Syn hesis o 4’/5’-Spi ocyclop opana ed U idine and D-
Xylou idine De i a i es and hei Ac i i y agains he Hu-
man Respi a o y Syncy ial Vi us
Ch is oph Kllmann,† S enja M. Wieche ,§ Pe e G. Jones,‡ Thomas Pie schmann,§ and Daniel B. We z*,†
†Technische Uni e si ä B aunschweig, Ins i u e o O ganic Chemis y and ‡Technische Uni e si ä B aunschweig, Ins i u e
o Ino ganic and Analy ical Chemis y, Hagen ing 30, 38106 B aunschweig, Ge many
§ Ins i u e o Expe imen al Vi ology, TWINCORE, Cen e o Expe imen al and Clinical In ec ion Resea ch; a Join Ven u e
Be ween he Medical School Hanno e (MHH) and he Helmhol z Cen e o In ec ion Resea ch (HZI), Hanno e , Feodo -
Lynen-S . 7, 30625 Hanno e
Suppo ing In o ma ion Placeholde
NH
O
ON
O
OH
HO
NH
O
O
N
O
OH
HO
HO
U idine cpUMP
NH
O
ON
O
OH
HO
iP COO (HO)2(O)PO
ABSTRACT: The Simmons-Smi h-Fu ukawa eac ion was used o gene a e 4’/5’-spi ocyclop opana ed u idine analogs om
elec on- ich exocyclic enol es e s. Du ing syn hesis he na i e hyd oxyla ion pa e n o he nucleoside is p ese ed and o e s he
possibili y o a la e s age 5’-phospho yla ion a he spi ocyclop opanol moie y. All syn hesized spi ocyclop opana ed u idine de i -
a i es, including he co esponding 5’-monophospha e (cpUMP), we e e alua ed wi h espec o hei an i i al ac i i y in an HRSV
assay showing modes , bu p omising ac i i y.
The syn hesis o nucleoside de i a i es o medical he apy
has been o majo in e es o se e al decades;1,2 nucleosides
ha e become a s iking and powe ul g oup o he apeu ic
agen s, especially in case o i al diseases and an i-cance
he apy. While an i i al agen s agains ce ain i uses such as
HIV-1, Hepa i is C i us, CMV o In luenza i us a e a ail-
able, ea men op ions o human espi a o y syncy ial i us
(HRSV) a e s ill limi ed.3
NH
O
O
N
O
OH
HO
iP COO
NH
O
O
N
O
OH
HO
O
O
O
Base
P O
O
O
P O
O
O
F
F
I II III
P e ious Wo k This Wo k
Figu e 1. Con o ma ional es ic ed cyclop opana ed nucleoside
de i a i es.
HRSV is a globally dis ibu ed nega i e s and RNA i us o he
amily Pneumo i idae ha causes a se e e disease bu den among
in an s, he elde ly and in immunocomp omised pa ien s.4–6 Apa
om a p ophylac ic monoclonal an ibody ha is
Scheme 1. Syn hesis o Spi ocyclop opana ed U i-
dine De i a i e 6.
BOMCl (6 equi )
NiP 2E (5 equi )
DCM, 0 °C o
3 d
(84%)
TBAF·3 H2O
(1.5 equi )
THF, , 1 h
(87%)
1) IBX (2.5 equi )
ACN, e lux
2) K2CO3 (6 equi )
(iP CO)2O (6 equi )
CH3CN, e lux, 3 h
(54%, only Z
o e 2 s eps)
ZnE 2 (5 equi )
CH2I2 (10 equi )
DCE, 50 °C
2 h
(54%, only
 acial)
NH
O
ON
O
OHHO
RO
NBOM
O
ON
O
OBOMBOMO
RO
NBOM
O
ON
O
OBOMBOMO
RO
NBOM
O
ON
O
OBOMBOMO
RO
NBOM
O
ON
O
OBOM
BOMO
NH
O
O
N
O
OH
HO
1 R =TBDPS 2 R = TBDPS
3 R = H 4 R = iP CO
5 R = iP CO 6 R = iP CO
RO RO
H2 (1 a m)
Pd/C (10%)
MeOH,
3.5 h
(quan )
gi en o child en a high isk o se e e in ec ion, only Rib-
a i in, a guanosine analog wi h b oad an i i al ac i i y, is ap-
p o ed o
Scheme 2. Syn hesis o Spi ocyclop opana ed U idine Monophospha e (cpUMP) 16.
