An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki–Miyaura and Buchwald–Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki–Miyaura coupling, and SNAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.

Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

Novel unsymmetrical organic sensitizers comprising donor, electron-conducting, and anchoring groups were engineered at a molecular level and synthesized for sensitization of mesoscopic titanium dioxide injection solar cells. The unsymmetrical organic sensitizers 3-(5-(4-(diphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic acid (D5), 3-(5-bis(4-(diphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic acid (D7), 5-(4-(bis(4-methoxyphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic acid (D9), and 3-(5-bis(4,4'-dimethoxydiphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic acid (D11) anchored onto TiO2 and were tested in dye-sensitized solar cell with a volatile electrolyte. The monochromatic incident photon-to-current conversion efficiency of these sensitizers is above 80%, and D11-sensitized solar cells yield a short-circuit photocurrent density of 13.90 +/- 0.2 mA/cm(2), an open-circuit voltage of 740 +/- 10 mV, and a fill factor of 0.70 +/- 0.02, corresponding to an overall conversion efficiency of 7.20% under standard AM 1.5 sun light. Detailed investigations of these sensitizers reveal that the long electron lifetime is responsible for differences in observed open-circuit potential of the cell. As an alternative to liquid electrolyte cells, a solid-state organic hole transporter is used in combination with the D9 sensitizer, which exhibited an efficiency of 3.25%. Density functional theory/time-dependent density functional theory calculations have been employed to gain insight into the electronic structure and excited states of the investigated species.

Molecular Engineering of Organic Sensitizers for Dye-Sensitized Solar Cell Applications

I was born on July 14, 1935 in Changchun, China, as a Japanese citizen. My family moved to Harbin when I was one and then to Seoul, Korea, two years before the end of World War II. I was admitted to an elementary school in Harbin at age six, a year earlier than normal, and I then went to Seoul as an eight-year old third grader. Shortly after the end of World War II in 1945, my family returned to Japan and moved into a house in Tokyo which my parents had purchased several years earlier and had miraculously survived many intensive bombings. A much more serious problem for my parents was how to feed a rapidly growing family of seven, with five children ranging from twelve to one. Their solution to this foodshortage problem was to move to an underdeveloped patch of land of a little less than one acre about 50 km southwest of the center of Tokyo. Although my father s attempt to become a farmer there was not very successful, this naturally wooded area called “Rinkan” in Yamato city, Kanagawa prefecture, became what I consider even now my “first hometown”, where I spent my junior high school (seventh–ninth grades), high school (tenth–twelfth grades), and college years (1953– 1958; five years as I needed to repeat my junior year due to gastrointestinal illness). Despite all these difficulties, I recall my early school years through to the ninth grade mostly with positive and enjoyable memories. Although I virtually never studied outside the classroom through to the ninth grade, I was quite alert and enjoyed most of the classes, with the exception of calligraphy and Japanese language. But, I enjoyed the after-school hours before darkness even more. Those short after-school hours in the nearly six-month-long Harbin winters were spent skating in the playground covered with ice. I hardly recall my indoor activities before darkness through to my ninth grade. Several classmates and I in our junior high school jointly collected naturally growing grasses for rabbits, and took care of chickens—which virtually every family in our area were raising for food and minor supplementary income—but we never forgot to set aside some time for playing ball games and so on. For some reason, I found a world atlas on our very modest bookshelf to be to my liking and almost daily looked at it in the evening, especially during my Harbin days. Even with this manner of approach, I luckily established myself as one of the top students throughout my elementary and junior high school years. My first setback, if only a temporary one, hit me when I applied for an “elite” high school in our prefecture called Shonan High School. Despite my superior scholastic standing, I was declared ineligible, because I was a year younger than my classmates. Luckily, several of my teachers at Yamato Junior High School, including my classroom teacher, S. Koyama, and music class teacher, T. Suzuki, who was the father of my future wife, Sumire, successfully persuaded Shonan High School officials to accept me. At Shonan, where only the top few of my 200-plus classmates at Yamato Junior High School attended, my lifestyle described above was no longer satisfactory. Nor was I sufficiently ambitious about my higher education. I soon noticed that the entire school was obsessed with a single notion of intensely training and successfully sending as many students as possible to several of the most highly rated universities, represented by the University of Tokyo, several other former Imperial Universities such as Kyoto, Osaka, and Nagaya, as well as Tokyo Institute of Technology. Throughout my first year at Shonan, I was still mostly limiting my studying to that in the classrooms, which led me to earn the 123rd place in scholastic standing among a little more than 400 classmates. After a brief moment of disappointment, I then realized that, whereas there were a little more than 100 students who were ahead of myself, there were also nearly 300 others behind me. Back in those days, about 30–40 students, including one-time repeaters, were successfully entering the University of Tokyo each year from Shonan. It then suddenly occurred to me that, if I studied as hard as I could, even I might have a legitimate chance of entering the University of Tokyo, which until then appeared far beyond my reach. For the first time in my life, I instantly became a selfmotivated and highly disciplined model student devoting most of my available time to intensive studying. I would wake up a couple of hours earlier than the rest and spend those extra hours in preparation for the classes each day. No more solitary explorations of my favorite Shonan seaside area, especially Enoshima Island, after classes. Each evening, I would study until after 11 pm, when I heard mother’s gentle

Magical power of transition metals: past, present, and future (Nobel Lecture).

The modified Julia olefination: alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds

Recent re-evaluations of the geological record of the earliest life on Earth have led to the suggestion that some of the oldest putative microfossils1 and carbonaceous matter were formed through abiotic hydrothermal processes2,3. Similarly, many early Archaean (more than 3,400-Myr-old) cherts have been reinterpreted as hydrothermal deposits rather than products of normal marine sedimentary processes2,4,5. Here we present the results of a field, petrographic and geochemical study testing these hypotheses for the 3,416-Myr-old Buck Reef Chert, South Africa. From sedimentary structures and distributions of sand and mud, we infer that deposition occurred in normal open shallow to deep marine environments. The siderite enrichment that we observe in deep-water sediments is consistent with a stratified early ocean6,7. We show that most carbonaceous matter was formed by photosynthetic mats within the euphotic zone and distributed as detrital matter by waves and currents to surrounding environments. We find no evidence that hydrothermal processes had any direct role in the deposition of either the carbonaceous matter or the enclosing sediments. Instead, we conclude that photosynthetic organisms had evolved and were living in a stratified ocean supersaturated in dissolved silica8,9 3,416 Myr ago.

Photosynthetic microbial mats in the 3,416-Myr-old ocean

The Utility of Phosphonate Carbanions in Olefin Synthesis

Phosphoramidate Anions: The Preparation of Carbodiimides, Ketenimines and Isothiocyanates

Nucleophilic substitution at phosphorus. The effect of ion association on the stereochemistry and rate of substitution at phosphorus in a six-membered ring phosphate

William S. Wadsworth

Papers

The Utility of Phosphonate Carbanions in Olefin Synthesis

Phosphoramidate Anions: The Preparation of Carbodiimides, Ketenimines and Isothiocyanates

Nucleophilic substitution at phosphorus. The effect of ion association on the stereochemistry and rate of substitution at phosphorus in a six-membered ring phosphate

A cyclic phosphate: base and metal acetate catalyzed ring opening

Nucleophilic displacements at phosphorus. Evidence for an SNl (P) mechanism