bluuebunny/crossref_metadata_2025 huggingface dataset:
Bayesian Models
Authors: Elsner James B. , Jagger Thomas H.
Published: November 2020

In this chapter, we focus on Bayesian modeling. Information about past hurricanes is available from instruments and written accounts. Written accounts are generally less precise than instrumental observations, which tend to become even more precise as technology advances. Here we show you how to build Bayesian models that make use of the available information while accounting for differences in levels of precision. We begin with a model for U.S. hurricane frequency and finish with a space–time model for basin-wide occurrences. We start with a model for predicting U.S. hurricane activity over the next three decades. The model is useful as a benchmark for climate change studies. The methodology was originally presented in Elsner and Bossak (2001) based on the formalism given in Epstein (1985). As you have seen throughout this book, the arrival of hurricanes on the coast is usefully considered a stochastic process, where the annual counts are described reasonably well by a Poisson distribution. The Poisson distribution is a limiting form of the binomial distribution with no upper bound on the number of occurrences and where the parameter λ characterizes the rate process. Knowledge of λ allows you to make statements about future hurricane frequency. Since the process is stochastic, your statements will be given in terms of probabilities (see Chapter 7). For example, the probability of ĥ hurricanes occurring over the next T years (e.g., 1, 5, 20, etc.) is . . . f (ĥ |λ,T) = exp(−λT) (λT)h/h! for h = 0,1,. . . , λ>0, and T > 0 (12.1) . . . The hat notation is used to indicate future values. The parameter λ and statistic T appear in the formula as a product, which is the mean and variance of the distribution. Knowledge about λ can come from historical written archives and instrumental records. It is logical for you to want to use as much of this information as possible before inferring something about future activity. This requires you to treat λ as a parameter that can be any positive real number, rather than as a fixed constant. One form for expressing your judgment about the values λ can take is through the gamma distribution.
Impact Models
Authors: Elsner James B. , Jagger Thomas H.
Published: November 2020

In this chapter, we show some broader applications of our models and methods. We focus on impact models. Hurricanes are capable of generating large financial losses. We begin with a model that estimates extreme losses conditional on climate covariates. We then describe a method for quantifying the relative change in potential losses over the decades. Financial losses from hurricanes are to some extent directly related to fluctuations in climate. Environmental factors influence the frequency and intensity of hurricanes at the coast as detailed throughout this book (see for example Chapters 7 and 8). So, it is not surprising that these same environmental signals appear in estimates of losses. Here loss is the economic damage associated with a hurricane’s direct impact. A normalization procedure adjusts the loss estimate from a past hurricane to what it would be if the same cyclone struck in a recent year by accounting for inflation and changes in wealth and population over the intervening time, plus a factor to account for changes in the number of housing units exceeding population growth. The method produces loss estimates that can be compared over time (Pielke et al. 2008). Here you focus on losses exceeding one billion ($ U.S.) that have been adjusted to 2005. The loss data are available in Losses.txt in JAGS format (see Chapter 9). Input the data by typing . . . > source("Losses.txt"). . . The log-transformed loss amounts are in the column labeled ‘y’. The annual number of loss events are in the column labeled ‘L’. The data cover the period 1900–2007. More details about these data are given in Jagger et al. (2011). You begin by plotting a time series of the number of losses and a histogram of total loss per event. . . . > layout(matrix(c(1, 2), 1, 2, byrow=TRUE), + widths=c(3/5, 2/5)) > plot(1900:2007, L, type="h", xlab="Year", + ylab="Number of Loss Events") > grid() > mtext("a", side=3, line=1, adj=0, cex=1.1) > hist(y, xlab="Loss Amount ($ log)", + ylab="Frequency", main="") > mtext("b", side=3, line=1, adj=0, cex=1.1) . . .
Viva Los Suns
Authors: Ross Andrew
Published: November 2020

In other Southwestern cities, like Tucson, El Paso, and Albuquerque, with Mexican urban cores that preexisted Anglo settlement, a cultural, if not political, condominium of power sharing had evolved over time. Phoenix was a more straightforward product of Anglo America. Notwithstanding that Trinidad Mejia Escalante, the wife of the founding father, Jack Swilling, was Mexican, the city’s origin myth was one of Anglos re-creating a city on top of Hohokam remnants, and it was reinforced by a strong presence of Mormon settlers in the East Valley, with their own version of white pioneerism. Anglo dominance was unquestioned for at least a century. As an early twentieth-century promoter put it, Phoenix was “a modern town of 40,000 people, and the best kind of people too. A very small percentage of Mexicans, negroes, or foreigners.” For sure, the public drama and energy of the civil rights era ushered some nonwhite politicians into high office—Raul Castro became governor and Alfredo Gutierrez senate majority leader in the late 1970s. But it was only in recent years that Anglo ascendancy had been challenged by the mercurial growth of the Latino population (according to the 2010 U.S. census, 30.8 percent of the state, 31.8 percent of Maricopa County, and 34.1 percent of Phoenix itself, all numbers that had more than doubled since 1990), spreading well beyond the traditional barrio districts where its political representatives had been contained. Anxiety about the decline of demographic and political dominance was a new wrinkle in the ongoing debate about population growth that Phoenix had long hosted. Historically, most of the anxiety about growth was founded, with good reason, on fears that water supplies would not be adequate for the rapidly expanding urban needs. Concerns about the deterioration of air quality, wilderness loss, and the overall environmental impact of urban sprawl had sharpened the anxiety over time. But the influx of Mexican immigrants from the south after the passage of NAFTA changed its tenor. Metro Phoenix had only 86,593 foreign-born residents in 1980, and by 2005, 612,850 were foreign-born, most of them from Mexico.
Wind Power in the United States
Authors: Valentine Scott
Published: November 2020