NH
O
ON
O
O
O
NBOM
O
ON
O
O
O
NH4OH
(25 % (w/w))
1,4-dioxane
, 1.5 h
(quan ) 1/3 NH4
NBOM
O
ON
O
O
O
N
O
ON
O
OH
HO
NBOM
O
ON
O
O
O
NBOM
O
ON
O
OH
HO
OH NH
O
ON
O
OH
HO
D2O
50 °C, 3 d
(quan )
BOMCl (2.5 equi )
NiP 2E (4 equi )
DCM, 0 °C o , 1 d
(89%)
NaOMe (0.3 equi )
MeOH, 0 °C, 3 h
(quan )
NBOM
O
ON
O
O
O
PCl(NiP 2)OCE (2 equi )
NiP 2E (5 equi )
DCM, 0 °C, 0.5 h
(55%)
NBOM
O
ON
O
O
O
NBOM
O
ON
O
O
O
1) BnOH (1.2 equi )
e azole (3 equi )
CH3CN, , 6 h
2) mCPBA (1.2 equi )
CH3CN, 0 °C, 0.5 h
(69% o e wo s eps)
BnB (5 equi )
TBAI (0.2 equi )
Cs2CO3 (2 equi )
DMSO, 50 °C, 12 h
(33%)
HCl (4 M)
1,4-dioxane
MeOH, , 10 h
(31%)
H2 (1 a m)
Pd/C (10%)
MeOH, , 5 h
(quan )
10
R = (CEO)(NiP 2)P
7
R = i
P CO
8
R = i
P CO
9
11
R = (CEO)(BnO)(O)P
12
R = O(BnO)(O)P
13
R = (BnO)2(O)P
14
R = (BnO)2(O)P
15
R = (HO)2(O)P
16
R = (HO)2(O)P
DMC (3.5 equi )
pTsOH (0.1 equi )
DCE, 50 °C, 3 h
(76%)
NH
O
ON
O
OH
HO
6
R =
i
P CO
2/3 NH3CH2CH2CN
RO RO RO
RO RO RO RO
HO
RO RO RO
ea men o RSV-in ec ed pa ien s.7 Ne e heless, side e ec s
o es ablished he apeu ics and he e olu ion o i al d ug e-
sis ance ha e e ealed a lack o app op ia e new d ug classes.
Du ing he las ew decades he cyclop opyl mo i has shown
as onishing biological e ec s in d ug de elopmen and was i-
nally in oduced as a spi ocyclop opana ion mo i o he D- i-
bose sca old by Mula d e al.8–11 Since hen, spi ocyclop opa-
na ions ha e been ealized a ca bons 2’, 3’ and 4’ by he addi-
ion o di luo ome hylene (I) o me hylene uni s, gene a ed
om me al eagen s o diazome hane (Figu e 1).8,12–14 Al-
hough 4’/5’-me hylene spi ocyclop opana ed u idine de i a-
i es ha e been syn hesized by he g oups o Boye and
Robins, one aspec o he na i e subs i u ion pa e n o he nu-
cleoside, namely he 5’-hyd oxyl g oup a he spi ocyclo-
p opane, has been neglec ed.8,15 In ac , conse a ion o he 5’-
hyd oxy mo i o polycyclic (II) o spi ocyclop opana ed
sys ems (III) p o es challenging, as li e a u e-known spi ocy-
clop opana ion p o ocols o nucleosides equi e elec onically
neu al, exocyclic, p ima y alkenes. S a ing ma e ials con ain-
ing elec on- ich alkenes a e associa ed wi h low yields unde
epo ed eac ion condi ions.16 Recen ly, ou lab success ully
in oduced he Simmons-Smi h-Fu ukawa me hod o he
spi ocyclop opana ion o elec on- ich enol es e sys ems o
a ious monosaccha ides o he pu pose o educing con o -
ma ional eedom along he C5/C6-bond o achie ing 5-C-
me hyla ion.17–19 Fu he , we ha e shown ha he s abili y o a
ee spi ocyclop opanol mo i depends on he ca bohyd a e
sca old. As isobu y ic es e s a e widely used in p od ug
s a egies, eleasing he inal d ug in i o a e enzyme-ca -
alyzed es e clea age, his p o ec ing g oup is sui able o p e-
se ing he spi ocyclop opanol mo i .20 Ne e heless, he ac i-
a ion o nucleosides in biological sys ems is ealized by en-
zyme-p omo ed phospho yla ion gi ing 5’-phospho yla ed nu-
cleo ides. The e o e, we en isioned a la e s age phospho yla-
ion p o ocol o gene a e 4’/5’-spi ocyclop opana ed u idine
monophospha e (cpUMP) om a cyclop opana ed p ecu so .
