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ABSTRACT: Studies have described a highly convergent plan toward the synthesis of leiodolide A (1), a potent cytotoxic sponge metabolite. The enantiocontrolled preparation of aldehyde 6 is achieved with the application of several advances of methodology for the synthesis of substituted 1,3-oxazoles. Efforts have examined the halogen dance reaction, the selectivity of Stille cross coupling reactions of 4-bromo-1,3-oxazoles, and nucleophilic displacement of the 2-phenylsulfonyl substitu-ent with organolithium reagents as preparatively useful reactions. These techniques have facilitated the efficient synthesis of 6 from the starting bromide 12, alkenylstannane 16 and the primary nonracemic alcohol 25. 

ABSTRACT: A convergent route toward the synthesis of leiodolide A (1) is described. Our studies explore reactions of the indium chloride-induced transmetallation of allylic stannane 32 for nucleophilic addition with nonracemic aldehyde 15. The stereoselective formation of the all-syn stereotriad was rationalized by in situ isomerization to produce the Z-allylindium reagent for subsequent anti-Felkin addition. The inversion of C17 stereochemistry led to an effective -allyl Stille cross cou-pling utilizing Z-alkenylstannane 11b. The Horner–Wadsworth–Emmons reaction provides macrolactone 37 which exhibits discrepancies as compared to reported NMR data for purported leiodolide A. 

The global food system puts enormous pressure on the environment. Managing these pressures requires understanding not only where they occur (i.e., where food is produced), but also who drives them (i.e., where food is consumed). However, the size and complexity of global supply chains make it difficult to trace food production to consumption. Here, we provide the most comprehensive dataset of bilateral trade flows of environmental pressures stemming from food production from producing to consuming nations. The dataset provides environmental pressures for greenhouse gas emissions, water use, nitrogen and phosphorus pollution, and the area of land/water occupancy of food production for crops and animals from land, freshwater, and ocean systems. To produce these data, we improved upon reported food trade and production data to identify producing and consuming nations for each food item, allowing us to match food flows with appropriate environmental pressure data. These data provide a resource for research on sustainable global food consumption and the drivers of environmental impact. 

Abstract The production and consumption of food is one of the main drivers of environmental change globally. Meanwhile, many populations remain malnourished due to insufficient or unhealthy diets. Increasingly, dietary shifts are proposed as a means to address both environmental and health concerns. We have a limited understanding of how dietary shifts could alter where food is produced and consumed and how these changes would affect the distribution of environmental pressures both globally and across different groups of people. Here we combine new food flow data linking producing to consuming country with environmental pressures to estimate how a global shift to each of four diets (Indian, EAT-Lancet, Mediterranean, and mean Food Based Dietary Guidelines (FBDGs)) could affect environmental pressures at the global, country income group, and country level. Globally, cumulative pressures decrease under the Indian, EAT-Lancet, and Mediterranean scenarios and increase under FBDGs. On average, low income countries increase their cumulative consumption and production pressures while high income countries decrease their consumption pressures, and typically decrease their production pressures. Increases in low income countries are likely due to the nutritional inadequacy of current diets and the corresponding increases in consumption quantities with a shift to our diet scenarios. Despite these increases, we believe that three out four of our simulated dietary shifts can be seen as a net benefit by decreasing global pressures while low income countries increase pressures to adequately feed their populations. Additionally, considering principles of fairness applied, some nations are more responsible for causing historical environmental pressures and should shoulder more of the change. To facilitate more equitable shifts in global diets, resources, capacity, and knowledge sharing of sustainable agricultural practices are critical to minimize the increases in pressures that low income countries would incur to adequately feed their populations. 

Methodology is described for synthesis of C6 derivatives of raloxifene, a prescribed drug for the treatment and prevention of osteoporosis. Studies explore the incorporation of electron-withdrawing substituents at C6 of the benzothiophene core. Effi-cient processes are also examined to introduce hydrogen bond donor and acceptor functionality. Raloxifene derivatives are evaluated with in vitro testing to determine estrogen receptor (ER) binding affinity and gene expression in MC3T3 cells. 