There is a lot of money on the line in America’s energy sector and where there is money, there is politics. In 2011, Exxon reported revenues of US$486 billion and after-tax profits of US$41 billion. Only 27 nations generated more GDP than Exxon generated in revenues. As of 2011, Exxon reported over US$214 billion invested into property, plant, and equipment. In short, there are a lot of sunk costs to defend. In the coal sector, America’s Peabody Energy, which is the world’s largest private sector coal company, posted US$8.077 billion in revenue in 2012. Understandably, America’s energy sector is one of the most hotly contested marketplaces in the world and in this marketplace, fossil fuel interests rule the roost. On the other hand, 9/11 and the ensuing military response have engendered a change in the ideological underpinnings of American energy security efforts. Even conservative factions that have typically supported a free trade energy policy have now begun to talk about the importance of ensuring control over domestic energy security. One study by Oak Ridge National Laboratory estimated that between 1970 and 2004, American dependence on foreign oil has cost the country $5.6–$14.6 trillion. This reflects both the cost of the oil and the direct economic consequences of macroeconomic shocks and transfers of wealth. Another more recent study estimated that oil dependence in the United States exceeded US$500 billion for 2008 alone. These claims are supported by trade data. The United States purchases more than 60% of its oil from foreign sources each year and the cost of petroleum products is the single largest contributor—48%—to the country’s US$700 billion trade deficit. Supply costs aside, one study recently concluded that the military costs in the Persian Gulf needed to protect oil assets and infrastructure range from US$50 billion to $100 billion per year; a second, independent study put the figure at between US$29 billion and $80 billion per year. The United States is spending billions each year to protect a supply chain that is in part responsible for financing terrorist activities such as the 2001 attack on New York’s World Trade Center buildings.
Scaling Down
Authors: Steinberg Paul F.
Published: November 2020

Dominical is a small town nestled on the Pacific coast of Costa Rica, where tropical forests spill onto the sandy shores of its world-renowned beaches. Dominical has a laid-back atmosphere of surf shops, open-air restaurants, and children in school uniforms weaving between the puddles and rocks on their way to class. But behind the scenes, something else is going on in Dominical. A clue can be found alongside the dirt road that runs through the center of town, where a billboard for Century 21 Real Estate depicts a happy couple overlooking their oceanfront property, accompanied by the English-language caption “Your Piece of Paradise!” The sign provides a glimpse of the larger forces at play in this remote corner of Central America. A frenzy of speculative real estate development is underway, led by foreigners vying for their own piece of paradise before the remaining lots are all sold by the local farmers whose families have inhabited the land for generations. One such farmer is Juan Carlos Madrigal. I visited Juan Carlos with a group of students in 2008 during one of my annual trips to Costa Rica, to learn more about how local landowners are coping with these pressures. This land has been in his family for a long time, its towering tropical forest encompassing tree plantations, bean, and cocoa crops, and sweeping views of the ocean. After a hike across the property, we cooled off in a swimming hole below a large waterfall, one of many in the area, which thundered down from the lush jungle above, the water volume swollen by seasonal rains. After toweling off we sat down and began the interview, discussing his vision for the future of this land. A humble yet dignified man with wrinkles deepened from decades of farming, Madrigal reported that a group of Americans had recently approached him with an offer to buy his property for a million dollars. Shaking his head, he said that of course he refused.
The Allure of Order: Rationalizing Schools from the Progressives to the Present
Authors: Mehta Jal
Published: November 2020

In late 2001, three months after the September 11 attacks, the No Child Left Behind Act (NCLB) passed both House and Senate with strong bipartisan majorities and was signed by a Republican president. Promising to use the power of the state to ensure that all children were proficient in reading and math by 2014, proponents heralded the act as the greatest piece of federal education legislation since the creation of the original Elementary and Secondary Education Act in 1965. By requiring the states to set high standards, pairing them with assessments that measured whether students were achieving those standards, and holding schools accountable if students failed to do so, NCLB, in the eyes of its sponsors, would close achievement gaps and make America’s schools the envy of the world. A decade later, the bloom is off the rose. While almost everyone today continues to share the aim of leaving no child behind, the act itself has come in for criticism from many quarters, to the point that Bush’s former Education Secretary Margaret Spellings declared that NCLB is now a “toxic brand” in American politics. Careful studies of the implementation of NCLB have shown that it has done what less bullish observers might have predicted from the outset. It has increased the focus on the education of poor and minority students, but it has not provided schools with needed tools to create higher quality schooling for these students. There has been improvement in some national test scores (e.g., 4th and 8th grade math), while others have remained largely unchanged (e.g., 4th and 8th grade reading). Even accounting for the progress in math, there is no sign that the reforms have had a significant impact in closing achievement gaps or in improving America’s mediocre international educational standing. Particularly in the most troubled schools, there has been rampant teaching to the test and some outright cheating. In-depth studies have shown that some schools now devote a large part of their year to test prep; Atlanta and DC public schools have both contended with widespread cheating scandals.
The Cultural Struggle for Control over Schooling: The Power of Ideas and the Weakness of the Educational Field
Authors: Mehta Jal
Published: November 2020

