Journal of the American Chemical Society
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3. B.J.vanLierop,J.A.M.Lummiss,D.E.Foggin“Olefin
However,toimproveHC-RCMinclose-to-neatconditions,process
engineersshallbeinvolved,aswethinkthatthefurtheroptimization
ismorerelatedtochemicalengineering(eg.choosingappropriatedis-
tillation/reactorequipment,optimizationofpumpingprotocol,stir-
ring,time,etc.)thentoolefinmetathesischemistryitself.Instead,we
seeourmainachievementinprovingthatproductionofmacrocycles
byRCMispossibleatconcentrationsneverreportedbefore,ifthe
correctconditionsandthecatalystareprovided.
Metathesis:eoryandPractice”(ed.K.Grela.)85−152(Wiley
andSons,2014).
4. R.Hanson,S.Maitra,R.Chegondi,J.L.Markleyin“Handbook
ofMetathesis”Vol.2(ed.R.H.Grubbs,D.J.O’Leary)1−170
(Wiley-VCH,2015).
5. S.Monfete,D.E.Fogg“EquilibriumRing-ClosingMetathesis”
Chem.Rev.109,3783−3816(2009).
6. A.Fürstner,O.R.iel,C.W.Lehmann,“StudyConcerningthe
EffectsofChelationontheStructureandCatalyticActivityof
RutheniumCarbeneComplexes”Organometallics,21,331-335
(2002).
9
Tosumup,weshowedforthefirsttimethatmacrocycliclactones,
ethersandketones(including7-memberedone)canbeobtainedin
highyieldandselectivityatconcentrations40to380timeshigher
thanthosetypicallyusedbyorganicchemistsforsimilarmacrocy-
clizations.UnlikeinclassicalRCM,inourmethodnoregularorganic
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7. a)A.Fürstner,K.Langemann,“ConformationallyUnbiased
MacrocyclizationReactionsbyRingClosingMetathesis”J.Org.
Chem.,61,3942−3943(1996);b)W.J.Wiegers,A.G.Van
Loveren,M.R.Hanna,D.Luccarelli,D.R.Bowen,M.H.Vock,
"Macrocyclic carbonates, processes for preparing same,
organolepticusesthereofandintermediatesusedinsaidprocess"
US4490544(1984);c)Forarecentreportshowingthatwhen
RCMisconducedat35mMconcentration,themacrocyclic
muskyieldisreducedalmostby½(from70to40%),see:T.K.
Olszewski, A. Tracz, A. Gawin, M. Bieniek, K. Skowerski,
“AmmoniumNHC-taggedolefinmetathesiscatalysts—influence
ofcounter-ionsoncatalyticactivity”NewJ.Chem.,42,8609-
8614(2018);d)SeeTable3.2inRef.3.
8. a)J.C.Conrad,M.D.Edelman,J.A.DuarteSilva,S.Monfete,H.
H. Parnas, J. L. Snelgrove, D. E. Fogg, “Oligomers as
IntermediatesinRing-ClosingMetathesis”J.Am.Chem.Soc.,
129,1024–1025(2007);b)ForadiscussionofJacobson-
StockmayertheoryinthecontextofRCM,seeJ.C.Conrad,D.E.
Fogg,“Ruthenium-CatalyzedRing-ClosingMetathesis:Recent
Advances,LimitationsandOpportunities”Curr.Org.Chem.,10,
185−202(2006).
9. Forselectedreviews,see:a)P.Kraf,J.A.Bajgrowicz,C.Denis,G.
Fráter “Odds and Trends: Recent Developments in the
Chemistry of Odorants” Angew. Chem., Int. Engl. Ed., 39,
2980−3010(2000);b)A. S. Williams, "eSynthesis of
MacrocyclicMusks"Synthesis,1707−1723(1999);c)G.Fráter,J.
