Synthesis of 4′/5′-Spirocyclopropanated Uridine and d -Xylouridine Derivatives and Their Activity against the Human Respiratory Syncytial Virus

Article abstract of DOI:10.1021/acs.orglett.9b02555

The Simmons-Smith-Furukawa reaction was used to generate 4′/5′-spirocyclopropanated uridine analogs from electron-rich exocyclic enol esters. During synthesis, the native hydroxylation pattern of the nucleoside is preserved and offers the possibility for a late stage 5′-phosphorylation at the spirocyclopropanol moiety. All synthesized spirocyclopropanated uridine derivatives, including the corresponding 5′-monophosphate (cpUMP), were evaluated with respect to their antiviral activity in an HRSV assay showing moderate, but promising activity.

Full text of DOI:10.1021/acs.orglett.9b02555

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of 4′/5′-Spirocyclopropanated Uridine and D‑Xylouridine
Derivatives and Their Activity against the Human Respiratory
Syncytial Virus
†
§
‡
§
Christoph Kollmann, Svenja M. Wiechert, Peter G. Jones, Thomas Pietschmann,
̈
,
†
and Daniel B. Werz*
†
‡
Technische Universitat
̈
Braunschweig, Institute for Organic Chemistry and Technische Universitat
̈
Braunschweig, Institute for
Inorganic and Analytical Chemistry, Hagenring 30, 38106 Braunschweig, Germany
§
Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research; a Joint Venture
Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover,
Feodor-Lynen-Str. 7, 30625 Hannover, Germany
*
S Supporting Information
ABSTRACT: The Simmons−Smith−Furukawa reaction was
used to generate 4′/5′-spirocyclopropanated uridine analogs
from electron-rich exocyclic enol esters. During synthesis, the
native hydroxylation pattern of the nucleoside is preserved and
offers the possibility for a late stage 5′-phosphorylation at the
spirocyclopropanol moiety. All synthesized spirocyclopropa-
nated uridine derivatives, including the corresponding 5′-monophosphate (cpUMP), were evaluated with respect to their
antiviral activity in an HRSV assay showing moderate, but promising activity.
he synthesis of nucleoside derivatives for medical therapy
has been of major interest for several decades;
1
,2
T
nucleosides have become a striking and powerful group of
therapeutic agents, especially in the case of viral diseases and
anticancer therapy. While antiviral agents against certain
viruses such as HIV-1, Hepatitis C virus, CMV, or Influenza
virus are available, treatment options for human respiratory
3
syncytial virus (HRSV) are still limited.
HRSV is a globally distributed negative strand RNA virus of
the family Pneumoviridae that causes a severe disease burden
among infants, the elderly, and in immunocompromised
Figure 1. Conformational restricted cyclopropanated nucleoside
derivatives.
4−6
patients.
Apart from a prophylactic monoclonal antibody
that is given to children at high risk of severe infection, only
Ribavirin, a guanosine analog with broad antiviral activity, is
approved for treatment of RSV-infected patients. Never-
polycyclic (II) or spirocyclopropanated systems (III) proves
challenging, as literature-known spirocyclopropanation proto-
cols for nucleosides require electronically neutral, exocyclic,
primary alkenes. Starting materials containing electron-rich
alkenes are associated with low yields under reported reaction
7
theless, side effects of established therapeutics and the
evolution of viral drug resistance have revealed a lack of
appropriate new drug classes. During the past few decades the
cyclopropyl motif has shown astonishing biological effects in
drug development and was finally introduced as a spirocyclo-
16
conditions. Recently, our lab successfully introduced the
Simmons−Smith−Furukawa method for the spirocyclopropa-
nation of electron-rich enol ester systems of various
monosaccharides for the purpose of reducing conformational
freedom along the C5/C6-bond or achieving 5-C-methyl-
8
−11
propanation motif of the D-ribose scaffold by Mulard et al.
Since then, spirocyclopropanations have been realized at
carbons 2′, 3′, and 4′ by the addition of difluoromethylene
17−19
ation.