Osteogenesis imperfecta (OI) is a hereditary bone disease in which gene mutations affect collagen formation, leading to a weak, brittle bone phenotype that can cause severe skeletal deformity and increased fracture risk. OI interventions typically repurpose osteoporosis medications to increase bone mass, but this approach does not address compromised tissue-level material properties. Raloxifene (RAL) is a mild anti-resorptive used to treat osteoporosis that has also been shown to increase bone strength by a-cellularly increasing bone bound water content, but RAL cannot be administered to children due to its hormonal activity. The goal of this study was to test a RAL analog with no estrogen receptor (ER) signaling but maintained ability to reduce fracture risk. The best performing analog from a previous analog characterization project, named RAL-ADM, was tested in an in vivo study. Female wildtype (WT) and Col1a2G610C/+ (G610C) mice were randomly assigned to treated or untreated groups, for a total of 4 groups (n=15). Starting at 10 weeks of age, all mice underwent compressive tibial loading 3×/week to induce an anabolic bone formation response in conjunction with RAL-ADM treatment (0.5 mg/kg; 5×/week) for 6 weeks. Tibiae were scanned via microcomputed tomography then tested to failure in four-point bending. RAL-ADM had reduced ER affinity, and increased post-yield properties, but did not improve bone strength in OI animals, suggesting some properties can be improved by RAL analogs but further development is needed to create an analog with decidedly positive impacts to OI bone. 

Several years ago, a small family of diterpenoid natural products attracted our attention as novel targets for synthesis studies. Initially, four compounds were independently characterized by the research teams of Vidari1 and Steglich.2 Trichoaurantianolides AeD (1e4 of Fig. 9.1) were isolated from fruiting bodies of the mushrooms Tricholoma aurantium and Tricholoma fracticum in 1995. Subsequent efforts of Stermer and coworkers3 described the isolation of the closely related lepistal (5) and lepistol (6) of Fig. 9.2 as the corresponding C8 deoxygenated compounds of this family. In addition, the corresponding acetate of trichoaurantianolide B was discovered and named as 6-O-aetyl- trichoaurantin (7).2 Structure assignments were based upon extensive nuclear magnetic resonance (NMR) studies, and the features of relative stereo- chemistry were confirmed by an X-ray crystallographic analysis of trichoaurantianolide B (2).1b,2 These original investigators described the trichoaurantianolides as examples of a new class of diterpenes named as neodolastanes that signified a structural relationship to the tricyclic metabo- lites of marine origins known as dolastanes as represented by dolatriol (8)4 and the clavularane 95 of Fig. 9.2. Neodolastanes were defined as substances in which the bridgehead methyl substituent appears in a vicinal relationship with respect to the isopropyl group as exemplified in 4,5-deoxyneodolabelline (10) of Fig. 9.2, a related class of marine natural products.6 Steglich and coworkers2 also indicated an assignment of absolute stereo- chemistry for 2 that was based on Hamilton’s applications of linear-hypothesis testing of crystallographic data. This seldom-used technique was in agreement with the proposed absolute configuration of 2 that was advanced by Vidari, based on an assessment of the observed Cotton effects in CD spectroscopy. In 2003, Ohta and coworkers7 reported the discovery of related neodolastanes tricholomalides A, B, and C (structures 11, 12, and 13 of Fig. 9.3) from Tricholoma sp. They concluded that the tricholomalides possessed the opposite absolute configuration claimed for the trichoaurantianolides. This conclusion was based upon the independent analysis of their circular dichroism studies. By application of the octant rule for substituent effects on cisoid a,b- unsaturated ketones,8 Ohta and coworkers suggested a revision of the prior assignment of absolute configuration for the trichoaurantianolides. This asser- tion was advanced in spite of the consistently positive specific rotations recorded in different solvents for trichoaurantianolides A, B, and C1,2 versus the negative values of tricholomalides A (11) and B (12) (compare values in Figs. 9.1 and 9.3). Note that tricholomalide C (13) only differs from trichoaurantianolide B (2) as a C-8 diastereomeric alcohol, presented in the antipodal series. The specific rotation of 13 was of little value since it was recorded as [a]0 (c 0.01, MeOH).7 In 2006, Danishefsky described a pathway for the total synthesis of racemic tricholomalides A and B, and this effort led to a revision of the relative C-2 stereochemistry (Fig. 9.3; revised structures 14 and 15).9 It seemed rather unusual that genetically similar fungi would produce closely related metabolites as enantiomers, but certainly this is not unprecedented. As a starting point, this issue lacked clarity, and we concluded that our synthesis plans must unambig- uously address the issues of absolute configuration. The chemistry of dolabellane and dolastane diterpenes has been reviewed.10 The proposed pathway for biosynthesis of the trichoaurantianolides and related compounds (Fig. 9.4) follows an established sequence from geranyl- geranyl pyrophosphate (16), which undergoes p-cation cyclization to initially form the eleven-membered ring of 17. The event is followed by a second cyclization to form the dolabellane cation 18, and this [9.3.0]cyclotetradecane skeleton is central to several families of natural products. Direct capture or elimination from 18 leads to the 3,7-dolabelladiene 19, which presents the most common pattern of unsaturation within this class. Compounds within this group are traditionally numbered beginning with C-1 as the bridgehead carbon bearing the methyl group rather than following the connectivity presented in ger- anylgeranyl 16. The cation 18 also undergoes a 1,2-hydrogen migration and elimination, which leads to a transannular cyclization yielding the 5e7e6 tri- cyclic dolastane 20. The secodolastanes, represented by 21, are a small collec- tion of marine natural products, which arise from oxidative cleavage of C10eC14 in the parent tricycle 20. In analogous fashion, the neodolabellane structure 22 is produced from 18 by stereospecific backbone migrations that result in the vicinal placement of the bridgehead methyl and isopropyl substituents. Transannular cyclizations, stemming from 22, yield the class of neodolastane diterpenes (23). Trichoaurantianolides and the related lepistal A (5) are the result of oxidations and cleavage of the C-ring (C4eC5) of 23, which leads to the features of an unusual butyrolactone system. The guanacastepenes, such as 24,11 and heptemerones, such as 25,12 are primary examples of the 5e7e6 neodolastane family, and these metabolites have also been isolated from fungi sources. A characteristic structural feature is the vicinal, syn-relationship of the bridgehead methyl and isopropyl sub- stituents as compared with the 1,3-trans relationship found in dolastanes (Fig. 9.2, structures 8 and 9). Guanacastepenes have proven to be attractive targets for synthesis studies.11,13 However, these fungal metabolites exhibit the antipodal, absolute stereochemistry as compared with neodolastanes from marine origins, such as sphaerostanol (26) (Fig. 9.5).14 

