The combinatorial synthesis of bicyclic privileged structures or privileged substructures
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.
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TL;DR: P palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners--including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations.
Abstract: The area of transition-metal-catalyzed direct arylation through cleavage of CH bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations
2,408 citations
TL;DR: A variety of reaction types have now been shown to be amenable to visible light photocatalysis via photoinduced electron transfer to or from the transition metal chromophore, as well as energy-transfer processes.
Abstract: Background Interest in photochemical synthesis has been motivated in part by the realization that sunlight is effectively an inexhaustible energy source.Chemists have also long recognized distinctive patterns of reactivity that are uniquely accessible via photochemical activation. However, most simple organic molecules absorb only ultraviolet (UV) light and cannot be activated by the visible wavelengths that comprise most of the solar energy that reaches Earth’s surface. Consequently, organic photochemistry has generally required the use of UV light sources. Visible light photocatalysis. ( A ) Transition metal photocatalysts, such as Ru(bpy) 3 2+ , readily absorb visible light to access reactive excited states. ( B ) Photoexcited Ru*(bpy) 3 2+ can act as an electron shuttle, interacting with sacrificial electron donors D (path i) or acceptors A (path ii) to yield either a strongly reducing or oxidizing catalyst toward organic substrates S. Ru*(bpy) 3 2+ can also directly transfer energy to an organic substrate to yield electronically excited species (path iii). bpy, 2,29-bipyridine; MLCT, metal-to-ligand charge transfer. Advances Over the past several years, there has been a resurgence of interest in synthetic photochemistry, based on the recognition that the transition metal chromophores that have been so productively exploited in the design of technologies for solar energy conversion can also convert visible light energy into useful chemical potential for synthetic purposes. Visible light enables productive photoreactions of compounds possessing weak bonds that are sensitive toward UV photodegradation. Furthermore, visible light photoreactions can be conducted by using essentially any source of white light, including sunlight, which obviates the need for specialized UV photoreactors. This feature has expanded the accessibility of photochemical reactions to a broader range of synthetic organic chemists. A variety of reaction types have now been shown to be amenable to visible light photocatalysis via photoinduced electron transfer to or from the transition metal chromophore, as well as energy-transfer processes. The predictable reactivity of the intermediates generated and the tolerance of the reaction conditions to a wide range of functional groups have enabled the application of these reactions to the synthesis of increasingly complex target molecules. Outlook This general strategy for the use of visible light in organic synthesis is already being adopted by a growing community of synthetic chemists. Much of the current research in this emerging area is geared toward the discovery of photochemical solutions for increasingly ambitious synthetic goals. Visible light photocatalysis is also attracting the attention of researchers in chemical biology, materials science, and drug discovery, who recognize that these reactions offer opportunities for innovation in areas beyond traditional organic synthesis. The long-term goals of this emerging area are to continue to improve efficiency and synthetic utility and to realize the long-standing goal of performing chemical synthesis using the sun.
1,859 citations
1,777 citations
TL;DR: Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously and has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects.
Abstract: Asymmetric multicomponent reactions involve the preparation of chiral compounds by the reaction of three or more reagents added simultaneously. This kind of addition and reaction has some advantages over classic divergent reaction strategies, such as lower costs, time, and energy, as well as environmentally friendlier aspects. All these advantages, together with the high level of stereoselectivity attained in some of these reactions, will force chemists in industry as in academia to adopt this new strategy of synthesis, or at least to consider it as a viable option. The positive aspects as well as the drawbacks of this strategy are discussed in this Review.
1,479 citations
TL;DR: To continue to be competitive with other drug discovery methods, natural product research needs to continually improve the speed of the screening, isolation, and structure elucidation processes, as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.
Abstract: Although traditionally natural products have played an important role in drug discovery, in the past few years most Big Pharma companies have either terminated or considerably scaled down their natural product operations. This is despite a significant number of natural product-derived drugs being ranked in the top 35 worldwide selling ethical drugs in 2000, 2001, and 2002. There were 15 new natural product-derived drugs launched from 2000 to 2003, as well as 15 natural product-derived compounds in Phase III clinical trials or registration at the end of 2003. Recently, there has been a renewed interest in natural product research due to the failure of alternative drug discovery methods to deliver many lead compounds in key therapeutic areas such as immunosuppression, anti-infectives, and metabolic diseases. To continue to be competitive with other drug discovery methods, natural product research needs to continually improve the speed of the screening, isolation, and structure elucidation processes, as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.
1,264 citations
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TL;DR: In this paper, a cross-coupling reaction is proposed for coupling 1 -Alkenylboron Derivatives: Synthesis of Conjugated Dienes 6.
Abstract: B. Other Catalyti; Process by Transition-Metal Complexes IV. Cross-Coupling Reaction A. Coupling of 1 -Alkenylboron Derivatives: Synthesis of Conjugated Dienes 6. Coupling of Arylboron Derivatives: Synthesis of Biaryls C. Coupling of Alkylboron Derivatives D. Coupling with Triflates E. Synthesis of Vinylic Sulfides F. Coupling with lodoalkanes: Alkyl-Alkyl CouDlino G. Coupling with Other Organic Halides and Boron Reagents V. Head-to-Tail Coupling VI. Carbonylative Coupling VII. Alkoxycarbonylation and Dimerization VIII. Conclusion 2457 2458 2458
10,937 citations
TL;DR: In this paper, a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach called click chemistry is defined, enabled, and constrained by a handful of nearly perfect "springloaded" reactions.
Abstract: Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.
9,069 citations
TL;DR: Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count are found to be important predictors of good oral bioavailability, independent of molecular weight.
Abstract: Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two cr...
5,191 citations
TL;DR: This chapter investigates the anatomy and taxonomy of protein structures, based on the results of three-dimensional X-ray crystallography of globular proteins.
Abstract: Publisher Summary This chapter investigates the anatomy and taxonomy of protein structures. A protein is a polypeptide chain made up of amino acid residues linked together in a definite sequence. Amino acids are “handed,” and naturally occurring proteins contain only L-amino acids. A simple mnemonic for that purpose is the “corncrib.” The sequence of side chains determines all that is unique about a particular protein, including its biological function and its specific three-dimensional structure. The major possible routes to knowledge of three-dimensional protein structure are prediction from the amino acid sequence and analysis of spectroscopic measurements such as circular dichroism, laser Raman spectroscopy, and nuclear magnetic resonance. The analysis and discussion of protein structure is based on the results of three-dimensional X-ray crystallography of globular proteins. The basic elements of protein structures are discussed. The most useful level at which protein structures are to be categorized is the domain, as there are many cases of multiple-domain proteins in which each separate domain resembles other entire smaller proteins. The simplest type of stable protein structure consists of polypeptide backbone wrapped more or less uniformly around the outside of a single hydrophobic core. The outline of the taxonomy is also provided in the chapter.
3,201 citations
TL;DR: The cross-coupling of organotin reagents with a variety of organic electrophiles, catalyzed by palladium, provides a novel method for generating a carbon-carbon bond.
Abstract: The cross-coupling of organotin reagents with a variety of organic electrophiles, catalyzed by palladium, provides a novel method for generating a carbon-carbon bond. Because this mild, versatile reaction is tolerant of a wide variety of functional groups on either coupling partner, is stereospecific and regioselective, and gives high yields of product, it is ideal for use in the synthesis of elaborate organic molecules. When the coupling reaction is carried out in the presence of carbon monoxide, instead of a direct coupling, carbon monoxide insertion takes place, stitching the two coupling partners together and generating a ketone.
2,991 citations