Further, we have shown that the stability of a free
spirocyclopropanol motif depends on the carbohydrate
scaffold. As isobutyric esters are widely used in prodrug
strategies, releasing the final drug in vivo after enzyme-
catalyzed ester cleavage, this protecting group is suitable for
(
I) or methylene units, generated from metal reagents or
8
,12−14
diazomethane (Figure 1).
Although 4′/5′-methylene
spirocyclopropanated uridine derivatives have been synthe-
sized by the groups of Boyer and Robins, one aspect of the
native substitution pattern of the nucleoside, namely the 5′-
hydroxyl group at the spirocyclopropane, has been ne-
Received: July 22, 2019
8
,15
glected.
In fact, conservation of the 5′-hydroxy motif for
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2
0
preserving the spirocyclopropanol motif. Nevertheless, the
activation of nucleosides in biological systems is realized by
enzyme-promoted phosphorylation giving 5′-phosphorylated
nucleotides. Therefore, we envisioned a late-stage phosphor-
ylation protocol to generate 4′/5′-spirocyclopropanated
uridine monophosphate (cpUMP) from a cyclopropanated
precursor.
during cyclopropanation. Following global deprotection by
hydrogenolysis, the use of palladium on charcoal secured the
spirocyclopropanated uridine derivative 6 (Figure 2). The
In this work, we present a synthetic approach to 4′/5′-
spirocyclopropanated uridine derivatives bearing a 5′-oxy
substitution pattern. The secondary alcohol at the spirocyclo-
propane motif was masked by a carboxylic ester or a
monophosphate. Finally, we investigated the potential
application of compounds 6, 16, 19, 20, and 21 as antiviral
agents against infection with HRSV.
As starting material we used the O5-silylated nucleoside 1,
which was prepared from uridine according to the reported
procedure by van Otterlo et al. Treatment with benzyloxy-
methyl chloride (BOMCl) afforded the fully protected
nucleoside 2 (Scheme 1). BOM was chosen to enable
Figure 2. X-ray crystal structure of compound 6 (50% ellipsoid
probability).
21
configuration of the isobutyric ester at the spirocyclopropane
motif and the previous α-facial diastereoselective cyclo-
propanation were confirmed by NOE and single-crystal X-ray
analysis (Figure 2 and Supporting Information). Determined
Scheme 1. Synthesis of Spirocyclopropanated Uridine
Derivative 6
by X-ray analysis, the D-ribose scaffold showed a E pucker,
3
with carbon 3′ lying 0.57 Å out of the ring plane (5′-O-1′-2′).
The χ-value (−140.40(17)°) of the nucleoside derivative
corresponds to the common anti-conformation. In comparison
to free uridine (1.507(3) Å), no significant effect of the
spirocyclopropane on the 4′−5′ bond length was observed
(
1.502(3) Å).
The isobutyric ester could not be replaced by a phosphoric
ester without reprotection of both N5 of the nucleobase and
the syn-diol motif at the furanose. Therefore, we used an acid-
catalyzed spiroketal formation with 1,1-dimethoxycyclohexane
(
DMC) leading to compound 7 in 76% yield. The following
reprotection of N5 with BOMCl proceeded easily, giving
compound 8 (89%). The isobutyric ester was finally cleaved by
alkaline reaction conditions using sodium methoxide in
methanol at 0 °C; ester cleavage at room temperature
promoted decomposition of the secondary alcohol at the
spirocyclopropane and hampered formation of product 9.
