bluuebunny/crossref_metadata_2025 huggingface dataset:
The Adrenal Glands
Authors: Auchus Richard J. , Parker Keith L.
Published: November 2020

The basic function of the adrenal glands is to protect the organism against acute and chronic stress, a concept popularized as the fight-or-flight response for the medulla and as the alarm reaction for the cortex. The steroid hormones of the cortex and the catecholamines of the medulla probably developed as protection against immediate stress or injury and more prolonged deprivation of food and water. In acute stress, catecholamines mobilize glucose and fatty acids for energy and prepare the heart, lungs, and muscles for action, while glucocorticoids protect against overreactions from the body’s responses to stress. In the more chronic stress of food and fluid deprivation, adrenocortical steroid hormones stimulate gluconeogenesis to maintain the supply of glucose and increase sodium reabsorption to maintain body fluid volume. Based on the widespread effects of its secreted products in multiple tissues, adrenal dysfunction is associated with protean manifestations. Diseases associated with adrenocortical hypofunction are relatively rare, while those associated with adrenocortical hyperfunction are slightly more common. However, both of these conditions are life threatening if untreated, and a high index of suspicion must therefore be maintained. Subtle increases in cortisol secretion or tissue sensitivity to glucocorticoids may be involved in many of the devastating effects of chronic stress, including visceral obesity, hypertension, diabetes mellitus, dyslipidemia, infertility, and depression. Moreover, exogenous glucocorticoids are widely used to treat numerous diseases and, when used in supraphysiological doses, can induce all of the manifestations of glucocorticoid excess. Perhaps because the adrenal medulla accounts for only 10 % of total sympathetic nervous activation, we can live quite well without it, and syndromes due to hypofunction are not clinically significant. However, conditions of excess catecholamine output due to tumors called pheochromocytomas are a rare but potentially life-threatening cause of secondary hypertension.
Glucose, Lipid, and Protein Metabolism
Authors: Clark Gregory O. , Kovacs William J.
Published: November 2020

The maintenance of life requires a constant supply of substrate for the generation of energy and preservation of the structure of cells and tissues. The process in principle is simple, yet the individual metabolic pathways and the regulation of substrate fluxes through these pathways can be complex. Energy is derived when fuel substrates are oxidized to carbon dioxide and water in the presence of oxygen, generating adenosine triphosphate (ATP). A portion of the ingested foodstuff is also utilized, either directly or after transformation into other substrates, to repair and replace cell membranes, structural proteins, and organelles. The remainder is stored as potential energy in the form of glycogen or fat. Under normal circumstances, each individual remains in a near-steady state where weight and appearance are stable over prolonged periods. In the short term, fuel metabolism changes dramatically several times a day during alternating periods of feeding and fasting. An anabolic phase begins with food ingestion and lasts for several hours. Energy storage occurs during this period when caloric intake exceeds caloric demands. The catabolic phase usually begins 4 to 6 hours after a meal and lasts until the person eats once again. During this phase, utilization shifts from exogenous to endogenous fuels, a change heralded by the mobilization of substrate stored in liver, muscle, and adipose tissue. Both anabolic and catabolic phases are characterized by specific biochemical processes regulated by distinct hormonal profiles. In the anabolic phase that follows ingestion of a mixed meal, substrate flux is directed from the intestine through the liver to storage and utilization sites. Glucose, triglyceride, and amino acid concentrations increase in plasma, whereas those of fatty acids, ketones (acetoacetic and β -hydroxy-butyric acids), and glycerol decrease. Both glycogen and protein synthesis begin in liver and muscle, while fatty acid synthesis and triglyceride esterification are stimulated in hepatocytes and adipose tissue. In the catabolic phase, the biochemical activities are reversed and the flux of fuel is directed from storage depots to liver and other utilization sites.
The Lacrimal System
Authors: Jordan David , Mawn Louise , Anderson Richard L.
Published: November 2020

The lacrimal system is made up of both the lacrimal secretory system and the nasolacrimal drainage system. The secretory system consists of the glands that make up the tear film (the lacrimal gland, the accessory glands of Krause and Wolfring, and the meibomian glands). The nasolacrimal drainage system consists of the puncta, canaliculi, lacrimal sac, and nasolacrimal duct. These two systems provide for the production and maintenance of the precorneal tear film as well as the drainage of tears from the eye. The normal functioning of these two systems is essential for proper optical refraction, preservation of corneal integrity, and ocular comfort. The physiology of tear production and distribution requires normal eyelid anatomy and mobility. Blinking spreads the tears vertically over the ocular surface. It also adds two important components to the tear film: lipid from the meibomian glands and mucin from the conjunctival goblet cells. The horizontal flow of tears to the medial canthus is along the tear meniscus at the eyelid margin. This requires normal contour and eyelid apposition to the globe and an adequately functioning orbicularis pump mechanism. Both of these functions can be compromised by horizontal and vertical eyelid laxity or by eyelid margin deformities. The lacrimal gland begins in embryologic development as epithelial buds arising from the conjunctiva of the superior temporal fornix. Canalization of the epithelial buds to form ducts begins in utero, but full development of the gland does not occur until three to four years postnatal. The lacrimal gland provides the principal aqueous secretory component of the tear film. It is located just behind the superolateral orbital rim within a depression in the lateral aspect of the orbital roof (the lacrimal gland fossa). The gland’s convex/concave shape reflects its location between the roof of the orbit and the globe. The gland is divided into a larger orbital lobe and a smaller palpebral lobe by the lateral horn of the levator aponeurosis. The orbital lobe lies behind the orbital septum and immediately above the lateral horn of levator.
Understanding the Effects of Menopausal Hormone Therapy: Using the Women’s Health Initiative Randomized Trials and Observational Study to Improve Inference
Authors: Anderson Garnet L. , Prentice Ross L.
Published: November 2020

