bluuebunny/crossref_metadata_2025 huggingface dataset:
Frameworks for Europe’s Past
Authors: Price T. Douglas
Published: November 2020

This book is about the prehistoric archaeology of Europe—the lives and deaths of peoples and cultures—about how we became human; the rise of hunters; the birth and growth of society; the emergence of art; the beginnings of agriculture, villages, towns and cities, wars and conquest, peace and trade—the plans and ideas, achievements and failures, of our ancestors across hundreds of thousands of years. It is a story of humanity on planet Earth. It’s also about the study of the past—how archaeologists have dug into the ground, uncovered the remaining traces of these ancient peoples, and begun to make sense of that past through painstaking detective work. This book is about prehistoric societies from the Stone Age into the Iron Age. The story of European prehistory is one of spectacular growth and change. It begins more than a million years ago with the first inhabitants. The endpoint of this journey through the continent’s past is marked by the emergence of the literate societies of classical Greece and Rome. Because of a long history of archaeological research and the richness of the prehistoric remains, we know more about the past of Europe than almost anywhere else. The prehistory of Europe is, in fact, one model of the evolution of society, from small groups of early human ancestors to bands of huntergatherers, through the arrival of the first farmers to the emergence of hierarchical societies and powerful states in the Bronze and Iron Ages. The chapters of our story are the major ages of prehistoric time (Stone, Bronze, and Iron). The content involves the places, events, and changes of those ages from ancient to more recent times. The focus of the chapters is on exceptional archaeological sites that provide the background for much of this story. Before we can begin, however, it is essential to review the larger context in which these developments took place. This chapter is concerned with the time and space setting of the archaeology of Europe.
The First Farmers
Authors: Price T. Douglas
Published: November 2020

The origins and spread of agriculture and a Neolithic way of life marked a major turning point in the evolution of human society. Farming changed everything. Our heritage as food collectors, consuming the wild products of the earth, extends back millions of years. Nevertheless, at the end of the Pleistocene some human groups began to produce their own food rather than collect it, to domesticate and control wild plants and animals, achieving what is perhaps the most remarkable transformation in our entire human past. Agriculture is a way of obtaining food that involves domesticated plants and animals. But the transition to farming is much more than simple herding or cultivation. It also entails major, long-term changes in the structure and organization of the societies that adopt this new way of life, as well as a totally new relationship with the environment. Hunters and gatherers largely live off the land in an extensive fashion, generally exploiting diverse resources over a broad area; farmers intensively use a smaller portion of the landscape and create a milieu that suits their needs. With the transition to agriculture, humans began to truly change their environment. Cultivation of plants and herding of animals, village society, and pottery did not originate in Europe. Domestication arrived from the ancient Near East. The Neolithic began in southwest Asia some 11,000 years ago and eventually spread into the European continent, carried by expanding populations of farmers. The mountains of western Iran and southern Turkey and the uplands of the Levant (the coastal region of the far eastern part of the Mediterranean, from the northeastern Sinai Peninsula through modern Israel, Lebanon, and Syria, and west along the modern Turkish coast) form an elevated zone somewhat cooler and wetter than much of the Near East. The area has been described as the Fertile Crescent. A variety of wild plants grow in abundance. This region was the natural habitat of many of the wild ancestors of the ﬁrst species of plants and animals to be domesticated at the end of the Pleistocene: the wild wheats and barleys, the wild legumes, and the wild sheep, goats, pigs, and cattle that began to be exploited in large numbers at the origins of agriculture.
Setting the Problem: The Deep Roots and Long Shadows of A Nation at Risk
Authors: Mehta Jal
Published: November 2020

Developments in the 1960s and 1970s brought schools under fire, but the modern American school reform movement began with the release of the famous A Nation at Risk report in 1983. Sponsored by the US Department of Education but largely written by a group of prominent academics, A Nation at Risk invoked crisis and framed a narrative so far reaching in its impact that it still governs the way we think about schooling 30 years later. Emphasizing the importance of education to economic competitiveness and the failings of American schooling in comparison with international competitors, A Nation at Risk presented a utilitarian and instrumental vision of education. It argued that schools, not society, should be held accountable for higher performance and that performance should be measured by external testing. As will be seen in the chapters to come, these assumptions underlay the state standards movement in the 1980s and 1990s and persist today in federal policy through No Child Left Behind. Much as the muckrakers shaped reform efforts in the Progressive Era and the Coleman Report did so to a lesser degree in the 1960s, A Nation at Risk powerfully framed the debate and set off a chain of events that resulted in the largest-ever eff ort to rationalize American schooling. A Nation at Risk has not been ignored in previous accounts of American educational history: it is often cited as a critical document in American school reform. I seek to build on this literature by examining, in more detail than previous work has, the creation, rhetoric, and reception of the report, as well as drawing on new state-level evidence to explore its impact. I also look deeper into the past, finding a more diverse set of antecedents than is usually identified, and further into the future, seeking to specify more precisely how A Nation at Risk affected subsequent reform efforts.
Rationalizing Schools: Patterns, Ironies, Contradictions
Authors: Mehta Jal
Published: November 2020

