Ge man Edi ion:DOI:10.1002/ange.201705006
Cycloaddi ion In e na ional Edi ion:DOI:10.1002/anie.201705006
Ru henium-Ca alyzed Azide–Thioalkyne Cycloaddi ionsinAqueous
Media:AMild, O hogonal, and Biocompa ible Chemical Liga ion
Paolo Des i o,Jos8R. Coucei o,H8lio Faus ino,Fe nando Llpez,* and Jos8L. Masca eÇas*
Abs ac : The de elopmen o e icien me al-p omo ed bio-
o hogonal liga ions emains as amajo scien i ic challenge.
Demons a ed he ein is ha azides unde go e icien and
egioselec i e oom- empe a u e annula ions wi h hioalkynes
in aqueous milieu when ea ed wi h ca aly ic amoun s o
asui able u henium complex. The eac ion is compa ible wi h
di e en biomolecules,and can be ca ied ou in complex
aqueous mix u es such as phospha e bu e ed saline,cell
lysa es, e al bo ine se um, and e en li ing bac e ia (E. coli).
Impo an ly, he eac ion is mu ually compa ible wi h he
classical CuAAC.
The coppe -ca alyzed azide–alkyne cycloaddi ion (CuAAC),
pa adigm o “click” chemis y,[1] can be conside ed among he
mos ele an chemical ans o ma ions disco e ed in he las
decades,wi h coun less applica ions in many a eas o
science.[2] Thebiological ele ance o his eac ion s ems
om i s obus ness and compa ibili y wi h aqueous media, as
well as om i s good bioo hogonali y.[3] Howe e , he
ans o ma ion s ill p esen s impo an limi a ions.Thus,in
addi ion o being ai ly incompa ible wi h hiols, he eac ion
is essen ially es ic ed o e minal alkynes,aconsequence o
amechanism which equi es he o ma ion o coppe
ace ylide in e media es (Scheme 1a). An impo an addi-
ional d awback has o do wi h he side eac i i y and oxici y
o coppe ions in biological con ex s.[4] Fu he mo e, o each
e icien con e sions in ypically dilu ed biological se ings,
he eac i e coppe (I) species need o be gene a ed in si u
using excess amoun s o acoppe (II) sou ce and sodium
asco ba e,a educ an which is no innocen in biological
con ex s.[5] These issues ha e been pa ially add essed by
using coppe -s abilizing ligands which enhance he biocom-
pa ibili y and kine ic o he eac ions.[6,7] Coppe - ee,s ain-
p omo ed annula ions ha e been shown o be an e icien
al e na i e,[8] howe e , hese eac ions also p esen limi a-
ions associa ed o he side- eac i i y o he eac an s.The e-
o e, he de elopmen o new bioo hogonal and biocompa -
ible eac ions which add ess some o he abo e limi a ions
emains as amajo challenge.[9] In pa icula , he disco e y o
obus and aqueous-compa ible me al-ca alyzed annula ions,
as al e na i es o he CuAAC, ep esen s ahighly appealing
goal.[10]
Se e al azide–alkyne cycloaddi ions using me als o he
han coppe ha e been desc ibed in ecen yea s,[11] bu only
he u henium a ian (RuAAC)[12] has shown ameaning ul
scope (Scheme 1b).[13] In con as o he CuAAC, which
encompasses dinuclea coppe in e media es such as Iand
II,[14] he u henium-p omo ed eac ion in ol es in e media e
species like III,which e ol e in o IV by oxida i e cyclo-
me ala ion, and e en ually o he iazole p oduc s.[15] In
keeping wi h his scena io, he RuAAC, essen ially de eloped
in o ganic sol en s, ole a es disubs i u ed alkynes bu can
p oduce mix u es o egioisome s.P obably, he no ion ha i
is no compa ible wi h wa e and ai a mosphe es has
p ecluded mo e bio ocused in es iga ions.[16,13] Recen da a
sugges ha some u henium complexes can p omo e he
p ocess in wa e , bu he eac ions equi e he mal ac i a ion
and p esen alimi ed scope.[17]
He ein, we demons a e ha ce ain u henium(II) com-
plexes can indeed ca alyze he cycloaddi ion be ween azides
and alkynes in wa e , and a oom empe a u e.Impo an ly,
Scheme 1. Key mechanis ic ea u es o CuAAC and RuAAC.
