Synthesis of Triazole-Containing Furanosyl Nucleoside Analogues and Their Phosphate, Phosphoramidate or Phoshonate Derivatives as Potential Sugar Diphosphate or Nucleotide Mimetics

Article abstract of DOI:10.1002/cplu.202000424

The synthesis of stable and potentially bioactive xylofuranosyl nucleoside analogues and potential sugar diphosphate or nucleotide mimetics comprising a 1,2,3-triazole moiety is reported. 3′-O-Methyl-branched N-benzyltriazole isonucleosides were accessed

Full text of DOI:10.1002/cplu.202000424

A Multidisciplinary Journal Centering on Chemistry
Accepted Article
Title: Synthesis of Triazole-Containing Furanosyl Nucleoside Analogs
and Their Phosphate, Phosphoramidate or Phoshonate
Derivatives as Potential Sugar Diphosphate or Nucleotide
Mimetics
Authors: Andreia Fortuna, Paulo J. Costa, M. Fátima M. Piedade, M.
Conceição Oliveira, and Nuno Manuel Xavier
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To be cited as: ChemPlusChem 10.1002/cplu.202000424
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01/2020

10.1002/cplu.202000424
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Synthesis of Triazole-Containing Furanosyl Nucleoside Analogs
and Their Phosphate, Phosphoramidate or Phoshonate
Derivatives as Potential Sugar Diphosphate or Nucleotide
Mimetics
Andreia Fortuna,[a,b] Paulo J. Costa,[b] M. Fátima M. Piedade,[a,c] M. Conceição Oliveira[c] and
Nuno M. Xavier*[a]
[a]
A. Fortuna, Prof. M. F. M. Piedade, Dr. N. M. Xavier
Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa
Ed. C8, 5º Piso, Campo Grande, 1749-016 Lisboa, Portugal
E-mail: nmxavier@fc.ul.pt
[b]
[c]
A. Fortuna, Dr. P. J. Costa
University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute
Campo Grande, C8 bdg, 1749-016 Lisboa, Portugal
Prof. M. F. M. Piedade, Dr. M. C. Oliveira
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa
Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Supporting information for this article is given via a link at the end of the document.
Abstract: The synthesis of novel, rather stable and potentially
bioactive xylofuranosyl nucleoside analogs and potential sugar
diphosphate or nucleotide mimetics comprising a 1,2,3-triazole
moiety is reported. 3ʹ-O-Methyl-branched N-benzyltriazole
isonucleosides were accessed in 5-7 steps and 42-54% overall
yields using a Cu(I)-catalyzed cycloaddition of 3-O-propargyl-1,2-O-
isopropylidene-α-D-xylofuranose with benzyl azide as key step.
Related isonucleotides were obtained by 5-O-phosphorylation of
acetonide-protected 3-O-propargyl xylofuranose and further “click”
cycloaddition or by Staudinger-phosphite reaction of a 5-azido N-
benzyltriazole isonucleoside. Hydroxy-, amino- or bromomethyl
triazole 5ʹ-isonucleosides were synthesized by thermal cycloaddition
of 5-azido 3-O-benzyl/dodecyl xylofuranoses with propargyl alcohol,
propargylamine or propargyl bromide. Better yields (82-85%) were
of polymerases or other enzymes involved in nucleic acid or
nucleotide biosynthesis, inducing inhibition of cell division or viral
replication.[1]
Despite the proven chemotherapeutic efficacy of nucleos(t)ide
analogs, some drawbacks are associated with their use, namely
their high polarity which results in low oral bioavailability and the
resistance that cancer or virus-infected cells exert against their
action. Among the relevant nucleoside-specific chemoresistance
mechanisms
are
the
downregulation
of
nucleoside
transporters,[2] hindering their passage to the intracellular
medium, and of nucleoside kinases,[3] leading to a decreased
formation of nucleoside phosphates, or the overexpression of
nucleotidases, which mediate dephosphorylation of the former
metabolites.[4] Nucleoside analogs or mimetics possessing
structural features that may allow them to overcome these
issues have been synthesized. Modifications at the nucleobase,
sugar moiety or the insertion of phosphate group analogs have
been performed aiming at nucleos(t)ide analogs of improved
bioavailability, cell-penetrating ability or stability to enzymatic
hydrolysis. These molecules include acyclic nucleos(t)ides,[5]
carbocyclic derivatives[6] or other sugar heteroanalog-containing
nucleosides,[7] nucleosides comprising uncommon glycosyl
obtained when using propargyl alcohol and
a
high 1,4-
regioselectivity was attained with propargyl bromide. Further O/N-
phosphorylation or Arbuzov reaction led to (triazolyl)methyl
phosphates, phosphoramidates or phosphonates. The latter were
converted into uracil nucleoside 5ʹ-(triazolyl)methyl phosphonates as
prospective nucleoside diphosphate mimetics.
units,[8]
C-nucleosides,[9]
nucleoside
alkyl/aryl
phosphodi/triesters,[10] phosphoramidates or H- or C-
phosphonates.[10,11]
Introduction
Nucleosides and nucleotides are key molecules in essential
biological events including nucleic acid synthesis, cell division,
cell signalling, and metabolism. The development of synthetic
analogues of these molecules, aiming at inhibiting nucleotide-
dependent processes/enzymes that are overactivated and play
crucial roles in diseases such as cancer or viral infections, has
been significantly explored. Various nucleoside and nucleotide
analogs have reached clinical application as chemotherapeutic
agents, acting mostly as nucleic acid antimetabolites, from which
cytarabine, gemcitabine or azidothymidine can be highlighted.[1]
Other biological effects of therapeutic relevance have been
reported for nucleos(t)ides and analogs, including antibiotic
properties, acting as inhibitors of crucial microbial cell
processes,[12] or ability to inhibit cholinesterases,[13] which are
important therapeutic targets for Alzheimer’s disease
symptomatic treatment. Among the described cholinesterase
inhibitors are our previously reported 5ʹ/6ʹ-isonucleosides,[13c‒f]
which comprise a nucleobase or an analogous nitrogeneous
heteroaromatic moiety N-linked to a sugar moiety at C-5 or C-6,
and D-glucofuranuronamide-based N-glycosyl triazoles.[13e]
Isonucleosides are rather stable nucleoside regioisomers since
their N-C bond linking the sugar and nucleobase units is less
susceptible to chemical or enzymatic hydrolysis than the N-
Their mechanism of action involves
a
kinase-mediated
conversion into di- and triphosphate nucleoside metabolites and
further incorporation into nucleic acids or alternatively, inhibition
1
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10.1002/cplu.202000424
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glycosidic bond present in nucleosides. Furanosyl 2ʹ/3ʹ-
isonucleosides displaying anticancer[14] and antiviral[15]
properties were reported.
The biological profile and efficacy of nucleos(t)ide analogs
encourage the development of new structures that may
circumvent the limitations of the clinically-used ones, exhibit
alternative mechanisms of action, and offer new therapeutic
opportunities. In this context, we report herein on the synthesis
of a variety of xylofuranose-based isonucleosides (A, B)
together with potential mimetics of sugar diphosphates (D) and
nucleotides (C, E) comprising a 1,2,3-triazole moiety (Figure 1).
The broad bioactivity profile associated with this motif,[16] its
ability for hydrogen-bond, ion-dipole, cation-π or π-stacking
interactions with amino acid residues or to coordinate metals,
enabling molecular recognition by enzymes or receptors, and its
high chemical and enzymatic stability are relevant aspects that
motivate its inclusion in new potentially bioactive structures.
Furthermore, this moiety can be straightforwardly accessed by
means of a Huisgen azide-alkyne cycloaddition reaction.[17]
Reported examples on furanosyl nucleoside analogs containing
a 1,2,3-triazole moiety[17h] revealed their propensity to exhibit
antiviral,[18] anticancer[19] or antifungal activities,[20] and to inhibit
nucleotide-dependent enzymes.[21] This N-heteroaromatic
system was included as a surrogate of a nucleobase in
Figure 1. General skeletons of triazole-containing isonucleosides (A, B),
isonucleotides (C), potential sugar diphosphate mimetics (D) and nucleotide
mimetics (E) exploited herein.
Results and Discussion
The synthesis of isonucleosides and related isonucleotides
comprising an O-(N-benzyltriazolyl)methyl system at
a
pentoxylofuranosyl template at C-3 (compounds of types A and
C, Figure 1) involved the access to 3-O-propagyl xylofuranosyl
derivatives as key synthons. Thus, diacetone-D-glucose (1,
Scheme 1) was subjected to O-propargylation (propargyl
bromide/sodium hydride), which was followed by selective mild
acidic hydrolysis of the primary acetonide (75% acetic acid
aqueous soln.) to furnish the 5,6-diol 2. Oxidative cleavage of 2
with sodium periodate and subsequent reduction of the formed
dialdofuranose with sodium borohydride afforded the 3-O-
propargyl xylofuranose 3. “Click” 1,3-dipolar cycloaddition
between 3 and benzyl azide in the presence of a copper
iodide/Amberlyste A-21 catalytic system provided the N-benzyl
triazole derivative 4 in quantitative yield.
isonucleosides of types
A and related isonucleotides C,
comprising a benzyltriazole motif linked by an oxymethylene
spacer to the xylofuranose unit at C-3 (3ʹ-O-methyl-branched
isonucleosides), and in 5ʹ-isonucleosides B containing hydroxy-,
amino- or bromomethyl triazole systems.
A
terminal
aminomethyl triazole isonucleoside was previously reported as a
moderate acetylcholinesterase inhibitor,[13c] which shows the
biological interest of this type of structure.
The synthesis of C-5 functionalized derivatives of this
isonucleoside was then exploited. In order to increase its
lipophilicity, a dodecyl moiety was introduced at OH-5 through
alkylation (dodecyl bromide/sodium hydride), affording 5.
Phosphorylation of the 3-O-propargylated derivative 3 with
diethyl phosphorochloridate in the presence of trimethylamine
and 4-dimethylaminopyridine (DMAP) gave the corresponding
phosphate triester 6, which upon Cu(I)-catalyzed cycloaddition
with benzyl azide provided the triazole-containing isonucleoside
5ʹ-diethyl phosphate 7 in 92% yield. On the other hand,
treatment of 3 with diphenylphosphoryl azide in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in toluene at 40 ºC
afforded the 5-O-diphenylphosphono xylofuranose derivative 8.
Even at a prolonged reaction time (16 h), no formation of a
secondary product resulting from the nucleophilic replacement of
the phosphate group by the azide anion occurred, as reported
for this methodology,[25] being the xylofuranos-5-yl diphenyl
phosphate 8 obtained as the sole product in 68% yield. Further
“click” cycloaddition with benzyl azide furnished the 5ʹ-diphenyl
Moreover, the triazole unit was also aimed as a potential neutral
and rather stable surrogate of a phosphate group in compounds
of types D and E. Such bioisosteric replacement was already
demonstrated to be feasible in the mimicry of glycosyl
phosphates,[22] nucleic acid oligonucleotides,[23] nucleoside
mono- or diphosphates,[21d] or nucleoside triphosphates.[24] Non-
charged phosphate group analogs such as di-O-ethyl/phenyl
phosphate, di-O-ethyl phosphoramidate or phosphonate
moieties were installed in the molecules, which may solve
polarity and low cell-penetrating ability concerns. Moreover, the
di-O-alkyl/aryl phosph(on)ate and phosphoramidate moieties
may undergo intracellular cleavage by phosphodiesterase-
mediated hydrolysis, releasing the free phosph(on)ate and
phosphoramidate isonucleosides, similarly to what occurs with
ester-type
nucleoside
phosph(on)ate
prodrugs.[11b]
In
compounds of types D and E, the combination of a phosphate
group analog with a triazole unit was intended to establish new
potential neutral diphosphate mimetics of higher stability, namely
the (triazolyl)methyl phosphate, phosphoramidate and
phosphonate systems. The (triazolyl)methyl phosphonate
fragment may render the molecules particularly stable due to
their non-hydrolytically cleavable P-C bond, which encouraged
the synthesis of prospective nucleoside diphosphate mimetics of
type E. Motivated by previous studies showing the biological
phosphate isonucleoside
9 in 74% yield, as a diphenyl
counterpart of isonucleotide 7.
efficacy of 3-O-benzyl and 3-O-dodecyl-containing furanosyl
8c, 13e]
nucleoside analogs,[8b,
3-O-benzyl and 3-O-dodecyl
groups were included in molecules having a xylofuranos-5ʹ-yl
triazole scaffold.
2
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structure of 12 (B, Figure 2) was compared with the X-ray
structure (A, Figure 2) and the agreement was excellent with a
root-mean square deviation (RMSD) of atomic positions of ~
0.09 Å (see Figure S37, in the Supporting Information). The
calculated values for the enthalpy (ΔH) and free energy (ΔG) of
the 1,4-disubstituted regioisomer (C, Figure 2) in toluene are
higher by ca. 55 kcal/mol relative to those obtained for the 1,5-
regioisomer (B, Figure 2), thereby supporting the observed
regioselectivity and indicating that 12 is most certainly the
thermodynamic product (Table 1). Similar energy differences in
favour of the 1,5-regioisomer were obtained when chloroform
was considered as solvent in the study, indicating that solvent
polarity has no effect on the regiochemical course of this
intramolecular 1,3-dipolar cycloaddition.
Scheme 1. Reagents and conditions: (a) C3H3Br, NaH, DMF, r. t., 16 h; (b)
AcOH (75% aq. soln.), r. t. 16 h., 96%, 2 steps. (c) NaIO4, THF/H2O (3:1), r. t.
4 h; (d) NaBH4, EtOH/H2O (2:1), r. t., 1 h, 57%, 2 steps; (e) BnN3, CuI/A-21,
CH2Cl2, r. t., 24 h, 98% (4), 92% (7), 74% (9); (f) C12H25Br, NaH, DMF, r. t., 16
h, 95%; (g) ClPO(OEt)2, NEt3, DMAP, CH2Cl2, r. t., 16 h, 98%; (h) DPPA, DBU,
toluene, r. t., 24 h, then 40 ºC, 16 h, 68%.
Since the installation of the N-benzyltriazole moiety on the
bisfuctionalized template 11 towards the desired 5-azido
isonucleoside appeared not to be feasible, an alternative
pathway consisting on the introduction of an azide functionality
on
the
5-hydroxylated
3-O-(N-benzyltriazolyl)methyl
For the synthesis of an isonucleoside phosphoramidate analog
of isonucleotide 7, the use of the 5-azido 3-O-propargyl
xylofuranose derivative 11 as precursor was firstly attempted
(Scheme 2). It was synthesized by 3-O-propargylation (propargyl
isonucleoside 4 was undertaken. Thus, 4 was subjected to a
sequence of tosylation (tosyl chloride/pyridine) and nucleophilic
displacement with sodium azide, leading to 14 in 78% overall
yield. Staudinger-type reaction of 14 with triethyl phosphite
afforded quantitatively the isonucleoside 5-phosphoramidate 15.
bromide/sodium
hydride)
of
5-azido-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranose (10),[26] which was completed
within a considerable shorter reaction time (5 min) than that
previously reported (2 h) under similar conditions.[27] However,
due to the presence of both alkynyl and azide moieties, this
compound was found to be unstable at room temperature and in
dichloromethane solution in the presence of the CuI/A-21
catalyst, envolved towards the fused tetracyclic 1,5-
dissubstituted triazole 12 through intramolecular 1,3-dipolar
cycloaddition. The 13C NMR signals for C-4 and C-5 of the
triazole moiety at 132.2 ppm and 135.2 ppm, respectively, were
indicative of a 1,5-disubstituted derivative,[28] while the fused
system in 12 was confirmed by the HMBC correlations between
protons H-5 of the sugar moiety with C-5 of the triazole unit and
between the oxymethylenic protons and both C-4/C-5 of the
triazole motif. The sole formation of 12 was previously reported
via an intramolecular thermal Huisgen cycloaddition of 11 in
toluene at 100 ºC, [27,29] a protocol which in our hands led to 12 in
67% yield.
Scheme 2. Reagents and conditions: (a) C3H3Br, NaH, DMF, r. t., 5 min.,
95%; (b) toluene, 100 ºC, 2 h, 67%; (c) TsCl, py, r. t., 16 h; (d) NaN3, DMF, 80
ºC, 16 h, 78%, 2 steps; (e) P(OEt)3, CH2Cl2, r. t., 48 h, 96%.
Although our NMR data for this compound were in conformity
with those reported,[27] no concordance was verified between our
single crystal X-ray structure (CCDC number 2004694, A,
Figure 2) with the published structure (CSD refcode DAQJOV;
CCDC number 264130) which corresponds to the L-xylo-
configured derivative (see Figure S36, in the Supporting
Information). The crystal structure of 12 obtained in this work
corresponds to the D-xylo-configured molecule with a fused
tetracyclic framework containing
a 7-membered ring (1,4-
oxazepane) between the triazole motif and the xylofuranose ring,
which adopts a C3-endo conformation. The bond lengths and
angles for the two enantiomers are analogous (see CIF file).
To gain insight into the observed experimental regioselectivity in
the thermal cycloaddition, density functional theory (DFT)
calculations (PBE1PBE/6-311G**) were performed on 1,5- and
1,4-disubstituted triazoles (12, 13) to investigate their relative
stability. The three-dimensional structures of 12 and 13 were
built using Pymol[30] and geometry optimization (B, C, Figure 2)
was performed using Gaussian 09[31] (see Computational Details
in the Exptl. Sect. for more informations). The DFT-optimised
Figure 2. (A) X-ray molecular structure of 12. (B, C) Optimized structures of
12 and 13 in toluene (PBE1PBE/6-311G**).
3
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coupling (2Ja,b = ca. 13 Hz) and the individual couplings with the
phosphorous atom (JH-a,P = 9.2 Hz and JH-b,P = 8.4 Hz). Moreover,
the 13C NMR signals for the triazole quaternary carbon atom
atoms (C-4 or C-5) of the (triazolyl)methyl phosphates 24-27
appeared as doublets due to coupling with the phosphorous
atom (JC,P = ca.7.5 Hz).
Table 1. Calculated enthalpy and Gibbs free energy for structures B and C.