Over the last decade, several large-scale randomized trials have reported results that disagreed substantially with the motivating observational studies on the value of various chronic disease–prevention strategies. One high-profile example of these discrepancies was related to postmenopausal hormone therapy (HT) use and its effects on cardiovascular disease and cancer. The Women’s Health Initiative (WHI), a National Heart, Lung, and Blood Institute–sponsored program, was designed to test three interventions for the prevention of chronic diseases in postmenopausal women, each of which was motivated by a decade or more of analytic epidemiology. Specifically, the trials were testing the potential for HT to prevent coronary heart disease (CHD), a low-fat eating pattern to reduce breast and colorectal cancer incidence, and calcium and vitamin D supplements to prevent hip fractures. Over 68,000 postmenopausal women were randomized to one, two, or all three randomized clinical trial (CT) components between 1993 and 1998 at 40 U.S. clinical centers (Anderson et al., 2003a). The HT component consisted of two parallel trials testing the effects of conjugated equine estrogens alone (E-alone) among women with prior hysterectomy and the effect of combined estrogen plus progestin therapy (E+P), in this case conjugated equine estrogens plus medroxyprogesterone acetate, among women with an intact uterus, on the incidence of CHD and overall health. In 2002, the randomized trial of E+P was stopped early, based on an assessment of risks exceeding benefits for chronic disease prevention, raising concerns among millions of menopausal women and their care providers about their use of these medicines. The trial confirmed the benefit of HT for fracture-risk reduction but the expected benefit for CHD, the primary study end point, was not observed. Rather, the trial results documented increased risks of CHD, stroke, venous thromboembolism (VTE), and breast cancer with combined hormones (Writing Group for the Women’s Health Initiative Investigators, 2002). Approximately 18 months later, the E-alone trial was also stopped, based on the finding of an adverse effect on stroke rates and the likelihood that the study would not confirm the CHD-prevention hypothesis.
The Need for Dimensional Approaches in Discerning the Origins of Psychopathology
Authors: Krueger Robert F. , Goldman Daniel
Published: November 2020

The 2008 meeting of the American Psychopathological Association was framed by a very challenging topic: causality. Indeed, setting aside any possible application in understanding psychopathology, causality is a deep concept—a fact that has kept philosophers gainfully employed for some time now. One thing is clear, however, at least in the behavioral sciences: If one wants to make credible causal claims, it helps to be able to directly manipulate the variables of interest. Indeed, some would go so far as to say that causality cannot be inferred without this kind of experimental manipulation. Through manipulation, one can systematically vary a variable of interest, while holding others constant, including the observational conditions. Consider, for example, how this is conveyed to new students in the behavioral sciences in a very useful text by Stanovich (2007). Stanovich (2007) first reviews the classic observation that simply knowing that two things (A and B) tend to occur together more often than one would expect by chance (a correlation) is not enough evidence to conclude that those two things have some sort of causal relationship (e.g., A causes B). To really claim that A causes B, ‘‘the investigator manipulates the variable hypothesized to be the cause and looks for an effect on the variable hypothesized to be the effect while holding all other variables constant by control and randomization’’ (p. 102). The implications of this experimental perspective on causality for psychopathology research are readily apparent: The situation is nearly hopeless, at least in terms of getting at the original, antecedent, distal causes of psychopathology. It is axiomatically unethical to manipulate variables to enhance the likelihood of psychopathology; we cannot directly manipulate things to create psychopathology in persons who do not already suffer from psychopathology. This is not to say that, once psychopathology is present, experimental designs are not fundamentally helpful in understanding the mechanisms underlying its expression. Indeed, the discipline of experimental psychopathology is founded on this premise, involving comparisons of the behaviors of persons with psychopathology and persons without psychopathology under precisely controlled conditions.
Teach to Search
Authors: Hoffmann Roald
Published: November 2020

George Pimentel was a wonderful man, whose heart and soul were in chemistry. And just as much in research, in which he excelled, as in teaching. From his writing it is clear that he did not separate the two. Nor do I, which is why I am happy and proud to be associated with an award given in George Pimentel’s name, and especially one in chemical education. I will speak of two themes: • The inseparability of teaching and research. And for that matter, of chemistry and the world. • The necessity of chemists to teach broadly, to speak to the general public. And the tensions that arise in the process. But before I launch into these subjects, let me say some words about how I feel about teaching and receiving this award. Whatever success I have had I owe to teaching. The logic or rhetoric of teaching underlies my research within chemistry and my writing outside of chemistry. As I began to think about this, I felt suddenly a little less guilty about receiving an award in chemical education. Let me tell you why I felt—feel—guilty. What am I—viewed by the community of chemistry as a researcher whose work has received ample recognition—doing getting an award that should be given to those who have toiled so hard, dedicating their lives to chemical education? When there aren’t too many of these awards around . . . A second source of guilt for me is that I suspect that a significant component in the thinking of the Pimentel award committee was my role in making the Annenberg/CPB television course in chemistry, The World of Chemistry. I was a member of the team, indeed, and my soul and sweat went into the project. But the part I played—more than just being a pretty face, true—was in fact much smaller than the parts of several other people, who really deserve recognition. I will tell you about those people in time.
Optic Nerve Examination
Authors: Woodruff Todd E.
Published: November 2020

