Issue Date: December 18, 2006
Chemistry Highlights 2006
Once a year, C&EN reviews the chemistry research developments we've reported on that seem among the most significant of the past 12 months. We evaluate the novelty and breakthrough nature of individual scientific developments covered in our news stories, select about two each month that seem likely to have the most long-lasting impact, and chronicle them in this end-of-the-year issue.
This year's research highlights span a wide range of chemical subdisciplines, from organic synthesis, carbohydrate chemistry, structural biology, and chemical analysis to computationally aided molecular design, chemical element discovery, nanotechnology, and space chemistry.
Efforts to identify the most significant research developments are always fraught with difficulties, as members of Nobel Prize selection committees and similar groups undoubtedly appreciate only too well. Nevertheless, we believe the selections we make each year are advances that will continue to shape and influence the field of chemistry, both in the near term and for a good number of years into the future.
In organic chemistry, key advances were made in both total synthesis and reaction development.
Several compounds whose total syntheses were avidly pursued either had potential or proven therapeutic value or had particularly vexing structural features. The first total synthesis of UCS1025A, a promising inhibitor of the enzyme telomerase, was achieved in a remarkably concise manner by Tristan H. Lambert and Samuel J. Danishefsky of Sloan-Kettering Institute for Cancer Research and Columbia University (J. Am. Chem. Soc. 2006, 128, 426). Telomerase inhibitors are potential anticancer agents because the enzyme is expressed selectively in most tumors. Several synthetic teams had been trying to synthesize UCS1025A, a fungus-derived natural product, so it could be obtained in sufficient amounts to allow the study of its activity and mechanism. Lambert and Danishefsky succeeded by synthesizing two precursors of the natural product and then simply joining them, an approach that sidestepped problems encountered in earlier efforts to assemble the structure incrementally.
Amid the threat of pandemic avian flu and the shortage of a key drug to counter it, a new synthesis was developed for oseltamivir phosphate, the active ingredient in the Roche antiviral drug Tamiflu (J. Am. Chem. Soc. 2006, 128, 6310). Conceived by Elias J. Corey's group at Harvard University, the enantioselective synthesis is shorter than Roche's production method, uses cheaper starting materials, and has about twice the overall yield. It avoids (–)-shikimic and (–)-quinic acids, complex starting materials that Roche uses in its commercial process that are expensive and in limited supply. Tamiflu itself has been available in insufficient supply for potential use against avian flu virus, and the Harvard group's synthesis offers a potential solution to the supply problem, Corey noted at the time the work was reported.
Meanwhile, the simple bicyclic compound 2-quinuclidone may not look like much of a synthetic challenge, but thanks to its twisted structure and its unusually labile amide linkage, it eluded synthesis for almost 70 years. Chemists had prepared substituted versions of 2-quinuclidone, but the parent molecule's reactivity made its synthesis extremely difficult. This year Brian M. Stoltz and Kousuke Tani at California Institute of Technology succeeded in synthesizing 2-quinuclidone and isolating and characterizing its tetrafluoroborate salt for the first time (Nature 2006, 441, 731). What did the trick was an intramolecular attack of an azide on a ketone in the presence of HBF4. The resulting intermediate rearranges, eliminating N2 in the process. The work could provide insights into protein and enzymatic processes, such as amide hydrolysis.
Among a multitude of reactions developed this year, two stand out.
First is the remarkable three-step catalyzed cascade reaction that enabled a complex tetrasubstituted cyclohexene carbaldehyde to be assembled in a single procedure from simple starting materials (Nature 2006, 441, 861). The three-step pathway, developed by Dieter Enders and coworkers at RWTH Aachen University, was inspired by tandem reactions that nature uses to biosynthesize natural products. The sequence uses a proline-based organocatalyst to drive two Michael-type reactions and an aldol condensation. It creates three new C-C bonds and establishes four stereocenters with high diastereoselectivity and complete enantioselectivity.