The values for the lowest energy regioisomer (12, structure B) were set as
reference.
1,5-disubstituted
1,4-disubstituted
triazole (B)
triazole (C)
ΔH (kcal/mol)
ΔG (kcal/mol)
0
0
55.7
55.1
5-Azido xyfuranoses were the precursors used for the synthesis
of a variety of xylofuranos-5ʹ-yl triazole isonucleosides B (Figure
1) and their derivatives comprising phosphate, phosphoramidate
or phosphonate groups as potential mimetics of sugar
diphosphates (D, Figure 1). Thus, the 5-azido 3-O-benzyl and 3-
O-dodecyl xylofuranose derivatives (18, 19) were synthesized by
tosylation of the partially protected xylofuranoses 16[13e] and
17[8c] and subsequent tosylate substitution with sodium azide
(Scheme 3). Thermal cycloaddition between the 3-O-benzylated
precursor 18 and propargyl alcohol in refluxing toluene afforded
the 4-hydroxymethyl-1-xylofuranosyl triazole 20 and the 1,5-
regioisomer 21 in 46% and 36% yields, respectively, which were
clearly identified based on the 13C NMR chemical shifts of their
triazole carbon signals. While in the 1,4-disubstituted triazole 20,
the signals for C-4 and C-5 appeared at 147.5 ppm and 123.0
ppm, respectively, in the 1,5-dissubstituted counterpart 21, C-4
and C-5 resonated at 133.3 ppm and 137.3 ppm, respectively.
These characteristic 13C NMR chemical shift differences
between 1,4- and 1,5-disubstituted triazoles were considered for
the structural assignment of the different regioisomers of the
further triazole derivatives described below.
Scheme 3. Reagents and conditions: (a) TsCl, py, r. t., 16 h; (b) NaN3, DMF,
80 ºC, 16 h, 80% (18), 77% (19)[8c], 2 steps; (c) C3H3OH, toluene, 110 ºC, 24 h,
46% (20), 36% (21), or 48 h, 54% (22), 31% (23); (d) ClPO(EtO)2, NEt3, DMAP,
CH2Cl2, r. t., 16 h, 78% (24), 68% (25), 81% (26), 93% (27).
Compound 20 was obtained as colourless crystals (prisms),
allowing its X-ray crystallographic analysis which confirmed the
1,4-regiochemistry at the triazole unit and revealed that the
xylofuranose ring adopts a C3-endo conformation (CCDC
number 2004693, Figure 3a). The crystal packing of this
C11(5)
compound revealed that the molecules forms
infinite
linear chains that are sustained by a OHN1 hydrogen bond
(dOHN1 = 2.02(5) Å) (Figure 3b). This motif is reinforced by a
non-classical H-bond C3HN2 (dC3HN2 = 2.59(3) Å). The overall
packing is completed by other four non classical H-bonds of the
type CHO (two intermolecular bonds), CHN and CH
(dC1HO4 = 2.47(4) Å, dC7HO1 = 2.49(3) Å, dC16HN2 = 2.62(3) Å,
Figure 3. (a) X-ray molecular structure of the 4-hydroxymethyl-1-xylofuranosyl
1
triazole 20; (b)
hydrogen bonds.
infinite chain synthon that is formed through OHN1
C1 (5)
The 5-O-protected azido furanoses 18 and 19 were also
subjected to thermal cycloaddition with propargylamine in
refluxing toluene (Scheme 4). The 5-azido-3-O-benzyl
xylofuranose derivative 18 were converted within 24 h into the 4-
and 5-aminomethyl-1-xylofuranosyl triazoles 28-29 in a modest
total yield of 6% and in a regioisomeric ratio of 1:1. This low
conversion could not be improved either with longer reaction
times or with an increase in the amount of propargylamine, with
most of 18 remaining unreacted. The 1,5-regioisomer 29 could
not be isolated, being inseparably contaminated with traces of
the starting material. On the other hand, when the 3-O-
dodecylated derivative 19 was subjected to similar cycloaddition
conditions, the 1,4- and the 1,5-disubstituted triazoles 30 and 31
were obtained in 20% yield each. Treatment of the
aminomethyltriazole 5ʹ-isonucleosides 28, 30 and 31 with diethyl
phosphorochloridate furnished the expected phosphoramidate
derivatives 32-34 in moderate yields (50-56%). The reaction
proceeded reasonably without base. In fact the addition of
dC12H
= 3.3(1) Å, respectively). A similar cycloaddition
procedure was applied to the 3-O-dodecyl counterpart 19,
leading again to the 1,4-disubstituted triazole 22 in a higher yield
(54%) than that obtained for the 1,5-dissubstituted congener 23
(31%).
The hydroxymethyltriazole 5ʹ-isonucleosides 20-23 were then
subjected to phosphorylation with diethyl phosphorochloridate
under basic conditions as already mentioned for 3. The
corresponding [(xylofuranos-5-yl)triazolyl]methyl phosphates 24-
27 were obtained in good to excellent yields (68-93%).
It is noteworthy to mention that in the case of the 1H NMR
spectra of the 4-phosphonoxymethyl-1-xylofuranosyl triazoles 24
and 26, the signal corresponding to the protons of the
oxymethylene group linked to the triazole unit appeared as a
doublet at ca. 5.2 ppm with a coupling constant of JCH2,P = 8.8 Hz,
while in the case of the 1,5-disubstituted regioisomers 25 and 27,
these protons resonated as doublet of doublets each (δ = ca. 5.3
and 5.2 ppm) from an ABX system resulting from the geminal
4
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trimethylamine and DMAP to the reaction medium proved to
promote the formation of side products, as detected by TLC.
In the 1H NMR spectra of the 4-phosphonoaminomethyl-1-
xylofuranosyl triazoles 32 and 33, the aminomethylenic protons
appeared as a doublet of doublet at ca. 4.2 ppm with coupling
with the phosphorous atom (JCH2,P = ca. 11 Hz) and with the
interaction (dC1HN2 = 2.40 Å). In these chains the adjacent
molecules are rotated 180º in order to have a more effective
packing (Figure 4b). These chains are linked to neighboring
ones by non-classical hydrogen bonds of the type CHO
(dC6HO1 = 2.53 Å and dC4HO2 = 2.64 Å) and of the genre CH
between the triazole group and the phenyl group (dC3H = 3.03
Å), fulfilling the 3D packing.
nitrogen-bound proton (JCH2 NH = 7 Hz). On the other hand, the
,
methylenic protons in the 1,5-disubstituted triazole 34 gave
A distinct 13C NMR spectral feature observed for the 1,4- and
1,5-regioisomers is the chemical shift for the bromomethylenic
carbon, which appears at ca. δ 21.7-21.8 ppm in the 4-
bromomethyl triazole derivatives 35/37 and at δ 17.5 ppm in the
5-bromomethyl congeners 36/38.
The different regiochemical outcome of the 1,3-dipolar
cycloaddition reactions of 18-19 with propargyl bromine
relatively to that achieved when using propargyl alcohol and
propargylamine, may be explained by the possibility of
stabilization of the 1,5-disubstituted hydroxy- (21, 23) and
aminomethyl (29, 31) triazole derivatives through hydrogen bond
interactions between the terminal hydroxyl or amino groups and
the furanose endocyclic oxygen atom. In the 5-bromomethyl-1-
xylosyl triazoles, not only these interactions are absent, but also
lone pair repulsions between the bromine and the ring oxygen
atoms, which are closer in the 1,5-regioisomers, may destabilize
their formation, resulting therefore in a high regioselectivity for
the 1,4-disubstituted derivatives.
signals corresponding to the parts A and B of an ABMX system
(ABM = 1H, X = 31P), showing the geminal coupling (2Ja,b
=
15.7) in addition to the individual 3J couplings with the
phosphorous atom (JH-a,P = 9.5, JH-b,P = 12.1) and with the
phosphonoamino proton (JH-a,NH = 9.5, JH-b,NH = 5.4). Similarly to
that observed in the 13C NMR spectra of their phosphate
counterparts 24-27, the triazole quaternary carbon atoms of the
(triazolyl)methyl phosphoramidates 32-34 resonated as doublets
with JC,P = ca. 6 Hz.
The bromomethyl triazoles 35, 37 and 38 were submitted to a
Michaelis-Arbuzov reaction with triethylphosphite at 110 ºC to
afford the [(xylofuranos-5-yl)triazolyl]methyl phosphonates 39-41
in yields ranging from 76% to 96%.
In the 1H NMR spectra of 39-41, the phosphonomethylenic
protons resonate between δ 3.5 to 3.2 ppm as parts A and B of
an ABX system, with geminal couplings (2Ja,b) of ca. 21 Hz and
individual three-bond 31P-1H couplings (JH-a,P and JH-b,P) of ca. 16
Hz. Their 13C NMR spectra showed both quaternary and
methinic carbon atoms of the triazole units resonating as
doublets with JC,P of ca. 7 Hz and 3-4 Hz, respectively. Moreover,
a large JC,P coupling of ca. 143-144 Hz was detected for the
phosphonomethylenic carbon atoms, whose signals appeared at
δ 24.3 ppm in the 1,4-dissubstituted phosphonomethyl triazoles
39-40 and at 21.9 ppm in the 1,5-disubstituted derivative 41.
The structural arrangement of [(furanos-5-yl)triazolyl]methyl
phosphonates as potential stable mimetics of sugar
Scheme 4. Reagents and conditions: (a) propargylamine, toluene, 110 ºC, 24
h, 3% (28), 3% (29), or 16 h, 20% (30), 20% (31); (b) ClPO(EtO)2, CH2Cl2, r.t.,
2 h, 56% (32), 50% (33), 52% (34).
diphosphates
comprising
a
hydrolytically-resistant
(triazolyl)methyl phosphonate system, motivated the insertion of
a nucleobase at the anomeric position at the skeleton towards
prospective nucleotide mimetics of type E (Figure 1). A 7-
methylguanosine-based molecule of this type of structure was
previously synthesized through cycloaddition between 5-azido
methylguanosine and propargylphosphonate in the context of
accessing potential inhibitors of a cytosolic 5ʹ-nucleotidase.[21d]
Thus, compounds 39-40 were converted into the corresponding
1,2-di-O-acetyl xylofuranosyl donors 42-43 through acidic
hydrolysis (65% trifluoroacetic acid aqueous soln.) of the 1,2-
acetonide group followed by acetylation (Ac2O/pyridine). Further
Vorbrüggen-type N-glycosidation[32] with uracil, which was
activated by silylation with bis(trimethylsilyl)acetamide (BSA),
was performed in the presence of trimethylsilyl triflate (TMSOTf)
in acetonitrile using a previously described microwave-assisted
protocol (65 ºC, 150 W, Pmax 250 Psi),[13a,13b] leading to the N1-
linked uracil nucleosides 44 and 45 in yields of 36% and 16%,
respectively. HMBC correlations between the anomeric proton
Towards the access to phosphonate analogs of 24-27 and 32-34,
the 5-azido xylofuranoses 18 and 19 were engaged in thermal
cycloaddition with propargyl bromide (Scheme 5). The reactions
employing both the 3-O-benzyl and 3-O-dodecyl precursors led
to 4-bromomethyl-1-xylosyl-1,2,3-triazoles 35, 37 as major
products in moderate yields (48-58%), along with the 1,5-
disubstituted regioisomers 36 and 38 obtained in only 2% and
5% yields, respectively.
X-ray diffraction analysis of the crystals obtained for the 3ʹ-O-
benzyl bromomethyl triazole 5ʹ-isonucleoside 35 proved its
structure in which the xylofuranose ring is in the C3-endo
conformation (CCDC number 2004692, Figure 4a). Although in
the packing of this compound the only intermolecular contacts
observed are non-classical H-bonds, there are similarities
between the crystalline structures of compounds 20 and 35. The
C11(5)
3D arrangement of 35 is composed by
infinite non linear
chains which are supported by
a non-classical C1HN2
5
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10.1002/cplu.202000424
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(H-1) and both C-2/C-6 of the uracil unit confirmed the
regiochemistry of the nucleosidic linkage.
3ʹ-O-Methyl-branched N-benzyltriazole isonucleosides and their
isonucleotides comprising 5ʹ-di-O-ethyl/phenyl phosphate and 5ʹ-
di-O-ethyl phosphoramidate groups, which are previously
unreported types of structural frameworks, were accessed by
efficient synthetic pathways from a 1,2-diacetonide-protected 3-
O-propargyl xylofuranose precursor. The CuI/Amberlyst A21-
catalyzed cycloaddition reactions with benzyl azide occurred in
high yields (92-98%) for the partially protected 3-O-propargyl
xylofuranose derivative and for its corresponding xylofuranos-5-
yl diethyl phosphate, while the xylofuranos-5-yl diphenyl
phosphate led to the corresponding triazole-containing
isonucleotide in a relatively lower yield (74%) most likely due to
the hiher steric hindrance arising from the diphenyl phosphate
moiety.
Triazole xylofuranos-5ʹ-yl isonucleosides containg C4/C5-linked
hydroxy-, amino- or bromomethyl groups were synthesized from
5-azido 1,2-O-isopropylidene xylofuranoses containing 3-O-
benzyl or 3-O-dodecyl groups. In general lower total yields (6%-
82%) were obtained for the thermal cycloaddition reactions
starting from the 3-O-benzylated xylofuranose precursor than
when using the 3-O-dodecyl counterpart (40-85%), which
reflects the higher steric constrain created by the O-benzyl
substituent. Significant lower conversions were achieved when
using propargyl amine, which is in accordance with its lower
electron-deficient character relatively to that of propargyl alcohol
or propargy bromide, being therefore the less reactive propargyl
derivative herein used in the Huisgen cycloaddition reactions.
Hydrogen-bond interactions, which may stabilize 5-hydroxy- and
5-aminomethyl-1-xylosyl triazoles, and lone electron pair
repulsions, which eventually destabilize their bromomethyl
counterparts, might explain the higher regioselectivity to 1,4-
dissubstitued triazoles when using propargyl bromide.
Figure 4. (a) X-ray molecular structure of the bromomethyl triazole 5ʹ-
1
isonucleoside 35; (b)
infinite non-linear chains that compose the 3D
C1 (5)
packing of this compound.
The
isonucleosides were efficiently converted into their [(xylofuranos-
5ʹ-yl)triazolyl]methyl phosphate, phosphoramidate and
hydroxy-,
amino-
and
bromomethyl
5ʹ-triazole
phosphonates, respectively, in which the structural fragment
linked at the furanose unit at C-5 is envisioned as potential and
relatively stable bioisostere of a disphosphate moiety. The
(triazolyl)methyl phosphoramidate skeleton is herein reported for
the first time. N-Glycosylation of uracil with 1,2-di-O-acetylated
5-[4-(phosphonomethyl)triazolyl] xylofuranoses afforded the
corresponding N1-linked uracil nucleosides as nucleotide-like
molecules. The low yields (16-36%) obtained in the
nucleosidation reactions may be due to the presence of the
electron-withdrawing (triazolyl)methyl phosphonate moiety in the
glycosyl donors, which affects their reactivity by destabilizing the
intermediate glycosyl oxocarbenium ion formed during the
reaction.
Scheme 5. Reagents and conditions: (a) C3H3Br, toluene, 110 ºC, 16 h, 48%
(35), 2% (36), or 48 h, 58% (37), 5% (38); (b) P(EtO)3, 110 ºC, 3 h, 83% (39),
96% (40), 76% (41); (c) TFA (65% aq. soln), r.t., 2 h (d) Ac2O, py, r.t., 1.5 h,
51% (42), 68% (43), 2 two steps; (e) uracil, BSA, TMSOTf, CH3CN, 65 °C,
MW, max. 150 W, 45 min, 36% (44), 16% (45).
In view of the bioactivity profile of nucleoside and nucleotide
analogs, the structures of the newly synthesized compounds,
which include innovative skeletons, make them interesting
candidates for biological evaluation.
Conclusion
Experimental Section
This contribution showed the synthesis of a diversity of new
isonucleosides, isonucleotides and potential nucleotide mimetics
based on xylofuranosyl moieties and containing a 1,2,3-triazole
unit, comprising a total of 30 molecules.
Chemistry
General methods: Chemicals were purchased from Sigma-Aldrich and
Alfa Aesar. The progress of the reactions was monitored by thin layer
chromatography (TLC) using Merck 60 F254 silica gel aluminum plates
6
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10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
with detection under UV light (254 nm) and/or by immersion on a solution
of 10 % H2SO4 in EtOH or with the Hanessian stain (solution of cerium
(IV) sulfate (0.2% w/v) and ammonium molybdate (5% w/v) in H2SO4 (6%
aq.) followed by heating (200 ºC). Flash column chromatography was
performed on silica gel 60 G (0.040–0.063 mm, E. Merck). NMR spectra
were acquired with a BRUKER Avance 400 spectrometer operating at
400.13 MHz for 1H, 100.62 MHz for 13C and at 161.91 MHz for 31P.
Chemical shifts are given in parts per million and are reported relative to
internal TMS, in the case of 1H NMR spectra in CDCl3, or relative to the
respective solvent peak as reference. 31P NMR Spectra were calibrated
according to the IUPAC recommendations for chemical shift
referencing.[33] Coupling constants (J) are reported in Hertz (Hz). Signal
assignments were made with aid from 2D NMR experiments (COSY,
HSQC, HMBC). High-resolution mass spectrometry (HRMS) analyses
1), 82.4 (C-2), 82.2 (C-3), 80.1 (C-4), 79.0 (C-2′), 75.6 (C-3′), 60.7 (C-5),
57.5 (C-1′), 26.9, 26.4 (2 × CH3, i-Pr). HRMS: calcd. for C11H18O5 [M +
Na]+ 251.0890; found 251.0895.
General procedure for the CuI/Amberlyst A-21 catalyzed
cycloaddition between 3-O-propargyl xylofuranose derivatives and
benzyl azide: To a solution of 3-O-propargyl derivative (0.88 mmol) in
CH2Cl2 (5 mL) under nitrogen atmosphere, benzyl azide (0.14 mL, 1.06
mmol) and CuI/Amberlyst A-21 (0.5 mmol.g–1, 0.1 mmol CuI, 200 mg)
were added. The mixture was stirred at room temperature for 24 h. The
catalyst was filtered off, the solvent was evaporated and the crude
residue was subjected to column chromatography.
3-O-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl-1,2-O-isopropylidene-α-D-
xylofuranose (4): Obtained according to the general CuI/A21
cycloaddition procedure, starting from 1,2-O-isopropylidene-3-O-
propargyl-α-D-xylofuranose (3, 200 mg, 0.88 mmol), benzyl azide (0.14
mL, 1.06 mmol) and in the presence of CuI/A-21 catalyst (0.1 mmol CuI,
200 mg). Purification by column chromatography (EtOA/petroleum ether,
1:1) afforded the title compound (310 mg, 98%) as a colourless oil.
were performed on
a High Resolution QqTOF Impact II mass
spectrometer from Bruker Daltonics equipped with an electrospray ion
source (ESI). Spectra were recorded in positive mode with external
calibration. Melting points were determined with a Stuart Scientific SMP 3
apparatus and are uncorrected. Optical rotations (589 nm, 20 ºC) were
acquired on a Perkin–Elmer 343 polarimeter.
20
1
= ‒ 33 (c = 1, in CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.48 (s, 1