•Small field of view but increased magnification •Significant degradation of the view from media opacities or small pupil •Lacks ability to perform stereoscopic examination •Useful when slit-lamp exam not possible •Most commonly used system •Variable magnification and field of view • Reasonable view through small pupil • Good stereoscopic view •Less degradation of view from media opacities than direct ophthalmoscope •The magnification and stereopsis obtained with a slit-lamp system is generally superior to that of a handheld or headlamp-based system. • Poor magnification, with wide field of view •Least degradation of view from media opacities •Value of stereopsis limited by poor magnification Fair to poor with small pupils •May be useful for bedside exam or in the operating room • The vertical diameter of the optic nerve can be easily estimated during a slit-lamp exam by the following method: 1. A thin slit beam is focused on the nerve through the lens of choice. 2. The vertical length of the beam is adjusted to match the height of the disc. 3. The length of the beam is read off the slit-lamp beam scale. 4. The scale reading is adjusted by the correction factor of the specific lens. •This estimation is reasonably accurate, but it tends to underestimate disc size in high levels of myopia, and overestimate in high hyperopia. • One can also use the scale projection of the direct ophthalmoscope to estimate nerve head size, with no correction factor needed. The small light cone of the direct ophthalmoscope subtends an angle of about 5 degrees, about the same size as an average optic disc, and can give a quick estimate of relative size. • Stereo-photographs are the most helpful but are more difficult to obtain in a reproducible manner. •Cameras with a prism-based fixed-angle method of taking simultaneous stereo-photos tend to produce more consistent results, but are more expensive. • While non-mydriatic cameras exist, images suffer when the pupil is smaller than 4 mm, and dilation is commonly employed to obtain the best images.
Management of Glaucoma Following Intraocular Procedures
Authors: Mudumbai Raghu C.
Published: November 2020

The development of glaucoma can occur postoperatively from corneal/refractive, cataract, and vitreoretinal surgery. Additionally, glaucoma may be noted after clinical procedures have been performed, including injections and laser procedures. This chapter is organized into two basic sections: postoperative and post-procedure glaucoma. Background: Currently little is known about the effect of refractive surgery in glaucoma patients or about patients who undergo refractive procedures and may go on to develop glaucoma. •IOP measurement
•Measurement of IOP after refractive surgery can be challenging. Corneal properties that are altered after refractive surgery include corneal thickness, corneal curvature, the structural integrity (stiffness or hysteresis), as well as the overlying tear film that interacts with instruments that measure IOP. Photorefractive keratectomy (PRK) additionally ablates portions of Bowman’s layer, which may change corneal resistance. Nomograms have been developed to adjust for IOP change after corneal alteration but usually take only corneak thickness into account, which has led to little success in their use. •Goldmann applanation tonometry (GAT) assumes corneal thickness = 520 microns. Thicker corneas will overestimate IOP and thinner corneas, which result from refractive procedures such as PRK and LASIK, will underestimate IOP. Therefore, GAT may have limited value in measuring true IOP following refractive surgery. Other tonometric devices, like Pascal dynamic contour tonometry, pneumatonometry, and the Reichert ocular response analyzer, may be more accurate. There does not appear to be any simple conversion table that can be referenced in correcting measured IOP after the cornea is altered surgically. Preoperative IOP is probably the most important variable that should be recorded. •The intraoperative pressure spike associated with LASIK may occur in select patients, leading to the development of glaucomatous optic neuropathy. • Pressure-induced stromal keratitis (PISK) is a condition related to steroid-induced elevated IOP that may occur after LASIK. The clinical appearance is similar to diffuse lamellar keratitis (DLK), where there is a diffuse interlamellar haze covering the flap. DLK is an inflamatory response where IOP is not elevated and requires topical steroid treatment for resolution.
Early Human Civilizations and River Deltas
Authors: Bianchi Thomas S.
Published: November 2020

For millennia, humans have been dependent upon rivers and their resources for food, transport, and irrigation, and by mid-Holocene times (about 5,000 years ago), humans harnessed hydraulic power that in part contributed to the rise of civilization. It is generally accepted that the earliest civilizations to develop such linkages with irrigation and cultivation of crops arose in the Old World, in Mesopotamia and the Levant, the Indus Valley, and the Central Kingdom, associated with, respectively, the Tigris, Jordan, Euphrates, and Nile; the Indus; and the Huang He (Yellow) and Changjiang (Yangtze) rivers—and, of course, their associated deltas. In this chapter, I examine the role of selected coastal deltas that were important in the development of these early Old World civiliza­tions, and how those people began to alter the shape and character of the highly productive and constantly changing deltaic environments. Before we begin, how­ever, I need to provide some basic definitions. First, I use the definition of civilization provided by Hassan, “a phenome­non of large societies with highly differentiated sectors of activities interrelated in a complex network of exchanges and obligations.” Second, I use the defini­tion of delta presented by Overeem, Syvitski, and Hutton, “a discrete shoreline protuberance formed where a river enters an ocean or lake, … a broadly lobate shape in plain view narrowing in the direction of the feeding river, and a sig­nificant proportion of the deposit … derived from the river”. Although I will at times discuss linkages between development of human settlements and river reaches upstream from the coastal delta, my primary focus in this chapter is on coastal deltaic regions, in particular those of the Nile, Indus, Yellow, and Yangtze rivers, which provide the best examples for link­ages between relatively recent early human populations and coastal deltas. I will address other deltas later in the book. My rationale for beginning this book with a discussion of the relationship between Old World civilizations and deltas is that this long- term interaction has been so dramatically altered over the past few millennia— essentially, it is a good relationship “gone bad.”
Exploring a Sustainable Future
Authors: Bianchi Thomas S.
Published: November 2020

