Fluorous synthesis: an alternative to organic synthesis and solid phase synthesis for the preparation of small organic molecules.
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Chemistry, Organic↗
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The impact of microwave-assisted organic synthesis in drug discovery.
Microwave-assisted organic synthesis has revolutionized organic synthesis. Small molecules can be built in a fraction of the time required by classical thermal methods. As a result, this technique has rapidly gained acceptance as a valuable tool for accelerating drug discovery and development processes. This article outlines the basic principles behind microwave technology and summarizes recent trends and areas in drug discovery where this technology has made an impact.
Chemistry, Organic↗
The CP molecule labyrinth: a paradigm of how endeavors in total synthesis lead to discoveries and inventions in organic synthesis.
Imagine an artist carving a sculpture from a marble slab and finding gold nuggets in the process. This thought is not a far-fetched description of the work of a synthetic chemist pursuing the total synthesis of a natural product. At the end of the day, he or she will be judged by the artistry of the final work and the weight of the gold discovered in the process. However, as colorful as this description of total synthesis may be, it does not entirely capture the essence of the endeavor, for there is much more to be told, especially with regard to the contrast of frustrating failures and exhilarating moments of discovery. To fully appreciate the often Herculean nature of the task and the rewards that accompany it, one must sense the details of the enterprise behind the scenes. A more vivid description of total synthesis as a struggle against a tough opponent is perhaps appropriate to dramatize these elements of the experience. In this article we describe one such endeavor of total synthesis which, in addition to reaching the target molecule, resulted in a wealth of new synthetic strategies and technologies for chemical synthesis. The total synthesis of the CP molecules is compared to Theseus' most celebrated athlos (Greek for exploit, accomplishment): the conquest of the dreaded Minotaur, which he accomplished through brilliance, skill, and bravery having traversed the famous labyrinth with the help of Ariadne. This story from Greek mythology comes alive in modern synthetic expeditions toward natural products as exemplified by the total synthesis of the CP molecules which serve as a paradigm for modern total synthesis endeavors, where the objectives are discovery and invention in the broader sense of organic synthesis.
Biological Factors↗
MAPOS: a computer program for organic synthesis design based on synthon model of organic chemistry.
The program MAPOS is a logically oriented computer program for computer-aided organic synthesis design suitable both for forward and retrosynthetic synthesis planning. It is based on the synthon model of organic chemistry, introduced by the authors. The fundamentals of the model as well as the basic algorithms are described. Examples of the use of the program are given.
Algorithms↗
Silicon carbide passive heating elements in microwave-assisted organic synthesis.
Microwave-assisted organic synthesis in nonpolar solvents is investigated utilizing cylinders of sintered silicon carbide (SiC)--a chemically inert and strongly microwave absorbing material--as passive heating elements (PHEs). These heating inserts absorb microwave energy and subsequently transfer the generated thermal energy via conduction phenomena to the reaction mixture. The use of passive heating elements allows otherwise microwave transparent or poorly absorbing solvents such as hexane, carbon tetrachloride, tetrahydrofuran, dioxane, or toluene to be effectively heated to temperatures far above their boiling points (200-250 degrees C) under sealed vessel microwave conditions. This opens up the possibility to perform microwave synthesis in unpolar solvent environments as demonstrated successfully for several organic transformations, such as Claisen rearrangements, Diels-Alder reactions, Michael additions, N-alkylations, and Dimroth rearrangements. This noninvasive technique is a particularly valuable tool in cases where other options to increase the microwave absorbance of the reaction medium, such as the addition of ionic liquids as heating aids, are not feasible due to an incompatibility of the ionic liquid with a particular substrate. The SiC heating elements are thermally and chemically resistant to 1500 degrees C and compatible with any solvent or reagent.
Journal Article↗
DNA-templated organic synthesis: nature's strategy for controlling chemical reactivity applied to synthetic molecules.
In contrast to the approach commonly taken by chemists, nature controls chemical reactivity by modulating the effective molarity of highly dilute reactants through macromolecule-templated synthesis. Nature's approach enables complex mixtures in a single solution to react with efficiencies and selectivities that cannot be achieved in conventional laboratory synthesis. DNA-templated organic synthesis (DTS) is emerging as a surprisingly general way to control the reactivity of synthetic molecules by using nature's effective-molarity-based approach. Recent developments have expanded the scope and capabilities of DTS from its origins as a model of prebiotic nucleic acid replication to its current ability to translate DNA sequences into complex small-molecule and polymer products of multistep organic synthesis. An understanding of fundamental principles underlying DTS has played an important role in these developments. Early applications of DTS include nucleic acid sensing, small-molecule discovery, and reaction discovery with the help of translation, selection, and amplification methods previously available only to biological molecules.