D
1,2-O-isopropylidene-3-O-propargyl-α-D-glucofuranose (2): To
a
H, H-3′), 7.42-7.33 (m, 3 H, Ph), 7.31-7.23 (m, 2 H, Ph), 5.92 (d, 1 H, H-1,
3J1,2 = 3.7), 5.52 (s, 2 H, CH2Ph), 4.81 (d, 1 H, part A of AB system, H-1′a,
2J1′a,1′b = 12.9), 4.67-4.59 (m, 2 H, H-1′b, H-2), 4.32 (ddd, 1 H, H-4), 4.08
(d, 1 H, H-3, J3,4= 3.3), 3.91-3.77 (m, 2 H, CH2-5, J5a,5b = 11.7, J4,5a
7.0, 3J4,5b = 5.5), 1.46 (s, 3 H, CH3, i-Pr), 1.29 (s, 3 H, CH3, i-Pr) ppm. 13
solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (1, 3 g, 11.5
mmol) in DMF (20 mL), at 0º C and under nitrogen atmosphere, sodium
hydride (60% 0.55 g, 13.8 mmol) was added. After stirring during 10 min,
propargyl bromide (80 wt.% soln. in toluene, 1.49 mL, 13.8 mmol) was
added. The reaction was stirred at room temperature overnight. Then, it
was diluted with diethyl ether and water was added. The phases were
separated and the aqueous phase was extracted with diethyl ether (2 ×).
The combined organic layers were died with anhydrous MgSO4, filtered
and the solvent was evaporated in vacuum. The obtained crude was
dissolved in aq. acetic acid soln (75%, 30 mL) and the reaction mixture
was stirred at room temperature overnight. After co-evaporation with
toluene, the residue was purified by column chromatography
3
2
3
=
C
NMR (100 MHz, CDCl3): δ 144.6 (C-2ʹ), 134.3 (Cq, Ph), 129.2, 128.9,
128.1 (CH, Ph), 122.3 (C-3ʹ), 111.7 (Cq, i-Pr), 105.1 (C-1), 82.4 (C-2),
82.3 (C-3), 80.1 (C-4), 63.1 (C-1ʹ), 59.5 (C-5), 54.4 (CH2Ph), 26.8, 26.3
(2 × CH3, i-Pr). HRMS: calcd. for C18H23N3O5 [M + H]+ 362.1710, found
362.1713; calcd. for C18H23N3O5 [M + Na]+ 384.1530; found 384.1532.
3-O-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl-5-O-dodecyl-1,2-O-
isopropylidene-α-D-xylofuranose (5): To a solution of 3-O-(1-benzyl-
1H-1,2,3-triazol-4-yl)methyl-1,2-O-isopropylidene-α-D-xylofuranose (4, 30
mg, 0.08 mmol) in DMF (2 mL), at 0º C and under nitrogen atmosphere,
sodium hydride (60%, 4 mg, 0.1 mmol) was added. After stirring during
10 min, dodecyl bromide (0.02 mL, 0.12 mmol) was added. The reaction
was stirred at room temperature overnight. Then, it was diluted with
diethyl ether and water was added. The phases were separated and the
aqueous phase was extracted with diethyl ether (2 ×). The combined
organic layers were died with anhydrous MgSO4, filtered and the solvent
was evaporated in vacuum. The residue was purified by column
chromatography (EtOAc/hexane, 1:3) to afford the title compound (42 mg,
(EtOAc/hexane, 1:4) to afforded the title compound (2.85 g, 96%, 2
= ‒ 35 (c =1, in CH2Cl2). 1H NMR (400 MHz,
20
steps) as a yellow oil.
 D