In this chapter, I will explore the concept of sustainability, as viewed in the United States and around the world, and examine how we have arrived at our current thinking about conservation practices in a continually evolving, complex geopolitical sphere. I will do this to link delta restoration with the broader, global issues of providing food and clean water as described in the United Nations Millennium Development Goals (http:// www.un.org/millenniumgoals). Many people have written on global environmental sustainability, so I will only briefly summarize these views here and conclude with a brief statement about delta sustainability. During the short time that humans have been on this planet, we have altered nearly 50% of the land surface, and 50% of the wetlands in the world have been lost—a consequence of the unsustainable mindset of human civilizations. Sustainability embodies “stewardship” and “design with nature,” with well-defined goals and an agreed upon “carrying capacity,” that can be developed and modeled by scientists and planners. The most popular definition of sustainability can be traced to a 1987 United Nations conference, in which sustainable development programs were described as those that “meet present needs without compromising the ability of future generations to meet their needs.” Robert Gillman, editor of In Context magazine, extends this goal-oriented definition by stating “sustainability refers to a very old and simple concept (The Golden Rule) … do unto future generations as you would have them do unto you.” These well-established definitions set forth an ideal premise, but they do not specify the human and environmental parameters needed to model and measure sustainable development. So, here are some more specific definitions: “Sustainable means using methods, systems and materials that won’t deplete resources or harm natural cycles.” Sustainability “identifies a concept and attitude in development that looks at a site’s natural land, water, and energy resources as integral aspects of the development.”
Best Synthetic Methods: Oxidation
Authors: Taber Douglass
Published: November 2020

Although the enantioselective oxidation of alkyl aryl sulﬁdes is well developed, much less is known about dialkyl sulﬁdes. Tsutomu Katsuki of Kyushu University has designed (J. Am. Chem. Soc. 2007, 129, 8940) an Fe(salan) complex that combines with aqueous H2O2 to oxidize alkyl methyl sulﬁdes in high ee. The oxidation of alcohols to aldehydes and ketones is one of the most widely practiced of synthetic transformations. Ge Wang of the University of Science and Technology in Beijing has developed (Chem. Lett. 2007, 36, 1236) a Mo catalyst that used aqueous H2O2 to effect this transformation. Secondary alcohols are oxidized more rapidly than primary alcohols. Vinod K. Singh of the Indian Institute of Technology, Kanpur, has found (Synth. Comm. 2007, 37, 4099) that the solid, inexpensive 6 can take the place of oxalyl chloride in the Swern oxidation. Viktor V. Zhdankin of the University of Minnesota, Duluth has devised (J. Org. Chem. 2007, 72, 8149) a polymer-bound hypervalent iodine reagent that is easily separated after use, and reoxidized for reuse. Enones such as 11 are versatile intermediates for organic synthesis. Makoto Tokunaga, now at Kyushu University, and Yasushi Tsuji, now at Kyoto University, have found (Tetrahedron Lett. 2007, 48, 6860) a Pd catalyst that, in the presence of O2 , will oxidize a cyclic ketone such as 10 to the enone. The direct oxidation of an alcohol to the acid is not always an efficient process, so the conversion of 12 to 13 would often be carried out over at least three steps. David Milstein of the Weizmann Institute of Science has devised (Science 2007, 317, 790) a Ru catalyst that effected the transformation in a single step, generating H2 as a byproduct as the oxidation proceeded. The oxidation of an aldehyde to the corresponding amide is also a useful transformation. Noritaka Mizuno of the University of Tokyo has designed (Angew. Chem. Int. Ed. 2007, 46, 5202) a Rh catalyst that can combine, in water, the aldehyde 14 and NH2OH to give the primary amide 15 . Johann Chan of Amgen Inc., Thousand Oaks, CA has found (J. Am. Chem. Soc. 2007, 129, 14106) a different Rh catalyst that mediated the oxidation of a sulfonamide to the nitrene, which under the reaction conditions inserted into the aldehyde H to give the amide 17.
Protection of Organic Functional Groups
Authors: Taber Douglass
Published: November 2020