How can we best understand the repeated eff orts to rationalize schools across the 20th century? Traditional approaches to explaining political phenomena—interest groups, institutions, partisan theories, and rational choice—are limited in their ability to explain this recurring impulse. Instead, a complementary set of cultural lenses—ideas, professions, fields, logics, moral power, and institutional vantage points—can shed more light on these repeated movements. Together, these perspectives also offer a different way of thinking about the nature of social and political contestation, one that is deeply cultural in its ontology and that integrates ideas, interests, and institutions, links the social and the political, and explains both continuity and change. In one sense, movements to “rationalize” schools have cycled across the 20th century. As will be discussed in more detail in the chapters to come, at three different times reformers have embraced the rationalization of schools. In the Progressive Era, a group of reformers, comprising mostly businessmen, city elites, and university professors, sought to shift power from large, local ward boards, which they viewed as parochial and unprofessional, to smaller boards controlled by professional elites. They made the superintendent the equivalent of the CEO of the school system and directed him to use the latest in scientific methods and modern management techniques to measure outcomes and to ensure that resources were being used efficiently to produce the greatest possible bang for the buck. The newly emerging science of testing was widely employed to ensure that teachers and schools were meeting standards and to sort students into appropriate tracks, with the aim of “efficiently” matching students with the curriculum appropriate to their ability. In the late 1960s and early 1970s, a second accountability movement sought to take hold of American schooling. Seeking to realize both a civil rights agenda of improving the quality of schooling and to satisfy more conservative concerns about the efficient spending of public dollars, state after state passed laws designed to inject greater accountability into the school system.
The Return of the Two Depressions (and an Anxious Postscript)
Authors: Shorter Edward
Published: November 2020

Before 1980 there had been two depressions, melancholia—also called endogenous depression—and nonmelancholia, called a number of terms such as reactive depression and neurotic depression. DSM-III flattened this distinction, abolishing the clinical distinction between the two with the homogenizing term major depression. To be sure, DSM-III reinserted the term melancholia in the discussion as a subtype of major depression, but only in letter, not in spirit. In the decades after 1980 melancholia returned, but to a landscape of mood disorder that had been leveled and laid waste by the concept of “depression.” In a world where everybody is depressed, nobody is melancholic. Emil Kraepelin had sent the diagnosis of melancholia into a death spiral. The psychoanalysts had little interest in the concept, aside from venerating a single essay of Freud, and the only people interested in keeping melancholia alive as a notion after the 1930s were the British who, with their admixture of Heidelberg science and homegrown common sense, had turned into shrewd psychopathologists. The textbook that Willi Mayer-Gross, a Heidelberg refugee, published in 1954 together with Eliot Slater and Martin Roth gave pride of place to involutional melancholia as the serious melancholic illness that oft en affected people at midlife and afterward. But world psychiatry after World War II marched to an increasingly American beat, and the Americans had little use for the antique term melancholia. The glossary of Alfred Freedman’s Comprehensive Textbook of Psychiatry, the world’s leading textbook first published in 1967, had scads of psychoanalytic terms but claimed of melancholia: “Old term for depression that is rarely used at the present time.” In Europe after World War II, endogenous depression was the serious variety and melancholia was deemed as “contaminated by Freud and the 19th century novels that degraded it to grief,” as Tom Ban, who trained in Budapest in the early 1950s, put it. “For Kraepelinians, grief and depression were not the same, and they excluded each other. Anyone who had an identifiable precipitating factor could not be labeled as having a depressive state.”
Save That Game: 1915– 1919
Authors: Lorbiecki Marybeth
Published: November 2020

On January 15, 1915, a week after returning from his father’s funeral and two days before his twenty-eighth birthday, Leopold handed in a memo on how to restore game in District 3. He proposed that Forest Service policy should: • Consider game animals as forest “products” (just as trees are); • Manage the wild species scientifically for count and quality; Set aside land for game refuges where hunting permits would be sold and limited; • Use the profits to pay rangers to work on predator control and enforce state game laws. A plan that covered these points, claimed Leopold, could successfully bring game back to the forests of the Southwest. Ringland gave the memo his ardent approval. He recognized that, in essence, Leopold was asking the Forest Service to expand its definition of its responsibilities, and the proposal had importance for forests nationwide. Ringland advised Leopold to schedule a meeting with a representative from the Washington, DC office, Leon Kneipp. Kneipp rejected Leopold’s plan. The Forest Service would not sink any money into an expensive gamble. Kneipp felt that rangers should protect game out of a sense of public duty, and not expect any pay or time off from their tasks to do so. Nor would the Forest Service set aside land for game refuges until the public demanded it. Needless to say, Leopold was disappointed. The rejection came at a time when he faced head on the shortsightedness of the Forest Service’s policies in the grazing office. Leopold could see no way to encourage new seedlings without granting fewer grazing permits. His supervisor, John Kerr, cared only about revenues. He pushed Leopold to increase the number of permits, as well as to work out the forms and petty details. The two ended up in daily headlocks. Frustration built up in Leopold like a mountain storm. Ringland hated to see one of his most innovative foresters wasted in paperwork. He knew he would lose Leopold if he didn’t act quickly to find a position that suited Aldo’s ambitions and abilities.
Aldo’s Students and Colleagues
Authors: Lorbiecki Marybeth
Published: November 2020