CDCl3): δ 5.90 (d, 1 H, H-1, 3J1,2 = 3.4), 4.60 (d, 1H, H-2), 4.34 (br. d, 1 H,
H-1′a, 2J1ʹa,1ʹb = 15.9), 4.27- 4.20 (m, 2 H, H-3, H-1′b), 4.15 (dd, 1 H, H-4,
3J3,4 = 2.8, 3J4,5 = 8.2), 3.97 (ddd, 1 H, H-5), 3.87 (dd, part A of AB system,
2
3
3
1 H, H-6a, J6a,6b = 11.5, J5,6a = 2.5), 3.75 (ddd, 1 H, H-6b, J5,6b = 5.7),
2.64-2.42 (m, 3 H, H-3′, OH-5, OH-6), 1.49 (s, 3 H, CH3, i-Pr), 1.31 (s, 3
H, CH3, i-Pr). 13C NMR (100 MHz, CDCl3): δ 112.1 (Cq, i-Pr), 105.3 (C-1),
82.2 (C-2), 81.6 (C-3), 79.9 (C-4), 79.2 (C-2′), 75.7 (C-3′), 69.1 (C-5),
64.4 (C-6), 57.7 (C-1′), 26.8, 26.3 (2 × CH3, i-Pr). HRMS: calcd for
C12H18O6 [M + H]+ 259.1176, found 259.1181; calcd. for C12H18O6 [M +
Na]+ 281.0996; found 281.1003.
95%) as a white solid.
ºC. H NMR (400 MHz, CDCl3): δ 7.44 (s, 1 H, H-3′), 7.42-7.32 (m, 3 H,
20 = ‒ 15 (c = 1, in CH2Cl2). m.p.: 42.7‒43.4
 D

