BEAK-PINES ORGANIC AREA ALLERTON …...BEAK-PINES ORGANIC AREA ALLERTON CONFERENCE 2 3 ALLERTON...

UNIVERSITY OF ILLINOIS SCHOOL OF CHEMICAL SCIENCES CHEMISTRY DEPARTMENT PRESENTS:

THE 28TH ANNUAL BEAK-PINES ORGANIC AREA ALLERTON CONFERENCE

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ALLERTON CONFERENCE HISTORY

OnOctober17,1987thefirstOrganicAreaAllertonConferencewasheldattheRobertAllertonHouseinMonticello,Illinois.Theintentoftheconferencewastoprovidestudentswithanopportunitytopresenttheirworkintheposterandlectureformatsandinformaldiscussionsofscientificmeetings,tofacilitatecommunication about ongoing work between research groups and to givestudentsorganizationaland leadershipexperience.TheOrganicAreaAllertonConferencehasbeenheldeachyearsincethefirstmeeting. TheideaforthisconferencewasdevelopedbyProfessorPeterBeakwhosecuredsupportfromtheMonsantoCompanythroughDr.TerryBalthazor(Ph.D.Martin, 1975). InMay 1987,Merck&Co. awarded SeemonH. Pines (Ph.D.,Leonard,1951)theDirectors’ScientificAwardforhisoutstandingcontributionstothedevelopmentofapracticalchemicalsynthesisofthedrugPrimaxin.Dr.Pinescontactedhisalmamaterandaskedhowthisgiftmightbeused.Inresponsetothisopportunity,theorganicchemistryfaculty(Beak,Broka,Coates,Curtin,Denmark, Katzenellenbogen, Leonard, Pirkle, Rinehart, Schuster, P. Shapley,SmithandZimmerman)offeredthreeproposalstoenhancethegraduateprogram.InalettertoDr.Pines,ProfessorScottDenmarkoutlinedthese,oneofwhichwastoprovidecontinuingsupportfortheAllertonConference.Pleasedbythisoption,Dr.Pinesdonatedthe$50,000awardtoendowtheconference.AsecondgiftfromSeemonPinesin1996providedforthe“SeemonPinesAward,”a$500prizeforthegraduatestudentwhodeliversthemostoutstandingpresentation.Additionalendowedsupportof$68,000wasprovidedbyMerckandthePinesestatein2004and2013-2014.Thefaculty,theorganicdivisionandtheObiterCompany provided funds as needed in some years. In 2010-2014 Peter andSandraBeakmadeendowmentdonations,whichtotal$370,000forperpetualsupportoftheOrganicAreaAllertonConference. TheAllertonConference is aunique featureof the graduate experienceat the University of Illinois. It is a celebration of outstanding science, in anatmosphereof collegiality thathasbeen thehallmarkof theUIUCChemistryDepartmentthroughoutitshistory.Theconferencehasbeensuccessfulbecauseoftheinitiativeandleadershipofgraduatestudents.Theyorganizeandleadtheconference,givethepresentations,chairandparticipateinthediscussionsandprovideguidancetotheirsuccessors.TheAllertonConferenceisanacademichighpointoftheyearandisclearlyfulfillingitsinitialpurpose.

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DR. SEEMON H. PINES

SeemonH. Pineswas born in Portland,Maine and educated in publicschools in Maine, New York, and Pennsylvania. He pursued undergraduatestudiesatLehighUniversity,whichwerepostponedfortwoyearsofserviceintheU.S.Navyfrom1944to1946.In1948,Dr.Pinesreceivedabachelor’sdegreeinchemicalengineering.HecontinuedhisacademiccareerattheUniversityofIllinoisandbecameamemberofProfessorNelsonLeonard’sgroup.Hereceivedamaster’sdegreein1949andaPh.D.in1951forhisthesistitled“TheClemmensenreductioncumrearrangementofα-aminoketones.” Aftergraduation,Dr.PinesjoinedMerckandCompanyasabenchchemist.HedevotedhisentirecareertoMerckandultimatelyachievedthepositionofVicePresidentofProcessResearchandDevelopmentbeforeretiringin1991.In1987,he received theDirector’sScientificAward, thehighesthonorMerckbestowsuponitsresearchersinrecognitionofoutstandingscientificachievements,forhisleadingroleinthecommercialdevelopmentofthebroadspectrumantibiotic,Primaxin.Thisworkisconsideredoneofthegreatestsyntheticchallengeseverbroughttocommercializationandthusisabenchmarkinthepharmaceuticalindustry.Asa central figureatMerck,Dr.Pineswas involved ina variety ofprojects, including the manufacturing process of niacin, glutamic acid, andpenicillin,andotherworkonmethyldopa,indomethacin,carbidopaandsulindac.Dr.PinesguidedtheMerckProcessGrouptoapreeminentpositioninsynthesisandprocesschemistry. After retiring from Merck in 1991, Dr. Pines spent time traveling anddocumentinghis experiences throughphotography.OnOctober13,2000,hewashonoredwiththe2000LASAlumniAchievementAwardfromtheUniversityofIllinoisinrecognitionofhislifetimeofoutstandingaccomplishments.OnMay18,2012,hediedattheageof86. WearehonoredandgratefulthatDr.PineschosetoallocatethemonetaryportionoftheDirector’sScientificAwardtotheOrganicChemistryDepartmentattheUniversityofIllinois.ThisgenerousgranthelpstosponsortheOrganicAreaAllertonConferenceeachyear,providingtheopportunitytocelebratetheaccomplishmentsofmembersofthedepartmentandfacilitatecommunicationamong various research groups.We look forward to honoring thememory ofDr. Pines this year with the Twenty-Seventh Annual Organic Area AllertonConference.

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PROF. PETER BEAK AND MRS. SANDRA BEAK

Sandra(B.Ed.Miami(Ohio),M.Ed.Illinois)taughtintheUrbanaSchoolsfor25years.SheparticipatedwiththeUniversitiesofIllinoisandEasternIllinoisin supervising student teachers and collaborated with Illinois in programswhichdeveloped languageacquisitionby international studentsandprovidedmulticulturaleducationforallstudents. Peter’s (B.A. Harvard, Ph.D. Iowa State) group made contributions tophysical organic studies of equilibria and reaction mechanisms and to thediscoveryanddevelopmentofnewsyntheticmethods. Inearlygasphaseandsolutionstudiesheestablishedthatthestabilitiesofprotomericisomersarehighlydependentonthemolecularenvironments,providedaphenomenologicaltheorytorationalizetheseeffects,anddevelopedamethodfortheequilibrationofthecorrespondingalkyltropicisomers.Investigationsofthiophillicadditionstothiocarbonylgroups,ofreactionsinvolvingcarboxyliumions, of novel photochemical rearrangements and of a model for orotidine5′-phosphatedecarboxylasewerecarriedoutinhisgroup. Theuseofintra/intermolecularhydrogen/deuteriumisotopeeffectswasdevelopedasamethodwhichprovidesinformationaboutprotontransferswhichmayoccurafterthetransitionstateofareaction.Beakdevelopedtheendocyclicrestrictiontesttosolvelong-standingquestionsaboutthetrajectoriesofreactionatnon-stereogenicheteroatoms.Thisworkestablishedthatfirstrowatomsaredisplacedby trigonalbipyramidal transition statesandsecondand third rowatomscanreactbythatpathwayorbyanadditionaleliminationprocess. Beak’sworkdevelopedconceptsandmethodsinorganolithiumcarbanionchemistry.Theintermediacyofdipolestabilizedcarbanionsandtheoperationofthecomplexinducedproximityeffectindirectedlithiationsprovidedanumberofusefulcarbonionicintermediatesforinvestigationandapplication.Hisdiscoveryanddevelopmentofdynamicthermodynamicresolutionprovidedanewstrategyforimprovementofenantioselectivesyntheses. Beak has received recognition for his teaching, service and researchincludingelectiontotheCenterforAdvancedStudy,theAmericanAcademyofArtsandSciencesandtheNationalAcademyofSciences.