Several noteworthy new developments in the protection and deprotection of alcohols have been reported. Andrea Bifﬁs of the Università di Padova has developed (Adv. Synth. Catal. 2007, 349, 2485) a Rh catalyst that effected silylation of alcohols such as 1 to the TES ether 2 at just 0.01% loading. Joshua Rokach of the Florida Institute of Technology has observed (Tetrahedron Lett. 2007, 48, 5289) that the reverse reaction, Rh-catalyzed desilylation of 3, was highly selective for the less congested site, even removing the usually less reactive TBS ether of 3 and leaving the more hindered TES ether. Hirokazu Tsukamoto of Tohoku University has devised (Tetrahedron Lett. 2007, 48, 8438) an improved procedure for the deprotection of allyl ethers such as 5. Filtration of the reaction mixture through polymer- bound diethanolamine removed > 95% of the Pd from the product. Patrick Pale of the Université Louis Pasteur has established (Tetrahedron Lett. 2007, 48, 8895) improved con- ditions for preparing diphenylmethyl ethers such as 10. The protecting group was removed with the Pd catalyst and ethanol. Amines can be activated for alkylation by N-formylation. Subsequent deformylation of the alkylated formamide 11 has been a challenge. Longqin Hu of Rutgers University has developed (Tetrahedron Lett . 2007, 48, 4585) microwave conditions that work well. Carbamates are stable, but esters are not. Protection of amides can also be important. Michael J. Zacuto of Merck Process in Rahway, NJ has optimized (J. Org. Chem. 2007, 72, 6298) the Rh-catalyzed deallylation of 13 to give 14. Carbonyl protection and deprotection is also important. Yoshihisa Kobayashi of the University of California, San Diego has devised (J. Org. Chem. 2007, 72, 3913) the isonitrile 15. Usually, the product 16 after Ugi condensation would be very difficult to hydrolyze. In the case of 16, mild acid effected cyclization to the acyl indole 17, which was easy to hydrolyze. In a different approach, Francesco Naso of the Università di Bari has shown (Chem. Commun. 2007, 3756) that acid chlorides such as 18 condensed with 19 to give the furan 20. Such furans are easily oxidized, liberating the starting acid.
Intermolecular and Intramolecular C-H Functionalization
Authors: Taber Douglass
Published: November 2020

Peter Legzdins of the University of British Columbia has described (J. Am. Chem. Soc. 2007, 129, 5372) a stoichiometric tungsten complex that speciﬁcally functionalized the primary H of an alkane 1 to give the organometallic 2. Neither the scope of the reactivity of 2 nor the functional group compatibility of this process have as yet been explored. Ruggero Curci of the Università di Bari has reported (Tetrahedron Lett. 2007, 48, 3575) the stereospecific hydroxylation of 1,3-dimethyl cyclohexane 4 to the diol 6. Yasuyuki Kita of Osaka University has developed (Organic Lett. 2007, 9, 3129) conditions for specific benzylic oxidation, converting 7 into 8 with high diastereocontrol. Larry E. Overman of the University of California, Irvine has established (Organic Lett. 2007, 9, 5267) that by using a slow H-atom donor, it was possible to effect intramolecular H abstraction, leading, by oxidation of the intermediate captodatively-stabilized radical, from 9 to the acetate 10. The target C-H of 9 is activated by being adjacent to the ring nitrogen. There are many other ways that nitrogen, easily oxidized, has been used to activate a C-H for bond formation. Takehiko Yoshimitsu and Tetsuaki Tanaka of Osaka University have established (Organic Lett. 2007, 9, 5115) a free-radical route for the homologation of a tertiary amine such as 11 with phenyl isocyanate 12. Chuan He of the University of Chicago has devised (Angew. Chem. Int. Ed. 2007, 46, 5184) an Ag catalyst for the oxidative cyclization of sulfamates such as 15. M. Christina White of the University of Illinois has developed (J. Am. Chem. Soc. 2007, 129, 7274) a ligand system that allows the diastereoselective Pd-mediated allylic oxidation of 16 to 17. The cyclization of 18 to 19 developed (J. Org. Chem. 2007, 72, 8994) by Renhua Fan of Fudan University is thought to be proceeding via H atom abstraction by an intermediate nitrogen radical. The oxidation of the amine 20 to the endocyclic enamine 21 reported (J. Am. Chem. Soc. 2007, 129, 14544) by Maurice Brookhart of the University of North Carolina depended on the ease of oxidative addition of an intermediate alkenyl Co complex into the C-H bond adjacent to the nitrogen. The multistep cyclization of 22 to 23 devised (Organic Lett. 2007, 9, 4375) by Philippe Renaud of the Universität Bern depended on the ease of H atom abstraction adjacent to nitrogen.
New Methods for Carbon-Carbon Bond Construction
Authors: Taber Douglass
Published: November 2020

Mohammad Navid Soltani Rad of Shiraz University of Technology has shown (Tetrahedron Lett. 2007, 48, 6779) that with tosylimidazole (TsIm) activation in the presence of NaCN, primary, secondary and tertiary alcohols are converted into the corresponding nitriles. Gregory C. Fu of MIT has devised (J. Am. Chem. Soc. 2007, 129, 9602) a Ni catalyst that mediated the coupling of sp3-hybridized halides such as 3 with sp3-hybridized organoboranes such as 4, to give 5. Usually, carbanions with good leaving groups in the beta position do not couple efficiently, but just eliminate. Scott D. Rychnovsky of the University of California, Irvine has found (Organic Lett . 2007, 9, 4757) that initial protection of 6 as the alkoxide allowed smooth reduction of the sulfide and addition of the derived alkyl lithium to the amide 7 to give 8. Doubly-activated Michael acceptors such as 11 are often too unstable to isolate. J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad has shown (Tetrahedron Lett. 2007, 48, 7546) that Baylis-Hillman adducts such as 9 can be oxidized in situ, with concomitant Sakurai addition to give 12. Rather than use the usual Li or Na or K enolate, Don M. Coltart of Duke University has found (Organic Lett. 2007, 9, 4139) that ketones such as 13 will condense with amides such as 14 to give the diketone 15 on exposure to MgBr2. OEt2 and i -Pr2 NEt. Simultaneously, Gérard Cahiez of the Université de Cergy (Organic Lett. 2007, 9, 3253) and Janine Cossy of ESPCI Paris (Angew. Chem. Int. Ed. 2007, 46, 6521) reported that Fe salts will catalyze the coupling of sp2 -hybridized Grignard reagents such as 17 with alkyl halides. John Montgomery of the University of Michigan has described (J. Am. Chem. Soc. 2007, 129, 9568) the Ni-mediated regio- and enantioselective addition of an alkynes 20 to an aldehyde 19 to give the allylic alcohol 21. In a third example of sp2 - sp3 coupling, Troels Skrydstrup of the University of Aarhus has established (J. Org. Chem. 2007, 72, 6464) that Negishi coupling with alkenyl phosponates such as 23 proceeded efficiently.
Construction of Alkenes, Alkynes and Allenes
Authors: Taber Douglass
Published: November 2020

