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  • 1
    Publication Date: 2013-10-29
    Description: Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation-dehydrogenation dual oxidation of a highly reactive poly(beta-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844076/" 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/PMC3844076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teufel, Robin -- Miyanaga, Akimasa -- Michaudel, Quentin -- Stull, Frederick -- Louie, Gordon -- Noel, Joseph P -- Baran, Phil S -- Palfey, Bruce -- Moore, Bradley S -- R01 AI047818/AI/NIAID NIH HHS/ -- R01AI47818/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 28;503(7477):552-6. doi: 10.1038/nature12643. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162851" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/biosynthesis ; Bacterial Proteins/chemistry/*metabolism ; Biocatalysis ; Bridged Compounds/metabolism ; Crystallography, X-Ray ; Cyclization ; Flavins/*metabolism ; Flavoproteins/chemistry/*metabolism ; Isotope Labeling ; Mixed Function Oxygenases/chemistry/*metabolism ; Models, Chemical ; Models, Molecular ; Oxidation-Reduction ; Polyketides/metabolism ; Protein Conformation ; Streptomyces/*enzymology/metabolism ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-04-21
    Description: New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as "classics". Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium). These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C-H oxidation (demonstrated on 100 grams), enabling the adoption of this C-H oxidation strategy in large-scale industrial settings without substantial environmental impact.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860034/" 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/PMC4860034/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Horn, Evan J -- Rosen, Brandon R -- Chen, Yong -- Tang, Jiaze -- Chen, Ke -- Eastgate, Martin D -- Baran, Phil S -- GM-097444/GM/NIGMS NIH HHS/ -- R01 GM073949/GM/NIGMS NIH HHS/ -- R01 GM097444/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 May 5;533(7601):77-81. doi: 10.1038/nature17431. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA. ; Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin 300457, China. ; Chemical Development, Bristol-Myers Squibb, New Brunswick, New Jersey 08903, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096371" target="_blank"〉PubMed〈/a〉
    Keywords: Allyl Compounds/chemistry ; Biological Products/chemical synthesis/chemistry ; Carbon/*chemistry ; *Chemistry Techniques, Synthetic ; Electrochemistry ; Green Chemistry Technology ; Hydrogen/*chemistry ; Oxidants/*chemistry ; Oxidation-Reduction ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2016-03-24
    Description: Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical structure and the medicinal potential of phorbol esters. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes, germacrenes, taxanes and ingenanes have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C-C bond constructions and C-H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833603/" 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/PMC4833603/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawamura, Shuhei -- Chu, Hang -- Felding, Jakob -- Baran, Phil S -- GM-097444/GM/NIGMS NIH HHS/ -- R01 GM097444/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 7;532(7597):90-3. doi: 10.1038/nature17153. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA. ; Front End Innovation, LEO Pharma A/S Industriparken 55, 2750 Ballerup, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007853" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Products/*chemical synthesis/chemistry/isolation & purification ; *Chemistry Techniques, Synthetic ; Diterpenes/chemical synthesis ; Molecular Structure ; Monoterpenes/chemistry ; Oxygen/chemistry/metabolism ; Phorbol Esters/chemical synthesis/chemistry/isolation & purification ; Phorbols/*chemical synthesis/*chemistry ; Stereoisomerism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2016-05-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Ming -- Baran, Phil S -- England -- Nature. 2016 May 18;533(7603):326-7. doi: 10.1038/533326a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27193674" 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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  • 5
    Publication Date: 2013-08-03