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PROF. KEVIN G. PINNEYBaylor University

Dr. Kevin G. Pinney joined the faculty in The Department of Chemistry andBiochemistryatBaylorUniversity in1993havingcompletedhisPh.D.atTheUniversityofIllinoisunderthedirectionofProf.JohnA.KatzenellenbogenfollowedbyaNIHPostdoctoralResearchFellowshipatTheUniversityofSouthCarolina.Dr.PinneyiscurrentlyaProfessorofChemistryatBaylorUniversityandisalsoamemberofTheInstituteofBiomedicalStudies.ThePinneyResearchGroupis typically composed of approximately fifteen to twenty members includinggraduateandundergraduatestudents,postdoctoralresearchassociates,andaresearchadministrativeassociate.Eachsummer,Dr.PinneyalsomentorsoneortwohighschoolstudentsthroughtheBaylorUniversityHighSchoolSummerScienceResearchProgram.Dr.KevinG.Pinneyhasextensivetraininginsyntheticorganicchemistryandhasadditionalresearchexpertiseinareasthatencompassmedicinal chemistry and biochemistry. Well-established research projects inthePinneyLaboratoryatBaylorUniversityfocusonunderstandingthesalientfeaturesofsmallmoleculemolecularrecognitionofselectedbioreceptorsincludingproteinsandenzymes.Specificresearchprojectsinclude:vasculardisruptingagents(VDAs)toselectivelystarvetumorsofoxygenandnutrients,inhibitorsoftubulinassemblyasantimitoticagents,inhibitorsofcathepsinLtolimitorarrestcancermetastasis,thesynthesisofbioreductivelyactivatableprodrugconjugates(BAPCs)designedtotargettumorhypoxiaasameansofimpartingselectivityinanticancerdrugdelivery,antibody-drugconjugates(ADCs)designedtoselectivelydeliver extremely potent small-molecule anti-cancer agents, and inhibitors ofcruzainaspotentialtreatmentagentsforChagas’disease. Nearlyalloftheseprojectsarecollaborative innaturebetween thePinneyGroup (syntheticandmedicinal chemistry) andTrawickGroup (biochemistry and cell biology) bothatBaylorUniversity. Dr.Pinneyistheauthorofover forty-fivepeerreviewedarticlesandbookchaptersandisaco-inventorontwenty-threeissuedpatentsalongwithseveralpendingpatentapplications.Researchfundingiscurrentlyprovided by grants from the National Institutes of Health (NIH), the CancerPreventionandResearchInstituteofTexas(CPRIT),andOxigeneInc.Dr.Pinneyservedanappointment(2010-2012)asamemberoftheSteeringCommitteeforthe“ChemistryinCancerResearch”(CICR)WorkingGroupassociatedwiththeAmericanAssociationofCancerResearch(AACR)andwashonoredtoreceivethe“TheCorneliaMarschallSmithProfessoroftheYearAward”atBaylorUniversityin2006,andtobenamedaMentoroftheYearforundergraduateSTEMresearchatBaylorUniversityin2014.

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8:00AM CHECK-IN/CONTINENTAL BREAKFAST

SESSION I: GREGORY KORTMAN, CHAIR

ANTHONY GRILLO (PROF. MARTIN D. BURKE)

OPENING REMARKS

Restoring Physiology in Protein Deficient Cells with Small Molecules

JUN LI (PROF. JEFFREY S. MOORE)

SUBHA MUKHERJEE (PROF. WILFRED A. VAN DER DONK)

ROBERT HICKLIN (PROF. PAUL J. HERGENROTHER)

STEPHEN AMMANN (PROF. M. CHRISTINA WHITE)

CAITLIN DEANE (PROF. DOUGLAS A. MITCHELL)

Mechanophore Activation at Hetero-interfaces

Mechanistic Studies on the Substrate-tolerant Lanthipeptide Synthetase ProcM

Break for poster session in the Gallery with snacks and coffeeTalks will resume in the library at 10:50AM

Stereochemically Complex and Structurally Diverse Small Molecules from Pleuromutilin: Synthesis, Structural Evaluation, and Biological Activity

Terminal Olefins to Chromans, Isochromans, and Pyrans via Allylic C–H Oxidation

Biosynthetic Engineering of Unnatural Natural Products

Tables will be assigned to each person previously. Tables will be seated and called to go through the buffet

Tables will be assigned to each person previously. Tables will be seated and called to go through the buffet

POSTER SESSION I

LUNCH IN MAIN DINING ROOM - GROUP I

LUNCH IN MAIN DINING ROOM - GROUP II

8:40AM

9:00AM

9:20AM

9:40AM

10:00AM

10:50AM

11:10AM

11:30AM

11:50AM

12:40AM

SCHEDULE OF EVENTS

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SESSION II: BRANDON BURKHART, CHAIR

DR. KEVIN G. PINNEY (BAYLOR UNIVERSITY)Small-Molecule, Tubulin Binding, Vascular Disrupting Agents as Anti-Cancer Therapeutics

HYUNG MIN CHI (PROF. SCOTT E. DENMARK)

CHIH-CHI CHU (PROF. SCOTT K. SILVERMAN)

SETH ENSIGN (PROF. KAMI L. HULL)

YUGANG BAI (PROF. STEVEN C. ZIMMERMAN)

Catalytic, Enantioselective, Intramolecular Carbosulfenylation of Olefins. Mechanistic Aspects: A Remarkable Case of Negative Catalysis

DNA-Catalyzed Conjugation of Nucleic Acids and Tyrosine Side Chain

Break for poster session in the Gallery with snacks and coffeeTalks will resume in the library at 3:50PM

Rhodium-Mediated Substrate Controlled Markovnikov and Anti-Markovnikov Hydroamination

Drug-functionalized Cell-penetrating Peptides for Enhanced Delivery and Binding in Myotonic Dystrophy Type 1 Treatment

POSTER SESSION II

BREAK

1:40PM

2:20PM

2:40PM

3:00PM

4:30PM

3:50PM

4:10PM

CLOSING REMARKS AND PRESENTATION OF SEEMON PINES AWARD4:50PM

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SESSION I: POSTERS

1. PATRICIA BLAIR (PROF. DOUGLAS A. MITCHELL) Derivatization of a Species-Selective Antibiotic for Probing its Mechanism of Action

2. ADAM HILL (PROF. MARTIN D. BURKE) Atypical Carotenoids as Potent Antilipoperoxidants

3. JEREMY HENLE (PROF. SCOTT E. DENMARK) Diversity Oriented, Computer-Guided Catalyst Design: A New Paradigm in Catalyst Design and Evaluation in Organic Synthesis

