bluuebunny/crossref_metadata_2025 huggingface dataset:
The Rise of Nervous Illness
Authors: Shorter Edward
Published: November 2020

It is much better, people think, for the nerves than the mind to be ill. The nerves are physical structures, and heal in the way that all organs of the body heal naturally. Disorders of the mind are frightening because they are so intangible, and, we think, may well lead to insanity rather than recovery. From time out of mind, people have privileged nervous illness over mental illness. From time out of mind, societies have had expressions for the varieties of frets, anxieties, and dyspepsias to which the flesh is heir. In France and England in the seventeenth and eighteenth centuries, one term was “vapours,” a reference from humoral medicine to supposed exhalations of the viscera that would rise in the body to affect the brain. A major apostle was London physician John Purcell, writing in 1702, of “those who have laboured long under this distemper, [who] are oppressed with a dreadful anguish of mind and a deep melancholy, always reflecting on what can perplex, terrify, and disorder them most, so that at last they think their recovery impossible, and are very angry with those who pretend there is any hopes of it.” He emphasized melancholia and anguish, and for him the “vapours” were something more than a mild attack of the frets. But this was not for everyone. Lady Mary Wortley Montagu, now 60 and living in exile in Italy, described to her estranged husband in 1749 Italian health care arrangements, and how physicians visited rich and poor alike. “This last article would be very hard if we had as many vapourish ladies as in England, but those imaginary ills are entirely unknown here. When I recollect the vast fortunes raised by doctors amongst us [in England], and the eager pursuit after every new piece of quackery that is introduced, I cannot help thinking there is a fund of credulity in mankind . . . and the money formerly given to monks for the health of the soul is now thrown to doctors for the health of the body, and generally with as little real prospect of success.”
A Different Kind of Nervous Breakdown—Melancholia
Authors: Shorter Edward
Published: November 2020

Feelings of low mood are not trivial. In 2010 the National Center for Health Statistics of the Department of Health and Human Services asked a random sample of the U.S. population about their mood. In reply to Do you feel hopeless?, 6.8%, or 1 in 15, said yes. In reply to Do you feel worthless?, 5.3% said yes. In reply to Do you feel that “everything is an effort”?, a whopping 16%, or one in seven, said yes. Low feeling is very common. Yet it is not melancholia. Historically, plenty of people have suffered from low moods. Today, few of us can stay in our beds because we have to earn a living. Yet it was once common for middle-class women, in households that had servants, to take to their beds when feeling down. In 1917, London literary figure Virginia Woolf, age 36, noted in her diary for October 25: “Owing to the usual circumstances, I had to spend the day recumbent.” She meant that she was having her period, and always had to lie down. Still, menstruation was not the only reason she went recumbent. Late in 1918 she had a tooth out and spent two weeks in bed, “and being tired enough to get a headache—a long dreary affair, that receded and advanced much like a mist on a January day.” “Here is a whole nervous breakdown in miniature,” she recorded in July 1926. “Sank into a chair, could scarcely rise; everything insipid; tasteless, colourless. Enormous desire to rest.” In November 1931 she was assailed by “a perpetual headache,” and “so took a month lying down.” On October 5, 1932, she said, “I spent yesterday in bed; headache; infinite weariness up my back: clouds forming in my neck; half asleep.” So this is the kind of nervous behavior that was congruent with people of her social class at that place and time. But there are deeper, more alarming notes.
Something Wrong with the Label
Authors: Shorter Edward
Published: November 2020

How did everyone become depressed? A depression needed to be created that could be applied to everyone. The drafters of the third edition of the American Psychiatric Association’s (APA) DSM series did this in 1980 by creating major depression. At the same time, the drafters completed the demolition of the nerve syndrome, which had been slowly unraveling. The analysts had removed neurotic depression from the nervous syndrome; psychiatry removed anxiety from the larger nervous picture with the diagnosis mixed anxiety-depression. And DSM-III completed the job by separating completely anxiety and depression, and fragmenting anxiety into a volley of meaningless microsyndromes. Fatigue was left completely out of the picture and ceased to be a psychiatric ailment. And obsessive thoughts had long vanished from the nervous picture into the vast anxiety basin, where they would tumble about with social anxiety, posttraumatic stress, and the like. Like moving pieces of furniture from the room, all the furniture was removed from the nervous room except depression. Of the unitary diagnosis of nerves, a disease of the entire body, nothing was left except major depression, an expandable diagnosis that could be applied to almost the entire population—and a series of minianxiety diagnoses pseudospecific for different settings in which anxiety might arise: parties (social anxiety disorder), trauma (posttraumatic stress disorder), public places (agoraphobia), and so forth. The shattering of the nervous syndrome was complete. In February 1973 the Board of the American Psychiatric Association decided that in the forthcoming edition of the World Health Organization’s International Classification of Diseases, scheduled for 1979, some minor terminological clarifications were necessary in the input of American psychiatry, including issues such as “problem-oriented records” and how, exactly, to classify levels of disabilities. These were not big problems, but they would necessitate another edition of the APA’s Diagnostic and Statistical Manual , the second edition of which has appeared in 1968 ; the Board asked the APA’s Reference Committee to get cracking, and in April the Reference Committee asked the Council on Research and Development to appoint a Task Force to revise DSM-II.
Drugs
Authors: Shorter Edward
Published: November 2020

