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.

Roflumilast foam 0.3% for adolescent and adult patients with seborrheic dermatitis: A randomized, double-blinded, vehicle-controlled, phase 3 trial.

BACKGROUND: The topical phosphodiesterase 4 inhibitor roflumilast has been studied in several dermatologic conditions. OBJECTIVE: Roflumilast foam 0.3% is being investigated as a topical treatment for seborrheic dermatitis (SD). METHODS: In this phase 3, double-blinded trial, patients with SD were randomly assigned (2:1 ratio) to once-daily roflumilast foam 0.3% or vehicle foam for 8 weeks. The primary efficacy outcome was Investigator Global Assessment (IGA) Success at week 8, defined as IGA of 0 (Clear) or 1 (Almost Clear) plus ≥2-point improvement from baseline. Safety was also assessed. RESULTS: 79.5% of roflumilast-treated and 58.0% of vehicle-treated patients met the primary endpoint (P < .001); statistically significant differences in IGA Success also favored roflumilast at week 2 (roflumilast: 43.0%; vehicle: 25.7%; P < .001) and week 4 (roflumilast: 73.1%; vehicle: 47.1%; P < .001). Roflumilast was well-tolerated with a low rate of treatment-emergent adverse events. LIMITATIONS: Study limitations include the 8-week treatment period for this chronic condition. CONCLUSIONS: Once-daily roflumilast foam was superior to vehicle in leading to IGA of Clear or Almost Clear plus ≥2-point improvement from baseline at 8 weeks in patients with SD. Longer trials are needed to determine durability and safety of roflumilast foam in SD.

Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: A 52-week, phase 2, open-label trial.

BACKGROUND: Efficacy and/or safety profiles limit topical psoriasis treatments. OBJECTIVE: Evaluate long-term effects of once-daily roflumilast cream 0.3% in patients with psoriasis. METHODS: In this open-label phase 2 trial, adult patients (N = 332) with psoriasis who completed the phase 2b parent trial or were newly enrolled applied roflumilast once-daily for 52 weeks. Safety and effectiveness were assessed. RESULTS: Overall, 244 patients (73.5%) completed the trial; 13 patients (3.9%) discontinued due to adverse events (AEs) and 3 (0.9%) due to lack of efficacy. Twelve patients (3.6%) reported treatment-related AEs; none were serious. ≥97% of patients had no irritation. No tachyphylaxis was observed with 44.8% of the patients achieving Investigator Global Assessment (IGA) Clear or Almost Clear at Week 52. LIMITATIONS: Intertriginous-IGA and Psoriasis Area and Severity Index (PASI) were not evaluated in all patients. CONCLUSIONS: In this long-term trial, once-daily roflumilast cream was well-tolerated and efficacious up to 64 weeks in patients in the earlier trial, suggesting it is suitable for chronic treatment, including the face and intertriginous areas.

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.

Validation of Acetylcholinesterase Inhibition Machine Learning Models for Multiple Species.

Acetylcholinesterase (AChE) is an important enzyme and target for human therapeutics, environmental safety, and global food supply. Inhibitors of this enzyme are also used for pest elimination and can be misused for suicide or chemical warfare. Adverse effects of AChE pesticides on nontarget organisms, such as fish, amphibians, and humans, have also occurred as a result of biomagnifications of these toxic compounds. We have exhaustively curated the public data for AChE inhibition data and developed machine learning classification models for seven different species. Each set of models were built using up to nine different algorithms for each species and Morgan fingerprints (ECFP6) with an activity cutoff of 1 µM. The human (4075 compounds) and eel (5459 compounds) consensus models predicted AChE inhibition activity using external test sets from literature data with 81% and 82% accuracy, respectively, while the reciprocal cross (76% and 82% percent accuracy) was not species-specific. In addition, we also created machine learning regression models for human and eel AChE inhibition to return a predicted IC50 value for a queried molecule. We did observe an improved species specificity in the regression models, where a human support vector regression model of human AChE inhibition (3652 compounds) predicted the IC50s of the human test set to a better extent than the eel regression model (4930 compounds) on the same test set, based on mean absolute percentage error (MAPE = 9.73% vs 13.4%). The predictive power of these models certainly benefits from increasing the chemical diversity of the training set, as evidenced by expanding our human classification model by incorporating data from the Tox21 library of compounds. Of the 10 compounds we tested that were predicted active by this expanded model, two showed >80% inhibition at 100 µM. This machine learning approach therefore offers the ability to rapidly score massive libraries of molecules against the models for AChE inhibition that can then be selected for future in vitro testing to identify potential toxins. It also enabled us to create a public website, MegaAChE, for single-molecule predictions of AChE inhibition using these models at megaache.collaborationspharma.com.

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.

Sustainability capacity of a vegetable gardening intervention for cancer survivors.