Across the 20th century and now a decade into the 21st, reformers have repeatedly seen the rationalization of schooling as the solution to the nation’s educational ills. Reformers have repeatedly claimed that by setting standards, using tests to measure progress towards those standards, and holding teachers accountable for progress, student achievement would improve and schools would better satisfy the goals of their external constituents. Conversely, educators have repeatedly countered that such a mechanistic model imposes a set of business values that should be foreign to schools; assigns responsibility to schools that belongs in part with families and neighborhoods; and in the name of science, squeezes out critical humanistic priorities of schooling. Round and round we go, with no end in sight. This chapter steps back from the details of such movements to look at the broader patterns, lessons, and implications of the repeated efforts to rationalize schools. One set of questions is about causes and patterns. Why, despite modest results, has so much energy been repeatedly expended in trying to rationalize schools? What patterns are common across time? Are the sources particular to education, or are there common causes that explain the rise of accountability movements in medicine, higher education, and other fields? And why have educators been comparatively less able to resist external accountability than practitioners in other fields? A second set of questions concerns the deeper assumptions embedded in efforts to rationalize schools. Choices we make about how to reform schools reflect a broader set of values about what we want for our students, how we regard our teachers, and what our vision of educational improvement is. More specifically, what are our assumptions about individual psychology, organizational sociology, and human nature? Why, at least in recent years, has the school reform movement combined such an optimistic, even utopian vision of what is possible for students with such a pessimistic, behaviorist view of how teachers need to be incentivized and motivated?
The Old Story: Metaphysics, Mid–Nineteenth Century Physics, and Neoclassical Economics
Authors: Nadeau Robert
Published: November 2020

In economics textbooks, the nineteenth century creators of neoclassical economics theory, Stanley Jevons, Léon Walras, Francis Ysidro Edgeworth, and Vilfredo Pareto, are credited with disclosing the dynamics of market systems and transforming the study of economics into a rigorously mathematical scientific discipline. There are, however, no mentions in these textbooks, or in all but a few books on the history of economic thought, of a rather salient fact. Neoclassical economic theory was created by substituting economic constructs derived from classical economics and associated with the invisible hand for physical variables in the equations of a badly conceived and soon-to-be outmoded mid–nineteenth century theory in physics. The theory in physics that the economists used as the template for their theories was developed from the 1840s to the 1860s. During this period, physicists responded to the inability of classical physics to account for the phenomena of heat, light, and electricity with a profusion of hypotheses about matter and forces. In 1847 Hermann-Ludwig Ferdinand von Helmholtz, one of the best known and most widely respected physicists at this time, posited the existence of a vague and ill-defined energy that could unify these phenomena. This served as a catalyst for a movement called energetics, in which physicists attempted to explain very diverse physical phenomena in terms of a unified and protean field of amorphous energy. Because the physicists were unable to specify the actual character of this energy and could not be precise about what was being measured, their theories were not subject to repeatable experiments under controlled conditions. The amorphous character of energy in the physical theories also obliged the physicists to appeal to the law of conservation of energy, which states that the sum of kinetic and potential energy in a closed system is conserved. This appeal was necessary because it was the only means of asserting that the vaguely defined system described in the theory somehow remains the “same” as it undergoes changes and transformations.
The Nervous Breakdown
Authors: Shorter Edward
Published: November 2020

Nervous breakdown has never been a medical term. It is a patients’ term, just as cerumen has always been a doctors’ term for ear wax. Yet patients once believed profoundly in nervous breakdowns as a psychiatric condition several pegs higher than nerves, until the great switch to depression. Even today, the concept of the nervous breakdown has a kind of subterranean existence in the patients’ folklore. Yet the nerve syndrome was a quite specific pattern of illness whereas the nervous breakdown was not. The nerve syndrome entailed anxiety, depression, fatigue, somatic illness, and obsessive concern. Looking back over historical records, we can see who had the nerve syndrome and who did not. Nervous breakdown shares only the term nerves in common with the nerve syndrome. It is a synonym for serious psychiatric illness of any kind, not a specific disorder. In a short story in Collier’s magazine in 1935, George, the hero, tries unsuccessfully to contact Josephine, on whom he has cast a lustful eye. “He saw no other girls. He went home nights and walked the floor and drank too many drinks and didn’t go to sleep until all hours.” The title of the story was “nervous breakdown,” but clearly George did not have a psychiatric illness. Here, on the other hand, is John F. O’Donnell, the chief of police in Denver, who shot himself to death in 1949. In a note that he left behind for his wife and son he said, “I feel like I am going to have a nervous breakdown and surely do not want to be a burden to you.” For Chief O’Donnell, a nervous breakdown was a nontrivial illness. Dr. John E. Eichenlaub, writing in Today’s Health in 1954, said, “You hear a lot of people say that a nervous breakdown ruins a person for life, that no one ever gets over one.” This is pretty serious business, not at all what George had. (Dr Eichenlaub went on to dispel readers’ fears.)
Ornithologists and Explorations: 1901– 1903
Authors: Lorbiecki Marybeth
Published: November 2020

Aldo and his family moved back into the Big House the spring after his grandparents’ deaths. Late in the summer, when the ragweed bloomed, Clara’s hay fever hit with its annual vengeance. To comfort her, the Leopolds retreated to the northwoods resort they visited each summer. The resort of Les Cheneaux embraced the outer edges of Marquette Island in Lake Huron. The island had not been logged recently, and a mix of tall pine, cedar, maple, fir, aspen, birch, and hemlock bristled over the land like fur. No roads and few trails cut through the woods. The Leopold cottage overlooked a mile-wide bay, where the sunsets were “indescribably beautiful.” Each day, a launch delivered groceries from the villages of Hessel and Cedarville on the Michigan coast. The island enticed the young adventurer—here, he could fish, hunt, swim, sail, camp, and play Daniel Boone. While the rest of the family golfed or socialized with other wealthy guests from the lakeless midwestern prairies, Aldo explored every pine thicket, rocky rivulet, and turn of beach on the six-mile island, blazing trails and making intricate maps. Once he shot a “sachet kitten” near the clubhouse and carved this message on the boardwalk: “Aldo Leopold killed a skunk here on August 20, 1901.” (When the boardwalk was finally torn down, the resort owners saved the board.) The “boys” in the family often packed up their canvas tents for week-long camp-outs by the lake. They would try to live off what they caught and picked. Aldo became a master at frying sourdough biscuits, cooking a wild stew over a smoking campfire, and using a Dutch oven. North was Aldo’s magical horizon. Frederic wrote: “In our young minds, we imagined that we were at the jumping-off place where to the north an endless wilderness extended to Hudson Bay and the arctic.” Aldo planned to someday paddle into the untouched lands of Canada, and he begged his father for a canoe. His father thought a rowboat suited them all just fine.
The Farmer as Conservationist … and Restorationist
Authors: Lorbiecki Marybeth
Published: November 2020