History has always known antidepressant remedies. In an era of faith, the faithful held to the Word as an augury of recovery: “cast down, but not destroyed.” But in a secular era and certainly by the middle of the twentieth century, pharmacological remedies were required. Indeed they were urgently indicated, for the diagnosis of depression itself was starting to spread. Because of Kraepelin and Freud, by 1940 depression had become a common term for serious psychiatric disease. An editorial in the Lancet called depression “perhaps the most unpleasant illness that can fall to the lot of man.” Depression was thus, while not terribly common, a considerable public health issue. What is puzzling in this story is that around 1940 depression began an inexorable, irreversible climb from awful but unusual to epidemic status. With the 1960s, depression started to become epidemic. One reason for the upswing in depression in mid-twentieth century was the cheering of the pharmaceutical industry. The drugs of the first generation of psychoactive medications were indicated for nervous disease, but there after the firms switched to depression because here were clearly the markets of the future. The early drugs represented an effective treatment for nervous disease. Their effect was sedation, and sedative drugs in medical practice go back to opium and to members of the belladonna family that have been known since Ancient times. Sedation means the process of calming, or allaying excitement. It does not necessarily involve the obtunding of consciousness, although large doses of sedatives may do that. Sedation means easing the pain of being, soothing the griefs and worries of existence, and calming the depressive and anxious agitation of the nervous syndrome. Although we all have worries and anxieties, we do not all have a pathological syndrome called nervousness. Historically, it was those with nerves who benefited from the early psychopharmacological treatments, beginning with the bromides at mid-nineteenth century. The first sedative made by chemical synthesis, chloral hydrate, was used clinically in 1869. A succession of sedatives from the organic chemical industry followed.
A Cowboy in Love: 1909– 1912
Authors: Lorbiecki Marybeth
Published: November 2020

Twenty-two-year-old Aldo Leopold arrived in Albuquerque, New Mexico Territory, in July 1909, burning with the “fervor of a sawdust evangelist.” The Forest Service had sent him to his first choice—District 3, encompassing the twenty-one forests of the South and Southwest. His duties were outlined in his manual: preserve a perpetual supply of timber for home industries, prevent destruction of forest cover (which regulates the flow of streams), and protect local industries from unfair competition in the use of forest and range. The district chief was Arthur Ringland, a stocky, energetic Yale graduate only a few years older than Leopold. Ringland sensed the new graduate’s enthusiasm and assigned him to the wildest lands in the district—the Apache National Forest in Arizona Territory. The land had originally belonged to the Apache Nation, but in 1886, the US Army forced most of the members onto a nearby reservation. This left but a few ranchers, farmers, and miners in the region. The forest headquarters rested in Springerville, Arizona, a two-day stagecoach ride from the last railroad stop. No automobiles carved tire treads over these plateaus and canyons. Travel was by foot, horse, or mule. Forest Assistant Leopold, the newest greenhorn among many, wasted no time in purchasing a feisty gray stallion called Jiminy Hicks, a saddle, a rope, and a few good roping lessons. Within the month, he also acquired pistols and a “rubber butt plate” for those long days in the saddle. The rubber plate came in handy since Aldo put in a good deal of time astride Jiminy Hicks. Throughout July and the beginning of August, Leopold inspected trees, marked them for cutting, planted seed plots, fixed fences, and met the other rangers. Working under Supervisor John D. Guthrie, Aldo contributed his two bits on policy decisions about grazing permits, water rights, and timber sales. Guthrie’s long hours and dedicated stance inspired the young ranger. The simplicity of life on the range, where one had to live out of a pack, made Leopold feel tough and free. On his own time, he hunted, mapped out the forest for himself, climbed mountains, and tested trout streams.
A Wild Proposal: 1919– 1924
Authors: Lorbiecki Marybeth
Published: November 2020

On August 1, 1919, Aldo was appointed to the second-highest position in District 3—Assistant Forester in Charge of Operations. Numerous foresters grumbled that Leopold didn’t deserve the job and was hardly suited to its enormous responsibilities. He hadn’t proven he was versed enough in all aspects of forestry management to handle the overarching tasks of inspecting every forest, reporting on what he found, and suggesting improvements. Leopold had a rigorous schedule to follow—three forests per summer, with a month at each. Since the Forest Service had no set inspection method, Leopold had to develop his own. His first reports were sketchy. He wrote more comments on rangers’ initiative and reading habits than on the details of their work or the conditions of their fire stations. During a late-summer tour of his old stomping ground, the Carson, Leopold roved further south into the Datil Forest. He fished away a Sunday at the headwaters of the Gila River and came away relaxed and refreshed. No telephone poles or roads cut across the landscape; there were just the pines; the trout; the tingle of fresh, pungent air; and a breeze alive with bird calls. Few areas like this remained in District 3. Was there, he wondered, a legal way to preserve the canyonlands around the Gila just as they were? That December, at a meeting of district foresters in Salt Lake City, Leopold heard about a young forest assistant named Arthur Carhart from District 2 in Colorado. Carhart, the Forest Service’s first landscape architect, had been dubbed the “Beauty Engineer” by his coworkers. Carhart had recommended that Trappers Lake, in the White River National Forest, be permanently preserved in a wilderness state—no so-called improvements. On his return trip, Leopold stopped by the D-2 offices to meet the man. Up to this point, attempts to set aside natural areas in the national forests led only to national parks or “primitive areas” that were open to later development. Leopold did not trust the park system to preserve any wilderness area intact.
Paths of Violence: 1939– 1945
Authors: Lorbiecki Marybeth
Published: November 2020