4. WEI LIU (PROF. M. CHRISTINA WHITE) General Allylic C–H Alkylation with Tertiary Nucleophiles

5. LONG M. LUU (PROF. STEVEN C. ZIMMERMAN) Development of Benzdiamidinium Ligands as Potential Therapeutic Agents for Myotonic Dystrophy Desease

6. MICHELLE RICHTER (PROF. PAUL J. HERGENROTHER) The Design, Synthesis, and Analysis of Small Molecules that Accumulate in Gram- Negative Bacteria

7. YANG SONG (PROF. JEFFREY S. MOORE) Multivalent Macromolecules Redirect Nucleation-dependent Fibrillar Assembly into Discrete Nanostructures

8. ZHAO WU (PROF. KAMI L. HULL) Rhodium-Catalyzed Amide Bond Formation

9. XILING ZHAO (PROF. WILFRED A. VAN DER DONK) Lantibiotics from the anaerobe Ruminococcus flavefaciens FD-1

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SESSION II: POSTERS

1. BRYON DROWN (PROF. PAUL J. HERGENROTHER) Development of High-Throughput Assay for PAR-Regulating Enzymes by Chemical Synthesis of Alternative Substrates

2. STANLEY EEY (PROF. SCOTT E. DENMARK) Catalytic, Stereospecific Syn-Dichlorination of Alkenes

3. SAMUEL N. GOCKEL (PROF. KAMI L. HULL) Palladium Catalyzed CO-Free Aminocarbonylation of Aryl Halides

4. JENNIFER HOU (PROF. MARTIN D. BURKE) Understanding How Imperfect Small Molecule Mimics of Missing Proteins Restore Physiology

5. JUYEON LEE (PROF. STEVEN C. ZIMMERMAN) Small Molecules Targeting the Toxic RNA in Myotonic Dystrophy Type 2

6. OLIVIA LEE (PROF. JEFFREY S. MOORE) Poly(phthalaldehyde) and Poly(vinyl carbonate sulfone)s as UV and Thermally Degradable Packaging for Transient Electronics

7. THOMAS OSBERGER (PROF. M. CHRISTINA WHITE) N-Boc Amines to Oxazolidinones via Pd(II)/Bis-sulfoxide / Brønsted Acid Co- catalyzed Allylic C-H Oxidation

8. JONATHAN TIETZ (PROF. DOUGLAS A. MITCHELL) Streptomonomicin: a Hydrophobic Lasso Peptide Antibiotic from the Halophilic Bacterium Streptomonospora alba

9. XIAO YANG (PROF. WILFRED A. VAN DER DONK) Selection of Cyclic Lanthipeptide for Disruption of Protein-protein Interactions

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SESSION I: SPEAKER ABSTRACTS

Restoring Physiology in ProteinDeficient Cells with Small Molecules

Anthony S. Grillo and Martin D. Burke

Many human diseases arise from the deficiency of critical protein function.Smallmoleculeswhich canpartially replicateprotein function represent apotentiallyempoweringalternativetreatmenttothesediseases.Inthisvein,thesmallmoleculenaturalproductamphotericinBhasrecentlybeenshowntorestoregrowthtoyeastdeficientinpotassiumuptake.Herein,wereporttherobustrestorationofvigorousandsustainablegrowthupontreatingayeaststrainlackingahighlyregulatedirontransportingproteincomplexwiththeinherentlylessselectiveandnon-regulatedtropolonenaturalproducthinokitiol.Severallinesofevidencedemonstratethatthisrestorationisduetothecapacityofhinokitioltobindandtransportiron.Collectively,thesefindingssuggestthisrescuephenomenon is general, and substantially brighten the prospect of treating diseasescausedbymissingproteinswithimperfectsmallmoleculesurrogates.

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Mechanophore Activation at Hetero-interfaces

Jun LiandJeffreyS.Moore

Moleculardesignofforce-sensitivemoleculesinpolymermechanochemistryhasbroughtnewconcepts insmartmaterials,yet itsusehasbeen limited tohomogenouspolymer systems. The nature of polymer mechanochemistry at interfaces, whichare arguably more important considering the prevalence of composite materials inindustrialapplications,remainsmostlyunexplored.Herewereportanovelsystemthatimplementsmechanophores as anchor points at hetero-interfaces. Silica nanoparticlesgraftedwithpoly(methylacrylate) (PMA)chainsanchoredbyamaleimide-anthracenecycloadductweresynthesizedtodemonstratemechanochemically-selectiveactivationofmechanophoresatheterogeneous interfaces.Byquantifying theanthracene-containingcleavedPMApolymers,whicharegeneratedviaretro[4+2]cycloadditionreactions,thefirstorderkineticcoefficientwasdetermined.Activationcharacteristicsofmechanophoresanchoredtoananoparticleexhibitbehaviorsimilartomechanophore-linkedpolymers,e.g., thresholdmolecularweightand linear increase in rate coefficientwithmolecularweightabovethethreshold.Thismodelsystemisthusvaluableasaprobetoteststressactivation of interfacially-bondedmechanophores and to design smart,mechanically-sensitiveandself-repairingcompositematerials.

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Mechanistic Studies on the Substrate-tolerant Lanthipeptide Synthetase ProcM

SubhaMukherjeeandWilfredvanderDonk

Lanthipeptidesarea classofpost-translationallymodifiedpeptideswith characteristiclanthionine (Lan) andmethyllanthionine (MeLan) thioethers.These cyclic thioether crosslinksconferstabilityandendowlanthipeptideswithvariousbiologicalactivities.Themechanismofcatalysis ofProcM, ahighly substrate-tolerant lanthipeptide synthetase,was investigated.WefoundthatProcMdehydratestheprecursorpeptideswithC-to-Ndirectionality.CyclizationbyProcMwasfoundtooccurinanorderedfashionwithcertainthioethercrosslinksformingfasterthantheothers.Ahybridligationstrategywasdevelopedtoprepareaseriesofsemi-syntheticsubstrateanalogs to furtherprobeenzymecatalysis.Throughassaysusing substratesbearingorthogonalcysteineside-chainprotection,spontaneousnon-enzymaticcyclizationeventswereruledout.Thefinalringtopologyofthematureprochlorosinsdependedontheorderofcrosslinkformation. Finally, synthetically generated intermediateswith non-native ring topologies didnotundergoringopeningtointerconverttonativeringtopologies.Thus,cyclizationbyProcMappearstobekineticallydriven.Suchinsightsareexpectedtoaidfutureeffortsinlanthipeptideengineering.