The farm lies about two hours away from the Shack but only historic inches away in concept. In the Driftless region of southwest Wisconsin, it bears upon it some of the beautiful contoured crop swirls of Coon Valley, telltale marks of Leopold’s influence. New Forest Farm, started by Mark and Jen Shepard, is restoration agriculture in action. The farm asks the land to do what it is tailored by nature to do best and then trains it artfully, holistically, and prodigiously for personal, natural, and commercial use. From the sky, it looks like a child’s fingerpainting in green, with curlycues and waves of varying shades, dotted with treetop spheres, winding around ridges and swells. Lovely, biologically diverse, and drought resistant. It has pocket ponds with connective rain-irrigation swales cut into the contours following gradual lines of gravity to disperse captured moisture into the roots and soil for storage. In the face of the worst drought since 1933, this farm stood out lush and lively, though the chestnuts, hazelnuts, and fruit trees produced a reduced harvest, saving their energies for survival. On the spring day we visited, three new shaggy, fawn-colored Highland cattle had just arrived—a mother, son, and calf—along with some new solar-powered electric fencing for pasturing paddocks. “The animals get to know the whole thing,” says Peter Allen, the land manager in his early thirties who expounds on the sequential grazing of the cattle, pigs, sheep, chickens, and turkeys. “They stay for a day in the paddock, and they’re ready to move on to the next when we open the gates.” A PhD student from UW-Madison’s Nelson Institute for Environmental Studies, Allen is applying precepts of wildlife and land ecology to the emerging field of restoration agriculture. He’s also a warm host and knowledgeable tour guide, handing out exciting details like the intoxicating cider made here.
The Land Ethic
Authors: Lorbiecki Marybeth
Published: November 2020

Cooking my house specialty, New Mexican green chili, I heard the knock at the back door and dried my hands to open it for my expected guest. Shyly, the young man in the collar offered a bouquet of bright spring flowers and another gift, the golden- sunned paperback copy of A Sand County Almanac. “I thought you might like this—it’s a favorite of mine.” He had no idea how beloved this book was to me, or the author. In this small gesture, I felt like he was unintentionally offering me a concrete symbol of the growing bridge between the spiritual ethics of Aldo Leopold the naturalist and scientist, and his beloved wife, Estella, the devout Roman Catholic. Leopold had once noted that we would not ever come to integrating a land ethic into our American culture until churches and faith communities got involved. This obviously makes sense when you consider that only a small percentage of the nation, and indeed the world, possess a depth of scientific and/or ecological literacy. But in 2014, over 75% of Americans (and 84% worldwide in 2010) self-described themselves as having a religious affiliation. Another substantially growing group consider themselves spiritual, though not affiliated or have “fallen away” from their original religious practice. Scientific findings though rationally convincing often have less power to move people in their decision making, or perspectives, than faith. In the past, this has often led to land damage rather than health, but as shown by Pope Francis’s recent actions, this paradigm is shifting. Leopold was a student of the Bible, and he observed that the Mosaic Decalogue of the Ten Commandments dealt with humans’ relationships with each other in society. Leopold stated that the human ethical relationship to the land community was an evolving process, just as was human-to-human morality, mentioning the evolvement of human understanding that slavery is wrong. Leopold, in his “Land Ethic” essay, cited that leading thinkers in the Bible, the prophets (such as Ezekiel and Isaiah), urged deeper understandings.
Best Synthetic Methods: Reduction
Authors: Taber Douglass F.
Published: November 2020

Heshmatollah Alinezhad of Mazandaran University, Iran. developed (Tetrahedron Lett. 2009, 50, 659) the reagent 3, a white powder that is stable for many months, as a hydride donor for the reductive amination of aldehydes and ketones. Jean-Marc Campagne of the Institut Charles Gephardt Montpellier established (Synlett 2009, 276) a simple microwave protocol for reducing aldehydes and ketones to the corresponding hydrocarbons that looks general enough to become the method of choice for this important transformation. Joanne E. Harvey of Victoria University of Wellington, in the course of a total synthesis of Aigialomycind D, observed (J. Org. Chem. 2009, 74, 2271) that despite the high reactivity of the monosubstituted alkene of 7, the conjugated alkene could be selectively reduced. Brian S. Bodnar of SiGNa Chemistry described (J. Org. Chem. 2009, 74, 2598) a simple procedure for the reduction of an ester such as 9 to the alcohol 10, using Na dispersed on silica gel. Takao Ikariya of the Tokyo Institute of Technology designed (Angew. Chem. Int. Ed. 2009, 48, 1324) a Ru complex for the hydrogenation of N-acylsulfonamides and N-acylcarbamates such as 11 to the corresponding alcohol, 12. Remarkably, Hideo Nagashima of Kyushu University demonstrated (Chem. Commun. 2009, 1574) that even in the presence of the ester, the amide of 13 could be selectively reduced to the enamine 14. The enamine could be hydrolyzed to the aldehyde or reduced to the amine, but it is also an activated intermediate, for instance, for Michael addition to ethyl acrylate or methyl vinyl ketone. Diimide (HN=NH) is a useful reagent for selective reduction, as illustrated by the conversion of 15 to 17 . David R. Carbery of the University of Bath devised (J. Org. Chem. 2009, 74, 3186) a convenient procedure for the in situ generation of diimide from 16 and hydrazine hydrate. The reductive cleavage of tertiary nitriles to the corresponding hydrocarbon under dissolving metal conditions has been known for some time (J. Org. Chem. 1996, 61, 4219). Reduction of secondary nitriles required more forcing conditions, with K metal and crown ether (Tetrahedron Lett. 1985, 26, 6103).
New Methods for C-C Bond Construction: The Burke Synthesis of (-)-Peridinin
Authors: Taber Douglass F.
Published: November 2020