In September 1939, Germany invaded Poland. During the dark months of 1939, 1940, and 1941, Europe exploded with tanks, bombs, and guns. The violent side of Hitler’s new German policies proved worse than Leopold had imagined possible. A letter arrived from Leopold’s host in Germany, Alfred Schottlaender. Schottlaender’s wife had turned him in to the secret police for making antiHitler comments. He had been interned both at Dachau and Buchenwald but had managed to escape to Kenya. He was writing to ask Aldo to help his brother, who was still in Germany. Leopold contacted those he knew, and a place was found in South Africa for Alfred’s brother. “My dear friend Leopold,” responded Alfred, “[You] have given me back the faith of faithfulness, truth, and friendship still existing on earth, which I nearly had lost after having lived to see such terrible disap­pointments in my own country which I loved so much and served all my life.” Violence seemed to be the common link between the many ways humans acted toward the land and toward each other. Leopold began to refer to con­servation as a movement toward “nonviolent land use,” where changes are made gradually and carefully, keeping the land community stable. Then the exploding violence hit the States: the Japanese attacked Pearl Harbor on December 7, 1941. The next day, Carl enlisted in the marines. On the edge of twenty-two, he had just begun graduate studies in wildlife ecology in Missouri. He hurried to marry Keena Rogers before leaving for combat. Luna enlisted in the army and was sent to California as an army engineer. Starker, who had married and was expecting a child, kept working, but dreaded the mail, which could carry a draft notice any day. Many of the Professor’s graduate and undergraduate students quit school to enlist. Vivian Horn resigned to do her part for the war effort. Sometime in 1942, a round robin of letters was begun between the department and those who had left. Each recipient added comments and sent the letter on to some­one else.
Love and the Restoration of Ourselves
Authors: Lorbiecki Marybeth
Published: November 2020

A little girl in Raytown, Missouri, used to spend part of almost every day in a special place in the woods near her house. The place had a calming effect on her. “Sometimes I go there when I’m mad . . . and then, just with the peacefulness, I’m better. I can come back home happy, and my mom doesn’t even know why.” In his book Last Child in the Woods, Richard Louv recounts the end of this fifth grader’s story. “And then they just cut the woods down. It was like they cut down part of me.” I know this same feeling. When I was her age, I watched the prairiesavannah I loved to explore turned into a housing development, chasing away my friends, the meadowlarks. I watched my aging Irish poet friend, Ken Olsen, try to fight the city to save the little bit of woods next to his house from being turned into an apartment complex. The loss nearly gave him a heart attack … or it did give him one, just not one that could be seen. Another friend mourned for weeks after the city cut down the oak in front of her apartment complex that offered dappled green shade to her fourth-floor home. It’s grief, pure and simple. But with all grief, life goes on, sometimes even when we don’t want it to. And there’s hope in that. The land systems long to rejuvenate, just as we long to have them back. Leopold’s restoration work at the Shack and the Arboretum have expanded exponentially, into every ecosystem on land and even into ocean ecosystems, such as coral reefs, kelp beds, tidal communities, and oyster beds. Because so much damage has been done, this is one of the most vibrant, growing, and needed areas of the Leopold legacy. Steven Brower, a landscape architect and Leopold family historian from Burlington, often walks the woods, caves, and bottomlands where Aldo roamed as a child. Brower’s eyes penetrate the landscapes with a kind of x-ray vision, seeing what once was underneath what is today.
Organic Functional Group Conversion
Authors: Taber Douglass F.
Published: November 2020

Pradeep Kumar of the National Chemical Laboratory, Pune, developed (Tetrahedron Lett. 2010, 51, 744) a new procedure for the conversion of an alcohol 1 to the inverted chloride 3. Michel Couturier of OmegaChem devised (J. Org. Chem. 2010, 75, 3401) a new reagent for the conversion of an alcohol 4 to the inverted fluoride 6. For both reagents, primary alcohols worked as well. Patrick H. Toy of the University of Hong Kong showed (Synlett 2010, 1115) that diethyl-lazodicarboxylate (DEAD) could be used catalytically in the Mitsunobu coupling of 7. Employment of 8 minimized competing acetate formation. In another application of hyper-valent iodine chemistry, Jaume Vilarrasa of the Universitat de Barcelona observed (Tetrahedron Lett. 2010, 51, 1863) that the Dess-Martin reagent effected the smooth elimination of a pyridyl selenide 10. Ken-ichi Fujita and Ryohei Yamaguchi of Kyoto University extended (Org. Lett. 2010, 12, 1336) the “borrowed hydrogen” approach to effect conversion of an alcohol 12 to the sulfonamide 13. Dan Yang, also of the University of Hong Kong, developed (Org. Lett. 2010, 12, 1068, not illustrated) a protocol for the conversion of an allylic alcohol to the allylically rearranged sulfonamide. Shu-Li You of the Shanghai Institute of Organic Chemistry used (Org. Lett. 2010, 12, 800) an Ir catalyst to effect rearrangement of an allylic sulfinate 14 to the sulfone. Base-mediated conjugation then delivered 15. K. Rama Rao of the Indian Institute of Chemical Technology, Hyderabad, devised (Tetrahedron Lett. 2010, 51, 293) a La catalyst for the conversion of an iodoalkene 16 to the alkenyl sulfide 17. Alkenyl selenides could also be prepared. James M. Cook of the University of Wisconsin, Milwaukee, described (Org. Lett. 2010, 12, 464, not illustrated) a procedure for coupling alkenyl iodides and bromides with N-H heterocycles and phenols. Hansjörg Streicher of the University of Sussex showed (Tetrahedron Lett. 2010, 51, 2717) that under free radical conditions, the carboxylic acid derivative 18 could be decarboxylated to the alkenyl iodide 19. Bimal K. Banik of the University of Texas–Pan American found (Synth. Commun. 2010, 40, 1730) that water was an effective solvent for the microwave-mediated addition of a secondary amine 21 to a Michael acceptor 20.
Advances in Organic Functional Group Transformation
Authors: Taber Douglass F.
Published: November 2020

