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Photoinduced decarboxylative azidation of cyclic aminoacidsDOI:10.1039/c8ob02702a

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Citation for published version (APA):Marcote, D. C., Street-Jeakings, R., Dauncey, E., Douglas, J. J., Ruffoni, A., & Leonori, D. (2019). Photoinduceddecarboxylative azidation of cyclic amino acids. Organic and Biomolecular Chemistry, 17(7), 1839-1842.https://doi.org/10.1039/c8ob02702a

Published in:Organic and Biomolecular Chemistry

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DOI:10.1039/x0xx00000x

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PhotoinducedDecarboxylativeAzidationofCyclicAminoacidsDavidC.Marcotea,RosieStreet-Jeakingsa,ElizabethDaunceya,JamesJ.Douglasb,AlessandroRuffoni*aandDanieleLeonori*a

The direct decarboxylative azidation of cyclicα -amino acids hasbeen achieved via visible light-mediated organo-photoredoxcatalysis.Thissyntheticstrategyallowsthesimplepreparationofazide-contaningbuildingblocksandhasbeenusedintheselectivemodificationofN-terminalprolineresiduesoftwodi-peptides.

The azide is among themost important functional groups inorganicchemistry, regularlyused inresearchprogramsaimedatdrugdiscovery,chemicalbiologyandmaterialscience.1Thisrelevancestemsfromtheeasebywhichorganicazidescanbeconverted into amines and amides (Staudingerreduction/ligation)aswellas triazoles (click-chemistrydipolarcycloaddition)(Scheme1A).2In general, alkyl azides are prepared by nucleophilicsubstitution of (pseudo)halides3d, Mitsunobu reaction3e onalcohols, or alkene hydro-azidation3a-c,g,f. More recentlymethodsfordirectsp3C–Hazidation4a-bhavebeendevelopedusingradicalstrategiesbasedonMn4candFe4dsystems.Theseapproaches have enabled the modification of very complexsubstrates via the functionalization of themost activated sp3C–H bonds (i.e. the functionalization of tertiary centres oversecondary). Radical approaches targeting the azidation ofspecificbutnon-activatedsp3-carbonshavegenerallyreliedinthe preparation of Barton-type esters and their followingdecarboxylation-azidation using high-energy UV-light or AIBNat elevated temperature.5More recently, Li6a and Jiao6bhavereported the direct oxidative conversion of carboxylic acidsintoalkylazidesusingsilver(I/II)catalystsandstrongoxidants(e.g.K2S2O8)instoichiometricamounts.Ascarboxylicacidsrepresentaveryversatilefeedstockforthegeneration of alkyl radicals using photoredox catalysis,7 wewere surprised to realise that no methodology has been

developed for their engagement in sp3-C azidation. Therealisation of this transformation would provide highcomplementarity to current methods both in terms ofsubstrate scope and functional group compatibility given themildconditionsnormallyassociatedtovisible-lightphotoredoxcatalysis. In this report,we describe the development of thefirst photoredox decarboxylative-azidation process. Themethodology described here utilises low cost and readilyavailableorganicdyesasphotocatalystsandithasbeenfoundparticularly useful for the modification of cyclic aminoacidsanddi-peptides.

Scheme1.A)Mostusedreactionsoforganicazidesinbio-organicchemistry.B)Decarboxylativeazidationproceduresinvolvingthegenerationofalkylradicals.

Our proposed reaction manifold is based on a classicalphotoredox reductive quenching cycle where visible light-excitation of a photocatalyst (PC g *PC) leads to the SET(single electron transfer) oxidation of a carboxylate startingmaterial (A) (Scheme 2).8 Following a fast decarboxylationprocess,theresultingalkylradical(B)canbeinterceptedbyanN3-containingSOMOphile(N3–Y)togivethedesiredproductC.Examples of commercially available N3-SOMOphiles are theZhdankin reagent9 (D) and aryl sulfonyl azides (E, F), whichhavebeenshowntoefficientlytransfertheazidegrouptoalkylradicals.10 A final SET between the radical generated upon

N3NN

N

MeO2C

Ph2PO

NH

Ph2PO[3+2] Huisgencycloaddition

Staudingerligation

CO2H CO2Hthis work

A) Azides and their manipulation

B) Decarboxylation-azidations

Ag(I/II)K2S2O8, Δ

• high-energy UV• AIBN, Δ

photoredoxcatalysis

O

ON

S

N3–X

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azide-transfer(Y•)andthereducedphotocatalyst(PC•–)wouldclosethephotoredoxcycleensuringcatalyticactivity.