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Stereochemically Complex and Structurally Diverse Small Molecules from Pleuromutilin: Synthesis, Structural Evaluation, and Biological Activity

RobertW.HicklinandPaulJ.Hergenrother

Complex natural products are often considered the end-point of syntheticendeavors,buttheyrepresentanadvantageousstartingpointforthesynthesisofnovelstructures of biological and theoretical interest. Many natural products containingcomplexringsystems,multiplestereogeniccenters,anddiverse functionalgroupsarereadilyavailable tosyntheticchemistsviacommercialsourcesor isolation.Fromsuchcomplex starting materials, dramatic structural alterations can be accessed rapidlythroughmanipulationofcoreringsystemsviaringdistortionreactions(ringformation,cleavage,expansion,contraction,andrearrangement).Thestructurallydiversemoleculesthuscreatedretainthemolecularcomplexityinherentintheinitialnaturalproductsandarehighlyvaluableforprobingbiologicalprocessesandinvestigatingunusualstructuralphenomena.Todemonstrate theutilityof complexnaturalproductsas feedstocks forcomplexmolecule synthesis,wehave transformed the commercially availablenaturalproductpleuromutilinintofivehighlydiversescaffoldsthataredramaticallydifferentfromeachotherandtheparentnaturalproduct.Oneofthesemoleculeswasidentifiedasanoveltypeoffenestrane,astrainedpolycycliccompoundpossessingahighlyplanarizedfour-coordinatecarbonatom.ThedegreeofplanarizationandtheeffectsofperipheralsubstituentsonscaffoldgeometrywereinvestigatedbychemicalderivatizationandX-raycrystallography.Biologicalevaluationofthecompoundsderivedfrompleuromutilinledtotheidentificationofacompoundwithpotentcytotoxicityinmultiplecancercelllines.Structure-activityrelationshipstudieshaveprovidedinsightintothepossiblemodeofactionforthisscaffoldandhaveledtotheidentificationofmoreactivederivatives.

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Terminal Olefins to Chromans, Isochromans, and Pyrans via Allylic C–H Oxidation

StephenE.Ammann,GrantT.Rice,andM.ChristinaWhite

Oxygenated heterocycles are important synthetic targets due to their broadpharmacological activity. Herin we describe a method for the synthesis of chroman,isochroman,andpyranmotifsviaacombinationofpalladium(II)C—HactivationandLewisacidco-catalysis.Forthefirsttime,thealcoholmotifwasshowntobeacompetentnucleophileunderouracidic conditions. Impressively, the reactionproceeds ingoodyields under simple uniform conditions irrespective to the electronic nature of thealcohol.MechanisticinsightssuggestthatthereactionproceedsviainitialC—Hactivationfollowedbyinner-spherereductiveeliminationofthepalladiumcomplex.

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Biosynthetic Engineering of Unnatural Natural Products

CaitlinD.DeaneandDouglasA.Mitchell

Plantazolicin(PZN)isaribosomallysynthesizedandposttranslationallymodifiedpeptide (RiPP) natural product which exhibits extraordinarily narrow-spectrumantibacterialactivityagainstthecausativeagentofanthrax,Bacillus anthracis.DuringPZNbiosynthesis,acyclodehydratasecatalyzescyclizationofcysteine,serine,andthreonineresidues in the precursor peptide to azoline heterocycles, and a dehydrogenase thencatalyzestheoxidationofmanyoftheseazolinestothiazolesand(methyl)oxazoles.Thefinalbiosyntheticstepsconsistofleaderpeptidecleavageandenzymaticdimethylationof thenascentN-terminus.Usingheterologouslyexpressedandpurifiedenzymes, theprecursorpeptidewasfullycyclizedandoxidizedin vitro,concordantwiththecyclizationpattern found in thenaturalproduct.Usinga suiteofvariantprecursorpeptides, thesubstratetoleranceofthesynthetasecomplexwaselucidatedin vitro.Despiteincreasedpromiscuity in vitro comparedtowhathasbeenpreviouslyobserved in vivo, thePZNbiosyntheticenzymes retainedexquisite selectivity incatalyzingcyclizationofmutantpeptidesonlyatpositionswhichcorrespondtothosecyclizedinthenaturalproduct.Acleavagesitewassubsequentlyengineeredtoremovetheleaderpeptide,yieldingfullymaturePZNvariantsafterenzymaticdimethylation.Productionofthesenovelvariantsthroughin vitrobiosynthesisfacilitatesthedeterminationoftheirantibacterialpotency,thusexpandingthegrowingpictureofthePZNstructure-activityrelationship.

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SESSION I: POSTER ABSTRACTS

Derivatization of a Species-Selective Antibiotic for Probing its Mechanism of Action

PatriciaM.BlairandDouglasA.Mitchell

Atypical Carotenoids as Potent Antilipoperoxidants

AdamG.Hill,HannahM.S.Haley,AlexI.Greenwood,ChadM.RienstraandMartinD.Burke

Asdrug-resistantpathogensposeanincreasingthreattohumanhealthworldwide,thereisaneedfornewantibacterialcompoundswithnovelandselectivetargets.Plantazolicin(PZN)isaribosomallyproducedpeptidewithextensiveposttranslationalmodifications thatexhibitsexquisiteselectivityforB.anthracis,thecausativeagentofanthrax,suggestingaspecies-specificandnovelmechanismofaction.Inordertodeterminethemoleculartarget,astructure-activityrelationshipstudyofPZNwasinitiatedtoidentifymoietiesessentialforbioactivity.Syntheticallyprepared truncations of the polyazole core of PZN displayed broader-spectrum antibacterialactivitybutwere lesspotent than the full-lengthnaturalproduct, suggesting the crucialityofthepolyheterocycliccoreinbioactivity.BasedontheabilitytomodifytheC-terminusofPZNwithout significantly affecting bioactivity, biotinylated and Cy5-labeled derivatives of PZNwereprepared.ThePZNprobes arebeing employed in affinitypurification andfluorescencemicroscopytodemonstratetheuniquemechanismofactionofPZN.

Peroxidationofpolyunsaturatedfattyacidshasbeenlinkedtoanincreasingnumberofhumandiseasesincluding,asthma,neurodegenerativediseasesandatherosclerosis.Weidentifiedthreeatypicalcarotenoidsisolatedfromorganismsthatthriveinenvironmentsofextremeoxidativestress and hypothesized that they may be potent antilipoperoxidants. Synthesis and directcomparisonofallthreeatypicalcarotenoidstoastaxanthin,thecurrentgoldstandardcarotenoidantilipoperoxidant,inahumancellmodeloflipidperoxidationshowedthatperidininisahighlypotentantilipoperoxidant.Furthermore,wehavebeguntoelucidateperidinin’smechanismofactioninaseriesofliposomeandsolutionphasestudieswhichshowthatitisarapidcatalyticquencherof lipidperoxyradicals.Finally, solid-stateNMRstudieshaverevealed thatdespiteextensiveliteraturedepictingastaxanthininthebilayer,itislocalizedprimarily(>66%)inalargeextramembraneousaggregate.

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Diversity Oriented, Computer-Guided Catalyst Design: A New Paradigm in Catalyst Design and Evaluation in Organic Synthesis

JeremyHenleandScottE.Denmark

General Allylic C–H Alkylation with Tertiary Nucleophiles

JenniferM.Howell,Wei Liu,AndrewJ.Young,M.ChristinaWhite

Theuseofcomputationalmethodstoprobeandinvestigatetheoriginsofcatalyticactivityandselectivityiswellknowninorganicsynthesis.Thesemethodsgenerallyrequiretransition-statecalculationsthatarenotamenabletopredictivemodeling.Intheselaboratories,wehavedevelopedamethodusing statistical 3Dchemoinformaticmethods toguide thedevelopmentofcatalysts.Bycombiningcombinatorialsynthesis toobtaindiverse librariesofcatalystswith3D-QSARmodelingmethods,meaningfullydiverseinitialscreeningsetscanbesystematicallygenerated.Thisstrategymaximizes thechance thataselectivecatalystwillbe found in initialscreeningstudies.Furthermodeldevelopmentcanleadtoefficientandfocusedprogresstowardselectivecatalyststructures.ThismethodiscurrentlybeingusedtodevelopnovelAPTCmethods.