Chemistry, Organic↗
Multi-component methodologies in solid-phase organic synthesis.
Solid-phase organic synthesis, particularly when used in conjunction with combinatorial techniques, is emerging as a revolutionary technology in chemistry. Multi-component reaction systems are particularly valued because several elements of diversity can be introduced in a single transformation thereby expanding the diversity of compound libraries. A variety of multi-component reactions have been successfully adapted for solid-phase technology as described in this review.
Chemistry, Organic↗
Fluorous synthesis: a fluorous-phase strategy for improving separation efficiency in organic synthesis.
Recovery and purification difficulties can limit the yield and utility of otherwise successful organic synthesis strategies. A "fluorous synthesis" approach is outlined in which organic molecules are rendered soluble in fluorocarbon solvents by attachment of a suitable fluorocarbon group. Fluorocarbon solvents are usually immiscible in organic solutions, and fluorous molecules partition out of an organic phase and into a fluorous phase in a standard liquid-liquid extraction. Simple yet substantive separations of organic reaction mixtures are achieved without resorting to chromatography. Because fluorous synthesis combines in many respects the favorable purification features of solid-phase synthesis with the favorable reaction, identification, and analysis features of traditional organic synthesis, it should prove valuable in the automated synthesis of libraries of individual pure organic compounds.
Benzamides↗
Computer-assisted analysis in organic synthesis.
The planning of alternative routes for the synthesis of complex organic molecules has been facilitated by the formulation of guiding strategies that can be applied to a broad range of problems. Analysis of organic synthesis can be carried out in the retrosynthetic direction, opposite to the actual process of chemical synthesis, or bidirectionally, that is, as a combined retrosynthetic and synthetic search. An interactive computer program is described which utilizes the general strategies of retrosynthetic analysis and an appropriate database to generate pathways of chemical intermediates for chemical synthesis of a particular target structure. Computer graphics and standard chemical structures are used for man-machine communication.
Chemical Phenomena↗
New developments in polymer-supported reagents, scavengers and catalysts for organic synthesis.
The ever-increasing demand for efficient syntheses of novel organic compounds with therapeutic potential remains the major driving force for the pharmaceutical industry to adopt novel technologies for organic synthesis. The use of polymer-supported reagents and scavengers is a powerful technique for integrated organic synthesis and purification. Polymer-supported reagents and scavengers can be used to selectively remove excess reagents and byproducts through simple filtration, rather than liquid-liquid extraction and chromatographic separation. In addition, polymer-supported reagents offer advantages that include the reaction of active intermediates by 'catch and release', selectivity, and immobilization of toxic reagents and byproducts. This review summarizes significant new advances in polymer-assisted solution-phase synthesis, and advances in microwave-assisted organic synthesis utilizing polymer-supported reagents and catalysts are also discussed. In view of previous review publications on this topic, only the literature from 2003 to date is included.
Catalysis↗
Membrane separation in green chemical processing: solvent nanofiltration in liquid phase organic synthesis reactions.
This paper describes ideas together with preliminary experimental results for applying solvent nanofiltration to liquid phase organic synthesis reactions. Membranes for organic solvent nanofiltration have only recently (during the 1990s) become available and, to date, have been applied primarily to food processing (vegetable oil processing, in particular) and refinery processes. Applications to organic synthesis, even at a laboratory feasibility level, are few. However, these membranes have great potential to improve the environmental performance of many liquid phase synthesis reactions by reducing the need for complex solvent handling operations. Examples that are shown to be feasible are solvent exchanges, where it is desired to swap a high molecular weight molecule from one solvent to another between separate stages in a complex synthesis, and recycle and reuse of homogeneous catalysts. In solvent exchanges, nanofiltration is shown to provide a fast and effective means of swapping from a high boiling point solvent to a solvent with a lower boiling point-this is a difficult operation by means of distillation. Solvent nanofiltration is shown to be able to separate two distinct types of homogeneous catalysts, phase transfer catalysts and organometallic catalysts, from their respective reaction products. In both cases the application of organic solvent nanofiltration allows several reuses of the same catalyst. Catalyst stability is shown to be an essential requirement for this technique to be effective. Finally, we present a discussion of scale-up aspects including membrane flux and process economics.
Biotechnology↗
Lipases and (R)-oxynitrilases: useful tools in organic synthesis.
The use of enzymes in organic solvents is currently of special relevance for the preparation of products of high added value. Lipases are the enzymes that have shown the greatest utility through enzymatic transesterification reactions. Over the last few years, we have shown the value of the enzymatic aminolysis and ammonolysis reactions for the preparation of amides and for the resolution of esters and amines. We have shown that the enzymatic alkoxycarbonylation is also of great utility in chemoselective reactions of natural products. Lyases, enzymes much less exploited in organic synthesis, are proving increasingly interesting, especially the use of (R)-oxynitrilases for the synthesis of optically active cyanohydrins.