As you walk into the current University of Wisconsin-Madison’s Department of Forest and Wildlife Ecology, on the second floor of Russell Laboratories, you’ll see it is a far cry from Leopold’s 424 Farm Place, next to the university cow barns. Even so, resting just outside the department’s office door is a handmade Leopold Bench—one of those simply designed pieces with crossed-plank legs holding up a plank seat and back. As the Environmental Protection Agency’s Landscaping site states: “To spy a Leopold bench in someone’s yard is to know something about the family who there resides. … Its form, resting alone under a tree or in congregation around a fire-pit, reminds us of Leopold’s thoughtfulness.” This handmade blond bench, though, is over a half-century old. It was a gift to the Professor from his department—and wood-burned into it are the names of Aldo’s secretaries and graduate students for him to remember them by, and now for us to do the same. The department, of course, has changed radically since Aldo unexpectedly left. It web page displays a photo of Aldo in the upper corner and lists twenty-two faculty members, four of whom are women (which he would have liked). The fields of expertise presented at first seem like Leopold methods and topics on steroids: forest biometry, forest genetics, molecular ecology, forest remote sensing, spatial analysis, modern climate change. Other specialties are perspectives he had already been integrating into his thinking and planning: landscape ecology, forest ecosystem ecology, tree physiology, forest and environmental history, conservation biology, land use/land cover change, hydrology, population dynamics, conservation management extension, resource policy, ecosystem management, society and natural resources. Scanning the expertise of the emeritus and affiliate faculty, you can see even further outgrowths of Leopold’s far-ranging, integrated thinking and imagining: forest pathology, natural resource and land economics, biogeochemistry, international forestry, development planning, recreation management, economic forecasting, forest soils, human behavior and resource management, nutrient and carbon cycling in forest, nursery, and urban ecosystems.
Oxidation and Reduction
Authors: Taber Douglass F.
Published: November 2020

Kiyotomi Kaneda of Osaka University devised (Angew. Chem. Int. Ed. 2010, 49, 5545) gold nanoparticles that efficiently deoxygenated an epoxide 1 to the alkene 2. Robert G. Bergman of the University of California, Berkeley, and Jonathan A. Ellman, now of Yale University, reported (J. Am. Chem. Soc. 2010, 132, 11408) a related protocol for deoxygenating 1,2-diols. Dennis A. Dougherty of Caltech established (Org. Lett. 2010, 12, 3990) that an acid chloride 3 could be reduced to the phosphonate 4. Pei-Qiang Huang of Xiamen University effected (Synlett 2010, 1829) reduction of an amide 5 by activation with Tf2O followed by reduction with NaBH4. André B. Charette of the Université de Montreal described (J. Am. Chem. Soc. 2010, 132, 12817) parallel results with Tf2O/Et3SiH. David Milstein of the Weizmann Institute of Science devised (J. Am. Chem. Soc. 2010, 132, 16756) a Ru catalyst for the alternative reduction of an amide 7 to the amine 8 and the alcohol 9. Shi-Kai Tian of the University of Science and Technology of China effected (Chem. Commun. 2010, 46, 6180) reduction of a benzylic sulfonamide 10 to the hydrocarbon 11. Thirty years ago, S. Yamamura of Nagoya University reported (Chem. Commun. 1967, 1049) the efficient reduction of a ketone to the corresponding methylene with Zn/HCl. Hirokazu Arimoto of Tohoku University established (Tetrahedron Lett. 2010, 51, 4534) that a modified Zn/TMSCl protocol could be used following ozonolysis to effect conversion of an alkene 12 to the methylene 13. José Barluenga and Carlos Valdés of the Universidad de Oviedo effected (Angew. Chem. Int. Ed. 2010, 49, 4993) reduction of a ketone to the ether 16 by way of the tosylhydrazone 14. Kyoko Nozaki and Makoto Yamashita of the University of Tokyo and Dennis P. Curran of the University of Pittsburgh found (J. Am. Chem. Soc. 2010, 132, 11449) that the hydride 18 (actually a complex dimer) could effect the direct reduction of a halide 17 and also function as the hydrogen atom donor for free radical reduction and as the hydride donor for the Pd-mediated reduction of an aryl halide.
Functionalization and Homologation of C-H Bonds
Authors: Taber Douglass F.
Published: November 2020