Hideki Yorimitsu and Koichiro Oshima of Kyoto University observed (J. Am. Chem. Soc. 2010, 132, 8878) that Rh-catalyzed addition of 2 to a terminal allene 1 generated an allylic organometallic, which coupled with electrophiles to give the branched product 3. Regan J. Thomson of Northwestern University devised (Nat. Chem. 2010, 2, 294) the reagent 5, which added to an aldehyde 4 to give the reduced allylically coupled product 6. Nuno Maulide of the Max-Planck-Institut, Mülheim, noted (Angew. Chem. Int. Ed. 2010, 49, 1583) the remarkable rearrangement of 7 to 8. Jon A. Tunge of the University of Kansas showed (Organic Lett. 2010, 12, 740) that nitronate allylation could be effected by the Pd-mediated decarboxylation of 9. Takashi Tomioka of the University of Mississippi developed (Organic Lett. 2010, 12, 2171) a convenient reagent for the conversion of an aldehyde 11 to the Z -unsaturated nitrile 12 . Xiaodong Shi of the University of West Virginia established (Organic Lett. 2010, 12, 2088) that Au-mediated rearrangement of 13 led to the Z -iodo enone 14. T. V. RajanBabu of Ohio State University developed (Organic Lett. 2010, 12, 2622) a Pd catalyst for the selective double functionalization of a terminal alkyne 15 to the stannane 16. The subsequent tandem Stille and Suzuki couplings proceeded efficiently. The controlled construction of tetrasubstituted alkenes is particularly challenging. Kohei Endo and Takanori Shibata of Waseda University put forward (J. Org. Chem. 2010, 75, 3469) what promises to be a general solution to this problem: the addition of the bis-boronate 17 to a ketone 18. Alkynes are usually prepared by direct alkylation. Gérard Cahiez of the Université de Paris 13 established (Angew. Chem. Int. Ed. 2010, 49, 1278) an alternative: the coupling of a Grignard reagent with a 1-bromoalkyne 20. Gregory B. Dudley of Florida State University developed (J. Org. Chem. 2010, 75, 3260) a complementary route to internal alkynes based on the fragmentation of 22. Enantiomerically pure allenes are ubiquitous components of physiologically active natural products. Weiping Tang of the University of Wisconsin optimized (J. Am. Chem. Soc. 2010, 132, 3664) the bromolactonization of a Z enyne 24 to give the allene 25.
Advances in Alkene Metathesis: The Hoveyda Synthesis of (+)-Quebrachamine
Authors: Taber Douglass F.
Published: November 2020

There are two major impediments to scaling up alkene metathesis: reducing the amount of the expensive Ru catalyst required, and minimizing residual Ru in the product. Robert H. Grubbs of Caltech developed (Organic Lett. 2009, 11, 1261) a family of silica-supported Ru complexes, exemplified by 1. At 0.75 mol % of 1, the rate of cyclization of 2 to 3 was maintained over eight cycles. The solution of product 3 showed < 5 ppb Ru. Hassan S. Bazzi and David E. Bergbreiter of the Texas A&M campuses in Qatar and College Station also reported (Organic Lett. 2009, 11, 665) a durable polymer-bound Ru metathesis catalyst that maintained its activity over many cycles. Most metathesis catalysts are strongly E selective. Amir H. Hoveyda of Boston College designed (J. Am. Chem. Soc. 2009, 131, 3844) a chiral Mo catalyst that was both highly enantioselective and strongly Z selective, converting the prochiral 4 into the alkene 6. Professor Hoveyda also took advantage (J. Am. Chem. Soc. 2009, 131, 8378) of the known propensity of Ru metathesis catalysts for H bonding, showing that metathesis of the prochiral cyclopropene 7 proceeded with remarkable diastereocontrol. This appears to be a generally useful protocol for assembling enantiomerically pure alkylated quaternary stereogenic centers. It is also possible to encapsulate the Ru catalyst. Ned B. Bowden of the University of Iowa pioneered the use of PDMS thimbles for this purpose. He has now shown (Organic Lett. 2009, 11, 33) that by subsequently adding AD-mix, cross-metathesis can be followed directly by enantioselective dihydroxylation. Ring-opening cross-metathesis of an unsymmetrical alkene such as 13 could give two different products. Alberto Avenoza and Jesús H. Busto of the Universidad de La Rioja established (J. Org. Chem. 2009, 74, 1736) that by tuning the electronic nature of the participating alkene, either product can be obtained with high selectivity. Metathesis can be used to close larger rings. Conformational effects are important. Motoo Tori of Tokushima Bunri University observed (Tetrahedron Lett. 2009, 50, 2225) that although 18 cyclized efficiently, the other three precursors that were diastereomeric on the cyclopentane ring did not undergo ring-closing metathesis.
Alkene and Alkyne Metathesis: (+)-Anamarine (Sabitha), ( ± )-Pseudotabersonine (Martin), Lactimidomycin (Fürstner)
Authors: Taber Douglass F.
Published: November 2020