Aldehyde-Lyases↗
Synthesis of (-)-longithorone A: using organic synthesis to probe a proposed biosynthesis.
We present a full report of our enantioselective synthesis of (-)-longithorone A (1). The synthesis was designed to test the feasibility of the biosynthetic proposal for 1 put forward by Schmitz involving intermolecular and transannular Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if the biosynthesis does involve these two Diels-Alder reactions, the intermolecular Diels-Alder reaction likely occurs before the transannular cycloaddition. The intermolecular Diels-Alder precursors, [12]-paracyclophanes 38, 49, 59, and 60, were prepared atropselectively, providing examples of ene-yne metathesis macrocyclization. The 1,3-disubstituted dienes produced from the macrocyclizations represent a previously unreported substitution pattern for intramolecular ene-yne metathesis. Protected benzylic hydroxyl stereocenters were used as removable atropisomer control elements and were installed by using a highly enantioselective vinylzinc addition to electron-rich benzaldehydes 26 and 27.
Bridged-Ring Compounds↗
Organic synthesis from reducing models of the atmosphere of the primitive earth with UV light and electric discharges.
The purpose of this paper is to compare the role of UV light and of electric discharges, the two most important sources of energy on the primitive earth, in the synthesis of organic compounds out of a reducing model of that atmosphere. Since Miller's experiments in 1953, most of the experimental simulations have been performed with electric discharges, and it has been assumed that UV radiations would give similar results. In order to check this assumption we have performed both experimental simulations in our laboratory. Experimental results indicate that this assumption was wrong in a large extent. Our four main conclusions are: 1. Unlike electric discharges, UV light is not an efficient source for producing unsaturated carbon chains. 2. UV light is efficient for producing nitriles in CH4--NH3 mixtures when the mole fraction of NH3 is very low while electric discharges need a higher mole fraction of NH3. 3. UV light is not able to produce nitriles from CH4--N2 mixtures while electric discharges produce important quantities of diversified nitriles from these mixtures. 4. UV light is not very efficient for producing aldehydes from CH4--H2O model atmosphere, electric discharges seem to be able to produce them more efficiently.
Atmosphere↗
[Experimental methods of the organic synthesis of substances of living organisms. 7. Biosynthesis of nueosides].
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Chemical Phenomena↗
The properties of resin supports and their effects on solid-phase organic synthesis.
Solvated resin supports are important carriers for solid-phase organic synthesis in combinatorial chemistry and high-throughput parallel synthesis. The physical properties of resin, resin swelling and dynamic solvation, effects of solvated supports on synthesis, kinetics, site interaction, and product purity are reviewed. Selective solvation of resin alters the local reactivity and accessibility of the bound substrate and the mobility of the entrapped reagent. Resin solvation changes during the course of the reaction when the attached substrate changes its polarity or other physicochemical properties. Selective adsorption determines the reaction kinetics and the action of a phase-transfer catalyst further improves the reaction on resin. Sites interact with each other in 1% DVB polystyrene resins to varying degrees depending on solvent, resin, and reactivity of the pendant groups. Total site isolation seems only achievable by controlling several factors simultaneously such as lower loading and steric hindrance. Through the proper selection of resin and solvent, alternating solvents to accommodate dynamic solvation of the resin, optimization of kinetics when changing solid supports and a careful control of resin impurities, solid-phase organic synthesis can lead to high quality combinatorial libraries.
Chemistry, Pharmaceutical↗
Semi-automated high throughput combinatorial solid-phase organic synthesis.
A semi-automated technique for massive parallel solid-phase organic synthesis based on a "split only" strategy is described. Two different types of purpose-oriented reaction vessels are used. The initial steps are performed in domino blocks, and the resin-bound intermediates then split into wells of a micro plate for the last combinatorial step. The domino block is a reaction block for manual and semi-automatic parallel solid-phase organic synthesis that simplifies liquid exchange and integrates common synthetic steps. The synthesis in micro plates does not use any filter for separation of resin beads from the supernatant liquid, and allows high throughput parallel synthesis on solid phase to be performed. This technique, documented on examples of diverse disubstituted benzenes, includes the use of gaseous cleavage in the last synthetic step and allows the synthesis of thousands of compounds per day in mg quantities.
Amino Acids↗
Advances in organic synthesis using polymer-supported reagents and scavengers under microwave irradiation.
Microwave-assisted and polymer-supported organic syntheses have emerged independently as versatile tools for rapid generation of organic molecules. Chemists are increasingly looking for a combination of both techniques for efficient organic synthesis. This review covers the recent literature on organic synthesis using microwave heating in conjunction with polymer-supported reagents and scavengers.
Chemistry, Organic↗