The second is a new type of chemoselective amide-forming ligation reaction developed by Jeffrey W. Bode and coworkers at the University of California, Santa Barbara, that provides a useful new way to join peptides (Angew. Chem. Int. Ed. 2006, 45, 1248) and synthesize β-peptide oligomers (J. Am. Chem. Soc. 2006, 128, 1452), proteins, and other complex molecules. The reaction creates native amide linkages between α-keto carboxylic acids and N-alkylhydroxylamines. It is nearly ideal because it's chemoselective (works in the presence of other functional groups), proceeds in water without catalysts or other reagents, and is atom economical (its sole by-products being water and carbon dioxide). A researcher called the reaction "the most promising new chemistry for chemical protein synthesis in at least a decade."
At the frontiers of carbohydrate chemistry, researchers developed a high-throughput technique for screening mutant glycosyltransferases (GTs) for desired activity. The work could lead to a new generation of designer sugars. Scientists have long wanted to use directed evolution to screen libraries of mutated GTs for promising new ones. But to carry this out, a way to detect GT-catalyzed reactions is needed, and none was available. Amir Aharoni and Stephen G. Withers of the University of British Columbia, Vancouver, and colleagues developed such a procedure (Nat. Methods 2006, 3, 609). They demonstrated its use by harnessing directed evolution to identify a mutant sialyltransferase that catalyzes sialic acid transfer to galactose with 400-fold higher catalytic activity than the parent enzyme and that also transfers sialic acid to a thiosugar acceptor, a new synthetic capability.
Structural biology moved to center stage with this year's Nobel Prize in Chemistry, which went to structural biologist Roger D. Kornberg of Stanford University for work on the molecular basis of eukaryotic transcription, the process by which the genetic code of DNA is converted into messenger RNA for later translation into proteins (C&EN, Nov. 20, page 74). Beginning in 2001, Kornberg and coworkers determined and analyzed high-resolution X-ray crystal structures of RNA polymerase and various complexes of RNA polymerase with DNA, RNA, nucleotides, and proteins. By combining information from these studies, they pieced together a detailed picture of the molecular processes underlying transcription.
In another structural biology advance, the first crystal structure of Dicer, an enzyme that initiates RNA interference (RNAi), was obtained this year by Jennifer A. Doudna of the University of California, Berkeley, and coworkers (Science 2006, 311, 195). RNAi—in which short RNAs bind to messenger RNA and thus block gene expression—has attracted considerable research interest and won a Nobel Prize in Physiology or Medicine this year for its discoverers. Molecular mechanisms explaining how Dicer participates in RNAi had been proposed but could not be verified because its structure was unknown. The structure obtained by Doudna and coworkers helped confirm that two metal ions in each of the enzyme's two RNase III domains participate in its catalytic mechanism.
Another noteworthy achievement in structural biology is stereo-array isotope labeling (SAIL), a technique developed this year by Masatsune Kainosho of Tokyo Metropolitan University and coworkers (Nature 2006, 440, 52). SAIL could make it possible to routinely determine the solution structures of proteins at least twice as large as those commonly determined by nuclear magnetic resonance spectroscopy (NMR).
In SAIL, chiral organic synthesis is used to prepare amino acids labeled with deuterium, carbon-13, and nitrogen-15, and a protein is then synthesized from the labeled amino acids. NMR spectra of the resulting SAIL proteins are simpler, less congested, and more easily interpretable than those of corresponding conventional proteins.
Kainosho and coworkers demonstrated the technique by using it to solve the structure of a 41-kDa maltodextrin-binding protein. SAIL is "a triumph and the achievement of a lifetime," commented Kurt Wüthrich of the Swiss Federal Institute of Technology, Zurich, who shared the 2002 Nobel Prize in Chemistry for work on NMR structure analysis.
In molecular biology, researchers gained important insights into the molecular mechanisms of cellular protein production, Alzheimer's disease, and RNA interference.
The first techniques that make it possible to observe the expression of single protein molecules in living cells in real time were the subject of two papers by X. Sunney Xie of Harvard University and coworkers (Science 2006, 311, 1600 and Nature 2006, 440, 358). In one study, the production of single molecules of a fluorescent, membrane-targeted fusion protein was visualized in live bacteria. In the other, fluorescence generated by the enzyme β-galactosidase in a microfluidic system was used to track protein production in living cells with single-molecule sensitivity. The work revealed that protein production occurs in bursts and that a variable number of expression events are included in each burst. The techniques allow protein production to be described with unprecedented precision and permit the visualization and quantification of proteins expressed in low copy numbers. Such information was not accessible with earlier techniques.