There have been several significant advances in N-alkylation using alcohols. Matthias Beller of Universität Rostock devised (Angew. Chem. Int. Ed. 2010, 49, 8126) a Ru catalyst for the amination of secondary and benzylic primary alcohols with ammonia. Dieter Vogt of the Eindhoven University of Technology reported (Angew. Chem. Int. Ed. 2010, 49, 8130) related transformations. Pei-Qiang Huang of Xiamen University showed (Chem. Commun. 2010, 46, 7834) that debenzylation of 3 in methanol led to the N-methyl amine 4. Parallel results have been reported with Ir (J. Am. Chem. Soc. 2010, 132, 15108), Au (Chem. Eur. J. 2010, 16, 13965), and Cu (Chem. Lett. 2010, 39, 1182). Peter J. Scammells of Monash University found (J. Org. Chem. 2010, 75, 4806) that demethylation of an N-oxide could be effected with Fe powder. Yao Fu and Qingxiang Guo of the University of Science and Technology of China N-vinylated (Tet. Lett. 2010, 51, 5476) a sulfonamide 7 with vinyl acetate and a Pd catalyst. Acyl amides could also be N-vinylated under these conditions. Hirokazu Urabe of the Tokyo Institute of Technology reported (Org. Lett. 2010, 12, 4137) that the stereodefined secondary sulfonamide of 9 could be displaced by an internal nucleophile, to give the product 11 with inversion of absolute configuration. Teruo Umemoto of IM&T Research devised (J. Am. Chem. Soc. 2010, 132, 18199) the remarkable fluorinating agent 13. In addition to converting secondary alcohols to the corresponding fluorides and ketones to gem-difluorides, 13 cleanly converted the carboxylic acids of 12 to trifluoromethyl groups. Paul G. Williard of Brown University demonstrated (Org. Lett. 2010, 12, 5378) that LDA converted an allyl ether 15 specifically to the (Z)-propenyl ether 16. Phil Lee Ho of Kangwon National University and Sunggak Kim of Nanyang Technological University could add (Angew. Chem. Int. Ed. 2010, 49, 6806) a phosphate to an alkyne 17 to make either the less substituted or the more substituted enol phosphate. Professor Kim reported (J. Org. Chem. 2010, 75, 7928) similar results with the addition of carboxylic acids.
Organic Functional Group Protection
Authors: Taber Douglass F.
Published: November 2020

Masato Kitamura of Nagoya University investigated (Chemistry Lett. 2009, 38, 188) the Ru-mediated deprotection of allyl ethers such as 1. The same catalyst was effective for the preparation of allyl ethers from the alcohol 2 and allyl alcohol. István E. Markó of the Université Catholique de Louvain showed (Organic Lett. 2009, 11, 2752) that SmI2 effected the reductive cleavage of an aryl ester 3, liberating the alcohol 4. Osamu Onomura of Nagasaki University found (Tetrahedron Lett. 2009, 50, 1466) that catalytic CuCl2 mediated the selective monoallylation of symmetrical diols such as 5. Péter Fügedi of the Hungarian Academy of Sciences, Budapest, observed (Tetrahedron Lett. 2009, 50, 2914) that TMSOTf catalyzed the selective reduction of 7 to the benzyl ether. BH3. NMe2 delivered the opposite regioisomer. Direct amination of an ester has been a long-sought transformation. Vladimir B. Birman of Washington University found (Organic Lett. 2009, 11, 1499) that 1,2,4-triazole 11 in combination with DBU was an effective catalyst for this reaction. Unactivated esters required higher reaction temperatures. Deprotection of amides often requires vigorous conditions, and the product free amines can be challenging to handle. Stefan G. Koenig of Sepracor Chemical Process devised (Organic Lett. 2009, 11, 433) a simple protocol for in situ formation and hydrolysis of the imidoyl chloride from 12 that delivered the amine hydrochloride 13 directly. Remarkably, benzamides are stable under these conditions. Hongmei Li of Merck Process devised (Tetrahedron Lett. 2009, 50, 1010) a related procedure: heating the more reactive trifluoroacetamide 14 with stoichiometric p-toluenesulfonic acid, and isolating the product as the p-toluenesulfonate salt 15. There has been a reluctance to use sulfonamide protecting groups, as they have been thought to be difficult to remove. Göran Hilmersson of the University of Gothenburg established (Organic Lett. 2009, 11, 503) that SmI2 instantaneously deprotected 16. Daniel E. Falvey of the University of Maryland designed (J. Org. Chem. 2009, 74, 3894) the benzyl ester 17, which was readily released under photolysis. Stanislaw Krompiec of the University of Silesia described (Tetrahedron Lett. 2009, 50, 1193) what appears to be a general strategy for the preparation of ortho esters such as 21.
Functional Group Protection
Authors: Taber Douglass F.
Published: November 2020

Bekington Myrboh of North-Eastern Hill University reported (Tetrahedron Lett. 2010, 51, 2862) a convenient procedure for the oxidative removal of a 1,3-oxathiolane 1 or a 1,3-dithiolane. Sang-Gyeong Lee and Yong-Jin Yoon of Gyeongsang National University developed (J. Org. Chem. 2010, 75, 484) the pyridazin-3(2H )-one 4 for the microwave-mediated deprotection of an oxime 3. Dario M. Bassani of Université Bordeaux 1 and John S. Snaith of the University of Birmingham devised (J. Org. Chem. 2010, 75, 4648) a procedure for the facile preparation of esters such as 6. Brief photolysis (350 nm) returned the parent carboxylic acid 7. Craig M. Williams of the University of Queensland prepared (Tetrahedron Lett. 2010, 51, 1158) the trithioorthoester 8 by iterative opening of epichlorohydrin. He found that the keto ester 9 could be efficiently released by Hg-mediated hydrolysis. Masatoshi Mihara of the Osaka Municipal Technical Research Institute established (Synlett 2010, 253) that even very congested alcohols such as 10 could be acetylated by acetic anhydride containing a trace of FeCl3. Colleen N. Scott, now at Southern Illinois University, developed (J. Org. Chem. 2010, 75, 253) a convenient procedure for the preparation of the hydridosilane 13, which on Mn catalysis added the alcohol 12 to make the unsymmetrical bisalkoxysilane 14. Sabine Berteina-Raboin of the Université d’Orléans found (Tetrahedron Lett. 2010, 51, 2115) that NaBH4 in EtOH cleanly removed the chloroacetates from 15. Both other esters and silyl ethers were stable under these conditions. Ram S. Mohan of Illinois Wesleyan University established (Tetrahedron Lett. 2010, 51, 1056) that Fe(III) tosylate in methanol selectively removed the alkyl silyl ether from 17 without affecting the aryl silyl ether. Alakananda Hajra and Adinath Majee of Visva-Bharati University effected (Tetrahedron Lett. 2010, 51, 2896) formylation of an amine 19 by heating with commercial 85% formic acid as the solvent in a sealed tube at 80°C. Although both primary and secondary amines could be effi ciently formylated, the primary amines were much more reactive. Doo Ok Jang of Yonsei University found (Tetrahedron Lett. 2010, 51, 683) that the conveniently handled CF3CCO2H (the acid chloride is a gas) could be activated in situ to selectively convert 22 into 24.
C-H Functionalization: The White Synthesis of 6-Deoxyerythronolide B
Authors: Taber Douglass F.
Published: November 2020