Masato Matsugi of Meijo University showed (J. Org. Chem. 2010, 75, 7905) that over five iterations, the fluorous-tagged Ru catalyst 1b was readily recovered and reused for the cyclization of 2 to 3. Hengquan Yang of Shanxi University reported (Chem. Commun. 2010, 46, 8659) that the Hoveyda catalyst 1a encapsulated in mesoporous SBA-1 could also be reused several times. Jean-Marie Basset of KAUST Catalysis Center, Régis M. Gauvin of Université Lille, and Mostafa Taoufik of Université Lyon 1 described (Chem. Commun. 2010, 46, 8944) a W catalyst on silica that was also active for alkene metathesis. Reto Dorta of the University of Zurich, exploring several alternatives, found (J. Am. Chem. Soc. 2010, 132, 15179) that only 4c cyclized cleanly to 5. Karol Grela of the Polish Academy of Sciences showed (Synlett 2010, 2931) that 3-nitropropene (not illustrated) participated in cross-metathesis when catalyst 1c was used. Shawn K. Collins of the Université de Montré al complexed (J. Am. Chem. Soc. 2010, 132, 12790) 6 with a quinolinium salt to direct paracyclophane formation. Min Shi of the Shanghai Institute of Organic Chemistry incorporated (Org. Lett. 2010, 12, 4462) the cyclopropene 8 in cross-metathesis, to give 10. A. Srikrishna of the Indian Institute of Science (Bangalore) constructed (Synlett 2010, 3015) the cyclooctenone 12 by ring-closing metathesis. LuAnne McNulty of Butler University established (J. Org. Chem. 2010, 75, 6001) that a cyclic boronic half acid 15, prepared by ring-closing metathesis, coupled with an iodoalkene 16 to deliver the diene 17 with high geometric control. Gowravaram Sabitha of the Indian Institute of Chemical Technology, Hyderabad, en route to (+)-anamarine 21, observed (Tetrahedron Lett. 2010, 51, 5736) that the tetraacetate 18b would not participate in cross-metathesis. Fortunately, 18a , an earlier intermediate in the synthesis, worked well. Stephen F. Martin of the University of Texas prepared (Org. Lett. 2010, 12, 3622) (±)-pseudotabersonine 24 by way of a spectacular metathesis that converted 22 to 23. Ring-closing alkyne metathesis was a key step in the total synthesis of lactimidomycin 27 reported (J. Am. Chem. Soc. 2010, 132, 14064) by Alois Fürstner of the Max-Planck- Institut Mülheim.
Enantioselective Preparation of Alcohols and Amines:The Suh Synthesis of (-)-Macrosphelide J
Authors: Taber Douglass F.
Published: November 2020

Keiji Maruoka of Kyoto University (J. Am. Chem. Soc. 2009, 131, 3450) and Yujiro Hayashi of the Tokyo University of Science (Chem. Commun. 2009, 3083) independently developed organocatalysts for the enantioselective α-benzoylation of aliphatic aldehydes such as 1. The product 3 can be readily carried on to, inter alia, either enantiomer of the epoxide. Chengjian Zhu of Nanjing University designed (Adv. Synth. Cat. 2009, 351, 920) a chiral salen complex that mediated the enantioselective opening of both cyclohexene oxide (4) and cyclopentene oxide. This reagent combination might also engage just one of the two enantiomers of a racemic cycloalkene epoxide. Lin Pu of the University of Virginia established (Organic Lett. 2009, 11, 2441) a BINOL catalyst for the addition of ethyl propiolate 7 to an aliphatic aldehyde 6 to give the alcohol 8 in high ee. In a complementary approach, Do Hyun Ryu of Sungkyunkwan University found (Angew. Chem. Int. Ed. 2009, 48, 4398) that an oxazaborolidinium salt catalyzed the addition of 7 to 9 to give 10 with high ee and high geometric control. Jianliang Xiao of the University of Liverpool devised (J. Am. Chem. Soc. 2009, 131, 6967) an Ir catalyst for the enantioselective reductive amination of a ketone 11 to the amine 13 . Karl B. Hansen, Yi Hsiao. and Feng Xu, then all at Merck/Rahway, showed (J. Am. Chem. Soc. 2009, 131, 8798) that it was possible to hydrogenate a vinylogous primary amide 14 to the amine 15 with high enantiocontrol. Takashi Ooi of Nagoya University designed (J. Am. Chem. Soc. 2009, 131, 7242) a chiral P-spiro tetraaminophosphonium catalyst that mediated the enantioselective addition of anilines to nitroalkenes such as 16. The product 18 could be carried on to the 1,2-diamine, or to the α-amino acid. Masahiro Terada of Tohoku University devised (Angew. Chem. Int. Ed. 2009, 48, 2553) a BINOL-derived phosphonic acid to catalyze the enantioselective 1,2-addition of the enamide 20 to the imine derived from 19. Yixin Lu of the National University of Singapore found (Organic Lett. 2009, 11, 1721) that a cinchona alkaloid-derived thiourea effectively catalyzed the enantioselective conjugate addition of nitroalkanes such as 22 to the acceptor 23.
C-N Ring Construction: The Synthesis of Decursivine by Mascal and by Jia
Authors: Taber Douglass F.
Published: November 2020