Justin Du Bois of Stanford University developed (J. Am. Chem. Soc. 2010, 132, 10202) a Ru catalyst for the stereoretentive hydroxylation of 1 to 2. John T. Groves of Princeton University effected (J. Am. Chem. Soc. 2010, 132, 12847) equatorial chlorination of the test substrate 3. Kenneth M. Nicholas of the University of Oklahoma found (J. Org. Chem. 2010, 75, 7644) that I2 catalyzed the amination of 5. Thorsten Bach of the Technische Universität München established (Org. Lett. 2010, 12, 3690) that the amination of 7 proceeded with significant diastereoselectivity. Phil S. Baran of Scripps/La Jolla compiled (Synlett 2010, 1733) an overview of the development of C-H oxidation. Tethering can improve the selectivity of C-H functionalization. X. Peter Zhang of the University of South Florida devised (Angew. Chem. Int. Ed. 2010, 49, 10192) a Co catalyst for the cyclization of 9 to 10. Teck-Peng Loh of Nanyang Technological University established (Angew. Chem. Int. Ed. 2010, 49, 8417) conditions for the oxidation of 11 to 12. Jin-Quan Yu, also of Scripps/La Jolla, effected (J. Am. Chem. Soc. 2010, 132, 17378) carbonylation of methyl C-H of 13 to give 14. Sunggak Kim, now also at Nanyang Technological University, established (Synlett 2010, 1647) conditions for the free-radical homologation of 15 to 17. Gong Chen of Pennsylvania State University extended (Org. Lett. 2010, 12, 3414) his work on remote Pd-mediated activation by cyclizing 18 to 19. Many schemes have been developed in recent years for the oxidation of substrates to reactive electrophiles. Gonghua Song of the East China University of Science and Technology and Chao-Jun Li of McGill University reported (Synlett 2010, 2002) Fe nanoparticles for the oxidative coupling of 20 with 21. Zhi-Zhen Huang of Nanjing University found (Org. Lett. 2010, 12, 5214) that protonated pyrrolidine 25 was important for mediating the site-selective coupling of 24 with 23. Y. Venkateswarlu of the Indian Institute of Chemical Technology, Hyderabad, was even able (Tetrahedron Lett. 2010, 51, 4898) to effect coupling with a cyclic alkene 28. AB3217-A 32, isolated in 1992, was shown to have marked activity against two spotted spider mites. Christopher R. A. Godfrey of Syngenta Crop Protection, Münchwilen, prepared (Synlett 2010, 2721) 32 from commercial anisomycin 30a. The key step in the synthesis was the oxidative cyclization of 30b to 31.
Stereocontrolled Construction of Arrays of Stereogenic Centers: The Mullins Synthesis of (-)-Lasiol
Authors: Taber Douglass F.
Published: November 2020

Hisashi Yamamoto of the University of Chicago devised (J. Am. Chem. Soc. 2010, 132, 7878) catalyst systems for the enantioselective epoxidation of a Z -homoallylic alcohol 1. Michael J. Krische of the University of Texas developed (J. Am. Chem. Soc. 2010, 132, 1760) a catalyst system for the highly stereoselective addition of the vinyl acetal 5 to an aldehyde 4. Joëlle Prunet of the University of Glasgow showed (Tetrahedron Lett. 2010, 51, 256) that the tandem cyclization/Julia olefination from 7 also proceeded with high stereocontrol. Professor Yamamoto established (J. Am. Chem. Soc. 2010, 132, 5354) that depending on conditions, the aldol condensation of 10 could be directed selectively toward either diastereomer of the product 12. James M. Takacs of the University of Nebraska effected (J. Am. Chem. Soc. 2010, 132, 1740) the enantioselective hydroboration of 10. The other geometric isomer of 10 gave the alternative diastereomer of 12, also with high ee. John Limanto and Shane W. Krska of Merck Process optimized (Organic Lett . 2010, 12, 512) the dynamic kinetic reduction of 13 , giving 14 with excellent diastereocontrol. Professor Krische extended (J. Am. Chem. Soc. 2010, 132, 4562) his reductive homologation to the (racemic) carbonate 15, delivering 16 with excellent dr and ee. Hirokazu Urabe of the Tokyo Institute of Technology showed (Organic Lett. 2010, 12, 1012) that a Grignard reagent under iron catalysis opened the epoxide 17, readily available by Jørgensen-Cordova epoxidation followed by homologation, with clean inversion and high regiocontrol. Fraser F. Fleming of Duquesne University developed (Organic Lett. 2010, 12, 3030) a general route to quaternary alkylated centers by alkylation of nitriles such as 19. Shigeki Matsunaga and Masakatsu Shibasaki of the University of Tokyo devised (J. Am. Chem. Soc. 2010, 132, 3666) a Ni catalyst for the stereoselective conjugate addition of the lactam 22 to a nitroalkene 21. Aldehydes can also be added to nitroalkenes with high dr and ee, as illustrated by the conversion of 24 to 26 reported (J. Am. Chem. Soc. 2010, 132, 50) by Bukuo Ni of Texas A&M University, Commerce.
Substituted Benzenes: The Kirsch Synthesis of Cybrodol
Authors: Taber Douglass F.
Published: November 2020