Scheme2.Proposedphotoredoxcyclefordecarboxylateazidation.

To assess our hypothesis, we started by investigating thereaction of SOMOphiles D–F with N-Boc-proline 1a as thecarboxylic acid (1a-Cs Eox = +0.95 V vs SCE in CH3CN) andseveralphotocatalysts.Attheoutsetwedecidedtorestrictourphotocatalyst screening to organic dyes as they areconsiderably less expensive and commercially available onlargerscale.11As illustrated inScheme3,wewerepleased tofindoutthatusingEastheSOMOphile,rhodamine6G(*Ered=+1.18VvsSCE inCH3CN)

12as thephotocatalystandK2CO3asthebase inDCEundergreenLEDs irradiation,2wasobtainedinapromising36%yield(entry1).

Scheme 3. Optimization of the decarboxylative azidation using 1. B)Luminescence-quenchingexperiments.

We then screened several bases and found thatbyusing themore soluble CsOBz and tetramethyl guanidine (TMG), the

yieldwasimprovedto90%and85%respectively(entries2-5).UndertheseconditionstheotherazidatingreagentsF(entry6)andD(entry7)provided2 inconsiderablyloweryields.Othersolvents (entries 8–11) and commonly used organo-photocatalysts (entries 12-16) were evaluated but theygenerallyprovided2withlowerefficiency.Control experiments confirmed the requirement for light,photocatalystandbase(entries17–19).Our mechanistic proposal is further supported byluminescence-quenching studies (Stern-Volmer analysis) thatrevealed1-Cs (kq = 2.1 10

9M–1 s–1) and notE to quench theexcited state of rhodamine 6G (Scheme 4A). Unfortunately,quantumyieldmeasurementhasnotbeenpossibleduetothelack of green-light actinometers. As a result, we cannotexclude the presence of radical chain propagations resulting,forexample,bythedirectoxidationofAbyY•(Scheme4B).

Scheme4.Luminescence-quenchingexperiments.

Withtheoptimisedreactionconditionsinhand,weevaluatedthe scope of the process (Scheme 5). Replacing the N-Bocprotecting groupwith theN-Cbzonprolinewaspossible andwe obtained 3 in good yield. Fluorinated pyrrolidines arecommon motifs in drugs for the treatment of diabetes (e.g.bisegliptin)13 and we successfully prepared C-2-azidatedbuildingblock4ingoodyieldbutlowdr.Theoctahydroindole-2-carboxylic acid core is found in many ACE inhibitors likeperindopril and was used (following N-Boc protection) toaccess 5 in high yield. The chemistry could also be used toobtaine C-2 azidated-N-Boc-indoline 6. Six-membered-ringN-Boc-aminoacids were evaluated next and we successfullyengagedpipecolicacid(giving7)aswellassubstratesbasedonmorpholine (8) and protected piperazine (9 and 10)heterocycles. Decarboxylative-azidation of tetrahydro-isoquinoline carboxylic acids was possible and enabled thepreparationofbuildingblocksfunctionalisedatC-1(11)andC-3(12)positions.Saturatedfour-memberedringN-heterocycles

*PC

A CB

PC

PC•–

CO2–

N3 Y

N3

SET

hν

SET

Y–

Y•

– CO2

commercially available SOMOphiles for radical azidation

IO

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N3

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O

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SMeO

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ED

F

N3

PC (5 mol%) base (2.0 equiv.)

solvent, r.t., 12 hvisible light

N N N3

1a(1.0 equiv.)

2

Y

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(2.0 equiv.)