A general method for intermolecular allylic C–H alkylation of terminal olefins withtertiary nucleophiles is presented. Palladium(II)/bis-sulfoxide catalysis affords alkylationproducts in good yield (avg. 64%)with excellent chemo-, region- and stereoselectivity (>20:1linear:branched,>20:1E:Z).Notably,bothactivated(aromatic,hetereoaromatic,1,4-dienes)andunactivatedaliphaticolefinsaresuccessfullyalkylatedforthefirsttimeunderthesamegeneralandmildreactionconditions.FacilediversificationofphenolicnaturalproductsisdemonstratedbycombiningknownallylationreactionswithallylicC–Halkylation.The tertiarynucleophilescopeisbroadandtolerantoflatentfunctionalitythatmaybefurtherelaborated.Thegeneralityof thismethod inboth reactionpartners enables itsuse to streamline synthesisvia expedientgenerationofmolecularcomplexity.UnderscoringthisconceptisatandemallylicC–Halkalation/Diels-AlderreactioncascadeusedtorapidlyfurnishthecommontricycliccorefoundintheclassIGalbulimimaalkaloids:areactivedieneisgeneratedviaintermolecularallylicC–Halkylationandsubsequentlyengagesincycloadditionwithadienophileinthetertiarynucleophile.

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Development of Benzdiamidinium Ligands as Potential Therapeutic Agents for Myotonic Dystrophy Desease

LongM.LuuandStevenC.Zimmerman

The Design, Synthesis, and Analysis of Small Molecules that Accumulate in Gram-Negative Bacteria

MichelleF.RichterandPaulJ.Hergenrother

Myotonicdystrophy type 1 (DM1), themost common formofmusculardystrophy, iscaused by a progressive expansion of the trinucleotide dCTG repeat. The transcribed rCUGrepeatsequestersthemuscleblind-likeprotein(MBNL1)intonuclearfoci,leadingtotheabnormalregulationofalternativesplicingofmorethan100pre-mRNAs.Herein,wereportoursuccessfuleffortstodiscoveranddevelopsmallmoleculeinhibitorsofther(CUG)n-MBNL1complex.Forexample,ligand1selectivelybindstoCUGrepeatsanddisplacesMBNL1fromitscomplexwiththeRNAinaDM1cellmodel,servingasa leadMBNL1-(CUG)exp inhibitor inourgroup.Themeasured KI of 1 is8μM.Structuralmodificationsof ligand1have led toadimeric ligand2 whoseinvitroKIis1000-foldlower.Ligand2iscellpermeable,relativelynon-toxictoHeLacells,andcapableofdissolvingupto80%ofnuclearfociatalowconcentration,leadingtoreversalofIRsplicinginaDM1cellmodel.

MultidrugresistantGram-negativebacteriahaveemergedasamajorpublichealthconcern.Theoutermembranesofthesepathogensarehighlyimpermeabletomostsmallmolecules,makingthemintrinsicallyresistanttomanyclinicallyusedantibiotics,includingdrugsoflastresortsuchasvancomycinanddaptomycin.Duetothecomplexityofthesystem,verylittleisknownaboutthepropertiesasmallmoleculemustpossessinordertoaccumulateinGram-negativebacteria;suchinformationhasthepotentialtogreatlyacceleratetheantibioticdiscoveryprocess.Hereinwedescribethedevelopmentofamethodtostudythephysicochemicalpropertiesnecessaryforsmallmolecule accumulation inGram-negativebacteria, aswell as insightsgainedusing thismethod.

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Multivalent Macromolecules Redirect Nucleation-dependent Fibrillar Assembly into Discrete Nanostructures

YangSongandJeffreyS.Moore

Rhodium-Catalyzed Amide Bond Formation

ZhaoWuandKamiL.Hull

Manipulatingthesizeandshapeofnon-covalentmultivalentassemblies isanongoingchallengeinthefieldofsupramolecularpolymers.Followingamechanisticapproach,wereasonedthatnucleation−elongationkineticspresentsuniqueopportunitiesforcontrolledgrowthsincethefinaloutcomeis likelytodependonthestructureanddynamicsofcritical-nucleusformation.Takingfibrillarassemblyofamyloidβ(Aβ)peptideasthemodelsystemofnucleation-dependentsupramolecularpolymerization,herewereportmultivalentpolymer−peptideconjugates(mPPCs)thatredirectfibrillarassemblyofAβtoformdiscretenanostructures.ThemPPCswererationallydesignedtotargetAβintermediatesformedpriortocriticalnucleation.Atomicforcemicroscopyand transmission electronmicroscopy studies show that in the presence ofmPPCs,Aβ self-assemblesintozero-dimensionaldiscretenanostructureswithlateraldimensionsapproximatelyin5−35nm,whileAβaloneself-assemblesintoone-dimensionalfibrilsinmicrometer.ThioflavinTkineticsfluorescenceassaysdemonstratethatmPPCssuppressAβfibrillogenesis.ThemPPCsmaythusrepresentaprototypicalmoleculardesignofmultivalentmacromoleculesabletocontrolthefinalshapeofsupramolecularpolymersassembledviaanucleation-dependentmechanism.

Establishedapproachesforamidebondsynthesisrelyonstoichiometricgenerationofanactivatedcarboxylatevia thereactionofcarboxylicacidsandactivecouplingreagents. Thesemethods,whilecommonlyemployed,areexpensiveandgeneratesignificantquantitiesofwaste.Assuch,thedevelopmentofaselectivetransitionmetal-catalyzedamidesynthesishasbeenanareaofsignificantfocusfororganometallicchemist.Herein,wereportachemoselectivedirectamidationofallylicalcoholsoraldehydeswithanamine,usingaRh(I)/BINAPcomplexasthecatalyst in a benzene/water bi-phasic systemandgenerating ethyl benzene or isopropanol astheonlystoichiometricbyproducts.Underourconditions,thedesiredamidesaregeneratedinmoderatetogoodyieldwithbothprimaryandsecondaryamines.

22


Lantibiotics from the anaerobe Ruminococcus flavefaciens FD-1

XilingZhaoandWilfredA.vanderDonk

Lanthipeptidesareaclassofribosomallysynthesizedandpost-translationallymodifiednatural products, a subset ofwhich display antimicrobial activity and are called lantibiotics.Lanthipeptidebiosyntheticmachineryisconserved,whichfacilitatesdiscoveryefforts.Genomemining revealed a lanthipeptide gene cluster within the anaerobic organism Ruminococcus flavefaciensFD-1thatrepresentsanexampleoflanthipeptidecombinatorialbiosynthesisinwhicha pair of enzymes could be responsible for themodification of twelve substrate peptides. Inordertosystematicallyassessthestructuresandbioactivitiesofthepeptidesencodedwithinthecluster,aheterologoushostandinvitroproductionstrategywasemployedtoaccessthemodifiedpeptides.Thepresenceofcharacteristicpost-translationalmodificationsintheprocessedpeptideswasconfirmedbychiralgas-chromatographymassspectrometryandtandemmassspectrometry.Furthermore,apreliminaryassessmentrevealedtheFlvApeptidestobeantibacterialandstudiesareunderwaytoquantifytheirantimicrobialactivity.