    Description: Ingenol is a diterpenoid with unique architecture and has derivatives possessing important anticancer activity, including the recently Food and Drug Administration-approved Picato, a first-in-class drug for the treatment of the precancerous skin condition actinic keratosis. Currently, that compound is sourced inefficiently from Euphorbia peplus. Here, we detail an efficient, highly stereocontrolled synthesis of (+)-ingenol proceeding in only 14 steps from inexpensive (+)-3-carene and using a two-phase design. This synthesis will allow for the creation of fully synthetic analogs of bioactive ingenanes to address pharmacological limitations and provides a strategic blueprint for chemical production. These results validate two-phase terpene total synthesis as not only an academic curiosity but also a viable alternative to isolation or bioengineering for the efficient preparation of polyoxygenated terpenoids at the limits of chemical complexity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jorgensen, Lars -- McKerrall, Steven J -- Kuttruff, Christian A -- Ungeheuer, Felix -- Felding, Jakob -- Baran, Phil S -- New York, N.Y. -- Science. 2013 Aug 23;341(6148):878-82. doi: 10.1126/science.1241606. Epub 2013 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23907534" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*chemical synthesis ; Catalysis ; Diterpenes/*chemical synthesis ; Euphorbia/chemistry ; Monoterpenes/*chemistry ; Oxidoreductases/chemistry ; Stereoisomerism
    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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  • 6
    Publication Date: 2012-12-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keasling, Jay D -- Mendoza, Abraham -- Baran, Phil S -- England -- Nature. 2012 Dec 13;492(7428):188-9. doi: 10.1038/492188a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235869" target="_blank"〉PubMed〈/a〉
    Keywords: Biotechnology/economics/*trends ; Chemistry Techniques, Synthetic/economics/*methods/trends ; *Synthetic Biology/economics/methods
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-12-04
    Description: Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 degrees C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518649/" 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/PMC3518649/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fujiwara, Yuta -- Dixon, Janice A -- O'Hara, Fionn -- Funder, Erik Daa -- Dixon, Darryl D -- Rodriguez, Rodrigo A -- Baxter, Ryan D -- Herle, Bart -- Sach, Neal -- Collins, Michael R -- Ishihara, Yoshihiro -- Baran, Phil S -- GM-073949/GM/NIGMS NIH HHS/ -- R01 GM073949/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Dec 6;492(7427):95-9. doi: 10.1038/nature11680. Epub 2012 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23201691" target="_blank"〉PubMed〈/a〉
    Keywords: Air ; Alkylation ; Biological Products/chemistry ; Carbon/*chemistry ; Drug Design ; Hydrogen/*chemistry ; Hydrogen Bonding ; Indicators and Reagents/chemistry ; Methylation ; Nitrogen/chemistry ; Pharmaceutical Preparations/chemistry ; Sulfinic Acids/chemistry ; Water ; Zinc/chemistry
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-12-19
    Description: Carbon-carbon (C-C) bonds form the backbone of many important molecules, including polymers, dyes and pharmaceutical agents. The development of new methods to create these essential connections in a rapid and practical fashion has been the focus of numerous organic chemists. This endeavour relies heavily on the ability to form C-C bonds in the presence of sensitive functional groups and congested structural environments. Here we report a chemical transformation that allows the facile construction of highly substituted and uniquely functionalized C-C bonds. Using a simple iron catalyst, an inexpensive silane and a benign solvent under ambient atmosphere, heteroatom-substituted olefins are easily reacted with electron-deficient olefins to create molecular architectures that were previously difficult or impossible to access. More than 60 examples are presented with a wide array of substrates, demonstrating the chemoselectivity and mildness of this simple reaction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271735/" 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/PMC4271735/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lo, Julian C -- Gui, Jinghan -- Yabe, Yuki -- Pan, Chung-Mao -- Baran, Phil S -- GM-097444/GM/NIGMS NIH HHS/ -- R01 GM097444/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Dec 18;516(7531):343-8. doi: 10.1038/nature14006.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25519131" target="_blank"〉PubMed〈/a〉
    Keywords: Alkenes/*chemistry ; Carbon/*chemistry ; Chemistry Techniques, Synthetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2014-09-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Villaume, Matthew T -- Baran, Phil S -- England -- Nature. 2014 Sep 18;513(7518):324-5. doi: 10.1038/513324a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25230652" target="_blank"〉PubMed〈/a〉
    Keywords: Alkenes/*chemical synthesis ; Animals ; Biological Products/*chemical synthesis ; Fatty Alcohols/*chemical synthesis ; Monosaccharides/*chemical synthesis ; Pyrans/*chemical synthesis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2015-08-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farmer, Marcus E -- Baran, Phil S -- England -- Nature. 2015 Aug 13;524(7564):164-5. doi: 10.1038/524164a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26268186" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry Techniques, Synthetic/*methods
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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