[*] P. Des i o, D .J.R.Coucei o, D .H.Faus ino,D . F. Lkpez,
P o . J. L. Masca eÇas
Cen o Singula de In es igaciknenQu&mica Biolkxica eMa e iais
Molecula es (CIQUS) and Depa amen o de Qu&mica O g#nica
Uni e sidade de San iago de Compos ela
15782 San iago de Compos ela (Spain)
E-mail: e nando.lop[email p o ec ed]
[email p o ec ed]
D .F.Lkpez
Ins i u o de Qu&mica O g#nica Gene al CSIC
Juan de la Cie a 3, 28006 Mad id (Spain)
Suppo ingin o ma ion and he ORCID iden i ica ion numbe (s) o
he au ho (s) o his a icle can be ound unde :
h ps://doi.o g/10.1002/anie.201705006.
T2017 The Au ho s. Published by Wiley-VCH Ve lag GmbH &Co.
KGaA. This is an open access a icle unde he e ms o he C ea i e
Commons A ibu ion-NonComme cial-NoDe i s License, which
pe mi suse and dis ibu ion in any medium, p o ided he o iginal
wo k is p ope ly ci ed, he use is non-comme cial and no modi ica-
ions o adap a ions a e made.
A
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10766 T2017 The Au ho s. Published by Wiley-VCH Ve lagGmbH &Co. KGaA,Weinheim Angew.Chem. In . Ed. 2017,56,10766 –10770
he eac ion is especially e icien when hioalkynes a e used
as eac ion pa ne s (Scheme 1c). Mo eo e , he p ocess is
mu ually compa ible wi h he CuAAC, ole an o di e en
ypes o biomolecules,including hiols,and can be ca ied ou
in ei he phospha e bu e ed saline,cell lysa es,o cell cul u e
media, e en in p esence o li ing bac e ia (E. coli).
A he ou se , we we e inspi ed by a epo o Jia, Sun, and
co-wo ke s on an i idium-p omo ed azide– hioalkyne cyclo-
addi ion.[18] Al hough he me hod was de eloped in anhy-
d ous CH2Cl2,anisola ed example in wa e using benzyl azide
caugh ou a en ion. Un o una ely,when we es ed he
eac ion o he hioalkyne 2a wi h he luo ogenic an h a-
cenyl-azide p obe 1a,[19] heyield o he co esponding
adduc s (3aa/3aa’’)was modes (Table 1, en y 1).[20] Rema k-
ably,w
hen using Cp*Ru(cod)Cl as ac
a alys ,[15a] we obse ed,
a e 24 hou s,asubs an ial o ma ion o he desi ed cyclo-
adduc s wi h excellen egioselec i i y (3aa/3aa’’=19:1, 58%
combined yield, en y 2). This good esul , oge he wi h he
p e iously demons a ed biocompa ibili y o his ype o
u henium complex,[21] p omp ed us o u he explo e he
p ocess.Doubling he equi alen s o 2a led o an excellen
yield o 99%o he desi ed iazoles a e 9hou s o s i ing a
oom empe a u e.Moni o ing he eac ion a di e en imes
con i med he o ma ion o he p oduc s in 78%yield a e
jus 30 minu es,wi h he a e being hen g adually educed
(en y 4).[22] Thepe o mance o [I (cod)Cl]2could no be
imp o ed by using 2equi alen s o hioalkyne,(en y 5). And
o he u henium(II) ca alys s,such as Cp*Ru(PPh3)2Cl,[12]
RuH2(CO)(PPh3)3,[17b] we e no e icien (en ies 6and 7). In
con as , he e ame [Cp*RuCl]4[23] was qui e e ec i e
(en y 8). The eac ion be ween 1a and 2a,could also be
ca ied ou in CH2Cl2.Howe e ,ob aining good yields
equi ed he use o anhyd ous sol en and ine a mosphe es
(en ies 9 s. 10), which is no necessa y in wa e . I looks like
he aqueous sol en is somewha p ecluding he u henium
species om being apidly deac i a ed.[24]
Thecycloaddi ion is also easible using a ypical in e nal
alkyne such as 2b,albei somewha slowe (10%less
con e sion a e 30 min), and i led o a5:1 mix u e o
egioisome s (Table 1, en y 11). O he alkynes such as 2c
we e un eac i e unde iden ical eac ion condi ions
(en y 12). Thehighe eac i i y o he hioalkyne pa ne
was clea ly isible in ac oss-compe i ion expe imen :when
he azide 1a was eac ed wi h a1:1 mix u e o 2a and 2b
(2 equi each), he iazole 3aa,a ising om he cycloaddi-
ion wi h he hioalkyne was exclusi ely obse ed in 98%
yield (en y 13). In e es ingly,NMR analysis o he in e ac-
ion be ween Cp*Ru(cod)Cl and he alkynes (in CD2Cl2)
demons a ed ha while 2a displaces he cod ligand a oom
empe a u e, 2bdoes no induce any change (see Pages S6–S9
o he Suppo ing In o ma ion). Analogous expe imen s
using [Cp*RuCl]4and 2a, e ealed apid o ma ion o
anew complex iden i ied as [Cp*Ru(2a)Cl],whe eas wi h
alkyne 2bno new u henium species could be de ec ed, e en
a e 3hou s.[25] Thus, he good pe o mance o hioalkynes
migh be in pa ela ed o hei abili y o s ongly coo dina e
he Cp*RuCl moie y a oom empe a u e.Addi ionally, he
p esence o he sul u a om should also a o he o ma ion o
he equi ed u henacyclic in e media e o ype IV (Sche-
me 1b).