Addition of phosphorus(V) species such as phosphoryl
chlorides afforded only traces of the desired phosphorylated
uridine derivative. However, phosphorus(III) species neatly
converted the secondary alcohol to the phosphoramidite 10,
after which the diisopropylamino group was substituted by
benzylic alcohol in a tetrazole-mediated reaction. The
emerging phosphite was subsequently oxidized to the
diastereomeric mixture of the corresponding phosphate 11
by the addition of mCPBA at 0 °C (69%). An aqueous solution
of ammonium hydroxide was used for selective cleavage of the
simultaneous deprotection of the nucleobase and the 2,3-syn-
diol motif by hydrogenolysis with palladium on charcoal in a
single step. Use of this hydrogenolytically cleavable ether
proved to be superior to other common protecting strategies
lacking orthogonality toward carboxylic esters or the
spirocyclopropane. Removal of the O5-silyl group by TBAF
afforded compound 3 in 87% yield. After oxidation of the
primary alcohol by IBX, the sensitive aldehyde was directly
subjected to further reaction without purification. Enolization
by potassium carbonate and subsequent esterification led to
compound 4 (54%). Although high diastereoselectivity was
reported for the corresponding literature-known enol acetates,
only the (Z)-configured diastereomer was isolated with the
2
5
cyanoethyl protecting group in quantitative yield. The
resulting phosphate ester was obtained as a mixed salt with
ammonium and ammonium propionitrile cations. Column
purification using triethylamine as an additive in the eluant led
to the corresponding triethylammonium salt but still remained
difficult (12a; see the Supporting Information). The following
steps were performed without further purification, as this
proved to be unnecessary. Benzylation of compound 12 was
applied for reasons of purification, as partially unprotected
phosphates prevented proper aqueous workup after ketal
cleavage. Treatment with hydrogen chloride in dioxane
delivered the deprotected 1,2-syn diol motif of the
spirocyclopropanated uridine monophosphate. In contrast to
2
2,23
isobutyrates.
Cyclopropanation of the exocyclic enol ester
was carried out by application of the Simmons−Smith−
Furukawa protocol, providing compound 5 exclusively as the
24,25
α-facial cyclopropanated diastereomer in 54% yield.
The
striking diastereoselectivity is assumed to be controlled by the
ether-protected O2 and O3, directing the zinc carbenoid
B
DOI: 10.1021/acs.orglett.9b02555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Spirocyclopropanated Uridine Monophosphate (cpUMP) 16
compound 6, only the partially deprotected nucleotide 15 was
obtained after palladium-mediated hydrogenolysis of 14,
leaving a hemiaminal at N5. Dissolving the nucleotide in
Scheme 3. Synthesis of Spirocyclopropanated D-Xylouridine
Scaffold 19
D O at 50 °C furnished complete hydrolysis of the hemiaminal
2
under formation of the desired cpUMP nucleotide 16 (Scheme
2
7
2
). The process of temperature-promoted hydrolysis, giving
1
rise to an increasing signal set of cpUMP, was monitored by H
NMR spectroscopy (see Supporting Information).
D-Xylose scaffolds are valuable synthetic precursors for the
28
preparation of further 3′-substituted derivatives. Structural
elucidation experiments by NMR revealed D-xylose nucleosides
2
9
to adopt strictly a 3′-endo conformation. In order to
investigate the conformational impact of 4′/5′-spirocyclo-
propanations on the ring flexibility of uridine, we submitted 6,
showing a E-conformation, to a four-step 3′-epimerization.
3
Thereby, 17 was prepared by a modified procedure of an
Scheme 4. Preparation of Esterified D-Xylo Nucleoside 20
and D-Ribo Nucleoside 21
30
analogous synthesis by Kreutz. Epimerization of carbon 3′
was performed by prior oxidation of the hydroxy group using
31
Dess−Martin periodinane (50%). The 3-oxonucleoside 18
was diastereoselectively reduced by NaBH4 delivering the
32,33
desired D-xylose nucleoside as the major diastereomer.
Successive desilylation by application of TBAF at lower
temperature afforded 19 in 67% yield over two steps (Scheme
3
).
Interestingly, NMR investigations showed that 4′/5′-
spirocyclopropanation effectively guided the uridine structure
from the native 3′-endo conformation to a E pucker, as
3
34
36,37
observed in X-ray analysis of compound 6. Nevertheless, this
effect does not survive the 3′-epimerization. Changing the
molecular configuration at 3′ causes a retransformation to a 3′-
endo pucker, as indicated by the strongly reduced coupling
tion.
Compared to the 2′-deoxyribose backbone of DNA,
the δ-value of compound 6 (137.6°) fits the region of the DNA
B-form given by the scatterplot of Dickerson et al.
38
According to the established prodrug strategy we sought to
increase the membrane solubility and permeability of our
nucleoside derivatives by decreasing the hydrophilicity. For
this purpose, both spirocyclopropanated compounds 19 and 6
were esterified twice by application of isobutyric anhydride in
pyridine. Compounds 20 and 21 were obtained in 59% and
98% yield, respectively.
