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Martin D Burke - One of the best experts on this subject based on the ideXlab platform.
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from Synthesis to function via iterative assembly of n methyliminodiacetic acid boronate building blocks
Accounts of Chemical Research, 2015Co-Authors: Junqi Li, Anthony S Grillo, Martin D BurkeAbstract:ConspectusThe study and optimization of small Molecule function is often impeded by the time-intensive and specialist-dependent process that is typically used to make such compounds. In contrast, general and automated platforms have been developed for making peptides, oligonucleotides, and increasingly oligosaccharides, where Synthesis is simplified to iterative applications of the same reactions. Inspired by the way natural products are biosynthesized via the iterative assembly of a defined set of building blocks, we developed a platform for small Molecule Synthesis involving the iterative coupling of haloboronic acids protected as the corresponding N-methyliminodiacetic acid (MIDA) boronates. Here we summarize our efforts thus far to develop this platform into a generalized and automated approach for small Molecule Synthesis. We and others have employed this approach to access many polyene-based compounds, including the polyene motifs found in >75% of all polyene natural products. This platform further ...
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Synthesis of Many Different Types of Organic Small Molecules Using One Automated Process.
ChemInform, 2015Co-Authors: Steven G. Ballmer, Eric P Gillis, Seiko Fujii, Michael Schmidt, Andrea M. E. Palazzolo, Jonathan W. Lehmann, Greg F. Morehouse, Martin D BurkeAbstract:Small-Molecule Synthesis usually relies on procedures that are highly customized for each target.
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Synthesis of many different types of organic small Molecules using one automated process
Science (New York N.Y.), 2015Co-Authors: Steven G. Ballmer, Eric P Gillis, Seiko Fujii, Michael Schmidt, Andrea M. E. Palazzolo, Jonathan W. Lehmann, Greg F. Morehouse, Martin D BurkeAbstract:Small-Molecule Synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the Synthesis of 14 distinct classes of small Molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block–based Synthesis platform to include even C sp3 -rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small Molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-Molecule Synthesis.
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z 2 bromovinyl mida boronate a readily accessible and highly versatile building block for small Molecule Synthesis
ChemInform, 2011Co-Authors: Eric M Woerly, Justin R Struble, Nagarjuna Palyam, Sean P Ohara, Martin D BurkeAbstract:The Synthesis of the bifunctional (Z)-olefin building block (II) is developed and the utility the product in a variety of Pd-catalyzed cross-coupling reactions is demonstrated.
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z 2 bromovinyl mida boronate a readily accessible and highly versatile building block for small Molecule Synthesis
Tetrahedron, 2009Co-Authors: Eric M Woerly, Justin R Struble, Nagarjuna Palyam, Sean P Ohara, Martin D BurkeAbstract:Iterative cross-coupling represents a potentially general approach for the simple, efficient, and flexible construction of natural products, pharmaceuticals, and materials. N-Methyliminodiacetic acid (MIDA) boronates represent a promising platform for the development of this type of Synthesis strategy. This report describes the discovery that vinyl MIDA boronate (1) is an air- and chromatographically stable compound that can be conveniently prepared on a multigram scale and serve as a versatile starting material for the preparation of a range of new MIDA boronate building blocks. Analogous to tert-butylethylene, 1 is also an excellent substrate for olefin cross-metathesis, providing access to a range of trans-alkenyl MIDA boronates as single stereoisomers. An improved Synthesis of the very versatile bifunctional building block trans-(2-bromovinyl) MIDA boronate (2) is also described. Collectively, these results contribute to the expanding generality of the iterative cross-coupling approach.
Amir H. Hoveyda - One of the best experts on this subject based on the ideXlab platform.
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catalytic z selective cross metathesis in complex Molecule Synthesis a convergent stereoselective route to disorazole c1
ChemInform, 2015Co-Authors: Alexander W H Speed, Richard R Schrock, Tyler J Mann, Robert V Obrien, Amir H. HoveydaAbstract:The diastereo- and enantioselective preparation of the macrocyclic natural product (IV) with anticancer and antifungal activities is described which comprises the title reaction as a key step.
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catalyst controlled stereoselective olefin metathesis as a principal strategy in multistep Synthesis design a concise route to neopeltolide
Angewandte Chemie, 2015Co-Authors: Miao Yu, Richard R Schrock, Amir H. HoveydaAbstract:Molybdenum-, tungsten-, and ruthenium-based complexes that control the stereochemical outcome of olefin metathesis reactions have been recently introduced. However, the complementary nature of these systems through their combined use in multistep complex Molecule Synthesis has not been illustrated. A concise diastereo- and enantioselective route that furnishes the anti-proliferative natural product neopeltolide is now disclosed. Catalytic transformations are employed to address every stereochemical issue. Among the featured processes are an enantioselective ring-opening/cross-metathesis promoted by a Mo monoaryloxide pyrrolide (MAP) complex and a macrocyclic ring-closing metathesis that affords a trisubstituted alkene and is catalyzed by a Mo bis(aryloxide) species. Furthermore, Z-selective cross-metathesis reactions, facilitated by Mo and Ru complexes, have been employed in the stereoselective Synthesis of the acyclic dienyl moiety of the target Molecule.