Wi h hese eac ion condi ions in hand, we analyzed he
scope o he me hod (RuA AC). Despi e he ela i ely poo
wa e solubili y o many o he azides and hioalkynes, he
eac ions p o ed o be gene al a oom empe a u e,and he
co esponding iazoles we e ob ained in good yields and wi h
excellen egioselec i i ies (Table 2). Thus,a yl and alipha ic
subs i uen s ei he a ached o he sul u a om o o he
e minal posi ion o he alkyne we e ole a ed (e.g. 3aa–a ).
Te minal o ime hylsilyl-subs i u ed hioalkynes (2g,2h)
p o ided he co esponding adduc s 3ag and 3ah in good
yields.Impo an ly,no only he an h acenyl and benzyl azide
(1a,1b)pa icipa ed in he p ocess,bu alipha ic azides such
as (2-azidoe hyl)benzene (1c)o 2-azidoe han-1-ol (1d)also
eac ed cleanly o p o ide he co esponding iazoles (3ca,
3ce,3de). p-Tolyl azide eac ed wi h 2a o p o ide 3ea wi h
amode a e 40%yield, a alue ha could be imp o ed up o
61%byusing [Cp*RuCl]4as aca alys . In e es ingly,di e en
ypes o luo opho e-equipped isubs i u ed iazoles could
be gene a ed by ei he using adansyl-based azide (such as in
3 a)o byinco po a ing acouma in moie y,ei he as pa o
he hioalkyne (e.g. 3aj)o o he o ganic azide (3ga and
3ha). Addi ionally, ollowing wo k de eloped by Wase and
co-wo ke s,[26] 2- hioglucose and acys eine-con aining dipep-
ide we e selec i ely hio-alkynyla ed wi h EBX eagen s.
G a i yingly,al hough he low wa e solubili y o he hio-
Table 1: Iden i ica iono eac ion condi ionsinwa e .[a]
En y Ca . (Xmol%) 1a/2Sol .
[h]
Con
[%][b]
3/3’’[b] Yield
[%][b,c]
1[I (cod)Cl]2(2.5) 1:1 H2O24421:0 29
2Cp*Ru(cod)Cl (5) 1:1 H2O246519:1 58
3Cp*Ru(cod)Cl (5) 1:2 H2O999 19:1 99
4Cp*Ru(cod)Cl (5) 1:2 H2O0.5 80 19:1 78
5[I (cod)Cl]2(2.5) 1:2 H2O24361:0 20
6Cp*Ru(PPh3)2Cl(5) 1:2 H2O244723:1 17
7RuH2(CO)(PPh3)3(5) 1:2 H2O240 –0
8[Cp*RuCl]4(1.25) 1:2 H2O249914:1 99
9[d] Cp*Ru(cod)Cl (5) 1:2 CH2Cl229917:1 99
10 Cp*Ru(cod)Cl (5) 1:2 CH2Cl224418:1 37
11[e] Cp*Ru(cod)Cl (5) 1:2 H2O999 5:1 95[e]
12[ ] Cp*Ru(cod)Cl (5) 1:2 H2O2410–<5[ ]
13[g] Cp*Ru(cod)Cl (5) 1:4 H2O499 19:1[h] 98[h]
[a] Unless o he wise no ed, 2a (1–2 equi ),wa e ,and 1a (1 equi ,
75 mm)we e sequen ially added unde ai o a ial con aining he ca alys
( ha had been kep unde N2), and he mix u e was s i ed a RT.
[b] De e mined by 1HNMR spec oscopy o he c ude eac ion mix u e
wi h an in e nal s anda d. [c] Combined yield o 3/3’’.[d] Ca ied ou unde
an ine a mosphe e in anhyd oussol en . [e] Ca ied ou wi h 2b.
P oduc s: 3ab/3ab’’.[ ]Ca ied ou wi h 2c.P oduc s: 3ac/3ac’’.[g] Ca -
ied ou using bo h 2aand 2b(2 equi each). [h] P oduc s: 3aaand 3aa’’.
cod=1,5-cyclooc adiene.