BACKGROUND: Health behavior interventions, especially those that promote improved diet and physical activity, are increasingly directed toward cancer survivors given their burgeoning numbers and high risk for comorbidity and functional decline. However, for health behavior interventions to achieve maximal public health impact, sustainability at both the individual and organizational levels is crucial. The current study aimed to assess the individual and organizational sustainability of the Harvest for Health mentored vegetable gardening intervention among cancer survivors. METHODS: Telephone surveys were conducted among 100 cancer survivors (mean age 63 years; primarily breast cancer) completing one-of-two Harvest for Health feasibility trials. Surveys ascertained whether participants continued gardening, and if so, whether they had expanded their gardens. Additionally, surveys were emailed to 23 stakeholders (Cooperative Extension county agents, cancer support group leaders, and healthcare representatives) who were asked to rate the intervention's ability to generate sustained service and produce benefits over time using the eight-domain Program Sustainability Assessment Tool (PSAT). RESULTS: The survey among cancer survivors (91.9% response rate) indicated that 85.7% continued gardening throughout the 12 months following intervention completion; 47.3% expanded their gardens beyond the space of the original intervention. Moreover, 5.5% of cancer survivors enrolled in the certification program to become Extension Master Gardeners. The survey among stakeholders generated a similar response rate (i.e., 91.3%) and favorable scores. Of the possible maximum of 7 points on the PSAT, the gardening intervention's "Overall Capacity for Sustainability" scored 5.7 (81.4% of the maximum score), with subscales for "Funding Stability" scoring the lowest though still favorably (5.0) and "Program Evaluation" scoring the highest (6.3). CONCLUSIONS: Data support the sustainability capacity of the Harvest for Health vegetable gardening intervention for cancer survivors. Indeed, few interventions have proven as durable in terms of individual sustainability. Furthermore, Harvest for Health's overall organizational score of 5.7 on the PSAT is considered strong when compared to a previous review of over 250 programs, where the mean overall organizational PSAT score was 4.84. Thus, solutions for long-term funding are currently being explored to support this strong, holistic program that is directed toward this vulnerable and growing population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02150148.

Effect of Roflumilast Cream vs Vehicle Cream on Chronic Plaque Psoriasis: The DERMIS-1 and DERMIS-2 Randomized Clinical Trials.

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis. Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis. Design, Setting, and Participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively. Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks. Main Outcomes and Measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points). Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2. Conclusions and Relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389.

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.

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.

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.

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.

Phylogeny and systematics of the Proterodiplostomidae Dubois, 1936 (Digenea: Diplostomoidea) reflect the complex evolutionary history of the ancient digenean group.

The Proterodiplostomidae Dubois, 1936 is a relatively small family of diplostomoidean digeneans parasitising the intestines of reptilian hosts associated with freshwater environments in tropical and subtropical regions. The greatest diversity of proterodiplostomids is found in crocodilians, although some parasitise snakes and turtles. According to the most recent revision, the Proterodiplostomidae included 17 genera within 5 subfamilies. Despite the complex taxonomic structure of the family, availability of testable morphology-based phylogenetic hypotheses and ancient hosts, molecular phylogenetic analyses of the group were practically lacking. Herein, we use novel DNA sequence data of the nuclear lsrRNA gene and mitochondrial cox1 gene from a broad range of proterodiplostomid taxa obtained from crocodilian, fish, and snake hosts on four continents to test the monophyly of the family and evaluate the present morphology-based classification system of the Proterodiplostomidae in comparison with the molecular phylogeny. This first detailed phylogeny for the Proterodiplostomidae challenges the current systematic framework. Combination of molecular phylogenetic data with examination of freshly collected quality specimens and re-evaluation of morphological criteria resulted in a number of systematic and nomenclatural changes along with a new phylogeny-based classification of the Proterodiplostomidae. As the result of our molecular and morphological analyses: (i) the current subfamily structure of the Proterodiplostomidae is abolished; (ii) three new genera, Paraproterodiplostomum n. g., Neocrocodilicola n. g. and Proteroduboisia n. g., are described and Pseudoneodiplostomoides Yamaguti, 1954 is restored and elevated from subgenus to genus level; (iii) two new species, Paraproterodiplostomum currani n. g., n. sp. and Archaeodiplostomum overstreeti n. sp., are described from the American alligator in Mississippi, USA. Comparison of the structure of terminal ducts of the reproductive system in all proterodiplostomid genera did not support the use of these structures for differentiation among subfamilies (or major clades) within the family, although they proved to be useful for distinguishing among genera and species. Our study includes the first report of proterodiplostomids from Australia and the first evidence of a snake acting as a paratenic host for a proterodiplostomid. A key to proterodiplostomid genera is provided. Questions of proterodiplostomid-host associations parasitic in crocodilians are discussed in connection with their historical biogeography. Our molecular phylogeny of the Proterodiplostomidae closely matches the current molecular phylogeny of crocodilians. Directions for future studies of the Proterodiplostomidae are outlined.

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.

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.