35
constant between H1 and H2 (Scheme 4). Converting 6 to
the respective 5′-phosphate 16 led only to a minor effect on
3
the ring conformation ( J
= 6.9 Hz). For a more detailed
H1−H2
and comparative view on the torsion angles of compound 6
and other conformationally restricted ribose and 2′-deoxy-
ribose nucleosides in DNA, see the Supporting Informa-
C
DOI: 10.1021/acs.orglett.9b02555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. Antiviral activity and cell toxicity of compounds 6, 16, 19, 20, and 21 compared to the antiviral guanosine analog ribavirin. Mean and
standard deviations of three to four independent experiments are shown.
To determine the antiviral activity of the spirocyclopropa-
nated uridine nucleosides, their inhibitory effect was
exemplarily tested against the negative strand RNA virus
HRSV. Thereby, HEp2 cells were infected with HRSV in the
presence of various compound concentrations. Ribavirin, the
only nucleoside analog licensed as an RSV targeting antiviral
therapeutic, was used as assay control. In the tested dose range,
compounds 6, 16, and 19 showed no antiviral effect (Figure
the ring conformation in comparison to an axially oriented 3′-
hydroxy group. For two uridine derivatives, we observed
moderate antiviral activity in an HRSV inhibition assay. For a
transfer of our developed methodology to cytosine, guanine,
and adenine nucleosides, we expect a proper protecting
strategy for the nucleobase to be necessary.
39
ASSOCIATED CONTENT
■
3
). In contrast, compounds 20 and 21 inhibited viral infection
*
S
Supporting Information
when used at concentrations of 100 μM or 33 μM,
respectively. Although the antiviral effect was moderate, it
occurred independently of any overt cytotoxic effect,
suggesting that the observed effect was attributable to direct
inhibition of HRSV infection rather than to indirect effects
caused by compromised cell viability. Moreover, nucleoside 21
was more effective than compound 20, providing the first hints
for optimizing the anti-HRSV activity of these spirocyclopro-
panated uridine nucleosides.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02555.
Detailed experimental procedures, analytical data for all
new compounds, and crystal data for 6 (PDF)
Accession Codes
CCDC 1935067 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
The antiviral activity of nucleoside analogs depends on
several factors. The compounds have to permeate the cell
4
0
membrane and be phosphorylated by the host cell
4
1,42
machinery
in order to be incorporated into the nascent
viral RNA, thus causing chain termination or mutations by
4
3
base mispairing in genome replication. In our case,
extracellular phosphorylation of compound 6 did not render
compound 16 antiviral. However, compounds 20 and 21,
which are more lipophilic than their derivatives, compound 19
and 6, possess an antiviral activity at high doses. Further
experiments are needed to conclude whether this is because of
improved cell membrane penetration of these molecules.
Moreover, it will be interesting to see whether spirocyclo-
propanated uridine nucleosides have broad spectrum antiviral
activity or are HRSV specific inhibitors.
In conclusion, we have demonstrated an access to 4′/5′-
spirocyclopropanated uridine derivatives while preserving the
native hydroxylation pattern of the nucleoside. Further, we
have generated the first spirocyclopropanated nucleotide of
uridine applying the Simmons−Smith−Furukawa protocol as
the key step. NMR analysis of a spirocyclopropanated D-xylose
scaffold showed a minor impact of the spirocyclopropane on
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: d.werz@tu-braunschweig.de.
ORCID
Daniel B. Werz: 0000-0002-3973-2212
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Christina Grethe (TWINCORE) for expert
technical assistance. We thank the Studienstiftung des
deutschen Volkes (Promotionsstipendium to C.K.) and the
Fonds der Chemischen Industrie (Promotionsstipendium to
C.K.) for funding. Work in the T.P. laboratory was supported
by a grant from the Helmholtz-Alberta initiative for infectious
D
DOI: 10.1021/acs.orglett.9b02555
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
disease research (HAI-IDR). We thank Dr. Kerstin Ibrom (TU
Braunschweig) for her kind support. HRSV luciferase reporter
virus was a generous gift from Marie-Anne Rameix-Welti
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