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alkynyla ed p o ec ed dipep ide 2k demanded he use o
small amoun s o acosol en (i.e CH2Cl2,5–10% ol.), i s
eac ion wi h 1a and 1 p oceeded e icien ly, hus a o ding
he desi ed p oduc s 3akand 3 kin good yields.The eac ion
be ween an alkynyla ed hioglucose and 1a ook place
smoo hly in wa e o gi e he iazole 3al in 64%yield.
We nex explo ed he bioo hogonali y o he chemis y
by pe o ming he eac ion in ei he he p esence o di e en
biomolecula addi i es o unde biologically ele an con-
di ions (Table 3). G a i yingly, he RuA ACcould be e i-
cien ly ca ied ou in he p esence o glu a hione (20 old
excess espec o he [Ru];en y 1), di e en aminoacids
(en y 2), and e en in he p esence o a andom minip o ein
(en y 3). Thedesi ed iazole was ob ained in mode a e o
excellen yields and simila egioselec i i ies compa ed o
hose ob ained in pu e wa e (>15:1). The eac ion could also
be ca ied ou in phospha e-bu e ed saline (PBS;en y 4).
Addi ionally, equen ly used cul u e cell media, such as
DMEM, e al bo ine se um (FBS), and Hela cell lysa es a e
also excellen eac ion media, so he iazole 3aa was
ob ained in yields a ying om 77 o 91%, (en ies 5–7).
Analogue eac ions in hese media be ween (2-azidoe hyl)-
benzene (1c)and he hioalkyne 2e ga e good yields o 3ce
(see Table S3).
A his poin , i was o in e es o con as he pe o m-
ances o he RuA ACand CuAACinwa e o es ablish
s eng hs and weaknesses o each me hod. Thus,weca ied
ou pa allel expe imen s using (2-azidoe hyl)benzene (1c;
75 mm), 5mol%o each ca alys , and ei he 2e ( o Ru) o
phenylace ylene ( o Cu). While he u henium-p omo ed
eac ion was signi ican ly as e han he coppe coun e pa ,
when using CuSO4and sodium asco ba e o he la e (60%
s.22% yield, a e 2h), he CuAACbecame as e by
including addi i es such as BTTAA (75%yield a e 2h;see
Table S4). Impo an ly, he CuAAC ailed wi h in e nal
alkynes,including hioalkynes like 2a and, no su p isingly,
i is essen ially inhibi ed in he p esence o hiols like
glu a hione (0%yield a e 24 h). In con as , he RuA AC
wo ks e ec i ely e en in he p esence o a20- old excess o
glu a hione (75%yield), and p o ides he p oduc s wi h bo h
in e nal and e minal hioalkynes (as shown in Table 2). On
he weak side, he e iciency o he RuA ACdec eases upon
dilu ion (16%yield a 250 mm), while he ligand-accele a ed
CuAACp o ided a57% yield unde simila mic omola
condi ions (see Pages S11–S13).
Thelack o eac i i y o in e nal hioalkynes in he
p esence o coppe ca alys s sugges ed ha he CuAACand
he RuA ACcould be mu ually o hogonal.[27] G a i yingly,
he enginee ed diyne 4was quan i a i ely con e ed in o he
bis( iazole) 5,wi hou c oss- eac i i y,bype o ming
aCuAACwi h he dansyl azide 1 ,and subsequen in si u
addi ion o he u henium ca alys and he an h acenyl azide
1a(1 equi wi h espec o hioalkyne;Scheme 2). Conside -
ing he sca ci y o mu ually compa ible bioo hogonal eac-
Table 2: Scope o he RuA AC in wa e a oom empe a u e.[a]
[a] Reac ion condi ions: 2(2 equi ), wa e ,and 1a(1 equi ,75mm)we e
sequen iallyadded unde ai o a ial con aining Cp*Ru(cod)Cl
(5 mol%) which had been kep unde N2.The ial was closed, and he
mix u e s i ed a RT o 15–24 h. Regioselec i i ies (3/3’’)we e >18:1
unless o he wise no ed (de e mined by 1HNMR analysis o he c ude
eac ion mix u es wi h an in e nal s anda d).Yield o isola ed pu e 3,
unless o he wise no ed. Yields o he eac ions ca ied ou in anhyd ous
CH2Cl2unde an ine a mosphe e a e shown wi hin b acke s. [b] Yield o
3de e mined by 1HNMR analysis o he c ude eac ion mix u e wi h an
in e nal s anda d. [c] Co esponds o a18:1mix u e o 3ca/3ca’’.