23

Small-Molecule, Tubulin Binding, Vascular Disrupting Agents as Anti-Cancer Therapeutics

KevinPinney,BaylorUniversity

Small-molecule, anti-cancer agents continue to show promise in numerous cancertreatmentregimens,employedassingleagentsormoreoftenincombinationwithothertreatmentmodalities.Aformidablechallengeliesintheabilitytoselectivelytargetappropriatetherapeuticmoleculestowardscancercellsorcrucialcomponentsofthetumormicroenvironment.Progressivestructure-activity relationship observations have guided a process of synthetic molecularevolutionresultinginthediscoveryofavarietyofhighlypotentinhibitorsoftubulinassembly(polymerization). These compounds demonstrate dual-functionality in regard to biologicalactivity,actingbothasantiproliferativeagentsandasvasculardisruptingagents(VDAs),whichselectivelydisruptbloodflowtotumors.Interestingly,bothofthesemechanismsarebasedonthe ability of these compounds to interactwith the tubulin-microtubule protein system, andit is importanttonotethattheVDAmechanismofactionisdistinctfromthatofangiogenesisinhibitingagents(AIAs)thathavegainedtractionintheclinic.Thediscoveryanddevelopmentofdihydronaphthalene,benzosuberene,andindole-basedanticanceragentswillbepresentedalongwithapreliminaryassessmentoftheirabilitytofunctionbothantiproliferativelyandasVDAs.Certainoftheseanti-canceragentsdemonstratesub-nanomolar(topico-molar)cytotoxicity(in vitro)againstavarietyofhumancancercelllinesandarealsoexemplaryintheirabilitytoeffecttumorvasculardamage(in vitro and in vivoassessment).Strategiesfortheselectivetargetingoftheseagentsasantibody-drugconjugates(ADCs)andseparatelytowardstumorhypoxiawillbedescribed.

SESSION II: SPEAKER ABSTRACTS

24

Catalytic, Enantioselective, Intramolecular Carbosulfenylation of Olefins. Mechanistic Aspects: A Remarkable Case of Negative Catalysis

HyungMinChiandScottE.Denmark

In the course of developing an enantioselective, Lewis base/Brønsted acid co-catalyzed carbosulfenylation of alkenes, a seemingly contradicting phenomenon of acatalystinhibitingastoichiometricreactionwasobserved.Intheabsenceofcatalyst,thebackgroundreactionrateswerecomparabletoorgreaterthanthecatalyzedprocess,despitetheobservationofhighlyenantioenrichedproductwhenachiral,nonracemiccatalystwasemployed.DetailedkineticandspectroscopicstudiesrevealedthattheconversionoftheLewisbasepre-catalysttothecatalyticallyactivespecieswasresponsiblefortheobservedcomparable reactivity. Specifically, the equimolar formation of the byproducts of thecatalystactivation,sulfonateionandphthalimide,bufferedtheBrønstedacid,resultingininhibitionoftheuncatalyzedracemicpathway.Therefore,theoperatingbackgroundreactionundercatalyticconditionscannotberepresentedbysimplyomittingthecatalyst.


25


DNA-Catalyzed Conjugation of Nucleic Acids and Tyrosine Side Chain

Chih-ChiChuandScottK.Silverman

Deoxyribozymesaresingle-strandedDNAoligonucleotidesidentifiedbyinvitroselectionthatcatalyzevariouschemicalreactions.WepreviouslyreportedDNAcatalyststhatjointyrosine-containingpeptidestoRNAinonestepbyreactionwiththehydroxylgroupof the tyrosine side chainand theα-phosphateof a5’-triphosphorylatedRNA.OureffortstowardsthisgoalrequiredtetheringthepeptidesubstratetoaDNAanchoroligonucleotide.Here,weestablishdirectinvitroselectionusinguntethered,freepeptidesubstrates. Sucha strategyutilizes an azido-modifiedpeptide as the substrateduringthe selection step and Cu(I)-catalyzed azide-alkyne cycloaddition in the subsequentcapturestepwithanalkyne-modifiedoligonucleotidetoenablePAGE-shiftseparationofthecatalyticallyactiveDNAsequences.ThisapproachenablesimpositionofselectionpressurebyreducingthepeptideconcentrationandleadstoadeoxyribozymethathasalowerapparentKmvalueof~100μMpeptide.Inaddition,wedemonstratethefeasibilityofusingphosphorimidazolide(Imp)asanalternativeelectrophiletotriphosphate(ppp),notingthatImpcanbereadilyplacedateitherthe5’-endor3’-endofeitherRNAorDNA.ThisapproachprovidessyntheticflexibilityingenerationofoligonucleotidesubstratesfordeoxyribozymesandthereforeexpandsthescopeofDNA-catalyzedpeptide-nucleicacidconjugation.ThesefindingsestablishanovelandgeneralizableapproachofjoiningunprotectedpeptidetonucleicacidinonestepusingDNAcatalysts.

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Rhodium-Mediated Substrate Controlled Markovnikov and Anti-Markovnikov Hydroamination

SethC.EnsignandKamiL.Hull

Thecatalyticadditionofanamineacrossanunsaturatedcarbon-carbonbondhasbeenoneofthemostintractablechallengesinorganometallicchemistryfordecades.Hy-droaminationisparticularlyappealingasanatom-economicalsolution.However,thisseeminglyfacilereactioniscomplicatedbyhighactivationenergiesandhighlynegativeentropyvalues.Topromotethisotherwisedemandingtransformation,wehaveshownthatremoteLewis-basicdirectinggroupscanbeusedtobindthemetalcenterandin-creasethereactivityofanotherwiseelectronicallyunactivatedolefin.Inaddition,thisgroupoftenenforcesahighdegreeofregioselectivityasitproceedsthroughafavoredmetallacycleintermediate. N-allyl iminesundergoRh-catalyzedhydroamination to form1,2-diaminesandthe Markovnikov product while homoallyl amines form 1,4-diamines and the anti-Markovnikovproduct.Thesereactionsaretolerantofavarietyofsecondarycyclicamines,arefunctionalgrouptolerantand(inthecaseofN-allylimines)showahighdegreeofdiastereoselectivity. The formationof 1,4-diamines to generate the anti-Markovnikovproductrepresentsanunprecedentedreportofarhodium-catalyzedtransformation.


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Drug-functionalized Cell-penetrating Peptides for Enhanced Delivery and Binding in Myotonic Dystrophy Type 1 Treatment

YugangBai,LienNyugen,ZiyuanSong,JianjunChengandStevenZimmerman

Recentdevelopment in (CUG)n-RNAsmallmoleculebinders showedpotentialfor treatment ofmyotonic dystrophy type 1 (DM1).However,many difficulties existbeforethedrugcouldbeusedininvitroandinvivostudies,suchaslowwatersolubility,highcytotoxicityateffectivedosage,andcellmembranepenetrability.Inaddition,asamereRNAbinder,thedrugmoleculesonlyoccupiesthebindingsitesof(CUG)ninsteadofremovingit.Asarationaldesigntosolvetheseproblems,smallmoleculesthatwereknowntobindto(CUG)nrepeatwereconjugatedontothesidechainsofcell-penetratingpeptides(CPPs)byclick-chemistry.TheCPPsgreatlyimprovedthewater-solubilityofthehydrophobicdrug,preventingaggregation,andeffectively transporting them intothecells.Inaddition,theresultingmulti-valentdrugpolymerscouldhavedramaticallyimprovedbindingaffinitytowards(CUG)nrepeat,aswellasreducedcellulartoxicity.Peptideswithdifferent length,drug loadingandhelicitywereevaluatedusingmodelcells.Overall,theexceptionallyhighbindingaffinityandefficientdrugdeliveryallowedfullfunctionrecoveryinsplicingreversalstudies.ShortRNA-cleavingpeptidecouldalsobe conjugatedonto theCPPs, granting the conjugates the ability todegrade the toxicRNAuponbinding.