Researchers this year showed experimentally that damage to cells by protein aggregation in Alzheimer's disease can be reduced by inhibiting a key cell signaling pathway, and they proposed two molecular mechanisms for the way cells protect themselves from toxic protein aggregates. In one mechanism, protein aggregates are disassembled so they can't harm cells. The second, which likely is activated when the first is overtaxed, protects cells by converting small toxic aggregates into less toxic larger assemblies, perhaps so they can be stored until they can be disposed of properly. The researchers found that modulating the activity of these two processes in a worm model of Alzheimer's increased the worm's lifespan and reduced cell toxicity from protein aggregation.
The study was carried out by Andrew Dillin of Salk Institute for Biological Studies, La Jolla, Calif., Jeffery W. Kelly of Scripps Research Institute, and coworkers (Science 2006, 313, 1604). They identified the two mechanisms by using RNAi to manipulate the expression of transcription factors that control lifespan and kinetic assays to monitor protein aggregation and disaggregation. The findings revealed molecular targets to which future Alzheimer's medications might be directed.
The 2006 Nobel Prize in Physiology or Medicine honored the discoverers of RNAi, the gene-silencing mechanism in which double-stranded RNA causes messenger RNA from specific genes to degrade. Biologists Andrew Z. Fire of Stanford University School of Medicine and Craig C. Mello of the University of Massachusetts Medical School, Worcester, shared the award. Since its discovery, RNAi has become widely used as a research tool for studying gene function, and it is also being investigated intensely as a potential therapeutic approach for silencing disease-related genes.
In analytical chemistry, researchers devised a way to use nanoscale secondary ion mass spectrometry (nanoSIMS) to image lipid bilayers with spatial resolutions of under 100 nm (Science 2006, 313, 1948). The method could lead to a better understanding of biological membranes. Methods for characterizing biological membranes generally work only at resolutions under 10 nm or over 300 nm, so this new technique opened a previously inaccessible range of resolving power. Steven G. Boxer and Mary L. Kraft of Stanford University and coworkers developed and demonstrated the new nanoSIMS method, in which samples are bombarded by tightly focused beams of cesium ions. These cesium ions continuously ablate the surface to generate low-molecular-weight secondary ions that can be identified and measured by MS.
In computational chemistry, a family of nearly 3,000 artificial cytochrome P450 enzymes was created this year by recombining sections of three natural cytochrome P450s, oxidative enzymes that play a key role in the metabolism of drugs and toxins (PLoS Biol. 2006, 4, e112). The aim was to create potentially useful new cytochrome P450s that did not arise in nature and to identify key sequence determinants of folding and function. Frances H. Arnold and Christopher R. Otey of California Institute of Technology and coworkers used a computational program called SCHEMA to guide the creation of the new protein sequences and increase the likelihood that they would fold and function. The method could prove useful in creating variants of many other types of proteins, not just cytochrome P450s.
In inorganic chemistry, researchers produced previously elusive molecules and atoms.
The first procedures for generating diatomic phosphorus (P2) or its synthetic equivalent in solution under mild conditions were developed this year by Christopher C. (Kit) Cummins and coworkers at MIT (Science 2006, 313, 1276). The methods promise to greatly expand accessibility to compounds containing the P2 moiety, such as phosphine ligands for new catalysts.
In one technique, a niobium phosphide anion reacts with a chloroiminophosphane to yield an "eliminator" complex. At 65 oC in solution, this complex releases P2 as a transient intermediate, which can react to form a variety of products. In a second procedure, Cummins and coworkers formed a tungsten pentacarbonyl adduct that, under even milder conditions (room temperature), generates another transient intermediate that reacts like P2. The researchers are currently looking for P2 species with longer lifetimes than those of the two intermediates they identified in their study.
An experiment begun in 2002 produced three atoms of the heaviest superheavy element yet, element 118, which belongs just below radon in the periodic table. Yuri T. Oganessian and coworkers at the Joint Institute for Nuclear Research in Dubna, Russia, in collaboration with a group at Lawrence Livermore National Laboratory, bombarded a target enriched in californium with an energetic beam of calcium ions. After thousands of hours of bombardment, the team detected three series of nuclear events that signify the creation and nearly instantaneous demise of three atoms of element 118 (Phys. Rev. C 2006, 74, 044602). In 2002, the same team observed the creation of a single atom of element 118, but the work could not be reproduced conclusively until this year.