[d] Ca ied ou wi h [Cp*RuCl]4(1.25 mol%).
Table 3: Analysis o he biocompa ibili y o he me hod.[a]
En y Condi ions[b] Con .[%][c] 3/3’[c] Yield [%][c,d]
1H
2O/glu a hione 80 19:1 60
2H
2O/His +Fmoc-ala 93 18:1 82
3H
2O/Pep ide 39 aa (0.5 mm)9923:1 98
4PBS 99 18:1 97
5cell cul u ed media (DMEM) 99 15:1 84
6 e al bo ine se um (FBS) 88 17:1 77
7cell lysa es (Hela) 99 16:1 91
[a] Reac ion condi ions: 2a (2 equi ) was added o asuspension o
Cp*Ru(cod)Cl (5 mol%), 1a (1 equi ,75mm), and he addi i e, in he
selec ed milieu, and he esul ing mix u e was s i ed o 24 h. [b] The
addi i es in en ies 1–2 a e in 20- old excess wi h espec o he
u henium ca alys . [c] De e mined by 1HNMR analysis o he c ude
eac ion mix u e using an in e nal s anda d. [d] Combined yield o 3aa/
3aa’’.
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10768 www.angewand e.o g T2017 The Au ho s. Published by Wiley-VCH Ve lag GmbH &Co. KGaA,Weinheim Angew.Chem. In . Ed. 2017,56,10766 –10770
ions, he possibili y o using bo h annula ions in andem in
one po is ce ainly p omising.[27]
Finally,and impo an ly,we ound ha he RuA ACcan
also be ca ied in he p esence o bac e ia (E. coli)wi hou
comp omising hei iabili y.The e o e,incuba ion o PBS
con aining Ecoli wi h 1a (1 mm), 2a (2 mm), and Cp*Ru-
(cod)Cl (100 mm)led o a apid inc ease in he luo escence.
A e 24 hou s,cen i uga ion and analysis in apla e eade o
bo h he ex acellula supe na an and he me hanol/wa e
(8:2) ex ac s o he esul ing bac e ia pelle showed acom-
bined inc ease in luo escence o eigh imes wi h espec o
con ols (see Figu e S29). Impo an ly, he luo escence was
mainly concen a ed inside he bac e ia, and he p oduc 3aa
was also de ec ed by HPLC-ESI. Analysis o he op ical
densi y o he bac e ial cul u es e ealed ha nei he he
ca alys no he eac an s a e meaning ully oxic (see
Table S5).
In summa y,weha e disco e ed anew me hodology o
achie e ca aly ic,o hogonal chemical annula ions in wa e ,
a oom empe a u e.The eac ion is p omo ed by speci ic
u henium(II) ca alys s,wo ks e icien ly wi h a a ie y o
azides and hioalkynes,and can be ca ied ou in p esence o
biomolecules (glu a hione,aminoacids,pep ides). The eac-
ion is also e icien in phospha e bu e ed saline,and in
complex biological media such as cell lysa es and e al bo ine
se um, and e en in p esence o li ing bac e ia. Impo an ly,
he eac ion is mu ually compa ible wi h he classical
CuAAC, hus p o iding he op ion o andem bio hogonal
p ocesses.
Acknowledgmen s
This wo k has ecei ed inancial suppo om Spanish g an s
(SAF2016-76689-R and SAF2013-41943-R), he Xun a de
Galicia (2015-CP082 and Cen o Singula de In es igacilnde
Galicia acc edi a ion 2016-2019 ED431G/09), he Eu opean
Union (Eu opean Regional De elopmen Fund -ERDF),
and he ERC (Ad .G an 340055). We also hank he O eo-
Cinqa ne wo k CTQ2016-81797-REDC,and T. Seeda and V.
F aga o p elimina y expe imen s.
Con lic o in e es
Theau ho s decla e no con lic o in e es .
Keywo ds: alkynes ·azides ·chemical liga ions ·
click chemis y · u henium
How oci e: Angew.Chem. In . Ed. 2017,56,10766–10770
Angew.Chem. 2017,129,10906–10910
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Scheme 2. Tandem CuAAC and RuA AC in wa e .
A
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Communica ions
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Manusc ip ecei ed:May 15, 2017
Re ised manusc ip ecei ed: June 25, 2017
Accep edmanusc ip online: July 6, 2017
Ve sion o eco d online: Augus 3, 2017
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10770 www.angewand e.o g T2017 The Au ho s. Published by Wiley-VCH Ve lag GmbH &Co. KGaA,Weinheim Angew.Chem. In . Ed. 2017,56,10766 –10770