Barry M. Trost and Justin Du Bois of Stanford University described (Org. Lett. 2011, 13, 3336) the cyclization of 1 to the activated aziridine 2. Liming Zhang of the University of California, Santa Barbara, rearranged (Angew. Chem. Int. Ed. 2011, 50, 3236) the propergylic amine 3 to the azetidinone 4 by N-H insertion of an intermediate Au carbene. Xiao Zheng and Pei-Qiang Huang of Xiamen University effected (J. Org. Chem. 2011, 76, 4952) reductive coupling of 6 with 7 to deliver the ester 8 . Eiji Tayama of Niigata University found (Tetrahedron Lett. 2011, 52, 1819) that 9 could be alkenylated with 10 with substantial retention of absolute configuration. Duncan J. Wardrop of the University of Illinois at Chicago, en route to a synthesis of (-)-swainsonine, observed (Org. Lett. 2011 , 13, 2376) high diastereocontrol in the cyclization of 12 to 13. Iain Coldham of the University of Sheffield also observed (J. Org. Chem. 2011, 76, 2360) substantial diastereoselection in the cyclization of 14 to 15. Robert E. Gawley of the University of Arkansas established (Org. Lett. 2011, 13, 394) that exposure of metalated 16 to just 5 mol % of a chiral ligand was sufficient to enable enantioselective coupling, to deliver 17. Christian Nadeau of Merck Frosst effected (J. Am. Chem. Soc. 2011, 133, 2878) enantioselective addition to the pyridinium salt 19 to give 20. Jiyong Hong of Duke University observed (Org. Lett. 2011, 13, 796) that enantiomerically pure 21 cyclized to the cis diastereomer of 22. With the Hayashi catalyst, cyclization could be driven toward the trans diastereomer, 22, enabling the synthesis of (+)-myrtine. Dawei Ma of the Shanghai Institute of Organic Chemistry found (Org. Lett. 2011, 13, 1602) that the Hayashi catalyst also directed the relative and absolute outcome in the addition of 24 to 23 , to give the piperidine 25. Donn G. Wishka of Pfizer/Groton devised (J. Org. Chem. 2011, 76, 1937) a practical route to the cis-substituted azepane 27, by Beckmann rearrangement of the enantiomerically pure 26 followed by reduction and oxidative cleavage.
Alkaloid Synthesis: (+)-Preussin (Britton), (±)-Xenovenine (Livinghouse), (+)-Subincanadine F (Li), (±)-Strychnine (Reissig),(-)-Virginiamycin M2 (Panek)
Authors: Taber Douglass F.
Published: November 2020

Aldehydes such as 1 are readily available by direct enantioselective chlorination. Robert Britton of Simon Fraser University found (Org. Lett. 2010, 12, 4034) that the addition of the kinetic ketone enolate 2 gave the anti aldol 3. Condensation of the chlorohydrin 3 with a primary amine led to the cyclic pyrrolinium salt, that was reduced with high diastereocontrol to (+)-preussin 4. Tom Livinghouse of Montana State University developed Sc catalysts for the cyclization of γ-amino terminal alkenes such as 5. In contrast, addition to internal alkenes was sluggish. He has now shown (Org. Lett. 2010, 12, 4271) that a thiophene substituent activated the internal alkene for addition, enabling the facile synthesis of (±)-xenovenine 7. Chaozhong Li of the Shanghai Institute of Organic Chemistry found (Chem. Commun. 2010, 46, 8436) that ferrocenium ion cleanly oxidized the enolate of the β-keto ester 8, effecting cyclization to 9. The D-tryptophan-derived ester that directed the relative and absolute configuration of the cyclization could readily by removed, delivering (+)-subincanadine F 10. In a complementary approach to indole alkaloid synthesis, Hans-Ulrich Reissig of the Freie Universität Berlin devised (Angew. Chem. Int. Ed. 2010, 49, 8021) the elegant SmI2 -mediated double cyclization of 11 to 12. This set the stage for the assembly of (±)-strychnine 13. James S. Panek of Boston University used (Angew. Chem. Int. Ed. 2010, 49, 6165) the enantiomerically pure allylic silanes that he has developed to construct the chloroaldehyde 14. He found that the reductive cyclization to 15 was best carried out with SmI2 in benzene. SmI2 has the virtue that it is soluble in common organic solvents, so it can readily be deployed even on a micromolar scale. It is also versatile, because its reducing power can be tuned by the solvent in which it is dissolved.
New Methods for Carbocyclic Construction: The Kim Synthesis of Pentalenene
Authors: Taber Douglass F.
Published: November 2020

Daesung Lee of the University of Illinois, Chicago, taking advantage of the facile insertion of an alkylidene carbene into a C-Si bond, established (J. Am. Chem. Soc. 2010, 132, 6640) a general method for the conversion of an α-silyl ketone 1 into the silyl cyclopropene 3. Christopher D. Bray of Queen Mary University showed (J. Org. Chem. 2010, 75, 4652) that the sulfonyl phosphonate 5 converted the enantiomerically pure epoxide 4 into the cyclopropane 6. Paul Margaretha of the University of Hamburg observed (Organic Lett. 2010, 12, 728) smooth photochemical combination of 7 and 8 to give 9 with high diastereocontrol. Tõnis Kanger of the Tallinn University of Technology devised (Organic Lett. 2010, 12, 2230) the three-component coupling of 10, 11, and diethyl amine to give, after reduction, the highly substituted cyclobutane 12. Min Shi of the Shanghai Institute of Organic Chemistry uncovered (J. Org. Chem. 2010, 75, 902) an interesting new thermal rearrangement: the conversion of 13 to 14. José G. Ávila-Zárraga of the Universidad Nacional Autónoma de México applied (Tetrahedron Lett. 2010, 51, 2232) Pd catalysis to the cyclization of the epoxy nitrile 15, redirecting the reaction from the expected cyclobutane to the cyclopentanol 16. Ullrich Jahn of the Academy of Sciences of the Czech Republic effected (J. Org. Chem. 2010, 75, 4480) the oxidative radical cyclization of 17 to 18. Initial deprotonation of the substrate with t -BuMgCl switched the product to the trans diastereomer. Jonathan W. Burton of the University of Oxford employed (Organic Lett. 2010, 12, 2738) a related oxidative cyclization for the diastereoselective conversion of 19 to 20. E. J. Corey of Harvard University reported (Organic Lett. 2010, 12, 300) a new ligand for the enantioselective Ni-mediated reduction of 21 to 22. Shu-Li You, also of the Shanghai Institute of Organic Chemistry, established (J. Am. Chem. Soc. 2010, 132, 4056) that the alcohol 23, readily prepared by oxidation of p -cresol, could be cyclized to the crystalline 25 in high ee.
The Williams Synthesis of (-)-4-Hydroxydictyolactone
Authors: Taber Douglass F.
Published: November 2020