Masayuki Inoue of the University of Tokyo designed (Organic Lett. 2009, 11, 3630) a linker that specifically directed C-H hydroxylation, as illustrated by oxidation of 1 to 2. Phil S. Baran of Scripps/La Jolla detailed (Nature 2009, 459, 824; Angew. Chem. Int. Ed. 2009, 48, 9705) some of the factors that direct reactivity in intermolecular C-H hydroxylation. Ning Jiao of Peking University devised (Angew. Chem. Int. Ed. 2009, 48, 7094) a protocol for the direct oxidation of a methylated aromatic 3 to the nitrile 4. Armando J. L. Pombeiro of TU Lisbon developed (Adv. Synth. Cat. 2009, 351, 2936) a procedure for C-H carboxylation, converting 5 into 6. Maurizio Fagnoni of the University of Pavia showed (Chem. Commun. 2009, 7351) that sunlight was sufficient to promote the addition of cyclohexane 7 to methyl acrylate to give 8. Jin-Quan Yu, also of Scripps/La Jolla, established (J. Am. Chem. Soc. 2009, 131, 9886) conditions for the selective Pd-mediated coupling of 9 to iodobenzene to give 10. Alexei V. Novikov of the University of North Dakota demonstrated (Tetrahedron Lett. 2009, 50, 6963; Heterocycles 2009, 78, 2531) that both diazo sulfonates such 11 and the related diazo sulfones cyclized smoothly under Rh catalysis to give the six-membered ring products. In the course of a synthesis of the Psoralea corylifolia –derived bakuchiol, the adduct from the cyclization of 11 was converted into the vinylated product 12. C-H bonds can also be activated electronically by proximal functional groups. Yong-Min Liang of Lanzhou University observed (J. Org. Chem. 2009, 74, 7464) that an N-aryl cyclic amine 13 could be oxidized to the syn diacetoxylated product 14. Note that the α-acetoxy group of 14 is activated for ionization and further bond formation. Yuhong Zhang of Zhejiang University, Hangzhou, found (Organic Lett. 2009, 11, 3730) that the activated intermediate from the oxidation of 15 coupled with a silyl enol ether to deliver the coupled product 16. Bernd Plietker of the Universität Stuttgart devised (Angew. Chem. Int. Ed. 2009, 48, 5752) a Ru catalyst for the coupling of an alkyne 18 to an α,β-unsaturated ester 17 to give the diene 19. Both disubstituted alkynes and more complex α,β-unsaturated esters participated as well. Gregory K. Friestad of the University of Iowa observed (Organic Lett. 2009, 11, 819) that an N-vinyl amide 20 could be homologated to the ester 22.
C-H Functionalization: The Chen Synthesis of Celogentin C
Authors: Taber Douglass F.
Published: November 2020

Christian R. Goldsmith of Auburn University developed (Synlett 2010, 1377) a method for radical chlorination of 1 using commercial peracetic acid. Noritaka Mizuno of the University of Tokyo devised (Nat. Chem. 2010, 2, 478) a bulky polyoxometalate that mediated the selective hydroxylation of the secondary C-H bonds of 3. Christina White of the University of Illinois showed (Science 2010, 327, 566) that Fe-mediated C-H oxidation is sensitive to the expected electronic effects, so that 5 was selectively oxidized to 6. Irena S. Akhrem of the A. N. Nesmeyanov Institute of Organoelement Compounds established (Tetrahedron Lett. 2010, 51, 259) that a C-H bond of 7 could be efficiently converted to a C-C bond. Melanie S. Sanford of the University of Michigan extended (Organic Lett. 2010, 12, 532) directed palladation to 9, effecting selective acetoxylation of the methyl group. Herman O. Sintim of the University of Maryland observed (Angew. Chem. Int. Ed. 2010, 49, 3964) that the O-linked diazoamide 11 selectively cyclized to 12. The corresponding C-linked diazoamide gave only five-membered ring formation. Yasushi Obora and Yasutaka Ishii of Kansai University devised (Organic Lett. 2010, 12, 1372) conditions for the selective allylic amination of 13. Marvin J. Miller of the University of Notre Dame developed (Tetrahedron Lett. 2010, 51, 328) the nitrosoisoxazole 16 for the allylic amination of 15. David A. Powell of Merck Frosst established (J. Org. Chem. 2010, 75, 2726) a protocol for the selective amination of the aromatic methyl group of 18. Ying-Yeung Yeung of the National University of Singapore effected (Organic Lett. 2010, 12, 2128) selective allylic oxidation of 21 with a hypervalent iodine reagent. Gullapalli Kumaraswamy of the Indian Institute of Chemical Technology, Hyderabad, allylated (J. Org. Chem. 2010, 75, 3916) an amine 23 using commercial aqueous t -BuOOH. Corey R. J. Stephenson of Boston University used (J. Am. Chem. Soc. 2010, 132, 1464) visible light to activate 26 for homologation to 27. In the course of a synthesis of the bicyclic nonribosomal peptide celogentin C, isolated from the seeds of the plumed cockscomb Celosia argentea, Gong Chen of Pennsylvania State University took advantage (Angew. Chem. Int. Ed. 2010, 49, 958) of Pd activation to effect specific coupling of the iodoindole 29 with the leucine derivative 28. On a 4-gram scale, this coupling proceeded in 85% yield.
Best Synthetic Methods: Reactions of Alkenes
Authors: Taber Douglass F.
Published: November 2020