In his wo k, we p esen a syn he ic app oach o 4’/5’-spi ocy-
clop opana ed u idine de i a i es bea ing a 5’-oxy subs i u ion
pa e n. The seconda y alcohol a he spi ocyclop opane mo i
was masked by a ca boxylic es e o a monophospha e. Fi-
nally, we in es iga ed he po en ial applica ion o compounds
6, 16, 19, 20 and 21 as an i i al agen s agains in ec ion
wi h HRSV.
As s a ing ma e ial we used he O5-silyla ed nucleoside 1,
which was p epa ed om u idine acco ding o he epo ed
p ocedu e by an O e lo e al.21 T ea men wi h benzy-
loxyme hyl chlo ide (BOMCl) a o ded he ully p o ec ed nu-
cleoside 2 (Scheme 1). BOM was chosen o enable simul ane-
ous dep o ec ion o he nucleobase and he 2,3-syn-diol mo i
by hyd ogenolysis wi h palladium on cha coal in a single s ep.
Use o his hyd ogenoly ically clea able e he p o ed o be su-
pe io o o he common p o ec ing s a egies lacking o hogo-
nali y owa ds ca boxylic es e s o he spi ocyclop opane. Re-
mo al o he O5-silyl g oup by TBAF a o ded compound 3 in
87% yield. A e oxida ion o he p ima y alcohol by IBX, he
sensi i e aldehyde was di ec ly subjec ed o u he eac ion
wi hou pu i ica ion. Enolisa ion by po assium ca bona e and
subsequen es e i ica ion led o compound 4 (54%). Al hough
high dias e eoselec i i y was epo ed o he co esponding
li e a u e-known enol ace a es, only he (Z)-con igu ed di-
as e eome was isola ed wi h he isobu y a es.22,23 Cyclop opa-
na ion o he exocyclic enol es e was ca ied ou by applica-
ion o he Simmons-Smi h-Fu ukawa p o ocol, p o iding
compound 5 exclusi ely as he α- acial cyclop opana ed di-
as e eome in 54% yield.24,25 The s iking dias e eoselec i i y
is assumed o be con olled by he e he -p o ec ed O2 and O3,
di ec ing he zinc ca benoid du ing cyclop opana ion. Follow-
ing global dep o ec ion by hyd ogenolysis, using palladium on
cha coal, secu ed he spi ocyclop opana ed u idine de i a i e
6 (Figu e 2). The con igu a ion o he isobu y ic es e a he
spi ocyclop opane mo i and he p e ious α- acial dias e eose-
lec i e cyclop opana ion we e con i med by NOE and sin-
gle-c ys al X- ay analysis (Figu e 2 and Suppo ing In o ma-
ion). De e mined by X- ay analysis, he D- ibose sca old
showed a 3E pucke , wi h ca bon 3’ lying 0.57NÅ ou o he
ing plane (5’-O-1’-2’). The χ- alue (-140.40(17)°) o he nu-
cleoside de i a i e co esponds o he common an i-con o ma-
ion. In compa ison o ee u idine (1.507(3)NÅ), no signi ican
e ec o he spi ocyclop opane on he 4’-5’ bond leng h was
obse ed (1.502(3)NÅ).