1
3
Ph), 7.30-7.22 (m, 2 H, Ph), 5.87 (d, 1 H H-1, J1,2 = 3.7), 5.51 (s, 2 H,
CH2Ph), 4.75 (d, part A of AB system, 1 H, H-1ʹa, 2J1ʹa,1ʹb = 12.4), 4.65 (d,
of AB system, 1 H, H-1ʹb), 4.60 (d, 1 H, H-2), 4.33 (td, 1 H, H-4), 3.99 (d,
1 H, H-3, 3J3,4 = 3.0), 3.65-3.54 (m, 2 H, CH2-5, 2J5a,5b = 10.1, 3J4,5a = 6.2,
J4,5b = 6.0), 3.48-3.32 (m, 2 H CH2-1′′), 1.57-1.44 (m, 5 H, CH2-2′′, CH3, i-
Pr), 1.34-1.17 (m, 21 H, CH3, i-Pr, CH2-3ʹʹ to CH2-11ʹʹ), 0.87 (t, 3 H, CH3-
12ʹʹ, J = 6.8). 13C NMR (100 MHz, CDCl3): δ 145.3 (C-2′), 134.6 (Cq, Ph)
129.3, 128.9, 128.2 (CH, Ph), 122.4 (C-3′), 111.8 (Cq, i-Pr), 105.1 (C-1),
82.5 (C-2), 82.2 (C-3), 79.0 (C-4), 71.9 (C-1ʹʹ), 67.8 (C-5), 64.0 (C-1ʹ),
54.3 (CH2Ph), 32.0, 29.8, 29.8, 29.7, 29.6, 29.5 (C-2′′ to C-9′′) 26.9, 26.4
(2 × CH3, i-Pr), 26.2 (C-10ʹʹ), 22.8 (C-11ʹʹ), 14.3 (C-12ʹʹ). HRMS: calcd for
C30H47N3O5 [M + H]+ 530.3588, found 530.3594; calcd for C30H47N3O5 [M
+ Na]+ 552.3408, found 552.3421.
1,2-O-Isopropylidene-3-O-propargyl-α-D-xylofuranose (3): To
a
solution of 1,2-O-isopropylidene-3-O-propargyl-α-D-glucofuranose (2,
2.85 g, 11 mmol) in THF/H2O (22 mL, 3:1) at 0 ºC, sodium metaperiodate
(NaIO4, 4 g, 18.7 mmol) was added and the mixture was stirred at room
temperature for 4 h. The mixture was then diluted with EtOAc and it was
filtered over celite. The phases were separated and the aqueous phase
was extracted with EtOAc (2 ×). The combined organic layers were dried
with anhydrous MgSO4, filtered and concentrated under vacuum. The
resulting residue was dissolved in EtOH/H2O (22 mL, 2:1) and at 0ºC,
sodium borohydride (NaBH4, 567 mg, 15 mmol) was added. The mixture
was stirred at room temperature for 1 h. Then, EtOAc was added. The
mixture was washed with water and the aqueous phase was extracted
with EtOAc (2 ×). The combined organic layers were washed with brine
soln. and were dried with anhydrous MgSO4. After filtration and
evaporation of the solvents under vacuum, the residue was subjected to
Diethyl
(5-deoxy-1,2-O-isopropylidene-3-O-propargyl-α-D-
xylofuranos-5-yl)phosphate (6): To a solution of 1,2-O-isopropylidene-
3-O-propargyl-α-D-xylofuranose (3, 100 mg, 0.44 mmol) in
dichloromethane (5 mL) under nitrogen atmosphere, triethylamine (0.09
mL, 0.66 mmol) was added. The mixture was cooled at 0 ºC and diethyl
phosphorochloridate (0.08 mL, 0.53 mmol) and DMAP (catalytic amount,
a spatula tip) were added. The solution was stirred at room temperature
for 16 h. Then, water was added to the solution, the phases were
column chromatography (EtOAc/hexane, 1:4) to afford the title compound
20
(1.44 g, 57%, 2 steps) as a colourless oil.
= ‒ 62 (c = 1, in CH2Cl2).