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Development of High-throughput Screen for PAR-regulating Enzyme by Chemical Synthesis of Alternative Substrate

BryonS.DrownandPaulJ.Hergenrother

Catalytic, Stereospecific Syn-Dichlorination of Alkenes

AlexanderJ.Cresswell,† StanleyT.-C.Eey†andScottE.Denmark

Poly(ADP-ribosyl)ation is an important post-translationalmodification responsible forregulatingDNAdamagerepair,transcription,chromatinstructure,andtelomeremaintenance.Despite PAR being recognized as a valid target for anticancer therapy, modulation andmeasurementofPARmetabolismremainschallenging.HerewereportthedesignandsynthesisofasubstrateanalogueforanenzymeresponsibleforregulatingPARmetabolism.Thissubstrateenabledthedevelopmentandexecutionofahigh-throughputscreenforinhibitorsofthisenzyme.

Assomeoftheoldestorganicchemicalreactionsknown,theionicadditionsofelementalhalogens such asbromine and chlorine to alkenes areprototypical examplesof stereospecificreactions,typicallydeliveringvicinaldihalideswithexceptionalanti-diastereoselectivity.Whilstthe invention of enantioselective variants is an ongoing challenge, the ability to overturn theinnatediastereoselectivityof these transformations isalsoa largelyunsolvedproblem. In thiswork,wedescribe thefirst catalytic, syn-stereospecificdichlorinationof alkenes, employingagroup transfer catalyst based on a redox-active main group element (i.e., selenium). Thus,with diphenyl diselenide (PhSeSePh) (5mol%) as the pre-catalyst, benzyltriethylammoniumchloride(BnEt3NCl)asthechloridesource,andanN-fluoropyridiniumsaltastheoxidant,awidevariety of functionalized cyclic and acyclic 1,2-disubstituted alkenes, including simple allylicalcohols,deliversyn-dichlorideswithexquisitestereocontrol.Thismethodologyisexpectedtofindapplicationsinstreamliningthesynthesisofpolychlorinatednaturalproductssuchasthechlorosulfolipids.

†Theseauthorscontributedequally.

SESSION II: POSTER ABSTRACTS

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Palladium Catalyzed CO-Free Aminocarbonylation of Aryl Halides

SamuelN.GockelandKamiL.Hull

Understanding How Imperfect Small Molecule Mimics of Missing Proteins Restore Physiology

JenniferHou and Martin D. Burke

Theamideisanimportantfunctionalgroupoftenfoundinbiologicallyactivecompoundsor in key intermediates towards the total synthesis of these compounds.With the advent oftransitionmetalcatalysis,thecarbonylationofarylhalideswithCOandamineshasbecomeapowerfulapproachtowardsamideformation.Thesemethodologiessufferadrawbackintheuseofsuperstoichiometricand,insomecases,highpressuresofhighlytoxicCO.Specializedreactors,storageprocedures,andlaboratoryequipmentareallrequiredfortheexecutionofthischemistry.Therefore, significant efforts have been put into developing CO-free aminocarbonylationprotocols.Herein,wereport thediscoveryanddevelopmentofaCO-freeaminocarbonylationreaction using CsOH•H2O and reagent quantities of chloroform as the carbonyl source. Thereactionishighlyfunctionalgrouptolerant,allowingforthecouplingofawidevarietyofaryliodidesandbromideswithprimaryandsecondaryaminestofurnishamidesingoodchemicalyield.Byharnessingthedivergentmechanismbywhichtheamidecarbonylisformed,weaimtorealizenewtransformationsandstructuresthatarenotaccessiblebytraditionalcarbonylation.

Diseases caused by an excess of protein function can be treated by small moleculeinhibitors.However, in the caseofdiseases causedbydysfunctionalormissingproteins, thisapproachistypicallyineffective.Severalstrategiestotrytoaddressthelatterincludegenetherapyordirect replacement of themissingprotein (e.g. insulin to treatdiabetes).However, despiteimportantprogress,todatemorethan30humandiseasescausedbydysfunctionalormissingionchannelproteinsremainincurable,demonstratingtheneedfornewtherapeuticstrategies.WedemonstratedthattheionchannelformingsmallmoleculeAmphotericinB(AmB)wasabletovigorouslyandsustainablyrestorephysiologyinagrowthdeficientstrainofyeastSaccharomyces cerevisiae(S. cerevisiae)lackingpotassiumtransporterproteinsTrk1pandTrk2p.Wehypothesizethat ion channel forming small molecules work in collaboration with cellular networks ofcontributing proteins, involved in promoting physiological transmembrane ion gradients, torestore physiology in S. cerevisiae. Our findingswill lay the foundation for the utilization ofimperfectsmallmoleculemimicsasaviablenewstrategyforthetreatmentofdiseasescausebymissingordysfunctionalproteinsandwillguidetherationaldesignofderivativeswithenhancedtherapeuticeffectivenessforthebettermentofhumanhealth.

XBr/I

+ NH

R2R1

Pd(OAc)2 (cat.)DPE-Phos

CsOH•H2OToluene, 80ºC

CCl

Cl

ClH+ X

N

OR1

R2

73-94%

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Small Molecules Targeting the Toxic RNA in Myotonic Dystrophy Type 2

LienNguyen,JuYeonLeeandStevenC.Zimmerman

Poly(phthalaldehyde) and Poly(vinyl carbonate sulfone)s as UV and Thermally Degradable Packaging for Transient Electronics

OliviaP.Lee,HectorLopezHernandez,Seung-KyunKang,JoshuaA.Kaitz,BoraInci,ChanWooPark,NancyR.Sottos,ScottR.White,JohnA.Rogers,JeffreyS.Moore

Myotonicdystrophy type 2 (DM2) is causedby an expansionofCCTG repeats in thezinc-fingerproteingene(ZNF9)inchromosome3.PathogenesisofthediseaseinvolvesatoxicRNAgain-of-function.ThetranscribedCCUGrepeatssequesterasignificantalternativesplicingregulator, muscleblind-like protein 1 (MBNL1), blocking MBNL1 from its normal function,therebyleadingtothediseasephenotype.WereportaseriesofligandsthatinhibittheMBNL1-r(CCUG)ninteractionaspotentialtherapeuticagentsforDM2.Theyarebasedonbisamidiniumgroovebinderwithtriaminopyrimidinerecognitionunit.Comparedtothepreviouslyreportedtriaminopyrimidine-acridine conjugate (ligand2),which is poorlywater-soluble andnot cell-permeable,thesenewligandsareperfectlywater-solublewithverylowcytotoxicity.TheoptimizedligandmaintainedtheinhibitionpotencyoflowmicromolarKivaluetoMBNL1-r(CCUG)8. More importantly,theligandsarethefirsttoshowthedispersionoftheMBNL1-r(CCUG)ndiseasefociinDM2modelcellculture.