The isobu y ic es e could no be eplaced by a phospho ic es-
e wi hou ep o ec ion o bo h N5 o he nucleobase and he
syn-diol mo i a he u anose. The e o e, we used an acid-ca -
alyzed spi oke al o ma ion wi h 1,1-dime hoxycyclohexane
(DMC) leading o compound 7 in 76% yield. The ollowing
ep o ec ion o N5 wi h BOMCl p oceeded easily, gi ing com-
pound 8 (89%). The isobu y ic es e was inally clea ed by al-
kaline eac ion condi ions using sodium me hoxide in
me hanol a 0N°C; es e clea age a oom empe a u e p o-
mo ed decomposi ion o he seconda y alcohol a he spi ocy-
clop opane and hampe ed o ma ion o p oduc 9. Addi ion o
phospho us (V) species such as phospho yl chlo ides a o ded
only aces o he desi ed phospho yla ed u idine de i a i e.
Howe e , phospho us (III) species nea ly con e ed he sec-
onda y alcohol o he phospho amidi e 10, a e which he di-
isop opylamino g oup was subs i u ed by benzylic alcohol in a
e azole-media ed eac ion. The eme ging phosphi e was sub-
sequen ly oxidized o he dias e eome ic mix u e o he co e-
sponding phospha e 11 by he addi ion o mCPBA a 0N°C
(69%). An aqueous solu ion o ammonium hyd oxide was
used o selec i e clea age o he cyanoe hyl p o ec ing g oup
in quan i a i e yield.25 The esul ing phospha e es e was ob-
ained as a mixed sal wi h ammonium and ammonium p opi-
oni ile ca ions. Column pu i ica ion using ie hylamine as an
addi i e in he eluan led o he espec i e ie hylammonium
sal bu s ill emained di icul (12a, see he Suppo ing In o -
ma ion). The ollowing s eps we e pe o med wi hou u he
pu i ica ion as his p o ed o be needless. Benzyla ion o com-
pound 12 was applied o easons o pu i ica ion, as pa ially
unp o ec ed phospha es p e en ed p ope aqueous wo k-up a -
e ke al clea age. T ea men wi h hyd ogen chlo ide in diox-
ane deli e ed he dep o ec ed 1,2-syn diol mo i o he spi ocy-
clop opana ed u idine monophospha e. In con as o com-
pound 6, only he pa ially dep o ec ed nucleo ide 15 was ob-
ained a e palladium-media ed hyd ogenolysis o 14, lea ing
a hemiaminal a N5. Dissol ing he nucleo ide in D2O a 50 °C
u nished comple e hyd olysis o he hemiaminal unde o ma-
ion o he desi ed cpUMP nucleo ide 16 (SchemeN2).27 The
p ocess o empe a u e-p omo ed hyd olysis, gi ing ise o an
inc easing signal se o cpUMP, was moni o ed by 1H NMR
spec oscopy (see Suppo ing In o ma ion).
Scheme 3. Syn hesis o Spi ocyclop opana ed D-Xylou idine
Sca old 19.
NH
O
ON
O
OTBDMS
HO
NH
O
ON
O
OH
HO
TBDMSCl (2.2 equi )
AgNO3 (2.2 equi )
Py (5 equi )
THF, , 16 h
(81%)
DMP (2 equi )
DCM, , 3 h
(50%)
6
17 R = OCiP
18 R = OCiP
1) NaBH4 (1.1 equi )
MeOH, 0 °C, 0.5 h (d 5.9:1)
2) TBAF·3 H2O (1.1 equi )
THF, 0 °C, 3 h
(67% o e wo s eps)
NH
O
ON
O
OTBDMS
O
19 R = OCiP
RO
RO
RO
D-Xylose sca olds a e aluable syn he ic p ecu so s o he
p epa a ion o u he 3’-subs i u ed de i a i es.28 S uc u al
elucida ion expe imen s by NMR e ealed D-xylose nucleos-
ides o adop s ic ly a 3’-endo con o ma ion.29 In o de o in-
es iga e he con o ma ional impac o 4’/5’-spi ocyclop o-
pana ions on he ing lexibili y o u idine, we submi ed 6,
showing a 3E-con o ma ion, o a ou -s ep 3’-epime isa ion.
