click chemistry

1. Introduction: Beyond the Paradigm of Carbonyl Chemistry Life on Earth requires the construction of carbon – carbon bonds in an aqueous environment. Carbonyl (aldol) chemistry is nature�s primary engine of CÿC bond formation. Not only do the requisite carbon electrophiles (carbonyls) and nucleo- philes coexist in water, but water provides the perfect environment for proton shuttling among reactants, which is required for reversible carbonyl chemistry. With CO2 as the carbon source and a few good carbonyl chemistry based reaction themes, nature achieves astonishing structural and functional diversity. Carbonyl chemistry is used to make a modest collection of approximately 35 simple building blocks, which are then assembled into biopolymers. The enzymatic polymers serve, in concert with increments of energy provided by adenosine triphosphate, as selective catalysts which prevent nature�s carbonyl chemistry based syntheses from collapsing into chaos. Since many biosynthetic pathways require a unique enzyme for each step, the enzyme- control strategy required a heavy investment of time and resources for catalyst development. With a few billion years and a planet at her disposal, nature has had both time and resources to spare, but we, as chemists on a human timescale, do not. Nevertheless, carbonyl-based reactions have always been profoundly appealing to students and practitioners of organic chemistry. It is our contention that organic synthesis con- ducted, as it has been, in imitation of nature�s carbonyl chemistry is ill-suited for the rapid discovery of new molecules with desired properties. Many transformations that form “new” carbon – carbon bonds are endowed with only a modest thermodynamic driving force. In particular, equilibrium “aldol” reactions are often energetically favorable by less than 3 kcal molÿ1.[1] For these processes to reach completion in the laboratory, an additional “push” must be provided, often by application of Le Chatelier�s principle (for example, azeotropic removal of water), by coupling the desired process to an exothermic co- reaction (for example, a strong “base” ‡ a strong “acid”), or by virtue of favorable entropic considerations (such as intramolecular ring closure) without enthalpic penalties (such as formation of strained rings). Thus, due in effect to the loss of one “equivalent” of ester, resonance stabilization, the first Click Chemistry: Diverse Chemical Function from a Few Good Reactions Hartmuth C. Kolb, M. G. Finn, and K. Barry Sharpless* Dedicated to Professor Daniel S. Kemp Examination of nature�s favorite mol- ecules 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 polysac- charides 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 CÿC 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 libra- ries through heteroatom links (CÿXÿC), an approach we call “click chemistry”. Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect “spring-load- ed” 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. Keywords: combinatorial chemistry · drug research · synthesis design · water chemistry [*] Prof. K. B. Sharpless, Prof. M. G. Finn Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla, CA 92037 (USA) Fax: (‡1)858-784-7562 E-mail : sharples@scripps.edu Dr. H. C. Kolb Vice President of Chemistry Coelacanth Corporation East Windsor, NJ 08520 (USA) REVIEWS Angew. Chem. Int. Ed. 2001, 40, 2004 – 2021 � WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4011-2005 $ 17.50+.50/0 2005 REVIEWS K. B. Sharpless et al. 2006 Angew. Chem. Int. Ed. 2001, 40, 2004 – 2021 step of the intermolecular Claisen condensation (for example, two molecules of ethyl acetate!ethyl acetoacetate- ‡ethanol), is endothermic by approximately 11 kcal molÿ1, but the next step—deprotonation of the b-ketoester to its enolate—is highly exothermic and drives the process to completion when a stoichiometric amount of the alkoxide base is provided. Approximately 30 years ago the develop- ment of kinetically controlled enolate chemistry, enabled by even stronger bases like lithium diisopropylamide, provided the ultimate form of this type of reaction control. Natural products of bewildering complexity are synthesized almost routinely in this manner by the elite practitioners of the art, so it is obviously a powerful strategy, and the best work in this area is fascinating to study as a rich source of new insights into factors which affect chemical reactivity. However, as dis- cussed below, we believe that this approach ultimately pulls organic synthesis in troubling directions, the most insidious problem being the complexity engendered by the need for global protection and deprotection of protic functional groups. “The most fundamental and lasting objective of