 D
1H NMR (400 MHz, CDCl3): δ 5.84 (d, 1 H, H-1, 3J1,2 = 3.0), 4.54 (d, 1 H,
H-2), 4.27-4.15 (m, 2 H, H-4, H-1′a, 2J1ʹa,1ʹb = 16.4), 4.16-4.04 (m, 2 H, H-
1′b, H-3), 3.83-3.69 (m, 2 H, CH2-5, 2J5a,5b = 11.8, 3J4,5a = 5.9, 3J4,5b = 5.4),
2.80 (br. s, 1 H, OH), 2.47 (m, 1 H, H-3′), 1.41 (s, 3 H, CH3, i-Pr), 1.23 (s,
3 H, CH3, i-Pr). 13C NMR (100 MHz, CDCl3): δ 112.0 (Cq, i-Pr), 105.2 (C-
7
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10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
separated and the aqueous phase was extracted with CH2Cl2. The
combined organic layers were dried with anhydrous MgSO4, filtered and
the solvent was evaporated under vacuum. Purification by column
chromatography (EtOAc/hexane, 1:3) afforded the title compound (157
afforded the title compound (118 mg, 74%) as a colourless oil.
20 = ‒
 D

1
21 (c = 1, in CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.54 (s, 1 H, H-3′),
7.39-7.12 (m, 15 H, 3 × Ph), 5.90 (d, 1 H, H-1, J1,2 = 3.6), 5.49, 5.44 (2 d,
AB system, 2 H, CH2Ph, Ja,b = 15.1), 4.73 (d, part A of AB system, 1 H,
H-1ʹa, J1ʹa,1ʹb = 11.9), 4.65 (d, 1H, H-2), 4.57-4.33 (m, 4 H, H-1ʹb H-4, H-
5a, H-5b), 4.01 (br. s, 1 H, H-3), 1.48 (s, 3 H, CH3, i-Pr), 1.32 (s, 3 H, CH3,
mg, 98 %) as a colourless oil.
20 = ‒ 24 (c = 1, in CH2Cl2). 1H NMR
 D

3
(400 MHz, CDCl3): δ 5.86 (d, 1 H, H-1, J1,2 = 3.7), 4.58 (d, 1 H, H-2),
4.39 (ddd, 1 H, H-4), 4.24-4.00 (m, 9 H, H-3, H-5a, H-5b, 2 × CH2, Et,
2
i-Pr). 13C NMR (100 MHz, CDCl3): δ = 150.44 (d, Cq, Ph, JC,P = 7.5),
4
4
CH2-1ʹ), 2.47 (t, 1 H, H-3ʹ, J1ʹa,3ʹ = J 1ʹb,3ʹ = 2.3), 1.44 (s, 3 H, CH3, i-Pr),
1.32-1.23 (m, 9 H, 2 × CH3, Et, CH3, i-Pr). 13C NMR (100 MHz, CDCl3): δ
112.0 (Cq, i-Pr), 105.2 (C-1), 82.0 (C-2), 81.1 (C-3), 78.8 (C-2ʹ), 78.7 (d,
150.36 (d, Cq, Ph, 2JC,P = 7.4), 134.6 (Cq, Ph), 129.9, 129.1, 128.8, 128.2,
125.6 (CH, 3 × Ph), 123.0 (C-3ʹ) 120.12 (d, CH-o, Ph, 3JC-P = 4.9), 120.10
3
(d, CH-o, Ph, JC-P = 4.9), 112.1 (Cq, i-Prop), 105.3 (C-1), 81.9 (C-2),
3
2
C-4, JC-4,P = 8.5), 75.5 (C-3′), 64.8 (d, C-5, JC-5,P = 5.3), 63.99 (d, CH2,
Et, 2JC-P = 5.9), 63.97 (d, CH2, Et, 2JC-P = 5.9), 57.5 (C-1′), 26.8, 26.3 (2 ×
81.4 (C-3), 78.2 (d, C-4, 3JC-4,P = 9.4), 65.6 (d, C-5, 2JC-5,P = 5.7), 63.7 (C-
1ʹ), 54.2 (CH2Ph), 26.9, 26.3 (2 × CH3, i-Pr). 31P NMR (162 MHz, CDCl3):
δ ‒ 12.1 ppm. HRMS: calcd for C30H32N3O8P [M + H]+ 594.2000, found
594.2004.
CH3, i-Pr), 16.1 (d, 2 × CH3, 2 × Et, JC,P = 6.9). 31P-RMN (162 MHz,
3
CDCl3): δ ‒ 1.28. HRMS: calcd. for C15H25O8P [M + H]+ 387.1179, found
387.1179; calcd. for C15H25O8P [M + Na]+ 365.1360, found 365.1358.
5-Azido-5-deoxy-1,2-O-isopropylidene-3-O-propargyl-α-D-
Diethyl
[3-O-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-5-deoxy-1,2-O-
(7): Obtained
xylofuranose (11): To
a
solution of 5-azido-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranos-5-yl]phosphate
according to the general CuI/A21 cycloaddition procedure, starting from
5-O-diethylphosphono-1,2-O-isopropylidene-3-O-propargyl-α-D-
xylofuranose (6, 100 mg, 0.27 mmol), benzyl azide (0.06 mL, 0.44 mmol)
in the presence of CuI/A-21 catalyst (0.05 mmol CuI, 100 mg).
Purification by column chromatography (EtOAc/petroleum ether, 1:2)
afforded the title compound (125 mg, 92%) as pale yellow oil.
23 (c = 1, in CH2Cl2). H NMR (400 MHz, CDCl3): δ 7.58 (s, 1 H, H-3′),
7.41-7.25 (m, 5 H, Ph), 5.89 (d, 1 H, H-1, 3J1, 2 = 3.7), 5.55, 5.50 (2 d, AB
isopropylidene-α-D-xylofuranose (10,[26] 600 mg, 2.8 mmol) in DMF (15
mL), at 0º C and under nitrogen atmosphere, sodium hydride (60% in
mineral oil, 132 mg, 3.3 mmol) was added. After stirring during 10 min,
propargyl bromide (0.36 mL, 3.3 mmol) was added. The reaction was
stirred at room temperature during
5 min, whereupon completed
conversion was shown by TLC. Then, the mixture was diluted with diethyl
ether and water was added. The phases were separated and the
aqueous phase was extracted with diethyl ether (2×). The combined
organic layers were dried with anhydrous MgSO4, filtered and the solvent
was evaporated in vacuum. The crude was subjected to column
20 = ‒
 D

1
2
system, 2 H, CH2Ph, Ja,b = 15.0), 4.77 (d, 1 H, part A of AB system, H-
2
1ʹa, J1ʹa,1ʹb = 12.2), 4.66-4.59 (m, 2 H, H-1ʹb, H-2), 4.40 (ddd, 1 H, H-4),
chromatography (EtOAc/hexane, 1:5) to afford the title compound (673
4.25-4.00 (m, H-3, CH2-5, 2 × CH2, Et), 1.48 (s, 3 H, CH3, i-Pr), 1.34-1.26
(m, 9 H, 2 × CH3, Et, CH3, i-Pr). 13C NMR (100 MHz, CDCl3): δ 144.7 (C-
2ʹ), 134.7 (Cq, Ph), 129.2, 128.8, 128.2 (CH, Ph), 122.9 (C-3ʹ), 112.0 (Cq,
mg, 95 %) as a yellow oil.
= ‒ 25 (c = 1, in CH2Cl2). 1H NMR (400
20
 D