Products such as 3 and 6 are usually prepared by phosphonate condensation. J. S. Yadav of the Indian Institute of Technology, Hyderabad found (Tetrahedron Lett. 2008, 49, 4498) that the cation-exchange resin Amberlyst-15 in CH2Cl2 mediated the condensation of a terminal alkyne such as 1 with an aldehyde to give the enone 3. Similarly, Teruaki Mukaiyama of Kitasato University showed (Chemistry Lett. 2008, 37, 704) that tetrabutylammonium acetate mediated the condensation of 5 with an aldehyde such as 4 to give the ester 6. David M. Hodgson of the University of Oxford described (J. Am. Chem. Soc. 2008, 130, 16500) the optimization of the Schlosser protocol for the condensation of a phosphorane with an aldehyde 7 followed by deprotonation and halogenation, to deliver the alkenyl halide 9 with good geometric control. Jun Terao of Kyoyo University and Nobuaki Kambe of Osaka University accomplished (Chem. Commun. 2008, 5836) the homologation of a halide such as 10 to the corresponding allylic Grignard reagent 12. Primary, secondary and tertiary halides worked well. Jennifer Love of the University of British Columbia developed (Organic Lett. 2008, 10, 3941) a Rh catalyst for the addition of thiols to terminal alkynes such as 13, and found that the product thioether 14 coupled smoothly with Grignard reagents to deliver the 1,1-disubstituted alkene 15. Glenn C. Micalizio, now at Scripps Florida, established (J. Am. Chem. Soc. 2008, 130, 16870) what appears to be a general method for the construction of Z-trisubstituted alkenes such as 18. The Ohira protocol has become the method of choice for converting an aldehyde 19 to the alkyne 21. We have found (Tetrahedron Lett. 2008, 49, 6904) that the reagent 20 offers advantages in price, preparation and handling. Bo Xu and Gerald B. Hammond of the University of Louisville observed (Organic Lett. 2008, 10, 3713) that an allene ester such as 22 is readily homologated to the alkyne 23. Ashton C. Partridge of Massey University extended (Tetrahedron Lett. 2008, 49, 5632) condensation with the aryl phosphonate 25 to porphyrin aldehydes, leading to alkynes such as 26.
C-O Ring Containing Natural Products: Paeonilactone B (Taylor), Deoxymonate B (de la Pradilla), Sanguiin H-5 (Spring), Solandelactone A (White), Spirastrellolide A (Paterson)
Authors: Taber Douglass
Published: November 2020

Richard J. K. Taylor of the University of York has developed (Angew. Chem. Int. Ed. 2008, 47, 1935) the diasteroselective intramolecular Michael cyclization of phosphonates such as 2. Quenching of the cyclized product with paraformaldehyde delivered ( + )-Paeonilactone B 3. Roberto Fernández de la Pradilla of the CSIC, Madrid established (Tetrahedron Lett. 2008, 49, 4167) the diastereoselective intramolecular hetero Michael addition of alcohols to enantiomerically-pure acyclic sulfoxides such as 4 to give the allylic sulfoxide 5. Mislow-Evans rearrangement converted 5 into 6, the enantiomerically-pure core of Ethyl Deoxymonate B 7. The ellagitannins, represented by 10, are single atropisomers around the biphenyl linkage. David R. Spring of the University of Cambridge found (Organic Lett. 2008, 10, 2593) that the chiral constraint of the carbohydrate backbone of 9 directed the absolute sense of the oxidative coupling of the mixed cuprate derived from 9, leading to Sanguiin H-5 10 with high diastereomeric control. A key challenge in the synthesis of the solandelactones, exemplified by 14, is the stereocontrolled construction of the unsaturated eight-membered ring lactone. James D. White of Oregon State University found (J. Org. Chem. 2008, 73, 4139) an elegant solution to this problem, by exposure of the cyclic carbonate 11 to the Petasis reagent, to give 12. Subsequent Claisen rearrangement delivered the eight-membered ring lactone, at the same time installing the ring alkene of Solandelactone E 14. AD-mix usually proceeds with only modest enantiocontrol with terminal alkenes. None the less, Ian Paterson, also of the University of Cambridge, observed (Angew. Chem. Int. Ed. 2008, 47, 3016, Angew. Chem. Int. Ed. 2008, 47, 3021) that bis-dihydroxylation of the diene 17 proceeded to give, after acid-mediated cyclization, the bis-spiro ketal core 18 of Spirastrellolide A Methyl Ester 19 with high diastereocontrol.
Stereocontrolled Construction of C-N Rings: The Vanderwal Synthesis of Norfluorocurarine
Authors: Taber Douglass
Published: November 2020