synthesis is not production of new compounds, but production of properties.” George S. Hammond, Norris Award Lecture, 1968 If useful properties are our goal—for example, better pharmaceuticals—then the use of complicated synthetic strategies is justified only if they provide the best way to achieve those properties. The bioactive natural products that have most intrigued synthetic organic chemists have frame- works which are difficult to construct largely because there are too many contiguous carbon – carbon bonds. However, these are not the only kinds of molecules that can have useful biological effects. The long and admirable history of natural products synthesis, culminating as it has in the protection- laden schemes of kinetic carbonyl chemistry, perhaps blinds us to the possibility of developing synthetic strategies that enable much more rapid discovery and production of molecules with a desired profile of properties. K. Barry Sharpless and his co- workers have discovered and devel- oped many widely used catalytic oxidation processes, including the first general methods for stereose- lective oxidation—the Sharpless re- actions for asymmetric epoxidation, dihydroxylation, and aminohydrox- ylation of olefins. His mentors at Dartmouth College (BA in 1963), Stanford University (PhD in 1968 and postdoctoral research), and Harvard University (further post- doctoral research) were Prof. T. A. Spencer, Prof. E. E. van Tamelen, Prof. J. P. Collman, and Prof. K. Bloch, respectively. Before 1990, when he became W. M. Keck Professor of Chemistry at The Scripps Research Institute, Prof. Sharpless was a member of faculty at the Massachusetts Institute of Technology (1970 – 77, 1980 – 90) and Stanford University (1977 – 80). Prof. Sharpless�s honors include the Chemical Sciences Award of the National Academy of Sciences (of which he is a member), the Roger Adams and Arthur C. Cope Awards from the American Chemical Society, the Tetrahedron Award, the King Faisal Prize, the Prelog Medal, the Wolf Prize, and honorary doctorates from five American and European universities. The Sharpless research group continues to search for new homogeneous oxidation catalysts and for transition metal catalyzed asymmetric processes. M. G. Finn received his PhD degree from the Massachusetts Institute of Technology, working with Prof. K. B. Sharpless. This was followed by an NIH postdoctoral fellowship with Prof. J. P. Collman at Stanford University. He joined the faculty of the University of Virginia in 1988, and moved to his present position on the faculty of the Department of Chemistry and The Skaggs Institute for Chemical Biology at The Scripps Research Institute in 1998. His group has studied the reactivity of Fischer carbene complexes, metal-substituted phosphorus ylides, and a variety of transition metal catalyzed processes. His current interests include methods for combinatorial catalyst discovery and the use of viruses as molecular building blocks. Hartmuth Kolb received his PhD in synthetic organic chemistry under the supervision of Prof. S. V. Ley at Imperial College in London. After two years of postdoctoral study with Prof. K. B. Sharpless at The Scripps Research Institute, he joined the Central Research Laboratories of Ciba – Geigy in Basel. Four years later, he moved to Princeton, New Jersey, to join the Coelacanth Corporation, a high-performance chemistry company founded by K. B. Sharpless and A. Bader. Currently, he is Vice President of Chemistry at the Coelacanth Corporation. His research interests include natural product and carbohydrate synthesis, investigation of reaction mechanisms, molecular modeling, medicinal chemistry, process chemistry, and combinatorial chemistry. M. G. FinnK. B. Sharpless H. C. Kolb REVIEWSClick Chemistry Angew. Chem. Int. Ed. 2001, 40, 2004 – 2021 2007 2. A “Process Chemistry” Point of View The molecules produced by living systems have always fascinated and inspired synthetic organic chemists. As our skills and tools have advanced, the compounds chosen for synthesis have become ever more challenging. So it is no surprise that today�s favorite targets are found among the most diabolically complex natural substances ever discov- ered—the various secondary metabolites produced by plants and microorganisms for self-defense. No expense or effort is spared to synthesize even minute quantities of these extra- ordinary molecules.[2, 3] The pharmaceutical industry, a direct scion of natural products chemistry,[4] has not been put off by difficult syntheses and many compounds being explored today as drug candidates represent substantial synthetic challenges.