CO2H

Entry

123456789

1011

1213141516

171819

Base

K2CO3NaHCO3CsHCO3CsOBzTMG

CsOBzCsOBzCsOBzCsOBzCsOBzCsOBz

CsOBzCsOBzCsOBzCsOBzCsOBz

CsOBz–

CsOBz

N3–Y

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EEEEE

EEE

solvent

DCEDCEDCEDCEDCEDCEDCE

CH2Cl2CH3CN

THFDMF

DCEDCEDCEDCEDCE

DCEDCEDCE

yield (%)

3651559085501551547230

3239113415

–––

PC

rhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6Grhodamine 6G

methylene blueriboflavine

mesityl acridinium4CzIPNeosin Y

–rhodamine 6Grhodamine 6G

light

green LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDsgreen LEDs

blue LEDsblue LEDsblue LEDsblue LEDs

green LEDs

green LEDsgreen LEDs

–

A) Stern-Volmer analysis

B) Possibility for radical chain propagation

Y–Y•

– CO2A BCO2

–SET

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are frequently used in medicinal chemistry programmes andwesuccessfullyappliedthereactiontotheC-2-azidationofN-Boc-azetidine (13).14 Extension of this methodology to non-cyclic aminoacids is a current limitation of the protocol anddespite extensive re-optimization of the process we did notmanage to achieve the decarboxylative-azidation of, forexample,protectedphenylalanine(14).Secondaryandprimarycarboxylicacidsaresometimesdifficultto engage in oxidative decarboxylative protocols and cannotbe used as starting materials in this strategy. Tertiarysubstrates however are amenable as demonstrated by theformationof17and18whichcanbeusedtoaccessderivativesof amantadine and memantidine, two blockbuster drugs forthe treatment of the Parkinson and Alzheimer diseasesrespectively. In this case however, optimum yields wereobtainedusingmesitylacridinium15asthephotocatalyst.

Scheme5.Scopeofthereaction.aTMGwasusedasthebase.bMesAcrBF4wasusedasthephotocatalyst.

To showcase theutilityof thismethodologyweevaluated itsapplicability in the late-stagemodificationof terminalprolineresidues embedded in peptide structures.13 Pleasingly,commercially available Cbz-Gly-Pro-OH (1r) and Boc-Pro-Pro-OH (1s) dipeptides were competent substrate and providedtheazidatedproducts19 and20 in goodyieldsbut lowdr inthe caseof20. To thebest of our knowledge this is the first

example of late-stage modification of peptides bydecarboxylation-azidation.

ConclusionsIn conclusion, we have developed the first visible-lightmediated process that enables the preparation of organicazides by oxidative decarboxylation. The methodology hasbeensuccessfullyapplied to thesynthesisof severalnovelα-N-Boc-amino-azides building blocks and the late-stagefunctionalizationofdipeptides.D.L. thanksEPSRCfora researchgrant (EP/P004997/1).A.R.thankstheMarieCurieActionsforaFellowship(703238).D.C.M. thanks theXuntadeGalicia for a Fellowship. E.D. thanksAstraZenecaforaPhDCaseAward.

ConflictsofinterestTherearenoconflictstodeclare.

Notesandreferences

1 (a)H.C.Kolb,M.G.Finn,K.B.Sharpless,Angew.Chem.Int.Ed.,2001,40, 2004. (b)V.V. Rostovtsev, L.G.Green,V.V.Fokin,K.B.SharplessAngew.Chem.Int.Ed.,2002,41,2596.(c)H.C.Kolb,K.B.Sharpless,DrugDiscoveryToday,2003,8,1128.(d)S.Brase,C.Gil,K.Knepper,V.Zimmerman.Angew.Chem. Int. Ed., 2005, 44, 5188. (e) E. J. Moses, A. D.Moorhouse,Chem.Soc.Rev.,2007,36,1249.(f)S.Brase,K.Banert, Organic Azides: Syntheses and Applicatins, Eds.Wiley:2009. (g) F.Amblard, J.H.Cho,R. F. Schinazi,Chem.Rev., 2009, 109, 4207. (h) R. K. Iha, K. L. Wooley, A. M.Nystrom,D. J. Burke,M. J. Kade, C. J. Hawker,Chem. Rev.,2009,109,5620.

2 (a) H. Staudinger, J.Meyer,Helv. Chim. Acta, 1919,2, 635.(b) R. Huisgen, Angew. Chem., 1963, 75, 604. (c) I. C.Schilling, N. Jung,M. Biskup, U. Scherpers, S. Brase,Chem.Soc. Rev., 2011, 40, 4840. (d) E. Lallan, R. Riguera, E.Fernandez-Magia,Angew.Chem.Int.Ed.,2011,50,8794.(e)P.Thirumurugan,D.Matosiuk,K.Jozwiak,Chem.Rev.,2013,113,4905.

