternary center that is challenging to access in optically active format via direct Pictet-Spengler cyclizations with tryptamine, a metal-promoted 6- endo-dig cyclization of an enyne to establish the second core quaternary center, and regiospecific functionalizations of the resultant complex diene to finalize the target structure. The distinct and efficient nature of the developed solution is highlighted by several unsuccessful approaches and unexpected rearrangements.

Total Synthesis of the Caged Indole Alkaloid Arboridinine Enabled by aza-Prins and Metal-Mediated Cyclizations.

Although alkaloid natural products possess incredible diversity when considered broadly, certain domains are sometimes shared by several members, even from different sub-collections. Such homology can point to potential synthetic strategies. Herein, we highlight how such an analysis of the natural product arboridinine pinpointed two key elements of structural similarity that suggested the value of a metal-mediated 6-endo-dig cyclization to fashion its tetracyclic indolenine core, as well as the need to develop what could be considered a reversed polarity aza-Prins cyclization to deliver its tertiary allylic alcohol and final cage structure. The power of the latter design element is highlighted by several failures in achieving similar functional group patterning through more traditional aza-Prins and Mannich cyclization strategies. Overall, these operations fueled an inaugural 13-step racemic synthesis of the target; exploration of varied solutions for the enantioselective preparation of a key 7-membered indole-containing piece afforded a 16-step formal asymmetric solution.

Anti-Müllerian hormone levels before and after uterine artery embolization.

OBJECTIVE: To determine the effects of uterine artery embolization (UAE) on ovarian reserve as measured by Anti-Müllerian hormone (AMH) levels. MATERIAL AND METHODS: Non-randomized, observational study of 89 women 23-40 years of age who received UAE. Control hormone levels were measured prior to UAE and the first post-embolization measurement was taken at various times post-procedure (mean = 190 ± 229 days). RESULTS: Historical work verified by our earlier work has shown that AMH levels decline with age. Regression analysis allows us to determine whether UAE contributes to a greater decline in AMH values over that naturally occurring with aging. The effect of the procedure was found to contribute no deleterious effect to the natural decline in AMH levels. In addition, multiple blood draws were obtained from 32 patients up to 47 months post-UAE. Regression studies with these patients as their own controls showed no long-term diminishment of ovarian reserve due to the UAE procedure. CONCLUSIONS: Earlier reported data are consistent with larger sample size. UAE does not affect ovarian reserve in women <40 as evidenced by no significant change in AMH levels after embolization. Women who are of reproductive age and have uterine fibroids can consider UAE without concern for adverse effects on their fertility.

Mannich-type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine-containing Alkaloids.

Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich-type additions to nitrones, one using ß-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of ß-N-hydroxy-aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (-)-lobeline and (-)-sedinone.

Durable Clinical Effectiveness With Paclitaxel-Eluting Stents in the Femoropopliteal Artery: 5-Year Results of the Zilver PTX Randomized Trial.

BACKGROUND: This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent [BMS]), and provisional DES versus provisional BMS. METHODS AND RESULTS: Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS. CONCLUSIONS: The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00120406.