[5] While it sharpens the skill and fraternal esteem of the research team, implicit in the decision to pursue a complex drug target is the acceptance of enormous constraints on the scope of the structure space to be explored. When natural products are the models, it usually takes so long to synthesize analogues in a given series that even the most ambitious exploratory efforts, viewed objectively, are often superficial. The process of probing structure – activity relationships (SAR) in these situations has a perverse tendency to discover the “best” candidates in difficult synthetic territory, near the outer limits of “accessibility.” Difficult syntheses also tend to arise when trying to reach patentable structural territory after original discoveries have been made by a competitor. The time required for SAR probing and then synthesis of enough of the better compounds for pharmacokinetic and toxicity profiling is staggering, and goes a long way toward explaining why this phase of pharmaceutical research takes so long. And yet, buoyed by the eventual success in obtaining complex target structures, discovery chemists and top exec- utives alike display little concern for issues of synthetic accessibility. Ignored is the fact that any lead or development series that has supply problems risks inadequate SAR conclusions and development decisions. The story of the carbapenem antibiotic thienamycin[6–8] is illustrative: it re- quired six years of superb effort by several research groups in both industry and academia to develop the final therapeutic agent (meropenem,[9] a derivative of thienamycin) after the initial synthesis of thienamycin was published.[10a] The AIDS protease inhibitor Crixivan (indinavir) provides a more recent example—a very difficult synthesis at nearly commodity- chemical scale.[10b] Only at the end are issues of process development considered, and synthesis on production scale is often expensive. Nevertheless, the prospect of a blockbuster drug is such a powerful motivator for a synthesis team that the job nearly always gets done. The crucial point is that the cost which complex synthesis adds to the final drug, while substantial, is insignificant compared to all the “hidden” costs imposed on the speed and quality of the discovery/develop- ment phase by this same complex style of synthesis. In other words, the way organic synthesis is done has pervasive effects on the entire process of drug discovery, development, and N O CO2H S NH2 OH H H N O CO2H S OH H H N H O NMe2 N H N OH O Ph OH N O NHtBu N Thienamycin Meropenem Indinavir manufacture. If a more modular, faster style of synthesis were to prove effective, lower manufacturing costs should be the least of its benefits. Lead structures should not be syntheti- cally “precious”, and one should be able to jump easily from one series to another. As it is now, most discovery endeavors suffer from being too invested in structure, when function is what is sought. Consider how nature synthesizes her most important molecules, the primary metabolites. While the aforementioned secondary metabolites have extensive networks of contiguous carbon – carbon bonds, and have claimed the lion�s share of synthetic organic chemists� attention, it is reversible conden- sation processes involving carbon – heteroatom connections that are used to assemble polynucleotides, polypeptides, and polysaccharides—the three families of macromolecules that are central to life processes. By embracing the strategy of making large oligomers from small building blocks, nature is also a consummate combinatorial chemist[11] and achieves astonishing diversity from less than 40 monomers. These building blocks contain at most six contiguous CÿC bonds, with the exception of the three aromatic amino acids. Thus, nature is a promiscuous creator of carbon – heteroatom connections, choosing this method to encode and express information. Nature�s ability to create and control biomolecular diversity is largely dependent on the exquisitely selective catalysts she deploys. Our devices for managing reactivity and selectivity are much less sophisticated, particularly with respect to CÿC REVIEWS K. B. Sharpless et al. 2008 Angew. Chem. Int. Ed. 2001, 40, 2004 – 2021 bond formation. Therefore, the chemist who plans a synthesis that requires the construction of CÿC bonds that are not present or latent (for example, CHÿCX‡base!CˆC) in the available starting materials is asking for trouble, particularly if such a synthesis must be reliable for a number of substrates (as for combinatorial searches or SAR studies) or applicable to practical, large-scale production. Problems are less likely if one only needs to unite, functionalize, and/or reorganize starting materials and intermediates in ways which do not require de novo CÿC bond construction. If such “new” CÿC bonds are required, it is best to make them intramolecular- ly,[12] but it is better still to leave the really tough CÿC bond synthesis to nature.