Swadeshmukul Santra of the University of Central Florida described (Tetrahedron Lett. 2009, 50, 124) a simple preparation of silica nanoparticles that efficiently catalyzed the anti-Markovnikov addition of thiophenol to alkenes (illustrated) and also to alkynes. Akiya Ogawa of Osaka Prefecture University devised (Tetrahedron Lett. 2009, 50, 624) a protocol for the photoinduced hydrophosphinylation of an alkene 3 to the phosphine oxide 4. Xavi Ribas and Miquel Costas of the University of Girona developed (Adv. Synth. Cat. 2009, 351, 348) a manganese catalyst for the epoxidation of alkenes with 30% H2O2. Masahito Ochiai of the University of Tokushima established (J. Am. Chem. Soc. 2009, 131, 1382) an iodoarene-catalyzed oxidation of an alkene 7 to the keto acid 9. If, as is likely, isolated alcohols are stable under these conditions, this will be a useful complement to RuO4 cleavage. Several methods are available for homologating unactivated alkenes. Sven Doye of the Universität Oldenburg observed (Angew. Chem. Int. Ed. 2009, 48, 1153) that a Ti catalyst could effect the addition of N-methyl aniline 10 to the alkene 3, to give the branched product 11 . The reaction also worked well in an intramolecular sense. Note that in this process, a C-H bond is also converted to a C-C bond. Kiyoshi Tomioka of Kyoto University reported (Organic Lett. 2009, 11, 2007) that the Suzuki coupling of the hydroboration product from 12 with the iodo alkene 13 was best supported by AsPh3. Teck-Peng Loh of Nanyang Technological University showed (J. Am. Chem. Soc. 2009, 131, 1372) that the homologation of an isolated alkene 15 with an acrylate ester 16 could also be carried out under oxidative conditions to give the diene 17. Weiping Su of the Fujian Institute of Research on the Structure of Matter found (Organic Lett. 2009, 11, 2341) that similar oxidative conditions effected the decarboxylative addition of an aromatic acid such as 18 to an alkene to give the substituted styrene 19. Kian L. Tan of Boston College took advantage (Organic Lett. 2009, 11, 2764) of a chelating ligand to direct the regioselective hydroformylation of an allylic sulfonamide 20. Isolated internal alkenes were stable under these conditions.
Enantioselective Preparation of Alkylated Stereogenic Centers
Authors: Taber Douglass F.
Published: November 2020

Jon D. Stewart of the University of Florida established (Chem. Commun. 2010, 46, 8558) a scalable enzymatic reduction of geranial 1 to citronellal 2. Andreas S. Bommarius of Georgia Tech reported (Chem. Commun. 2010, 46, 8809) related studies. Isamu Shiina of the Tokyo University of Science developed (J. Am. Chem. Soc. 2010, 132, 11629) a nucleophilic catalyst for the kinetic resolution of α-chiral carboxylic acids such as 3. David W. C. MacMillan of Princeton University devised (J. Am. Chem. Soc. 2010, 132, 13600) a protocol for the enantioselective benzylation of an aldehyde 5. Kian L. Tan of Boston College (J. Am. Chem. Soc. 2010, 132, 14757) and Shannon S. Stahl and Clark R. Landis of the University of Wisconsin (J. Am. Chem. Soc. 2010, 132, 14027) developed the regioselective enantioselective hydroformylation of alkenes such as 7 with chelating substituents. Masaya Sawamura of Hokkaido University (J. Am. Chem. Soc. 2010, 132, 879) and others (Org. Lett. 2010, 12, 2438; Tetrahedron Lett. 2010, 5592, 6018) effected enantiospecific allylic coupling, as in the conversion of 9 to 10 . James P. Morken, also of Boston College, achieved (J. Am. Chem. Soc. 2010, 132, 10686) enantioselective allylation of 11. Ben L. Feringa of the University of Groningen devised (J. Am. Chem. Soc. 2010, 132, 13152) a protocol for net enantioselective conjugate addition to an α, β-unsaturated alde hyde 14. Gary A. Molander of the University of Pennsylvania found (J. Am. Chem. Soc. 2010, 132, 17108) that coupling of 16, prepared by enantioselective conjugate addition, proceeded with inversion. Naoya Kumagai and Masakatsu Shibasaki of the Institute of Microbial Chemistry effected (J. Am. Chem. Soc. 2010, 132, 10275) enantioselective alkynylation of the thioamide 18, and Takahiro Nishimura and Tamio Hayashi of Kyoto University achieved (Chem. Commun. 2010, 46, 6837) conjugate alkynylation of the nitroalkene 20. Several other protocols (Angew. Chem. Int. Ed. 2010, 49, 5780, 7299, 8145; J. Am. Chem. Soc. 2010, 132, 14373; J. Org. Chem. 2010, 75, 7829) have been developed for the catalytic enantioselective construction of arylated stereogenic centers.
Stereocontrolled C-N Ring Construction: The Takayama Synthesis of Lycoposerramine-C
Authors: Taber Douglass F.
Published: November 2020

