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  • 1
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    Organometallic palladium reagents for cysteine bioconjugation (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-10-30
    Description: Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody-drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vinogradova, Ekaterina V -- Zhang, Chi -- Spokoyny, Alexander M -- Pentelute, Bradley L -- Buchwald, Stephen L -- 1F32GM101762/GM/NIGMS NIH HHS/ -- GM-110535/GM/NIGMS NIH HHS/ -- GM-58160/GM/NIGMS NIH HHS/ -- R01 GM058160/GM/NIGMS NIH HHS/ -- U54A1057159/PHS HHS/ -- England -- Nature. 2015 Oct 29;526(7575):687-91. doi: 10.1038/nature15739.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26511579" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Organic chemistry: A radical approach to diversity (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-12-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Parsons, Andrew T -- Buchwald, Stephen L -- England -- Nature. 2011 Dec 7;480(7376):184-5. doi: 10.1038/480184a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158236" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry Techniques, Synthetic/*methods ; *Drug Design ; Halogenation/*radiation effects ; Pharmaceutical Preparations/*chemistry ; Photochemical Processes/*radiation effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Controlled acceleration and inhibition of bergman cyclization by metal chlorides (1995)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1995-08-11
    Description: The Bergman cyclization has been the subject of renewed interest with the discovery of naturally occurring enediyne-based antitumor agents that cleave DNA by means of an aromatic diradical. These natural substrates have a means to trigger this cycloaromatization process. Control of this reaction by substrate modification would allow aromatic diradicals to be generated selectively. In the studies presented here it is disclosed that the Bergman cyclization of 1,2-bis(diphenyl phosphinoethynyl) benzene was accelerated by a factor of 〉30,000 by the addition of palladium(II) chloride or platinum(II) chloride and was inhibited by the addition of mercury(II) chloride.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warner, B P -- Millar, S P -- Broene, R D -- Buchwald, S L -- New York, N.Y. -- Science. 1995 Aug 11;269(5225):814-6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17778739" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Zirconocene complexes of unsaturated organic molecules: new vehicles for organic synthesis (1993)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1993-09-24
    Description: Transition metals are known to stabilize high-energy species and to activate otherwise unreactive ones. The zirconocene unit stabilizes highly strained alkynes and alkenes, allowing their use in selective carbon-carbon bond-forming reactions. This unit also increases the reactivity of unactivated molecules, enabling them to participate in nontraditional transformations. A general route has been developed that allows a wider variety of unsaturated fragments to participate in these reactions. The use of these zirconocene complexes in organic synthesis has led to the development of novel routes to a number of polyfunctionalized organic molecules.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Broene, R D -- Buchwald, S L -- CA 09112/CA/NCI NIH HHS/ -- GM 34917/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1993 Sep 24;261(5129):1696-701.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Insitute of Technology, Cambridge 02139.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8378769" target="_blank"〉PubMed〈/a〉
    Keywords: Organometallic Compounds/chemical synthesis/*chemistry ; Zirconium/*chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Formation of ArF from LPdAr(F): catalytic conversion of aryl triflates to aryl fluorides (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-08-15
    Description: Despite increasing pharmaceutical importance, fluorinated aromatic organic molecules remain difficult to synthesize. Present methods require either harsh reaction conditions or highly specialized reagents, making the preparation of complex fluoroarenes challenging. Thus, the development of general methods for their preparation that overcome the limitations of those techniques currently in use is of great interest. We have prepared [LPd(II)Ar(F)] complexes, where L is a biaryl monophosphine ligand and Ar is an aryl group, and identified conditions under which reductive elimination occurs to form an Ar-F bond. On the basis of these results, we have developed a catalytic process that converts aryl bromides and aryl triflates into the corresponding fluorinated arenes by using simple fluoride salts. We expect this method to allow the introduction of fluorine atoms into advanced, highly functionalized intermediates.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038120/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watson, Donald A -- Su, Mingjuan -- Teverovskiy, Georgiy -- Zhang, Yong -- Garcia-Fortanet, Jorge -- Kinzel, Tom -- Buchwald, Stephen L -- GM46059/GM/NIGMS NIH HHS/ -- R01 GM046059/GM/NIGMS NIH HHS/ -- R37 GM046059/GM/NIGMS NIH HHS/ -- R37 GM046059-18/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Sep 25;325(5948):1661-4. doi: 10.1126/science.1178239. Epub 2009 Aug 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19679769" target="_blank"〉PubMed〈/a〉