Stephen L. Buchwald of MIT established (J. Am. Chem. Soc. 2010, 132, 14076) a Pd-catalyzed protocol for conversion of an aryl triflate 1 to the halide 2. Jie Wu of Fudan University prepared (Tetrahedron Lett. 2010, 51, 6646) aromatic halides from the corresponding carboxylic acids. Yong-Chua Teo of Nanyang Technological University described (Tetrahedron Lett . 2010, 51, 3910) the Mn-mediated conversion of 3 to 5, suggesting a benzyne intermediate. Takanori Shibata of Waseda University effected (Synlett 2010, 2601) the direct Ru-mediated coupling of aryl halides with amines, and Paul Helquist of the University of Notre Dame prepared (J. Org. Chem. 2010, 75, 4887) anilines by coupling aryl halides with NaN3 . Chao-Jun Li of McGill University devised (Tetrahedron Lett. 2010, 51, 5486) the Pd-catalyzed decarbonylative Heck coupling of 6 with 7 to give 8. Mats Larhed of Uppsala University showed (Angew. Chem. Int. Ed. 2010, 49, 7733) that Pd could also catalyze the decarboxylative coupling of an aromatic acid 9 with a nitrile to give the ketone 10. Dennis G. Hall of the University of Alberta found (Tetrahedron Lett. 2010, 51, 4256) that an areneboronic acid could promote the Zr-catalyzed ortho condensation of a phenol 11 with an aldehyde, leading to 12, which could then be carried on to a range of other products. Professor Hall also showed (Angew. Chem. Int. Ed. 2010, 49, 2883) that areneboronic acids are stable to many standard organic transformations, and that the product boronic acids can be readily purified by extraction into sorbitol/Na2CO3. Professor Buchwald reported (J. Am. Chem. Soc. 2010, 132, 14073) an optimized source of Pd for the Suzuki-Miyaura coupling, allowing the room-temperature participation even of unstable boronic acids such as 13. Wing-Yiu Yu of the Hong Kong Polytechnic University observed (J. Am. Chem. Soc. 2010, 132, 12862) that 17 was an effective donor for the Pd-catalyzed ortho C-H amination of 16. Nicholas C. O. Tomkinson of Cardiff University uncovered (Synlett 2010, 2471) the facile rearrangement of 19 to 20. Professor Buchwald described (J. Am. Chem. Soc. 2010, 132, 9990) the coupling of 21, prepared from the aryl halide, with 22 to give the benzofuran 23.
Other Methods for Carbocyclic Construction: The Porco Synthesis of (-)-Hyperibone K
Authors: Taber Douglass F.
Published: November 2020

Varinder K. Aggarwal of the University of Bristol described (Angew. Chem. Int. Ed. 2010, 49, 6673) the conversion of the Sharpless-derived epoxide 1 into the cyclopropane 2. Christopher D. Bray of Queen Mary University of London established (Chem. Commun. 2010, 46, 5867) that the related conversion of 3 to 5 proceeded with high diastereocontrol. Javier Read de Alaniz of the University of California, Santa Barbara, extended (Angew. Chem. Int. Ed. 2010, 49, 9484) the Piancatelli rearrangement of a furyl carbinol 6 to allow inclusion of an amine 7, to give 8. Issa Yavari of Tarbiat Modares University described (Synlett 2010, 2293) the dimerization of 9 with an amine to give 10. Jeremy E. Wulff of the University of Victoria condensed (J. Org. Chem. 2010, 75, 6312) the dienone 11 with the commercial butadiene sulfone 12 to give the highly substituted cyclopentane 13. Robert M. Williams of Colorado State University showed (Tetrahedron Lett. 2010, 51, 6557) that the condensation of 14 with formaldehyde delivered the cyclopentanone 15 with high diastereocontrol. D. Srinivasa Reddy of Advinus Therapeutics devised (Tetrahedron Lett. 2010, 51, 5291) conditions for the tandem conjugate addition/intramolecular alkylation conversion of 16 to 17. Marie E. Krafft of Florida State University reported (Synlett 2010, 2583) a related intramolecular alkylation protocol. Takao Ikariya of the Tokyo Institute of Technology effected (J. Am. Chem. Soc. 2010, 132, 11414) the enantioselective Ru-mediated hydrogenation of bicyclic imides such as 18. This transformation worked equally well for three-, four-, five-, six-, and seven-membered rings. Stefan France of the Georgia Institute of Technology developed (Org. Lett. 2010, 12, 5684) a catalytic protocol for the homo-Nazarov rearrangement of the doubly activated cyclopropane 20 to the cyclohexanone 21. Richard P. Hsung of the University of Wisconsin effected (Org. Lett. 2010, 12, 5768) the highly diastereoselective rearrangement of the triene 22 to the cyclohexadiene 23. Strategies for polycyclic construction are also important. Sylvain Canesi of the Université de Québec devised (Org. Lett. 2010, 12, 4368) the oxidative cyclization of 24 to 25.
The Dixon Synthesis of (-)-Nakadomarin A
Authors: Taber Douglass F.
Published: November 2020