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catalytic z selective cross metathesis in complex Molecule Synthesis a convergent stereoselective route to disorazole c1
Journal of the American Chemical Society, 2014Co-Authors: Alexander W H Speed, Richard R Schrock, Tyler J Mann, Robert V Obrien, Amir H. HoveydaAbstract:A convergent diastereo- and enantioselective total Synthesis of anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route is the application of catalytic Z-selective cross-metathesis (CM). Specifically, we illustrate that catalyst-controlled stereoselective CM can be performed to afford structurally complex Z-alkenyl–B(pin) as well as Z-alkenyl iodide compounds reliably, efficiently, and with high selectivity (pin = pinacolato). The resulting intermediates are then joined in a single-step operation through catalytic inter- and intramolecular cross-coupling to furnish the desired 30-membered ring macrocycle containing the critical (Z,Z,E)-triene moieties.
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molybdenum based complexes with two aryloxides and a pentafluoroimido ligand catalysts for efficient z selective Synthesis of a macrocyclic trisubstituted alkene by ring closing metathesis
Angewandte Chemie, 2013Co-Authors: Chenbo Wang, Richard R Schrock, Fredrik Haeffner, Amir H. HoveydaAbstract:Macrocyclic ring-closing metathesis (RCM) has had an enormous impact on organic chemistry;[i,ii] such influence has been in spite of the absence of reliable stereoselective catalyst-controlled protocols. High stereoselectivity is crucial to applications in complex Molecule Synthesis: a non-discriminating RCM, often performed late stage in a multi-step route, can be costly (overall yield reduction by ≥50%). We have reported that with Mo- or W-based mono-aryloxide pyrrolide (MAP) complexes, macrocyclic disubstituted Z olefins can be obtained efficiently and stereoselectively.[iii] Another problem, more challenging and strategically distinct, relates to Synthesis of macrocyclic trisubstituted alkenes;[ii] re-routing through diyne RCM[iv]/alkyne functionalization is not an attractive option in such instances.
Eric P Gillis - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of Many Different Types of Organic Small Molecules Using One Automated Process.
ChemInform, 2015Co-Authors: Steven G. Ballmer, Eric P Gillis, Seiko Fujii, Michael Schmidt, Andrea M. E. Palazzolo, Jonathan W. Lehmann, Greg F. Morehouse, Martin D BurkeAbstract:Small-Molecule Synthesis usually relies on procedures that are highly customized for each target.
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Synthesis of many different types of organic small Molecules using one automated process
Science (New York N.Y.), 2015Co-Authors: Steven G. Ballmer, Eric P Gillis, Seiko Fujii, Michael Schmidt, Andrea M. E. Palazzolo, Jonathan W. Lehmann, Greg F. Morehouse, Martin D BurkeAbstract:Small-Molecule Synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the Synthesis of 14 distinct classes of small Molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block–based Synthesis platform to include even C sp3 -rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small Molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-Molecule Synthesis.