Transient electronics capable of programmed self-destruction eliminates the needto recover environmental sensors, biomedical implants, and clandestine devices. Currentpackagingreliesonbulkwaterasthesoletrigger,limitingtheapplicationoftheseelectronicsinwetenvironment.Weexploreadditionaltriggersbyinvestigatingtwolow-ceiling-temperaturepolymers: cyclicpoly(phthalaldehyde) (cPPA) andpoly(olefin sulfone)s. Blendfilmsof cPPAandphotoacidgeneratordegradeuponUVirradiation,leadingtoterminationoftheon-boardelectronicswithin20min.Wealsoshowthethermaldegradationofpoly(vinyltert-butylcarbonatesulfone),whichdecomposesintovolatilemoleculesat80°Cin20min,leaving<5wt%residue.Wearecurrentlydeterminingthedegradationkineticsandmechanismtoenabledesignsofnewtransientpackagingresponsivetofluoride,radiofrequency,andhumidity.

O

NN

NCCl3

CCl3

hn

OO

O

O

OO

n

OHC CHO

O

NN

NCCl2

CCl3

HC l +

n

A. Ligand 1. Triaminopyrimidine-‐acridine conjugate. B. Bisamidinium-‐based ligands with different substitution patterns and linker lengths.

A B


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N-Boc Amines to Oxazolidinones via Pd(II)/Bis-sulfoxide / Brønsted Acid Co-catalyzed Allylic C-H Oxidation

ThomasJ.OsbergerandM.ChristinaWhite

Streptomonomicin: a Hydrophobic Lasso Peptide Antibiotic from the Halophilic Bacterium Streptomonospora alba

JonathanI.TietzandDouglasA.Mitchell

APd(II)/bis-sulfoxide/BrønstedacidcatalyzedallylicC—Hoxidationreactionforthesyn-thesis of anti-oxazolidinonesfromsimpleN-Bocaminesisreported.Arangeofoxazolidinonesarefurnishedingoodyields(avg.63%)andexcellentdiastereoselectivities(avg.15:1)tofurnishproductswithdifferentregiochemistryfromthosepreviouslyobtainedusingallylicC—Hami-nationreactions.Wepresentapplicationsofthismethodtothesynthesisofhydroxyaminoacids,individuallyandasalate-statestrategyfortheformationofaminoalcoholmotifsinpeptideset-tings,aswellasthesynthesisofabiologicallyrelevantaminosugar.Thisprocessmarksthefirstuseofanaprotic,non-acidicnucleophileinaPd(II)/sulfoxidecatalyzedallylicC-Hoxidation.Mechanistic studies suggest the roleof thephosphoric acid is to furnishaPd(II)bis-sulfoxidephosphatecatalystthatpromotesallylicC—Hcleavageandπ-allylPdfunctionalizationwithaweakoxygennucleophile,andtopromotecatalystregeneration.

Increasing ratesof antibiotic resistanceand theburdenofnaturalproduct rediscoverynecessitate the development of strategies to accelerate secondary metabolite discovery. Onesuch strategy is to investigate “neglected” organisms: those without sequenced genomes orcharacterized metabolism. Herein we report the characterization of streptomonomicin, thefirst natural product isolated from the neglected halophilic bacterial genus Streptomonospora. StreptomonomicinisanunusuallyhydrophobicpeptidethatformsalassostructurewhereinaC-terminaltailisthreadedthroughanN-terminalring,endowingconformationalrestraintstothemolecule.BacteriaresistanttostreptomonomicinharbormutationstoWalR,atwo-componentsignalingresponseregulatorinvolvedincellwallmetabolism,andexhibitstrikingphenotypicdefects.CompletegenomesequencingofStreptomonospora albaindicatesthatitsgrowinggenushasprolificanddiversebiosyntheticpotential.

R

HN O

O S SOO

Ph PhPd(OAc)2

RO

HNO

BuO P OHO

OBu

1, 10 mol%

50 mol %

RCO2H

NH2

OH

O

Me OHNHMe

OMe

23

H

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Selection of cyclic lanthipeptide for disruption of protein-protein interactions

XiaoYangandWilfredvanderDonk

Manyimportantbiologicalandpathologicalprocessesaremediatedbyprotein–proteininteractions(PPI).Usingpeptidesorsmallmoleculestointerferewiththeseinteractionscouldopenthedoortocontrolovercellularevents.CyclicpeptidesholdmuchpromiseforinhibitingPPIduetotheirstructuralmimicofthenativeligands,reducedconformationalflexibility,andstabilityagainstcellularcatabolism. Lanthipeptidesareagroupofribosomallyproducedcyclicpeptidescontainingthioetherlinkages that could serve as potential candidates for PPI inhibitors. Here we described theconstructionofnovelcycliclanthipeptidelibrariesinE. coliwithasubstrate-toleratesynthetaseProcMdiscoveredfromthecyanobacteriaProchloroloccusMIT9313,andthein vivoselectionforinhibitorsthatdisruptTsg101-GaginteractionduringHIVbuddingprocessasaproofofconcept.

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PAST AWARD RECIPIENTS

2014 Seemon Pines Travel Award

Allows accomplished graduate students to visit their undergraduate schools and present their research

Marshall Brennan - Northeastern UniversityMatthew Endo - Seattle University

Christopher Schwalen - Cooper Union

2013 Spencer Peck2012 Kyle Dunbar2011 Joseph Bair2010 Eric Woerly2009 Diana West2008 John Whitteck2007 Douglas Davis2006 Kenneth Fraunhoffer 2005 Benjamin Leslie2004 Rebecca Coppins 2003 Joseph Rule2002 Gregory Beutner 2001 Anobel Tamrazi 2000 Matthew Epperson 1999 David Anderson 1998 Ewa Fredette1997 Ryan Prince 1996 Jim Nelson

Seemon Pines Award

For the most outstanding talk at the Allerton Conference

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ALLERTON COMMITTEE

2014 Allerton Committee

Gregory Kortman (Co-Chair) – HullBrandon Burkhart (Co-Chair) – Mitchell

Chih-Chi Chu – Silverman Chantal Garcia de Gonzalo – Van der Donk

Bryon Drown – Hergenrother Rulin Ma – White

Andrea Palazzolo – BurkeJulio Serrano – Zimmerman Craig Seymour – Denmark

Yang Song – Moore

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INDEX OF PRESENTERS

Stephen Ammann........................................................Yugang Bai....................................................................Patricia Blair...................................................................Hyung Min Chi..............................................................Chih-Chi Chu................................................................Caitlin Deane................................................................Bryon Drown..................................................................Stanley Eey....................................................................Seth Ensign.....................................................................Samuel Gockel.............................................................Anthony Grillo................................................................Jeremy Henle................................................................Robert Hicklin................................................................Adam Hill.......................................................................Jennifer Hou..................................................................Olivia Lee......................................................................JuYeon Lee....................................................................Jun Li..............................................................................Wei Liu............................................................................Long Luu........................................................................Subha Mukherjee..........................................................Thomas Osberger..........................................................Kevin Pinney..................................................................Michelle Richter............................................................Yang Song.....................................................................Jonathan Tietz...............................................................Zhao Wu........................................................................Xiao Yang......................................................................Xiling Zhao.....................................................................

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