[13] There is, however, still plenty of room for discovery: Guida and co-workers have estimated the pool of “reasonable” drug candidates (�30 non-hydrogen atoms; �500 daltons; con- sisting of only H, C, N, O, P, S, F, Cl, and Br; likely to be stable at ambient temperature in the presence of water and oxygen) at between 1062 and 1063 discrete molecules.[14] With this kind of structure space available,[15] we contend that it makes little sense to search in hard-to-reach places for a desired function. Instead, we present here synthetic methods for drug discovery that adhere to one rule: all searches must be restricted to molecules that are easy to make. We hope to convince the reader that a wide diversity of interesting molecules can be easily made, and that the chances for achieving desirable biological activity are at least as good with such compounds as with the traditional target structures now favored by medic- inal chemists. 2.1. “Click Chemistry” Following nature�s lead, we endeavor to generate substan- ces by joining small units together with heteroatom links (CÿXÿC). The goal is to develop an expanding set of powerful, selective, and modular “blocks” that work reliably in both small- and large-scale applications. We have termed the foundation of this approach “click chemistry,” and have defined a set of stringent criteria that a process must meet to be useful in this context. The reaction must be modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by nonchromatographic methods, and be stereospecific (but not necessarily enantio- selective). The required process characteristics include simple reaction conditions (ideally, the process should be insensitive to oxygen and water), readily available starting materials and reagents, the use of no solvent or a solvent that is benign (such as water) or easily removed, and simple product isolation. Purification—if required—must be by nonchromatographic methods, such as crystallization or distillation, and the product must be stable under physiological conditions. It is important to recognize that click reactions achieve their required characteristics by having a high thermodynamic driving force, usually greater than 20 kcal molÿ1. Such pro- cesses proceed rapidly to completion and also tend to be highly selective for a single product: we think of these reactions as being “spring-loaded” for a single trajectory. Carbon – heteroatom bond forming reactions comprise the most common examples, including the following classes of chemical transformations: * cycloadditions of unsaturated species, especially 1,3-dipo- lar cycloaddition reactions, but also the Diels – Alder family of transformations; * nucleophilic substitution chemistry, particularly ring-open- ing reactions of strained heterocyclic electrophiles such as epoxides, aziridines, aziridinium ions, and episulfonium ions; * carbonyl chemistry of the “non-aldol” type, such as formation of ureas, thioureas, aromatic heterocycles, oxime ethers, hydrazones, and amides; and * additions to carbon – carbon multiple bonds, especially oxidative cases such as epoxidation, dihydroxylation, aziridination, and sulfenyl halide addition, but also Michael additions of NuÿH reactants. 2.2. Olefin-Based Organic Synthesis Consider, as a counterpoint to the pharmaceutical industry, the world of petrochemicals and the materials it has spawned (textiles, resins, plastics, etc.). The petrochemist�s starting materials are “gifts” prepared by the carbonyl-based synthe- ses of ancient organisms; in fossil oils are stored the energy of CO2-based photosynthesis, and, more importantly, countless carbon – carbon bonds. However, natural petroleum, being almost completely saturated, is useless for most organic synthesis needs. The petroleum industry is therefore based upon the manipulation of CÿC bond “currency”, which entails exchanging CÿC s bonds for new CÿC p bonds by “cracking”, and creating new CÿC p bonds at the expense of CÿH bonds by “reforming”. The products of these processes are a small number of reactive monomers, which are then assembled, with a battery of selective catalysts, into myriad useful materials. Thus, the manufacture of petrochemical products, based as it is on a modular, and supremely efficient, synthetic strategy, makes the energy expended on “upgrading” satu- rated hydrocarbons to olefins seem insignificant. In a general sense, life chemistry and petrochemistry have evolved identical strategies for the synthesis of substances with diverse functions/properties: modular assembly of spe- cially synthesized monomers under the control of selective catalysts. That one depends on reversible carbonyl chem