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Iterative Cross-Couplng with MIDA Boronates: Towards a General Platform for Small Molecule Synthesis
Aldrichimica acta, 2009Co-Authors: Eric P Gillis, Martin D BurkeAbstract:Most organic Molecules are inherently modular in their constitution. With respect to the Molecules found in living systems, this modularity is a direct consequence of the fact that nearly all biosynthetic systems are based on the iterative coupling of bifunctional building blocks.i For example, polypeptides are built from amino acids, oligonucleotides are derived from nucleotide monomers, and oligosaccharides are stitched together from individual sugar units. Interestingly, most small Molecule natural products are similarly constructed via the iterative coupling of bifunctional building blocks, e.g., polyketides from malonyl-CoA or methylmalonyl-CoA units, non-ribosomal peptides from amino acids, polyterpenes from isopentenyl pyrophosphate or dimethylallyl pyrophosphate, and fatty acids from malonyl-CoA.i Similarly, many man-made pharmaceuticals are also highly modular because they are constructed by using different reactions to assemble collections of small building blocks, typically cyclic and heterocyclic fragments and their associated appendages. Thus, modularity appears to be a remarkably general feature of many of the Molecules that are targeted for Synthesis in the laboratory. Despite this common modularity, the strategies utilized for making polypeptides, oligonucleotides, and oligosaccharides are very different than those typically used to prepare small Molecules. Specifically, all of the former classes of compounds are almost always constructed via iterative coupling of suitably-protected forms of their consituent monomers.ii Organic polymers are similarly prepared in this fashion.iii Due to the powerfully simple nature of this iterative coupling approach, these processes are now increasingly performed in a fully-automated fashion.ii,iii With peptides and oligonucleotides, the advanced development of such automation has made it possible for even non-chemists to routinely prepare these types of compounds for a wide range of applications. In stark contrast, it is typical for a synthetic chemist to develop a unique, customized strategy for each small Molecule that is targeted for preparation in the laboratory. As a result, the Synthesis of small Molecules remains a relatively complex, unsystematized, and inflexible process practiced almost exclusively by highly trained specialists. Driven by the hypothesis that the inherent modularity in small molucules remains largely underutilized, we have established a research program that aims to develop a unified strategy for the construction of these compounds via the iterative coupling of bifunctional building blocks.iv,v,vi,vii Specifically, we have targeted the development of building blocks representing substructures that appear frequently in natural products and man-made pharmaceuticals and the chemistry that will enable their precise union via iterative, metal-mediated cross-coupling reactions. In the idealized form of this envisioned “iterative cross-coupling” (ICC) approach, building blocks having all of the required functional groups preinstalled in the correct oxidation state and with the desired stereochemical relationships are iteratively united using only a single, stereospecific cross-coupling reaction (Figure 1). In addition to being simple, efficient, and potentially amenable to automation, the modularity of this approach makes it inherently well-suited for generating diverse collections of compounds simply by substituting modified building blocks into the same Synthesis pathway. It is anticipated that the advanced development of this ICC strategy will substantially enable the laboratory Synthesis of a wide range of natural products, pharmaceuticals, and organic materials, and may even extend the power of small Molecule Synthesis to the non-chemist. Figure 1 Analogous strategies for the Synthesis of peptides and small Molecules. As described in this review, N-methyliminodiacetic acid (MIDA) boronatesviii represent a highly promising platform for this type of Synthesis strategy. These building blocks are remarkably convenient to prepare, analyze, purify, and store. The MIDA boronate functional group is also stable to anhydrous cross-coupling conditions but easily hydrolyzed with mild aqueous base, thereby enabling the controlled, ICC of B-protected “haloboronic acids.”iv,v,vi In addition, MIDA boronates are remarkably stable to a wide range of common reaction conditions and chromatography, which makes possible the facile preparation of complex borane building blocks from simple MIDA boronate starting materials via multistep Synthesis.vi,vii Importantly, many MIDA boronate building blocks are now commercially-available worldwide from Sigma-Aldrich (www.sigmaaldrich.com/mida). This review aims to enable the effective utilization of this platform and the ICC strategy to promote the simple, efficient, and flexible construction of small Molecules.
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a simple and modular strategy for small Molecule Synthesis iterative suzuki miyaura coupling of b protected haloboronic acid building blocks
Journal of the American Chemical Society, 2007Co-Authors: Eric P Gillis, Martin D BurkeAbstract:We herein describe a simple and highly modular strategy for small Molecule Synthesis involving the iterative cross-coupling of B-protected bifunctional haloboronic acids. Enabling this approach, we have newly discovered that the pyramidalization of boronic acids via complexation with the trivalent ligand N-methyliminodiacetic acid inhibits their reactivity towards cross-coupling. This ligand is remarkably stable to anhydrous Suzuki−Miyaura conditions yet readily cleaved using mild aqueous base (1 M aqueous NaOH/THF, 10 min, 23 °C or saturated aqueous NaHCO3/MeOH, 23 °C, 6 h). Although the reactivity of aryl, heteroaryl, alkenyl, and alkyl boronic acids can vary dramatically, this methodology is effective for protecting and deprotecting all four classes of nucleophiles. Harnessing this potential, we achieved the first total Synthesis of the natural product ratanhine using the Suzuki−Miyaura reaction iteratively to bring together a collection of easily synthesized, readily purified, and highly robust buildi...
Stuart L. Schreiber - One of the best experts on this subject based on the ideXlab platform.
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Skeletal Diversity in Small-Molecule Synthesis Using Ligand-Controlled Catalysis
Journal of combinatorial chemistry, 2007Co-Authors: B. Lawrence Gray, Stuart L. SchreiberAbstract:Two Pd-catalyzed reductive transformations of diynes tethered through a silyl ether linkage were developed, where the reaction outcomes were controlled solely by selection of phosphine ligand. We screened Pd precatalysts, ligands, and additives to optimize conditions selective either for reductive cyclization or hydrogenation of this substrate class. Sixteen silyl ether-tethered diynes were prepared and subjected to the best catalyst/ligand combinations for each pathway. Silacyclic dienes and silyl-tethered enyne products of these reactions were elaborated to densely substituted, stereochemically- and appendage-rich, bicyclic and tricyclic small Molecules in 1–3 synthetic steps. These studies illustrate how small modifications to a transition-metal catalyst can be used to access a diverse set of small Molecules, in a fashion analogous to biosynthetic pathways such as terpene bioSynthesis, where minor changes to enzyme structure direct skeletal differentiation.