Forrest E. Michael of the University of Washington described (Organic Lett. 2009, 11, 1147) the Pd-catalyzed aminative cyclization of 1 to the differentially-protected diamine 3. Peter Somfai of KTH Chemical Science and Engineering observed (Organic Lett. 2009, 11, 919) that [1,2]-rearrangement of 4 proceeded to deliver 5 with near-perfect maintenance of enantiomeric excess. Tushar Kanti Chakraborty of the Central Drug Research Institute, Lucknow applied (Tetrahedron Lett. 2009, 50, 3306) the Ti(III) reduction of epoxides to the Sharpless-derived ether 6, leading to the pyrrolidine 7. Chun-Jiang Wang of Wuhan University devised (Chem. Commun. 2009, 2905) a silver catalyst that directed the absolute sense of the dipolar addition of 9 to 8 to give 10. Homoallyic azides such as 11 are readily prepared in high enantiomeric excess from the corresponding alcohol. Bernhard Breit of Albert-Ludwigs-Universität, Freiburg and André Mann of the Faculté de Pharmacie, Illkirch showed (Organic Lett. 2009, 11, 261) that Rh-mediated hydroformylation could be effected in the presence of the azide. Subsequent reduction delivered the piperidine 12. Jan-E. Bäckvall of Stockholm University applied (J. Org. Chem. 2009, 74, 1988) the protocol for dynamic kinetic asymmetric transformation (DYKAT) that he had developed to the cyanodiol 13. Remarkably, a single enantiomerically- pure diasteromer emerged, which he carried on to 14. Xiaodong Shi of West Virginia University found (Organic Lett. 2009, 11, 2333) that the stereogenic center of 17, even though it ended up outside the ring, directed the absolute configuration of the other centers of 18 as they formed. Jan Vesely of Charles University and Albert Moyano and Ramon Rios of the Universitat de Barcelona established (Tetrahedron Lett. 2009, 50, 1943) that an organocatayst directed the absolute configuration in the addition of 19 to 20 to give 21. Osamu Tamura of Showa Pharmaceutical University effected (Organic Lett. 2009, 11, 1179) cyclization of the malic acid-derived amide 22 to give 23 with high diastereocontrol.
Enantioselective Organocatalytic Construction of Carbocycles: The Nicolaou Synthesis of Biyouyanagin A
Authors: Taber Douglass
Published: November 2020

One of the more powerful routes to enantiomerically-pure carbocycles is the desymmetrization of a prochiral ring. Karl Anker Jørgensen of Aarhus University has found (J. Am. Chem. Soc. 2007, 129, 441) that many cyclic β-ketoesters, including the vinylogous carbonate 1, can be homologated with 2 to the corresponding alkyne 3, in high ee. Sanzhong Luo of the Chinese Academy of Sciences, Beijing, and Jin-Pei Cheng, of the Chinese Academy of Sciences and Nankai University, have shown (J. Org. Chem. 2007, 72, 9350) that the catalyst 6 mediated the selective addition of 4-substituted cyclohexanones such as 4 to the nitroalkene 5, establishing three new stereogenic centers. Organocatalysts, alone or complexed with activating metals, have also been used to effect enantioselective ring construction. E. J. Corey of Harvard University has established (J. Am. Chem. Soc. 2007, 129, 12686) that the proline-derived complex 10 will mediate the 2 + 2 addition of a cyclic enol ether with an acrylate to give the cyclobutane 11. Further elaboration led to the cyclohexenone 12. Armando Córdova of Stockholm University has described (Tetrahedron Lett. 2007, 48, 5835) a novel route to cyclopentanones such as 16, via tandem conjugate addition/intramolecular alkylation. Professor Jørgensen has reported (Angew. Chem. Int. Ed . 2007, 46 , 9202) the double addition of 18 to the unsaturated aldehyde 17 to give 20. Earlier last year, Yujiro Hayashi of the Tokyo University of Science had shown (Angew. Chem. Int. Ed. 2007, 46, 4922) that the double addition of the inexpensive 21 to 5 could, depending on conditions, be directed selectively to 22, 23, or 24. As illustrated by the conversion of 8 to 13, organocatalysis can be used to effect the enantioselective construction of polycarbocyclic products. The initial ring prepared in enantiomerically-pure form by organocatalysis can also set the chirality of a polycyclic system. Professor Corey has reported (J. Am. Chem. Soc. 2007, 129, 10346) that Itsuno-Corey reduction of the prochiral diketone 25 led to the ketone 27. Cyclization followed by oxidation and reduction then delivered estrone methyl ether 28.
Enantioselective Organocatalyzed Construction of Carbocyclic Rings
Authors: Taber Douglass
Published: November 2020