The eby, 17 was p epa ed by a modi ied p ocedu e o an anal-
ogous syn hesis by K eu z.30 Epime isa ion o ca bon 3’ was
pe o med by p io oxida ion o he hyd oxy g oup using
Dess–Ma in pe iodinane (50%).31 The 3-oxonucleoside 18
was dias e eoselec i ely educed by NaBH4 deli e ing he de-
si ed D-xylose nucleoside as he majo dias e eome .32,33 Suc-
cessi e desilyla ion by applica ion o TBAF a lowe empe a-
u e a o ded 19 in 67% yield o e wo s eps (Scheme 3).
In e es ingly, NMR in es iga ions showed ha 4’/5’-spi ocy-
clop opana ion e ec i ely guided he u idine s uc u e om
he na i e 3’-endo con o ma ion o a 3E pucke , as obse ed in
X- ay analysis o compound 6.34 Ne e heless, his e ec does
no su i e he 3’-epime iza ion. Changing he molecula con-
igu a ion a 3’ causes a e ans o ma ion o a 3’-endo pucke ,
as indica ed by he s ongly educed coupling cons an be-
ween H1 and H2 (Scheme 4).35 Con e ing 6 o he espec i e
5’-phospha e 16 led only o a mino e ec on he ing con o -
ma ion (3JH1-H2 = 6.9NHz). Fo a mo e de ailed and compa a i e
iew on he o sion angles o compound 6 and o he con o -
ma ional es ic ed ibose and 2’-deoxy ibose nucleosides in
DNA, see he Suppo ing In o ma ion.36,37 Compa ed o he 2’-
deoxy ibose backbone o DNA, he δ- alue o compound 6
(137.6N°) i s he egion o he DNA B- o m gi en by he sca -
e plo o Dicke son e al.38
Scheme 4. P epa a ion o Es e i ica ed D-Xylo Nucleoside 20
and D-Ribo Nucleoside 21.
NH
O
ON
O
OH
R
1
(
i
P CO)
2
O
(30 equi )
py , , 16 h
R
2
NH
O
ON
O
OOC
i
P
R
1
R
2
19
R
1
= OH; R
2
= H
3
J
H1-H2
0.9 Hz
6
R
1
= H; R
2
= OH
3
J
H1-H2
7.7 Hz
20
R
1
=
i
P COO; R
2
= H (59%)
21
R
1
= H; R
2
=
i
P COO (98%)
i
P COO
i
P COO
Acco ding o he es ablished p od ug s a egy we sough o in-
c ease memb ane solubili y and pe meabili y o ou nucleoside
Figu e 3. An i i al ac i i y and cell oxici y o compounds 6, 16, 19, 20 and 21 compa ed o he an i i al guanosine analog iba i in.
Mean and s anda d de ia ions o h ee o ou independen expe imen s a e shown.
de i a i es by dec easing he hyd ophilici y. Fo his pu pose,
bo h spi ocyclop opana ed compounds 19 and 6 we e es e i i-
ca ed wice by applica ion o isobu y ic anhyd ide in py idine.
Compounds 20 and 21 we e ob ained in 59% and 98% yield,
espec i ely.
Figu e 2. X- ay c ys al s uc u e o compound 6 (50% ellipsoid
p obabili y).