(-)-Nakadomarin A 4, isolated from the sponge Amphimedon sp. off the coast of Okinawa, shows interesting antifungal and antibacterial activity. The key step in the total synthesis of 4 reported (J. Am. Chem. Soc. 2009, 131, 16632) by Darren J. Dixon of the University of Oxford was the diastereoselective addition of the enantiomerically pure ester 1 to the prochiral nitroalkene 2. The assembly of 2 began with the linchpin ketophosphonate 5. Alkylation of the dianion of 5 with allyl bromide followed by direct condensation of the resulting monoanion with the diacetate 6 gave 7. On exposure to aqueous acid, 7 cyclized to the furan. Oxidation of the liberated primary alcohol followed by condensation with nitromethane then completed the preparation of 2. The starting material for the synthesis of 1 was the enantiomerically pure pyroglutamate derivative 8. Sulfide displacement followed by N-alkylation with the bromide 10 delivered 11 . Oxidation followed by deprotection then set the stage for the intramolecular Julia-Kocienski cyclization, which gave 12 with the expected (eight-membered ring) high geometric control. Addition of the ester 1 to Michael acceptors proceeded across the open face of the lactam, but it was still necessary to control the face of the nitro alkene 2 to which the lactam anion added. Catalysis of the addition with the urea 13 delivered 3 with 10:1 diasterocontrol. Mannich condensation of the nitroalkane 3 with formaldehyde and the amine 14 gave the bis-lactam 15, conveniently as a single diastereomer. After free radical removal of the nitro group, it was necessary to achieve selective reduction of the δ-lactam in the presence of the γ-lactam. Low-temperature LiAlH4 was found to be effective. Direct reduction of the resulting hemiaminal with formic acid led to the monolactam 16. The hemiaminal from monoreduction of 16 was found to be unstable and sensitive to overreduction. Nevertheless, exposure of 16 to Dibal at low temperature followed by acid-mediated cyclization delivered the diamine 17. Cyclization of the free base of 17 with the first generation Grubbs catalyst gave (-)-nakadomarin A 4 as the minor component of a 40:60 Z/E mixture. Carrying out the cyclization on the camphorsulfonate salt improved the ratio to 63:37 Z/E.
The Baran Synthesis of Vinigrol
Authors: Taber Douglass F.
Published: November 2020

The diterpene vinigrol 3, isolated from Virgaria nigra F-5408, has eluded total synthesis for more than 20 years. Attempts to construct the four-carbon bridge on a preformed cis-decalin have been unavailing. Phil S. Baran of Scripps/La Jolla solved (Angewandte Chem. Int. Ed. 2008, 47, 3054; J. Am. Chem. Soc. 2009, 131, 17066) this problem by adding the extra C-C bond of 1, which could then be cleaved in course of a Grob fragmentation, leading to 2. The preparation of 1 started with the dihydroresorcinol derivative 4. Diels-Alder addition of the ester 5 gave 6, with a modest 2:1 dr. Addition of allyl MgCl to the derived aldehyde 7 proceeded with 6:1 dr. The resulting triene was conformationally sufficiently constrained that cyclization to 8 proceeded at room temperature over 2 weeks, or more conveniently at 105°C for 90 minutes. With 8 in hand, oxidation to the ketone allowed installation of the additional methyl group of 9. Desilylation followed by OH-directed reduction set the relative configuration of 1 correctly for the Grob fragmentation to the Z -alkene 2. There were two remaining problems in the synthesis. The alkene of 2 had to be converted to the methylated tertiary alcohol, and the ketone had to be elaborated to the ene diol. Though seemingly straightforward, the congested tricyclic skeleton of 2 made many common transformations difficult. The solution to the first problem was found in the selective dipolar addition of bromonitrile oxide. Reduction of the ketone then enabled HO-directed hydrogenation of the alkene, which otherwise was resistant. Dehydration followed by reduction with LiAlH4 gave the desired methyl group bearing a primary amine, which was removed by free radical reduction of the corresponding isonitrile, to give 12. With 12 in hand, the end of the synthesis appeared to be in sight. In fact, the reduction of a variety of oxidized intermediates proved difficult. In the end, a sequence that did not require reduction proved effective. Dihydroxylation of 12 gave a diol, selective oxidation of which delivered the α-hydroxy ketone 13. Formation of the trisylhydrazone followed by Shapiro reaction gave the intermediate alkenyl anion, which was trapped with formaldehyde to give the long-sought vinigrol 3.
The Shair Synthesis of Cephalostatin 1
Authors: Taber Douglass F.
Published: November 2020

The cephalostatins and ritterazines, represented by cephalostatin 1 3, have the remarkable property of inducing apoptosis in apoptosis-resistant malignant cell lines. The total synthesis ( J. Am. Chem. Soc. 2010, 132, 275) of 3 by Matthew D. Shair of Harvard University required the practical preparation of the complex hexacyclic ketones 1 and 2. The preparation of 1 started with irradiation of commercial hecogenin acetate 4 to give the known aldehyde 5 . Reaction of 5 with N -phenyltriazolenedione 6 led to the ketal 7. Oxidative cleavage generated an aldehyde, which on reduction and allylation was converted to 8. Acid-mediated cyclization led to 9. The sidechain of 9 was removed, giving 10, which was selectively reduced, leading to 11. Intramolecular aldol condensation gave 12. The relative configuration of the spiroketal 1 was established by kinetic bromoetherification of the alcohol 13, followed by free radical reduction of the resulting tertiary bromide, and acid-catalyzed equilibration. The synthesis of 2 began with the inexpensive steroid 14. Following the Schönecker protocol, C-H functionalization led to the ketone 15. Pd-mediated coupling of the derived enol triflate with the alkyne gave 16, which was oxidized and cyclized to 17. Simmons-Smith conditions converted the dihydrofuran of 17 into the cyclopropane, which was again opened kinetically with Br (NBS) to set the relative configuration of the spiroketal. Free radical reduction followed by protection and oxidation then completed the preparation of 2. The coupling of 1 and 2 (not illustrated) to form the central pyrazine of 3 followed the precedent of Fuchs, combining the 2-azido ketone derived from 1 with the 2-amino methoxime derived from 2. Remarkably, tens of milligrams of 1 and of 2 were prepared, assuring a reasonable supply of 3 for further studies.
Planning the Individual Clinical Trial
Authors: Tansey Michael
Published: November 2020