One of the most practical ways to construct enantiomerically-enriched carbocyclic systems is to effect asymmetric transformation of preformed prochiral rings. Choon-Hong Tan of the National University of Singapore observed (Chem. Commun. 2008, 5526) that allylic halides such as 1 coupled with malonates such as 2 to give the α-methylene ketone 3 in high ee. Xinmiao Liang of the Dalian Institute of Chemical Physics and Jinxing Ye of the East China University of Science and Technology reported (Chem. Commun. 2008, 3302) that nitromethane 5 could be added to enones such as 4 to construct cyclic quaternary stereogenic centers such as that of 6. The addition of the cyclohexanone 7 to the acceptor 8 described (Chem. Commun. 2008, 6315) by Yixin Lu, also of the National University of Singapore led to the creation of two new cyclic stereogenic centers. Polycarbocyclic prochiral rings are also of interest. Teck-Peng Loh of Nanyang Technological University devised (Tetrahedron Lett. 2008, 49, 5389) the steroid AB donor 10, that added to crotonaldehyde 1 to give the single enantiomerically-pure diastereomer 12. Nitro alkenes are excellent Michael acceptors. Dieter Enders of RWTH Aachen took advantage of this (Angew. Chem. Int. Ed. 2008, 47, 7539) in developing the addition of aldehydes such as 14 to the nitroalkene 13. Intramolecular alkylation ensued, to deliver the product 15 as a single diastereomer. Guofu Zhong, also of Nanyang Technological University, established (Organic Lett. 2008, 10, 3425; Organic Lett. 2008, 10, 3489) an approach to cyclopentane construction based on the Michael addition of β-ketoesters such as 16 and 19 to nitroalkenes such as 17 and 20. Intramolecular nitro aldol (Henry) addition led to 18, while an intramolecular Michael addition delivered 21. Damien Bonne and Jean Rodriguez of Aix-Marseille Université employed (Organic Lett. 2008, 10, 5409) intramolecular dipolar cycloaddition to convert the initial adduct between 22 and 23 to the cyclopentane 24. They also prepared cyclohexane derivatives using this approach. The diketone 25 is prochiral. Benjamin List of the Max-Planck Institut, Mülheim devised (Angew. Chem. Int. Ed. 2008, 47, 7656) an organocatalyst that mediated the intramolecular aldol cyclization of 25 to 26 in high ee.
Stereocontrolled Carbocyclic Construction: (-)-Mintlactone (Bates), (-)-Gleenol (Kobayashi), (-)-Vibralactone C (Snider)
Authors: Taber Douglass
Published: November 2020

Nigel S. Simpkins, now at the University of Birmingham, found (Chem. Commun. 2008, 5390) that the prochiral cyclopropane amide 1 could be deprotonated to give, after alkylation, the substituted cyclopropane 3 with high enanantio- and diastereocontrol. In the course of a synthesis of (+)-Lineatin, Ramon Alibés of the Universitat Autònoma de Barcelona optimized (J. Org. Chem. 2008, 73, 5944) the photochemical cycloaddition of 4 and 5 to give, after reductive dechlorination, the cyclobutene 6. In a related reaction, José L. García Ruano and M. Rosario Martín of the Universidad Autónoma de Madrid observed (J. Org. Chem. 2008, 73, 9366) that the cycloaddition of 8 to 7 proceeded with high regio- and diastereocontrol, to give the cyclopentene 9. Joseph M. Ready of UT Southwestern in Dallas developed (Angew. Chem. Int. Ed. 2008, 47, 7068) a powerful new cyclopentannulation, condensing the cyclopropane derived from the addition of 11 to 10 with the protected ynolate 12 to give 13, in the presence of a modified Lewis acid catalyst. Chun-Chen Liao of the National Tsing Hua University, Hsinchu described (Angew. Chem. Int. Ed. 2008, 47, 7325) the oxidative ring contraction of the o-alkoxy phenol 14 to the cyclopentenone 15. Stéphane Quideau of the Université de Bordeaux reported (Organic Lett. 2008, 10, 5211) a related ring contraction. We uncovered (J. Org. Chem. 2008, 73, 9479) a simple protocol for the in situ conversion of an ω-alkenyl ketone such as 16 to the corresponding diazo compound, leading, via dipolar cycloaddition, to the adduct 17. Ulrich Zutter of Roche Basel described (J. Org. Chem. 2008 , 73, 4895), in a synthesis of Tamiflu, the hydrogenation of 19 to give the cyclohexane with all-cis diastereocontrol. Selective removal of the methyl ethers with trimethylsilyl iodide set the stage for enzymatic ester hydrolysis, delivering 20 in high ee.
The Sammakia Synthesis of the Macrolide RK-397
Authors: Taber Douglass
Published: November 2020

The polyene macrolide RK-397 3, isolated from soil bacteria, has antifungal, antibacterial and anti-tumor activity. Tarek Sammakia of the University of Colorado has described (Angew. Chem. Int. Ed. 2007, 46, 1066) the highly convergent coupling of 1 with 2, leading to 3. The preparation of 1 depended on the powerful methods that have been developed for acyclic stereocontrol. Beginning with the allylic alcohol 4, Sharpless asymmetric epoxidation established the absolute configuration of 5. Following the Jung “non-aldol aldol” protocol, exposure of 5 to TMSOTf delivered the aldehyde 6 in high de. Condensation of 6 with the lithium enolate of acetone also proceeded with high de. The resulting alcohol was protected as the MOM ether, to direct the stereoselectivity of the subsequent aldol condensation with 8. Selective β-elimination followed by reduction and protecting group exchange then gave 1. The preparation of 2 took advantage of the power of Brown asymmetric allylation. Allylation of the symmetrical 11 led to the diol 12. This was desymmetrized by selective acetonide formation, to give 13. Ozonolysis, reductive work-up, and protection of the newly-formed 1,3-diol gave 14, setting the stage for oxidation and asymmetric allylation to give 15. Reductive deprotection and oxidation then delivered the acetonide 2. The tris acetonide 16 was assembled by addition of the enolate derived from 1 to the aldehyde 2, followed by reduction and protection. Kinetically-controlled metathesis with 17 established the triene 18. Phosphonate-mediated homologation to the pentaene 19 followed by hydrolysis and Yamaguchi macrolactonization then completed the synthesis of the macrolide RK-397 3.