A.Bajgrowicz,P.Kraf “Fragrancechemistry”Tetrahedron,54,
7633−7703 (1998); d) A. Gradillas J. Pérez-Castells in
“Metathesis in Natural Product Synthesis” (ed. J. Cossy)
149−182(Wiley‐VCH,2010);d)Foroneofearlyindustrial
disclosuresonmacrocyclicmuskproductionbyRCM,see:Ref.
7b.
10. Uptodatestaticvacuumwasusedinolefinmetathesis(including
RCM)toremoveethylene,whichhasbeneficialeffecttothe
reactionoutcome.Forarepresentativereference,see:T.S.
Ahmed,R.H.Grubbs,"AHighlyEfficientSynthesisofZ-
Macrocycles Using Stereoretentive, Ruthenium-Based
MethatesisCatalyst"Angew.Chem.Int.Ed.,129,11365−11368
(2017).
solventssuchasanhydroustolueneorCHClareused,butratherin-
2 2
expensivenon-volatilediluents,suchasparaffinoilorPAO.Alsothe
useofprotectingatmosphere,Schlenktechniquesoragloveboxisno
needed,astheHC-RCMreactionscanbesetupinairandthenew
catalystsdesignedbyusareperfectlymoistureandairstable.
Itisastonishingthatdespiteofitslogicalsimplicity,thereisnodoc-
umentedapplicationofsuchBB-RCM/distillationprotocolinselec-
tiveproductionofmacrocyclesathighconcentrations.Probably,the
missingelementwasapropercatalyst,andmorespecifically,thecata-
lystpossessinglongevitycombinedwithactivitysufficienttoreact
withstericallyhinderedADMETpolymer.elowstabilityofclassi-
calRucatalystspropagatingspeciesundersuchdemandingcondi-
tionstranslatesintosevereisomerizationofdoublebondsbycatalyst
decompositionproducts,thustoformationofcomplicatedmixtures
28
ofproducts.equestforbetercatalystsforRCMiscontinuing
andwewerepleasedtofindthatafewofourcatalysts—originallyde-
signedtoofferhighfidelityinself-metathesisofα-olefins—alsomade
theselectivehigh-concentrationRCMofmacrocyclespossibleforthe
firsttime.
ASSOCIATED CONTENT
Materialsandmethods,synthesisofsubstrates,detailedexperimental
proceduresandcopiesofNMRspectraofproducts.ismaterialisavail-
ablefreeofchargeviatheInternetathtp://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*Correspondingauthor.Email:karol.grela@gmail.com
Author Contributions
†eseauthorscontributedequally.
11. A. Michrowska, R. Bujok, S. Harutyunyan, V. Sashuk, G.
Dolgonos, K. Grela, “Nitro-Substituted Hoveyda-Grubbs
RutheniumCarbenes:EnhancementofCatalystActivitythrough
Electronic Activation” J. Am. Chem. Soc., 126, 9318–9325
(2004).
12. H.Li,L.C.daSilva,M.D.Schulz,G.Rojas,K.B.Wagener,“A
reviewofhowtodoanacyclicdienemetathesisreaction”Polym.
Int.,66,7-12(2017).
13. For isomerization as unintended side-reaction encountered
duringself-metathesisofα-olefins,see:M.Rouen,P.Queval,E.
Borré,L.Falivene,A.Poater,M.Berthod,F.Hugues,L.Cavallo,
OBaslé,H.Olivier-Bourbigou,MMauduit,“SelectiveMetathesis
ACKNOWLEDGMENT
WearegratefultotheNationalScienceCentre(Poland)fortheNCN
MAESTROGrantNo.DEC-2012/04/A/ST5/00594forfundingthis
work.
REFERENCES
1. htps://www.nobelprize.org/nobel_prizes/chemistry/-
laureates/1939/ruzicka-lecture.pdf.
2. V.Martí-Centelles,M.D.Pandey,M.I.Burguete,S.V.Luis
“Macrocyclization Reactions: e Importance of Confor-
mational, Configurational, andTemplate-InducedPreorgani-
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