Hideki Yorimitsu and Koichiro Ochima of Kyoto University extended (Angew. Chem. Int. Ed. 2009, 48, 7224) Pd-catalyzed intramolecular carboamidation to the construction of aziridines such as 3. Hamdullah Kilic of Ataturk University showed (J. Org. Chem. 2009, 74, 9452) that aziridination of an allylic alcohol 4 could proceed with substantial diastereocontrol. Makoto Oba of Tokai University established (Tetrahedron Lett. 2009, 50, 5053) a route from a serine derivative 6 to the pyroglutamate 8 and developed a protocol for the conversion of 8 to 9. David Tanner of the Technical University of Denmark found (J. Org. Chem. 2009, 74, 5032) that tetramic acids such as 8 could also be efficiently α-arylated. Koichi Mikami of the Tokyo Institute of Technology devised (Angew. Chem. Int. Ed. 2009, 48, 6073) a gold catalyst for the enantioselective cyclization of 12 to 13. Hiroaki Sasai of Osaka University effected (J. Org. Chem. 2009, 74, 9274) double intramolecular amination, converting 14 into 15 in high ee. Kyungsoo Oh of IUPUI Indianapolis observed (Angew. Chem. Int. Ed. 2009, 48, 7420) that using the same ligand, Cu catalysis gave one enantiomer of 18 and Ag catalysis gave the opposite enantiomer. Liu-Zhu Gong of the University of Science and Technology, Hefei, devised (Organic Lett. 2009, 11, 4946) a chiral Brønsted acid that mediated the enantioselective condensation of 19, 20, and 21 to give 22. Roderick W. Bates of Nanyang Technological University found (Organic Lett. 2009, 11, 3706) that a gold catalyst mediated the cyclization of 23 to 24 with high diastereocontrol. Qi-Lin Zhou of Nankai University effected (Organic Lett. 2009, 11, 4994) the enantioselective reduction of racemic 25 under epimerizing conditions, leading to 26 with high stereocontrol. Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen established (Angew. Chem. Int. Ed. 2009, 48, 9339) conditions for the enantioselective addition of a diakyl zinc to the activated pyridine 27, to give 28 in high ee. Hiromitsu Takayama of Chiba University isolated (Tetrahedron Lett. 2002, 43, 8307) lycoposerramine- C 34 from Lycopodium serratum. Intrigued by preliminary studies of the biological activity but lacking material, he developed (Organic Lett. 2009, 11, 5554) a total synthesis, the key step of which was the intramolecular Pauson-Khand cyclization of 32 to 33.
Metal-Mediated Carbocyclic Construction: The Simpkins Synthesis of Ialibinones A and B
Authors: Taber Douglass F.
Published: November 2020

Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen devised (J. Am. Chem. Soc. 2010, 132, 14349) what promises to be a general strategy for the construction of enantiomerically pure cyclopropanes, based on conjugate addition to acceptors such as 1 . X. Peter Zhang of the University of South Florida developed (J. Am. Chem. Soc. 2010, 132, 12796) a Co catalyst for the enantioselective cyclopropanation of α-olefins such as 3. Seiji Iwasa of Toyohashi University of Technology designed (Angew. Chem. Int. Ed. 2010, 49, 8439) a resin-bound Ru catalyst that could be used repeatedly for the enantioselective cyclization of the ester 6. Rai-Shung Lin of National Tsing-Hua University showed (Angew. Chem. Int. Ed. 2010, 49, 9891) that a gold catalyst could expand the alkyne 8 to the cyclobutene 9. Takao Ikariya of the Tokyo Institute of Technology reported (J. Am. Chem. Soc. 2010, 132, 16637) a detailed study of the enantioselective conjugate addition of malonate 11 to cyclopentenone 10. Vladimir A. D’yakonov of the Russian Academy of Sciences, Ufa, showed (Tetrahedron Lett. 2010, 51, 5886) that a cyclic alkyne 13 could be annulated to the cyclopentenone 14. Shunichi Hashimoto of Hokkaido University also designed (Angew. Chem. Int. Ed. 2010, 49, 6979) a resin-bound Rh catalyst that could also be used repeatedly for the enantioselective cyclization of the ester 15. Tushar Kanti Chakraborty of the Central Drug Research Institute used (Tetrahedron Lett. 2010, 51, 4425) Ti(III) to mediate the diastereoselective cyclization of 17 to 18. Alexandre Alexakis of the University of Geneva extended (Synlett 2010, 1694) enantioselective conjugate addition of isopropenyl to the more difficult enone 19. Joseph P. A. Harrity of the University of Sheffield showed (Org. Lett. 2010, 12, 4832) that Pd could catalyze the rearrangement of 21 to 22. Strategies for the controlled construction of polycyclic ring systems are also important. Günter Helmchen of the Universität Heidelberg showed (J. Org. Chem. 2010, 75, 7917) that 23 was efficiently cyclized to the diene with Pt catalyst. The reaction could be carried out in the presence of the dienophile 24 to give 25 directly.
Carbocyclic Construction: The Deng Synthesis of (-)-Plicatic Acid
Authors: Taber Douglass F.
Published: November 2020