    Keywords: Catalysis ; Contrast Media ; Fluorides/*chemical synthesis/*chemistry ; Fluorine/*chemistry ; Fluorine Radioisotopes ; Hydrocarbons, Fluorinated/*chemical synthesis/*chemistry ; Isomerism ; Ligands ; Mesylates/*chemistry ; Molecular Structure ; Oxidation-Reduction ; Palladium/*chemistry ; Physicochemical Processes ; Positron-Emission Tomography
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 6
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    The palladium-catalyzed trifluoromethylation of aryl chlorides (2010)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2010-06-26
    Description: The trifluoromethyl group can dramatically influence the properties of organic molecules, thereby increasing their applicability as pharmaceuticals, agrochemicals, or building blocks for organic materials. Despite the importance of this substituent, no general method exists for its installment onto functionalized aromatic substrates. Current methods either require the use of harsh reaction conditions or suffer from a limited substrate scope. Here we report the palladium-catalyzed trifluoromethylation of aryl chlorides under mild conditions, allowing the transformation of a wide range of substrates, including heterocycles, in excellent yields. The process tolerates functional groups such as esters, amides, ethers, acetals, nitriles, and tertiary amines and, therefore, should be applicable to late-stage modifications of advanced intermediates. We have also prepared all the putative intermediates in the catalytic cycle and demonstrated their viability in the process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005208/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005208/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Eun Jin -- Senecal, Todd D -- Kinzel, Tom -- Zhang, Yong -- Watson, Donald A -- Buchwald, Stephen L -- GM46059/GM/NIGMS NIH HHS/ -- R01 GM046059/GM/NIGMS NIH HHS/ -- R37 GM046059/GM/NIGMS NIH HHS/ -- R37 GM046059-18/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2010 Jun 25;328(5986):1679-81. doi: 10.1126/science.1190524.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20576888" target="_blank"〉PubMed〈/a〉
    Keywords: Catalysis ; Fluorobenzenes/chemistry ; Hydrocarbons, Chlorinated/*chemistry ; Hydrocarbons, Fluorinated/*chemical synthesis/*chemistry ; Ligands ; Methylation ; Molecular Structure ; Oxidation-Reduction ; Palladium/*chemistry
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Identification and rescue of alpha-synuclein toxicity in Parkinson patient-derived neurons (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-10-26
    Description: The induced pluripotent stem (iPS) cell field holds promise for in vitro disease modeling. However, identifying innate cellular pathologies, particularly for age-related neurodegenerative diseases, has been challenging. Here, we exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein (alphasyn), a key protein involved in Parkinson's disease (PD). We generated cortical neurons from iPS cells of patients harboring alphasyn mutations, who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alphasyn toxicity led to identification of early pathogenic phenotypes in patient neurons. These included nitrosative stress, accumulation of endoplasmic reticulum (ER)-associated degradation substrates, and ER stress. A small molecule identified in a yeast screen (NAB2), and the ubiquitin ligase Nedd4 it affects, reversed pathologic phenotypes in these neurons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022187/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022187/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chung, Chee Yeun -- Khurana, Vikram -- Auluck, Pavan K -- Tardiff, Daniel F -- Mazzulli, Joseph R -- Soldner, Frank -- Baru, Valeriya -- Lou, Yali -- Freyzon, Yelena -- Cho, Sukhee -- Mungenast, Alison E -- Muffat, Julien -- Mitalipova, Maisam -- Pluth, Michael D -- Jui, Nathan T -- Schule, Birgitt -- Lippard, Stephen J -- Tsai, Li-Huei -- Krainc, Dimitri -- Buchwald, Stephen L -- Jaenisch, Rudolf -- Lindquist, Susan -- 5 R01CA084198/CA/NCI NIH HHS/ -- K01 AG038546/AG/NIA NIH HHS/ -- P50 AG005134/AG/NIA NIH HHS/ -- R01 CA084198/CA/NCI NIH HHS/ -- R01 GM058160/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Nov 22;342(6161):983-7. doi: 10.1126/science.1245296. Epub 2013 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24158904" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzimidazoles/chemistry/*pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Female ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Mutation ; Neurogenesis ; Neurons/*drug effects/metabolism/pathology ; Parkinson Disease/genetics/*metabolism ; Rats ; alpha-Synuclein/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Yeast reveal a "druggable" Rsp5/Nedd4 network that ameliorates alpha-synuclein toxicity in neurons (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-10-26