Abstract Achieving sustainable development requires understanding how human behavior and the environment interact across spatial scales. In particular, knowing how to manage tradeoffs between the environment and the economy, or between one spatial scale and another, necessitates a modeling approach that allows these different components to interact. Existing integrated local and global analyses provide key insights, but often fail to capture ‘meso-scale’ phenomena that operate at scales between the local and the global, leading to erroneous predictions and a constrained scope of analysis. Meso-scale phenomena are difficult to model because of their complexity and computational challenges, where adding additional scales can increase model run-time exponentially. These additions, however, are necessary to make models that include sufficient detail for policy-makers to assess tradeoffs. Here, we synthesize research that explicitly includes meso-scale phenomena and assess where further efforts might be fruitful in improving our predictions and expanding the scope of questions that sustainability science can answer. We emphasize five categories of models relevant to sustainability science, including biophysical models, integrated assessment models, land-use change models, earth-economy models and spatial downscaling models. We outline the technical and methodological challenges present in these areas of research and discuss seven directions for future research that will improve coverage of meso-scale effects. Additionally, we provide a specific worked example that shows the challenges present, and possible solutions, for modeling meso-scale phenomena in integrated earth-economy models. 

Abstract The deaths of massive stars are sometimes accompanied by the launch of highly relativistic and collimated jets. If the jet is pointed towards Earth, we observe a ‘prompt’ gamma-ray burst due to internal shocks or magnetic reconnection events within the jet, followed by a long-lived broadband synchrotron afterglow as the jet interacts with the circumburst material. While there is solid observational evidence that emission from multiple shocks contributes to the afterglow signature, detailed studies of the reverse shock, which travels back into the explosion ejecta, are hampered by a lack of early-time observations, particularly in the radio band. We present rapid follow-up radio observations of the exceptionally bright gamma-ray burst GRB 221009A that reveal in detail, both temporally and in frequency space, an optically thick rising component from the reverse shock. From this, we are able to constrain the size, Lorentz factor and internal energy of the outflow while providing accurate predictions for the location of the peak frequency of the reverse shock in the first few hours after the burst. These observations challenge standard gamma-ray burst models describing reverse shock emission.