(-)-4-Hydroxydictyolactone 3, representative of the cyclononene xenicanes isolated from the Dictyotacae algae, readily isomerizes thermally to the more stable ( Z )- 6,7-isomer. Attempts to directly form this strained ring system appeared to be fraught with difficulty. David R. Williams of Indiana University envisoned (J. Am. Chem. Soc. 2009, 131, 9038) that use of Suzuki coupling might ameliorate some of the strain, since at the point of commitment to bond formation, the Pd center would be included in the forming ring. This analysis led specifically to the trans ether 1, as cyclization of the trans ether appeared likely to be more facile than would cyclization of the alternative cis diastereomer. The first challenge was the assembly of the array the four contiguous alkylated stereogenic centers of 1. To this end, the Z secondary ester 7 was prepared from the acetonide 4 , available from mannitol, and ( R )-(+)-citronellic acid, prepared by oxidation of the commercial aldehyde. Addition of 7 to LDA led to decomposition, but inverse addition of LDA to a mixture of the ester, TMSCl, and Et3 N smoothly delivered the ketene silyl acetal. On warming, Ireland-Claisen rearrangement of the ketene silyl acetal led to the acid 8 with remarkable diastereocontrol. The last alkylated stereogenic center of 1 was installed by reductive cyclization of the formate ester 9. Again, the cyclization proceeded with remarkable diastererocontrol. Although the intramolecular reaction of in situ prepared allyl metals is well precedented, the addition to a formate ester had not previously been reported. Although 11 appears to be ready for the long-awaited Suzuki coupling, in fact the TIPS protecting group substantially slowed hydroboration. The free alcohol/methyl acetal was the best substrate for hydroboration, but the free alcohol entered into other side reactions. After extensive experimentation, a happy medium was found with the methyl acetal/TBS ether 1. Selenylation of the lactone 12 followed by oxidative elimination of the selenide delivered the expected Z alkene. Removal of the silyl protecting group had to precede introduction of the second alkene, as the product 3 deteriorated rapidly on exposure to the alkaline conditions of TBAF cleavage.
The Magnus Synthesis of ( ± )-Codeine
Authors: Taber Douglass F.
Published: November 2020

Although there have been many synthetic approaches to morphine and its methyl ether codeine 3, the pentacyclic structure of these Papaver alkaloids continues to intrigue organic chemists. Philip Magnus of the University of Texas devised (J. Am. Chem. Soc . 2009, 131, 16045) an elegant route to 3 based on the conversion of 1 to 2 by way of an intramolecular Michael addition. The starting point for the synthesis was the commercial bromoaldehyde 4. Coupling with 5 delivered the substituted biphenyl 6, which was carried on to the mixed bromo acetal 8. On exposure to fluoride ion, 8 was desilylated, and the intermediate phenoxide cyclized with impressive facility to give 1. Exposure of 1 to nitromethane delivered the tetracyclic 2. This reaction apparently was initiated by Henry addition of the nitromethane to the aldehyde. The intramolecular Michael addition of the intermediate Henry adduct then proceeded to give the desired cis diastereomer of the newly formed ring. Finally, loss of water gave 2. Conjugate reduction of the nitroalkene 2 led to 9 with remarkable diastereocontrol. Exposure of 9 to LiAlH4 converted the nitro group to the amine and the enone to the allylic alcohol. On exposure to acid, the hemiacetal was hydrolyzed. The liberated aldehyde underwent reductive amination with the free amine, while at the same time ionic cyclization closed the ether ring. N-acylation completed the conversion to 10. The ether 10 had previously been converted to codeine and then, in a single demethylation step, to morphine. In that synthesis, the alkene of 10 was directly epoxidized. The resulting “up” epoxide reacted only sluggishly with phenylselenide anion, and the relative configuration of the resulting allylic alcohol had to be inverted by oxidation followed by reduction. In the current synthesis, exposure of the alkene 10 to dibromohydantoin under aqueous conditions to form the bromohydrin effected concomitant arene bromination, to give, after base treatment, the “down” epoxide 12. Phenylselenide opening of the epoxide was then facile, and the product allylic alcohol had the correct relative configuration for codeine and morphine. The extra Br was of no consequence, as it was removed by the final LiAlH4 reduction.
The Chen Synthesis of (-)-Nakiterpiosin
Authors: Taber Douglass F.
Published: November 2020