MHz, CDCl3)*: δ 5.88 (d, 1 H, H-1, J1,2 = 3.8), 4.61 (d, 1 H, H-2), 4.32-
4.22 (m, 2 H, H-4, H-1ʹa), 4.18 (dd, 1 H, H-1ʹb, 2J1′a,1′b= 16.0, J1ʹb,3′ = 2.4),
3
3
i-Pr), 105.2 (C-1), 82.1 (C-2), 81.6 (C-3), 78.6 (d, C-4, JC-4,P = 8.8), 64.4
4.07 (d, 1H, H-3, J3,4 = 3.2), 3.54 (dd, part A of ABX system, 1 H, H-5a,
2
2
(d, C-5, JC-5,P = 5.3), 64.09 (d, CH2, Et, JC-P = 5.9), 64.05 (d, CH2, Et,
2JC-P = 5.7), 63.8 (C-1ʹ), 54.3 (CH2Ph), 26.9, 26.3 (2 × CH3, i-Pr), 16.2 (d,
2J5a,5b = 12.6, 3J4,5a = 6.8), 3.46 (dd, part B of ABX system 1 H, H-5b, 3J4,
5b= 6.3), 2.49 (t, 1 H, H-3ʹ, 4J = 2.4), 1.47 (s, 3 H, CH3, i-Pr), 1.29 (s, 3 H,
CH3, i-Pr). 13C NMR (100 MHz, CDCl3)*: δ = 112.0 (Cq, i-Pr), 105.1 (C-1),
82.0 (C-2), 81.2 (C-3), 78.8 (C-2′), 78.7 (C-4), 75.5 (C-3′), 57.4 (C-1′),
49.3 (C-5), 26.8, 26.3 (2 × CH3, i-Pr). HRMS: calcd. for C11H15N3O4 [M +
H]+ 254.1135, found 254.1137. *NMR data were in accordance with
published data.[29]
2 × CH3, 2 × Et, JC,P = 6.8). 31P NMR (162 MHz, CDCl3): δ ‒1.26 ppm.
3
HRMS: calcd for C22H32N3O8P [M + H]+ 498.2000, found 498.2009.
Diphenyl
(5-deoxy-1,2-O-isopropylidene-3-O-propargyl-α-D-
xylofuranos-5-yl)phosphate (8):To a solution of 1,2-O-isopropylidene-
3-O-propargyl-α-D-xylofuranose (3, 100 mg, 0.44 mmol) in toluene (6
mL) under nitrogen, at 0 ºC, diphenylphosphoryl azide (0.11 mL, 0.53
mmol) and DBU (0.08 mL, 0.53 mmol) were added and the mixture was
stirred at room temperature for 24 h. Additional DBU (0.05 mL, 0.8
equiv.) was then added at 0 ºC and stirring was continued at 40 ºC for 16
h. The mixture was then washed twice with 2 M HCl soln. and water. The
organic phase was dried with anhydrous magnesium sulfate, filtered and
the solvent was evaporated under vacuum. The crude residue was
purified by column chromatography (EtOAc/hexane, 1:4) to afford the title
compound (138 mg, 68%) as a colourless oil.
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.42-7.15 (m, 10 H, 2 × Ph), 5.94
(d, 1 H, J1,2 = 3.7), 4.65 (d, 1 H, H-2), 4.54-4.40 (m, 3 H, H-4, H-5a, H-
5b), 4.19-4.09 (m, 3 H, CH2-1′, H-3), 2.47 (t, 1 H, H-3′, J1ʹa,3ʹ = J 1ʹb,3ʹ
2.2), 1.49 (s, 3 H, CH3, i-Pr), 1.33 (s, 3 H, CH3, i-Pr). 13C NMR (100 MHz,
3,5ʹ-Anhydro-5-deoxy-5-(5-hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-
O-isopropylidene-α-D-xylofuranose (12)[27]: A solution of 5-azido-5-
deoxy-1,2-O-isopropylidene-3-O-propargyl-α-D-xylofuranose (11, 60 mg,
0.23 mmol) in toluene (5 mL) was stirred at 110 ºC for 2 h. The solution
was concentrated under vacuum, the solid was filtered off and washed
with petroleum ether, affording the title compound as a white powder (40
mg, 67%). Crystallization from EtOAc resulted in colourless monocrystals
20
of 12-a.
= ‒ 12 (c = 1, in CH2Cl2). m.p.: 201.0‒203.1 ºC. HRMS:

 D
20 = ‒ 46 (c = 1, in
calcd for C11H15N3O4 [M + H]+ 254.1135, found 254.1136. NMR data
were in accordance with the published data.[27]

 D
3
4
4
=
5-Azido-3-O-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranose (14): To a solution of 3-O-(1-benzyl-
1H-1,2,3-triazol-4-yl)methyl-1,2-O-isopropylidene-α-D-xylofuranose
2
2
CDCl3): δ 150.52 (d, Cq, Ph, JC,P = 7.3), 150.49 (d, Cq, Ph, JC,P = 7.1),
129.8, 125.4, 120.2, 120.2 (CH, 2 × Ph) 112.2 (Cq, i-Pr), 105.3 (C-1),
82.1 (C-2), 81.1 (C-3), 78.8 (C-2′), 78.5 (d, C-4, 3JC-4,P = 8.6), 75.6 (C-3′),
(4,
300 mg, 0.83 mmol) in pyridine (12 mL), tosyl chloride (320 mg, 1.66
mmol) was added. The solution was left stirring at room temperature and
under nitrogen atmosphere for 16 h. It was then diluted with ethyl acetate
and washed with 2 M HCl soln. and water. The organic phase was dried
with anhydrous magnesium sulfate, filtered and the solvent was
evaporated under vacuum. The crude residue was dried under vacuum
and then it was dissolved in DMF (20 mL). To the resulting solution and
under nitrogen atmosphere, sodium azide (162 mg, 2.5 mmol) was
added and the mixture was stirred at 80 ºC for 16 h. Then, the mixture
was diluted with diethyl ether and water was added. The phases were
separated and the aqueous phase was extracted with diethyl ether (2 ×).
The combined organic layers were dried with anhydrous MgSO4, filtered
and the solvent was evaporated in vacuum. The crude was subjected to
column chromatography (EtOAc/hexane, 1:2) to afford the title compound
66.2 (d, C-5, JC-5,P = 6.2), 57.6 (C-1′), 26.9, 26.4 (2 × CH3, i-Pr). 31P
2
NMR (162 MHz, CDCl3): δ 12.06. HRMS: calcd. for C23H25O8P [M + H]+
461.1360, found 461.1362; calcd. for C23H25O8P [M + Na]+ 483.1179,
found 483.1183.
Diphenyl [3-O-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranos-5-yl]phosphate
(9):
Obtained
according to the general CuI/A21 cycloaddition procedure, starting from
1,2-O-isopropylidene-5-O-diphenylphosphono-3-O-propargyl-α-D-
xylofuranose (8, 124 mg, 0.27 mmol), benzyl azide (0.04 mL, 0.32 mmol)
in the presence of CuI/A-21 catalyst (0.06 mmol CuI, 120 mg).
Purification by column chromatography (EtOAc/petroleum ether, 1:3)
8
This article is protected by copyright. All rights reserved.

10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
20
D
(251 mg, 78 %, 2 steps) as a yellow oil.
= ‒23 (c = 1, in CH2Cl2).
were separated and the aqueous phase was extracted with diethyl ether
(2 ×). The combined organic layers were dried with anhydrous MgSO4,
filtered and the solvent was evaporated in vacuum. The crude was
subjected to column chromatography (EtOAc/hexane, 1:7) to afford the
title compound (684 mg, 80%, 2 steps) as a colourless oil. The NMR data
were in accordance with the reported data.[8b]