To de e mine he an i i al ac i i y o he spi ocyclop opana ed
u idine nucleosides, hei inhibi o y e ec was exempla ily
es ed agains he nega i e s and RNA i us HRSV. The e o e,
HEp2 cells we e in ec ed wi h HRSV39 in he p esence o a i-
ous compound concen a ions. Riba i in, he only nucleoside
analogue licensed as RSV a ge ing an i i al he apeu ic, was
used as assay con ol. In he es ed dose ange, compounds 6,
16 and 19 did no show any an i i al e ec (Figu e 3). In
con as , compounds 20 and 21 inhibi ed i al in ec ion when
used a concen a ions o 100NµM o 33NµM, espec i ely. Al-
hough he an i i al e ec was modes , i occu ed indepen-
den ly o any o e cy o oxic e ec , sugges ing ha he ob-
se ed e ec was a ibu able o di ec inhibi ion o HRSV in-
ec ion a he han o indi ec e ec s caused by comp omised
cell iabili y. Mo eo e , nucleoside 21 was mo e e ec i e
han compound 20, p o iding he i s hin s o op imizing he
an i-HRSV ac i i y o hese spi ocyclop opana ed u idine nu-
cleosides.
An i i al ac i i y o nucleoside analogs depends on se e al
ac o s. The compounds ha e o pe mea e he cell memb ane40
and be phospho yla ed by he hos cell machine y41,42 in o de
o be inco po a ed in o he nascen i al RNA, hus causing
chain e mina ion o mu a ions by base mispai ing in genome
eplica ion.43 In ou case, ex acellula phospho yla ion o
compound 6 did no ende compound 16 an i i al. Howe e ,
compounds 20 and 21, which a e mo e lipophilic han hei
de i a i es, compound 19 and 6, possess an an i i al ac i i y
a high doses. Fu he expe imen s a e needed o conclude
whe he his is because o imp o ed cell memb ane pene a-
ion o hese molecules. Mo eo e , i will be in e es ing o see
whe he spi ocyclop opana ed u idine nucleosides ha e b oad
spec um an i i al ac i i y o a e HRSV speci ic inhibi o s.

In conclusion, we ha e demons a ed an access o 4’/5’-spi o-
cyclop opana ed u idine de i a i es while p ese ing he na-
i e hyd oxyla ion pa e n o he nucleoside. Fu he , we ha e
gene a ed he i s spi ocyclop opana ed nucleo ide o u idine
applying he Simmons-Smi h-Fu ukawa p o ocol as he key
s ep. NMR analysis o a spi ocyclop opana ed D-xylose sca -
old showed a mino impac o he spi ocyclop opane on he
ing con o ma ion in compa ison o an axially o ien ed 3’-hy-
d oxy g oup. Fo wo u idine de i a i es, we obse ed mode -
a e an i i al ac i i y in an HRSV inhibi ion assay. Fo a ans-
e o ou de eloped me hodology o cy osine, guanine and
adenine nucleosides we expec a p ope p o ec ing s a egy o
he nucleobase o be necessa y.
ASSOCIATED CONTENT
Suppo ing In o ma ion De ailed expe imen al p ocedu es, analy -
ical da a o all new compounds, and c ys al da a (CIF) o 6. This
ma e ial is a ailable ee o cha ge ia he In e ne a h p://pub-
s.acs.o g.
AUTHOR INFORMATION
Co esponding Au ho
*E-mail: [email p o ec ed].
ORCID
Daniel B. We z: 0000-0002-3973-2212
No es
The au ho s decla e no compe ing inancial in e es .
ACKNOWLEDGMENT
We hank Ch is ina G e he (TWINCORE) o expe echnical as-
sis ance. We hank he S udiens i ung des deu schen Volkes (P o-
mo ionss ipendium o C.K.) and he Fonds de Chemischen Indus-
ie (P omo ionss ipendium o C.K.) o unding. Wo k in he T.P.
labo a o y was suppo ed by a g an om he Helmhol z-Albe a
ini ia i e o in ec ious disease esea ch (HAI-IDR). We hank D .
Ke s in Ib om (TU B aunschweig) o he kind suppo . HRSV lu-
ci e ase epo e i us was a kind gi om Ma ie-Anne Rameix-
Wel i (Uni e si é de Ve sailles S . Quen in) and Jean-F ançois
Éléue (Uni e si é Pa is Saclay.
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