In polymer chemistry, a team from Dow Chemical in Midland, Mich., and Freeport, Texas, made tailored olefin block copolymers available on a commercially viable scale for the first time by identifying catalysts that facilitate their polymerization (Science 2006, 312, 714). The catalysts made possible a continuous "chain shuttling" polymerization process that is more efficient and more economical than earlier commercial copolymer batch production processes. A specialist in the field commented that the strategy "opens a door to an entire new class of thermoplastic elastomers." On the basis of the new chain-shuttling technique, Dow introduced Infuse brand olefin block copolymers as a commercial product this summer. The copolymers' block architecture gives them better performance and processing properties than previous olefin elastomers, including faster set-up into desired forms, improved resistance to abrasion and deformation, and excellent elasticity.
In nanotechnology and materials, some of the year's key developments were in nanofabrication and semiconductor preparation.
Computer scientist Paul W. K. Rothemund of California Institute of Technology took DNA nanofabrication to a new level this year when he developed a technique that can be used to create DNA nanodesigns 10-fold more complex than any made previously (Nature 2006, 440, 297). Called DNA origami, Rothemund's method folds DNA into two-dimensional shapes or patterns. Stars, snowflake patterns, maps, and smiley faces, each about 100 nm wide, are among his tiny creations. Potential applications include electronics and molecular biology. "This is an exciting advance, which is likely to revolutionize pattern formation on this scale," commented DNA nanotechnology pioneer Nadrian C. Seeman of New York University.
A way to make semiconductors from a liquid precursor of solid silicon was developed this year by Masahiro Furusawa and Tatsuya Shimoda of Seiko Epson Corp., Yasuo Matsuki of JSR Corp., and coworkers (Nature 2006, 440, 783). The approach could make it possible to use low-cost ink-jet-printing methods instead of traditional vapor-deposition techniques to create displays and other microelectronic devices. Vapor deposition generally entails multiple refining, deposition, and etching steps, whereas liquid-based fabrication could be simpler, but previous efforts to develop liquid-based techniques had only limited success. In the new technique, a liquid silane precursor is squirted onto a substrate and then heated and UV-irradiated to produce polycrystalline silicon films having electronic performance comparable with that of films made by conventional deposition.
In space chemistry, researchers advanced the understanding of comets and astronomical clouds. The first detailed analysis of infrared emission spectra recorded during 2005's Deep Impact mission to comet Tempel 1 revealed that comets are made of an assortment of minerals, water, and other inorganic and organic materials (Science 2006, 313, 635). The study provided an unprecedented examination of the chemical nature of comet interiors and will help answer questions regarding the formation and evolution of solar system objects. The spectra included signatures of minerals such as magnesium-rich forsterite and iron-rich fayalite (both of which are in the olivine family); ferrosilite, an iron-rich pyroxene; and nontronite, a smectite clay containing iron, aluminum, and sodium. The spectra also contained signs of other minerals (such as amorphous carbon), polyaromatic hydrocarbons (which are linked to the source of organic material in the solar system), water ice, and metal sulfides. The work was carried out by Carey M. Lisse of the Applied Physics Laboratory at Johns Hopkins University and 16 other scientists at the University of Maryland, College Park; Caltech; and elsewhere.
For the first time, researchers observed in astronomical clouds large amounts of a negatively charged molecule: the hexatriyne anion, or C6H- (Astrophys. J. 2006, 652, L141). Until now, discoveries of compounds in space had been limited to 130 neutral molecules and 14 cations, with nary an anion among them. Detection of an anion in interstellar space overturns a widespread belief that radiation would quickly strip an anion of its extra electron, yielding a radical. The new finding, reported by Michael C. McCarthy, Patrick Thaddeus, and colleagues at the Harvard-Smithsonian Center for Astrophysics, in Cambridge, Mass., also solves a spectral puzzle, identifying C6H- as the source of a mysterious set of rotational lines discovered in a molecular cloud more than 10 years ago. Observers said the addition of anions to the mix of known molecules in space alters the field of interstellar chemistry.
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