    Description: alpha-Synuclein (alpha-syn) is a small lipid-binding protein implicated in several neurodegenerative diseases, including Parkinson's disease, whose pathobiology is conserved from yeast to man. There are no therapies targeting these underlying cellular pathologies, or indeed those of any major neurodegenerative disease. Using unbiased phenotypic screens as an alternative to target-based approaches, we discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-syn toxicity. Three chemical genetic screens in wild-type yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5/Nedd4. These same steps were perturbed by alpha-syn itself. Thus, NAB identifies a druggable node in the biology of alpha-syn that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi vesicle trafficking.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993916/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tardiff, Daniel F -- Jui, Nathan T -- Khurana, Vikram -- Tambe, Mitali A -- Thompson, Michelle L -- Chung, Chee Yeun -- Kamadurai, Hari B -- Kim, Hyoung Tae -- Lancaster, Alex K -- Caldwell, Kim A -- Caldwell, Guy A -- Rochet, Jean-Christophe -- Buchwald, Stephen L -- Lindquist, Susan -- 5R01GM069530/GM/NIGMS NIH HHS/ -- F32GM099817/GM/NIGMS NIH HHS/ -- F32NS061419/NS/NINDS NIH HHS/ -- GM58160/GM/NIGMS NIH HHS/ -- K01 AG038546/AG/NIA NIH HHS/ -- R01 GM058160/GM/NIGMS NIH HHS/ -- R15 NS075684/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Nov 22;342(6161):979-83. doi: 10.1126/science.1245321. Epub 2013 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24158909" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzimidazoles/chemistry/*pharmacology ; Caenorhabditis elegans ; Cells, Cultured ; *Cytoprotection ; Drug Evaluation, Preclinical ; Endosomal Sorting Complexes Required for Transport/*genetics ; Gene Regulatory Networks/*drug effects ; Neurodegenerative Diseases/*metabolism ; Neurons/*drug effects/metabolism ; Neuroprotective Agents/*pharmacology ; Parkinson Disease/metabolism ; Rats ; Saccharomyces cerevisiae/drug effects ; Saccharomyces cerevisiae Proteins/*genetics ; Small Molecule Libraries/chemistry/pharmacology ; Ubiquitin-Protein Ligase Complexes/*genetics ; Ubiquitin-Protein Ligases/*genetics ; alpha-Synuclein/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
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    ORGANIC CHEMISTRY. Catalytic asymmetric hydroamination of unactivated internal olefins to aliphatic amines (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-07-04
    Description: Catalytic assembly of enantiopure aliphatic amines from abundant and readily available precursors has long been recognized as a paramount challenge in synthetic chemistry. Here, we describe a mild and general copper-catalyzed hydroamination that effectively converts unactivated internal olefins-an important yet unexploited class of abundant feedstock chemicals-into highly enantioenriched alpha-branched amines (〉/=96% enantiomeric excess) featuring two minimally differentiated aliphatic substituents. This method provides a powerful means to access a broad range of advanced, highly functionalized enantioenriched amines of interest in pharmaceutical research and other areas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532314/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532314/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Yang -- Shi, Shi-Liang -- Niu, Dawen -- Liu, Peng -- Buchwald, Stephen L -- GM 58160/GM/NIGMS NIH HHS/ -- R01 GM058160/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):62-6. doi: 10.1126/science.aab3753.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA. ; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. sbuchwal@mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26138973" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
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  • 10
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    Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-03-29
    Description: The chirality, or 'handedness', of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844805/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844805/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shi, Shi-Liang -- Wong, Zackary L -- Buchwald, Stephen L -- GM-58160/GM/NIGMS NIH HHS/ -- R01 GM058160/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):353-6. doi: 10.1038/nature17191. Epub 2016 Mar 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27018656" target="_blank"〉PubMed〈/a〉
    Keywords: Amination ; Amino Alcohols/*chemical synthesis/*chemistry ; Catalysis ; *Chemistry Techniques, Synthetic ; Copper/*chemistry ; Molecular Structure ; Stereoisomerism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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