3 (a) P. Panchaud, p. Renaud, Adv. Synth. Catal., 2004, 346,925. (b) J.Waser, H. Nambu, E.M. Carreira, J. Am. Chem.Soc. 2005,127, 8294. (c) J.Waser,B.Gaspar,H.Nambu,E.M.Carreira,J.Am.Chem.Soc.,2006,128,11693.(d)Y.Ju,D.Kumar, R. S. Varma, J.Org. Chem., 2006,71, 6697. (e) J. E.Green, D. M. Bender, S. Jackson, M. J. O'Donnell, J. R.McCarthy, Org. Lett., 2009, 11, 807. (g) K. Weidner, A.Giroult, P. Panchaud, P. Renaud, J. Am. Chem. Soc. 2010,132, 17511 (f) H. Chen, W. Yang, W. Wu, H. Jiang, Org.Biomol.Chem.2014,12,3340.

4 (a)C.Viuf,M.Bols,Angew.Chem.Int.Ed.,2001,40,623.(b)Q.H.Deng,T.Bleith,H.Wadepohl,L.H.Gade,J.Am.Chem.Soc., 2013, 135, 5356. (c) H. Huang, T. M. Bergsten, J. T.Groves,J.Am.Chem.Soc.,2015,137,5300.(d)A.Sharma,J.F.Hartwig,Nature,2015,517,600

5 (a)D.S.Masterson,N.A.Porter,Org.Lett.2002,4,4253.(b)E.Nyfeler,P.Renaud,Org.Lett.,2008,10,985.

6 (a)C.Liu,X.Wang,Z.Li,L.Cui,C.Li,J.Am.Chem.Soc.,2015,137, 9820, (b) Y. Zhu, X. Li, X.Wang, X. Huang, T. Shen, Y.

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5 80%, dr 1.5:1

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8 76%

9 85%

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19 54%

20 68%, dr 1.5:1

14 –

Boc Cbz Boc Boc Boc

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DCE (0.1M), r.t., 12 h,green LEDs

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CO2H N3+ Si-Pr

i-Pr

i-Pr

O

ON3

1a–s(1.0 equiv.)

E(2.0 equiv.)

2–20

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Zhang,X.Sun,M.Zou,S.Song,N.Jiao,Org.Lett.,2015,17,4702

7 J.Xuan,Z.G.Zhang,W.J.Xiao,Angew.Chem.Int.Ed.2015,54,15632

8 (a) C. K. Prier, D. A. Rankic, D. W. MacMillan, Chem. Rev.2013,113,5322.(b)K.L.Skubi,T.R.Blum,T.P.Yoon,Chem.Rev.,2016,116,10035.(c)M.N.Hopkinson,B.Sahoo,J.–L.Li,F.Glorius,Chem.Eur.J.,2014,20,3874.

9 V.V.Zhdankin,A.P.Krasutsky,C. J.Kuehl,A. J.Simonsen,J.K.Woodward,B.Mismash,J.T.Bolz,J.Am.Chem.Soc.1996,118,5192.

10 K.Weidner,P.Renaud,Austr.J.Chem.,2013,66,341.11 N.A.Romero,D.A.Nicewicz,Chem.Rev.,2016,116,1007512 D.Magde,G.E.Rojas,P.G.Seybold,Photochem.and

Photobiol.1999,70,737.13 D.Klaus,BoehringerIngelheimInt,Patent:US884669514 D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W.

Thomas,D.M.Wilson,A.Wood,Nat.Chem.,2018,10,38315 S.Fukuzumi,K.Ohkubo,Org.Biomol.Chem.,2014,12,6059.16 S.J.McCarver,J.X.Qiao,J.Carpenter,R.M.Borzilleri,M.A.

Poss, M. D. Eastgate, M. M. Miller, D. W. C. MacMillan,Angew.Chem.Int.Ed.,2017,56,728.(b)S.Bloom,C.Liu,D.K.Kölmel,J.X.Qiao,Y.Zhang,M.A.Poss,W.R.Ewing,D.W.C.MacMillan,Nat.Chem.,2017,10,205,