Tehshik P. Yoon of the University of Wisconsin uncovered (J. Am. Chem. Soc. 2009, 131, 14604) conditions for the crossed photodimerization of acyclic enones. Minoru Isobe of Nagoya University extended (Synlett 2009, 1157) conjugate addition–intramolecular epoxide opening to substrates such as 4, leading to the cyclobutane 6 with high diastereocontrol. In the course of a total synthesis of (+)-brefeldin A, Jinsung Tae of Yonsei University established (Synlett 2009, 1303) conditions for the trans-selective cyclization of 7 to 8. Cyclization with TiCl4 gave the alternative cis diastereomer. Several methods have been put forward for the conversion of carbohydrate derivatives to carbocycles. Yeun-Mi Tsai of the National Taiwan University found (Tetrahedron Lett . 2009, 50, 3805) that acyl silanes such as 9 cyclized efficiently under free radical conditions, leading to the silyl ether 10. Tanmaya Pathak of the Indian Institute of Technology, Kharagpur, developed (Eur. J. Org. Chem. 2009, 872) the tandem conjugate addition– intramolecular alkylation conversion of 11 to 13. Slawomir Jarosz of the Polish Academy of Sciences, Warsawza, observed (Heterocycles 2009, 80, 1303) that the oxime derived from 14 cyclized to 15. The cyclization was accelerated by high pressure. Cyclohexanes can also be prepared from carbohydrates. Tony K. M. Shing of the Chinese University of Hong Kong showed (Organic. Lett. 2009, 11, 5070) that the nitrile oxide derived from 16 cyclized to 17, that he carried on to (-)-gabosine O. John K. Gallos of the Aristotle University of Thessaloniki described (Tetrahedron Lett. 2009, 50, 6916) related work. Paul E. Floreancig of the University of Pittsburgh devised (Organic. Lett. 2009, 11, 3152) conditions for the oxidative cyclization of 18 to 19. Ring closure proceeded with high equatorial selectivity. Kou Hiroya of Tohoku University found (J. Org. Chem. 2009, 74, 6623) that the single oxygenated stereogenic center of 20 directed the dissolving metal reduction–enolate trapping, leading to 21. Similarly, Susumu Kobayashi of the Tokyo University of Science showed (Synlett 2009, 1605) that the oxygenated stereogenic centers of 22 set the alkylated centers of 23. Many marine organisms are able to carry out brominative and chlorinative polyolefin cyclizations.
The Trost Synthesis of (-)-Pseudolaric Acid B
Authors: Taber Douglass F.
Published: November 2020

(-)-Pseudolaric acid B 3, isolated from the bark of the golden larch Pseudolarix kaempferi, shows potent antifungal activity. A key step in the total synthesis of 3 described (J. Am. Chem. Soc. 2008 , 130 , 16424) by Barry M. Trost of Stanford University was the free radical cyclization of 1 that established the angular ester and the trans ring fusion of 2 and thus of 3. To prepare the bicyclic skeleton of 1, the authors envisioned the Rh-mediated intramolecular addition of the alkyne of 11 to the alkenyl cyclopropane. The acyclic centers of 11 were established by Noyori hydrogenation of (equilibrating) racemic 4. One enantiomer reduced much more quickly than the other, leading to 5. The absolute configuration of the cyclopropane was set by Charette cyclopropanation of the monosilyl ether of the inexpensive diol 8. The two components were then coupled using a Corey-Schlosser protocol. Alkylation of the ylide 10 with 7 gave a new phosphonium salt, which in situ was deprotonated and condensed with the aldehyde 9 . The resulting betaine was deprotonated and quenched, then exposed again to base to give the trans alkene 11. It is important in this procedure to use PhLi as the base, because the alkyl lithium can displace the alkyl group on phosphorus. The product from Ru-catalyzed cyclization was the expected 1,4-diene 12 . Fortunately, it was found that TBAF desilylation led to concomitant alkene migration, to give the more stable conjugated diene 13. Selective epoxidation of the more electron-rich alkene fol lowed by exposure to strong base then delivered 14 , with the requisite angular oxygenation established. Pseudolaric acid B 3 would be derived from cyclization of the selenocarbonate of a tertiary alcohol. In fact, however, attempted cyclization of such selenocarbonates led only to decarboxyation and reduction. Even with the selenocarbonate 1 prepared from the secondary alcohol, the cyclization to 2 required careful optimization, including using not AIBN but azobis(dicyclohexylcarbonitrile) as the radical initiator. Acetylide addition to the ketone 15 could be effected with high diastereocontrol, but lactone construction proved elusive. Alkaline conditions led quickly to addition of the angular hydroxyl to the activated alkene in the seven-membered ring.
The Overman Synthesis of Briarellin F
Authors: Taber Douglass F.
Published: November 2020

Briarellin F 4 is an elegant representative of the complex polycyclic ethers produced by soft corals such as Briareum abestinum. Larry E. Overman of the University of California, Irvine, developed (J. Org. Chem. 2009, 74, 5458) a triply convergent approach to 4, the central feature of which was the Prins-pinacol combination of 1 with 2 to give 3. The aldehyde 2 was assembled by Wittig homologation of the aldehyde 5 with the phosphorane 6, followed by metalation and formylation. The aldehyde 10 was prepared by opening the enantiomerically pure epoxide 8 with the acetylide 9. Hydroboration of carvone 11 could not be effected with sufficient diastereocontrol. As an alternative, the mixture of diols was oxidized to the lactone 12 . Kinetic quench of the derived silyl ketene acetal followed by reduction led to the diastereomerically pure crystalline diol 13. This key intermediate will have many other applications in target-directed synthesis. The ketone 14 was converted to the alkenyl iodide 15 by stannylation of the enol triflate, followed by exposure of the stannane to N-iodosuccinimide. Addition of the alkenyl iodide 15 to the aldehyde 10 gave the diol 1 as an inconsequential 3:1 mixture of diastereomers. This mixture was combined with the aldehyde 2 to give, via Lewis acid–mediated rearrangement of the initially prepared acetal, the aldehyde 3 . The aldehyde 3 was readily decarbonylated by irradiation in dioxane. Face-selective Al-mediated epoxidation of the derived homoallylic alcohol proceeded with 10:1 selectivity, and subsequent MCPBA epoxidation of the cyclohexene was also secured with 10:1 facial control. This set the stage for the triflic anhydride–mediated closure of the six-membered ring ether. The Nozaki-Hiyama-Kishi cyclization of 18 proceeded with remarkable selectivity, delivering briarellin E 19 as a single diastereomer. Dess-Martin oxidation converted 19 into briarellin F 4.