All sites should be ready to enroll by the planned study start date. Realistically, this can only be achieved if the process is initiated 52 weeks before the planned start date. The components of each step and the associated timelines are described below. There may be considerable overlap of these steps, and the time needed to complete each one can vary greatly from project to project or study to study. This chapter gives an overview of the key activities and their timelines; details of how the activities are carried out are described in subsequent chapters. As always, these are guidelines, and flexibility is the key. Timelines are defined by the activities that need to be carried out and the time each activity will take. Some of these activities are necessarily sequential, as the next activity cannot start until the previous one has been completed. Some of these rate-limiting activities are defined as milestones, and time to their successful completion is used as a relative measure of efficiency. Metrics have a valuable role to play in process improvement, but a potential drawback is that people will concentrate disproportionately more effort on achieving what they know is being measured, sometimes to the neglect of other activities. It is therefore essential that what is being measured be a true and important measure of efficiency. One of the most popular metrics to measure the efficiency of the clinical trial startup process is how short the time is between availability of the final protocol and when the first patient is randomized, the shorter the better. This metric, so often quoted, is the most useless and misleading because the completion of the study depends not on when the first patient was randomized but on when the last patient was randomized. The mad rush to enter the first patient is therefore a futile endeavor unless everything is in place to ensure that all, or most, sites can start randomizing patients by the planned start date.
Of Chickens and Eggs: The Sponsor’s Dilemma
Authors: Tansey Michael
Published: November 2020

Q. Which comes first, the sites or the patients? A. The patients. Find the patients and the sites will follow. The main objective is to select only those sites that have definitively identified the required number of study-specific patients. To ensure that objective, whenever it is feasible, these patients should be lined up and ready to be enrolled before the sites are initiated. Screening is the means for identifying potential volunteers for a trial by assessing whether or not they satisfy the inclusion, exclusion, and other relevant criteria for a given study. Screening and identification can be carried out long before a study is scheduled to start. Recruitment is the formal process of getting agreement from patients that they will take part in a study and getting their informed consent. Patients who give informed consent can then be enrolled in the study. Some procedures to determine eligibility may need to be carried out immediately before enrollment, so the fact that a patient has been recruited does not automatically indicate that the patient will be enrolled. Enrollment is the process of entering a patient who has given consent into the study by carrying out whatever initial procedure is needed. The initial procedure may be randomization, a run-in phase, or dosing if the study is open label. . . .If the matter is one that can be settled by observation, make the observation yourself. Aristotle could have avoided the mistake of thinking that women have fewer teeth than men by the simple device of asking Mrs. Aristotle to keep her mouth open while he counted. . . . . . . —Bertrand Russell, philosopher. . . Everyone is aware of the uncertainty and inefficiency that characterize clinical research. It is therefore hard to explain why those few aspects that can be quantified with some degree of accuracy and certainty continue to be the very ones that are usually approached subjectively and irrationally. No two aspects illustrate this paradox more vividly (and no two aspects are more responsible for time delays, wasted money, and poor data) than poor clinical trial site selection and inadequate patient screening and identification before the study starts.
Dementia with Lewy Body and Parkinson's Disease Patients
Authors: Ahlskog J. Eric
Published: November 2020

Patients, spouses, families, and caregivers dealing with dementia face a host of complex issues, particularly when they must confront Dementia with Lewy Bodies or Parkinson's Disease. Until now there has been no guidebook for the general public to help navigate these challenging disorders. In Dementia with Lewy Bodies and Parkinson's Disease Dementia, Dr. J. Eric Ahlskog draws on 30 years of clinical and research work at Mayo Clinic to arm patients and families with crucial information that will enable them to work in tandem with their doctors. A diagnosis of dementia can be devastating, leaving families and caregivers struggling with a loved one's radically-impaired thinking and memory. When dementia is coupled with Parkinson's, which will develop in Parkinson's patients that live long enough, or with Lewy Bodies, which is the second leading cause of dementia behind Alzheimer's, the difficulties become even more daunting. And while these disorders are all too common, most people have little solid information about them. Too often doctors cannot spend the necessary time answering questions or discussing the specific challenges and treatments for these kinds of dementia during office visits. Arriving for a doctor appointment knowing the issues and treatment options beforehand gives patients and families an important head start. Dr. Ahlskog clearly explains all aspects of these disorders, their causes, symptoms, most effective drug treatments, proper doses, and which medications to avoid. He also discusses the complications that can arise in treating these conditions, given the variety of available medications and their possible side effects and interactions. While a cure does not yet exist, in this accessible, highly informative guidebook, Dr. Ahlskog shows that optimal medical treatment can markedly improve the quality of life for both patients and family.