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Synthesis and cellular profiling of diverse organosilicon small Molecules
Journal of the American Chemical Society, 2007Co-Authors: Annaliese K Franz, Philip D Dreyfuss, Stuart L. SchreiberAbstract:Small-Molecule Synthesis coupled with cellular profiling using multidimensional screening can be used to assess the impact of varying stereochemical and appendage contexts on biological activity. In this communication, we describe the Synthesis and cellular profiling of chiral organosilicon small Molecules derived from a crotylsilane annulation pathway. We considered that incorporating a main-group element, such as silicon, within the chiral environment of a more complex product could provide new structures where the distinctive chemical properties of silicon may contribute to new biological activity. The annulation of various indole-2,3-dione (isatin) reagents with functionalized crotylsilanes provides efficient access to spiro-oxindole structures for biological evaluation. The modular placement of aryl iodide functional groups in the isatin component can be used in appending processes for further substitution, such as conversion of the aryl iodide to various amido functionalities using the Buchwald amid...
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An oligomer-based approach to skeletal diversity in small-Molecule Synthesis.
Journal of the American Chemical Society, 2006Co-Authors: David Spiegel, Frank C. Schroeder, Jeremy R. Duvall, Stuart L. SchreiberAbstract:Access to small Molecules of widely varying molecular shapes has been identified as an enabling step in the discovery of biologically active materials. In this communication we introduce an approach to the systematic development of architecturally distinct chemical compounds based upon the assembly of reactive monomers into linear oligomers, each of which encodes a unique molecular framework under a common set of reaction conditions. Certain products of the initial chemical transformation (Ru-catalyzed metathesis reaction) encode additional skeletons upon treatment with a second common set of reagents (Diels−Alder dienophiles). Application of this oligomerization approach has led to the discovery of a previously unreported tandem ene-yne−yne metathesis−6π-electrocyclization−1,5-hydride migration that converts a linear substrate into a complex tricyclic 1,3-diene in a single step. Thus, the reported strategy might serve not only as a generator of skeletally diverse small Molecules but also as a discovery p...
Christopher N. Bowman - One of the best experts on this subject based on the ideXlab platform.
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Spatial and temporal control of the alkyne–azide cycloaddition by photoinitiated Cu(II) reduction
Nature Chemistry, 2011Co-Authors: Brian J Adzima, Christopher J. Kloxin, Youhua Tao, Cole A Deforest, Kristi S Anseth, Christopher N. BowmanAbstract:The click reaction paradigm is focused on the development and implementation of reactions that are simple to perform while being robust and providing exquisite control of the reaction and its products. Arguably the most prolific and powerful of these reactions, the copper-catalysed alkyne–azide reaction (CuAAC) is highly efficient and ubiquitous in an ever increasing number of synthetic methodologies and applications, including bioconjugation, labelling, surface functionalization, dendrimer Synthesis, polymer Synthesis and polymer modification. Unfortunately, as the Cu( I ) catalyst is typically generated by the chemical reduction of Cu( II ) to Cu( I ), or added as a Cu( I ) salt, temporal and spatial control of the CuAAC reaction is not readily achieved. Here, we demonstrate catalysis of the CuAAC reaction via the photochemical reduction of Cu( II ) to Cu( I ), affording comprehensive spatial and temporal control of the CuAAC reaction using standard photolithographic techniques. Results reveal the diverse capability of this technique in small Molecule Synthesis, patterned material fabrication and patterned chemical modification. The copper( I )-catalysed azide–alkyne cycloaddition is arguably the most prolific and powerful example of the click reaction paradigm. Here, photochemical reduction of Cu( II ) allows spatial and temporal control over the reaction for small-Molecule Synthesis, patterning of hydrogel formation and the in situ labelling of gels, with features as small as 25 micrometres being produced.
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spatial and temporal control of the alkyne azide cycloaddition by photoinitiated cu ii reduction
Nature Chemistry, 2011Co-Authors: Brian J Adzima, Christopher J. Kloxin, Cole A Deforest, Kristi S Anseth, Christopher N. BowmanAbstract:The copper(I)-catalysed azide–alkyne cycloaddition is arguably the most prolific and powerful example of the click reaction paradigm. Here, photochemical reduction of Cu(II) allows spatial and temporal control over the reaction for small-Molecule Synthesis, patterning of hydrogel formation and the in situ labelling of gels, with features as small as 25 micrometres being produced.