(-)-Nakiterpiosin 3, isolated from the thin encrusting sponge Terpios hoshinota, has an IC50 against murine P388 leukemia cells of 10 ng/mL. Chuo Chen of UT Southwestern Medical Center developed (J. Am. Chem. Soc. 2010, 132, 371) a practical synthetic route to 3 based on the convergent coupling of 1 and 2. The preparation of 1 was based on the intramolecular [4 + 2] cyclization of the furan 9, prepared by Friedel-Crafts acylation of furan 4 with maleic anhydride 5 . The absolute confi guration of the secondary alcohol was set by Noyori reduction, using sodium formate as the hydride source. The cyclization of 9 to 10 proceeded with high diastereocontrol, presumably by way of a chelated transition state. As expected, cyclization of the silyl ether of 9 delivered the complementary diastereomer. Because the cyclization of 9 was readily reversible, it was taken quickly to the bromide 11. Oxidative cleavage of the diol followed by selective reduction and protection then completed the synthesis of 1. The preparation of 2 began with the commercial bromo acid 12. The enantiomerically enriched epoxide 13 was constructed in the usual way by homologation of the aldehyde to the allylic alcohol followed by Sharpless epoxidation. On exposure to the Yamamoto catalyst, 13 smoothly rearranged to the aldehyde 14. Condensation of 14 with 15 then gave 16, with only minimal erosion of enantiomeric excess over the two steps. Unfortunately, 16 was the incorrect diastereomer, so it had to be inverted. With the aldehyde 17 in hand, conversion to the dichloride followed by functional group interchange completed the construction of 2 . Carbonylative coupling of 1 and 2 led to the enone 18. The photochemical Nazarov cyclization of 18 proceeded with the expected high diastereocontrol, to give, after epimerization, the desired trans-anti-trans product. Deprotection then completed the synthesis of (-)-nakiterpiosin 3. It is noteworthy that the full A-ring functionality of 3 was compatible with the conditions of the photochemical cyclization. The work of Chen toward the total synthesis of (-)-nakiterpiosin 3 led to a correction of the relative configurations both of the dichloromethyl substituent and of the secondary bromide.
The Tanino/Miyashita Synthesis of Solanoeclepin A
Authors: Taber Douglass F.
Published: November 2020

Building on the Tanino synthesis of glycinoeclepin (Organic Highlights, January 3, 2011), the hatch-stimulating substance for the soybean cyst nematode, Keiji Tanino of Hokkaido University and Masaaki Miyashita, now at Kogakuin University, described (Nat. Chem. 2011, 3, 484) a convergent synthesis of solanoeclepin A 3, the hatch-stimulating substance for the potato cyst nematode. A key step in the synthesis was the diastereoselective Diels-Alder cyclization of 1 to 2. The starting point for the synthesis was the conjugate addition of 5 to 3-methyl cyclohexenone 4, followed by aldol condensation. The secondary acetate corresponding to 6 was readily resolved by lipase hydrolysis. The next challenge was the installation of the angular vinyl group. Enone transposition gave 7, to which vinyl Grignard added with high diastereocontrol, leading to the diol 8. TMSOTf-mediated epoxide rearrangement with concomitant 1,2 vinyl shift then delivered 9. Epoxidation followed by Stork cyclization completed the construction of the cyclobutane 10. The allylic alcohol 12 was enantiomerically pure, so the relative configuration of the sidechain cyclopropane could be set by the Charette protocol. Grieco dehydration of 14 then gave 16, a latent form of the cyclobutanone of 3. Condensation of the ketone 17 with 18 delivered the expected keto enamine, which rearranged nicely on exposure to Tf2O to the aldehyde 19. Diastereoselective addition of the furyl lithium 20 followed by Pd-catalyzed coupling with 21 then completed the assembly of the Diels-Alder substrate 1. The Me2AlCl-mediated intramolecular Diels-Alder cyclization of 1 led to 2 with remarkable diastereocontrol. Oxidation gave 22, that was further oxidized to the protected enol 23. Reduction, alkene cleavage, and protecting group manipulation then set the stage for the final oxidation of 24 to solanoeclepin A 3.
Introduction: Cutting the Gordian Knot
Authors: Tansey Michael
Published: November 2020

Time and money have always been important, intertwined factors in the context of drug development, but never more important than they are now, especially time. There are many reasons why. Competition has never been as keenly felt. Fewer, larger companies spend huge amounts of money on research and development (R&D) and, for the most part, have the same targets. Worldwide, first launches of new medical entities (NME) are decreasing. In the 10 years from 2001 to 2010, the number fell from 31 to 21, and only one-third of these launches were by major companies, defined as those spending more than two billion dollars on R&D in 2009 (2011 CMR International R&D Factbook). Investment in innovative biotechnology has done little to change this so far. Market exclusivity (meaning the time during which a new entity has no competition on the market) has diminished to the point of being weeks, rather than the 10 years enjoyed by Imperial Chemical Industries (ICI) with the first beta blocker. A recent estimate for the loss of revenue for each day that a drug is in clinical trials is between $600,000 and $8,000,000 (J. Hess and S. Litalien, Cutting Edge White Paper). The five-month market advantage that celecoxib had over rofecoxib was worth between $500,000,000 and $750,000,000 and established a competitive edge that was never lost. So it doesn’t take a genius to appreciate the importance of time above other things because, unlike other things, time can never be recovered. Given these pressures, it would seem that making any improvement that would give a competitive advantage would be a priority. Although all the elements of drug development, from discovery to regulatory submission, are interdependent and important, the clinical phase of development is crucial for success or failure. Everything else becomes irrelevant if clinical benefit for the patient cannot be demonstrated. The careful, efficient management of this phase is essential to ensure that reliable data can be generated rapidly and cost-effectively. It should come as a surprise, then, that performance measurements for the clinical trial process show a continuing and steady worsening. A good dose of antidepressants is needed to be able to read them with equanimity. This is a small but relevant sample: •About 80% of trials do not meet their original enrollment times. (J. Hess and S. Litalien, Cutting Edge White Paper).