1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1 H, H-3′), 7.42-7.33 (m, 3 H, Ph),
3
7.31-7.26 (m, 2 H, Ph), 5.88 (d, 1 H, H-2, J1,2 = 3.7), 5.53 (s, 2 H, CH2,
Bn), 4.77 (d, 1 H, part A of AB system, H-1′a, J1′a,1′b = 12.3), 4.67-4.60
(m, 2 H, H-1′b, H-2), 4.28 (td, 1 H, H-4), 4.00 (d, 1 H, H-3, J3,4 = 3.2),
2
3
3.49 (dd, 1 H, part A of ABX system ABX, H-5a, 2J5a,5b = 12.3, 3J4,5a = 6.6),
3.41 (dd, 1H, part B of ABX system, H-5b, 3J4,5b = 6.9), 1.49 (s, 3 H, CH3,
i-Pr), 1.31 (s, 3 H, CH3, i-Pr). 13C NMR (100 MHz, CDCl3): δ 144.6 (C-2′),
134.4 (Cq, Ph), 129.2, 128.9, 128.1 (CH, Ph), 122.6 (C-3′), 112.0 (Cq, i-
Pr), 105.1 (C-1), 82.0 (C-2), 81.7 (C-3), 78.5 (C-4), 63.4 (C-1′), 54.3 (CH2,
Bn), 49.0 (C-5), 26.8, 26.2 (2 × CH3, i-Pr). HRMS: calcd. for C18H22N6O4
[M + H]+ 387.1775, found 387.1779; calcd. for C18H22N6O4 [M + Na]+
409.1595, found 409.1599.
General procedure for the thermal azide-alkyne cycloaddition
between
5-azido-3-O-protected
1,2-O-isopropylidene-α-D-
xylofuranoses and propargyl derivatives: To a solution of 5-azido-3-
O-protected 1,2-O-isopropylidene-α-D-xylofuranose (1 mmol) in toluene
(7 mL) under nitrogen, propargyl alcohol, propargylamine or propargyl
bromide (2 equiv.) was added. The reaction mixture was stirred under
reflux for 16-48 h. After concentration under vacuum, the residue was
subjected to column chromatography.
Diethyl N-[3-O-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuran-5-yl]phosphoramidate (15): To
a
solution of 5-azido-3-O-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl-5-deoxy-
1,2-O-isopropylidene-α-D-xylofuranose (14, 30 mg, 0.08 mmol) in CH2Cl2
(5 mL), triethyl phosphite (0.07 mL, 0.39 mmol) was added. The reaction
was stirred at room temperature for 48 h. The solution was concentrated
under vaccum and the residue was subjected to column chromatography
3-O-Benzyl-5-deoxy-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-
isopropylidene-α-D-xylofuranose (20) and 3-O-benzyl-5-deoxy-5-(5-
hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranose (21): Obtained according to the general procedure for
thermal azide-alkyne cycloaddition, starting from 5-azido-3-O-benzyl-5-
deoxy-1,2-O-isopropylidene-α-D-xylofuranose (18, 300 mg, 0.98 mmol)
and propargyl alcohol (0.11 mL, 1.96 mmol). The reaction was stirred for
24 h. Purification by column chromatography (EtOAc/Hex, 1:1) afforded
the 1,4-disubstituted triazole 20 (163 mg, 46%) as colourless crystals
and the 1,5-disubstituted regioisomer 21 (126 mg, 36%) as a colourless
oil.
(EtOAc/MeOH, 20:1) to afford the title compound (37 mg, 96%) as a
colourless oil.
= ‒3.6 (c = 1, in CH2Cl2). 1H NMR (400 MHz,
20

 D
CDCl3): δ 7.45 (s, 1 H, H-3′), 7.40-7.32 (m, 3 H, Ph), 7.30-7.24 (m, 2 H,
3
Ph), 5.87 (d, 1 H, J1,2 = 3.8), 5.51 (s, 2 H, CH2Ph), 4.76 (d, 1 H, part A
2
of AB system, H-1′a, J1′a,1′b = 12.4), 4.63-4.54 (m, 2 H, H-1′b, H-2), 4.25
3
3
(td, 1 H, H-4, 3J4,5a = J4,5b = 6.7, J3,4 = 3.3), 4.08-3.94 (m, 5 H, H-3, 2 ×
CH2, Et), 3.35 (dt, 1 H, NH, 2JNH,P = 10.7, 3JNH,5a = 3JNH,5b = 7.3), 3.24-3.06
(m, 2 H, H-5a, H-5b), 1.46 (s, 3 H, CH3, i-Pr), 1.32-1.24 (m, 3 H, CH3, i-Pr,
2 × CH3, Et). 13C NMR (100 MHz, CDCl3): δ 144.6 (C-2′), 134.5 (Cq, Ph),
129.3, 128.9, 128.3 (CH, Ph), 122.5 (C-3′), 111.8 (Cq, i-Pr), 105.1 (C-1),
Data for 20:
δ
= ‒ 40 (c = 1, in CH2Cl2). 1H NMR (400 MHz, CDCl3):
20
 D

3
7.60 (s, 1 H, H-5), 7.43-7.29 (m, 5 H, Ph), 5.98 (d, 1 H, H-1′, J1ʹ,2ʹ
=
3.7), 4.80-4.60 (m, 5 H, H-a, from CH2Ph, CH2OH, H-2′, H-5′a), 4.59-4.46
3
82.1 (C-2), 82.0 (C-3), 79.8 (d, C-4, JC-4,P = 5.1), 63.2 (C-1′), 62.47,
3
(m, 3 H, H-4′, H-b from CH2Ph, H-5′b), 4.00 (d, 1 H, H-3′, J3′,4′ = 2.7),
2
62.44 (2 d, 2 × CH2, Et, JCH2,P = 5.3), 54.3 (CH2, Bn), 39.7 (C-5), 26.8,
1.43 (s, 3 H, CH3, i-Pr.), 1.31 (s, 3 H, CH3, i-Pr.). 13C NMR (100 MHz,
CDCl3): δ 147.9 (C-4), 136.8 (Cq, Ph), 128.7, 128.3, 128.0 (CH, Ph),
123.0 (C-5), 112.1 (Cq, i-Pr.), 105.2 (C-1′), 81.9 (C-2′), 81.5 (C-3′), 78.8
(C-4′), 71.9 (CH2Ph) 56.0 (CH2OH), 49.2 (C-5′), 26.7, 26.2 (2 × CH3, i-Pr).
HRMS: calcd. for C18H23N3O5 [M + H]+ 362.1710, found 362.1716; calcd.
for [M + Na]+ 384.1530, found 384.1535.
26.4 (2 × CH3, i-Pr), 16.3 (d, 2 × CH3, Et, JC,P =7.2). 31P NMR (162 MHz,
CDCl3): δ 9.11. HRMS: calcd. for C22H33N4O7P [M + H]+ 497.2160, found
497.2176; calcd. for C22H33N4O7P [M + Na]+ 519.1979, found 519.1990.
5-Bromo-5-deoxy-1,2-O-isopropylidene-3-O-propargyl-α-D-
xylofuranose (15): To a solution of 1,2-O-isopropylidene-3-O-propargyl-
α-D-xylofuranose (3, 100 mg, 0.44 mmol) in CH2Cl2 (10 mL) under
nitrogen, triphenilphosphine (230 mg, 0.88 mmol) and carbon
tetrabromide (292 mg, 0.88 mmol) were added. The mixture was stirred
at room temperature and under nitrogen atmosphere for 24 h. The
mixture was concentrated under vacuum and the crude residue was
Data for 21:
= ‒ 32 (c = 1, in CH2Cl2). 1H NMR (400 MHz, CDCl3):
20

 D
δ 7.58 (s, 1 H, H-4), 7.44-7.27 (m, 5 H, Ph), 5.99 (d, 1H, H-1′, 3J1′,2′ = 3.7),
4.74-4.49 (m, 8 H, H-2′, H-4ʹ, CH2Ph, CH2OH, CH2-5ʹ, Ja,b (Bn) = 11.8),
2
4.10 (d, 1 H, H-3′, 3J3ʹ,4ʹ = 1.8), 1.41 (s, 3 H, CH3, i-Pr), 1.30 (s, 3 H, CH3,
i-Pr). 13C NMR (100 MHz, CDCl3): δ 137.3 (C-5), 136.8 (Cq, Ph), 133.3
(C-4), 128.7, 128.4, 128.0 (CH, Ph), 123.0 (C-1′), 112.4 (Cq, i-Pr), 105.1
(C-1ʹ), 82.0 (C-2ʹ), 81.7 (C-3ʹ), 79.6 (C-4ʹ), 72.1 (CH2Ph) 52.6 (CH2OH),
47.7 (C-5ʹ), 26.7, 26.2 (2 ×CH3, i-Pr). HRMS: calcd. for C18H23N3O5 [M +
H]+ 362.1710, found 362.1715; calcd. for [M + Na]+ 384.1530, found
384.1537.
subjected to column chromatography (EtOAc/hexane, 1:5) to afford the
20
title compound (30 mg, 24%) as a colourless oil.
= ‒37 (c = 1, in
 D

CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 5.92 (d, 1 H, H-1, J1,2 = 3.6),
3
4.68 (d, 1 H, H-2), 4.46 (ddd, 1 H, H-4), 4.34-4.24 (br.s, 2 H, H-1′a, H-1ʹb,
4
4
3
2J1ʹa,1ʹb = 16.1, J1ʹa,3ʹ = 2.3, J1ʹb,3ʹ = 2.3), 4.17 (d, 1 H, H-3, J3,4 = 2.9),
3.57-3.49 (m, 2 H, H-5a, H-5b, 2J5a,5b = 9.7, 3J4,5a = 8.7, 3J4,5b = 5.9), 2.50
4
(m, 1 H, H-3′, J = 2.3), 1.51 (s, 3 H, CH3, i-Pr), 1.33 (s,3 H, CH3, i-Pr).
5-Deoxy-3-O-dodecyl-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-
O-isopropylidene-α-D-xylofuranose (22) and 5-deoxy-3-O-dodecyl-5-
(5-hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranose (23): Obtained according to the general procedure for
thermal azide-alkyne cycloaddition, starting from 5-azido-5-deoxy-3-O-
dodecyl-1,2-O-isopropylidene-α-D-xylofuranose (19,[8c] 400 mg, 1.04
mmol) and propargyl alcohol (0.12 mL, 2.09 mmol). The reaction was
stirred for 48 h. Purification by column chromatography (EtOAc/Hex, 1:3)
afforded the 1,4-disubstituted triazole 22 (248 mg, 54%) and the 1,5-
disubstituted regioisomer 23 (143 mg, 31%) as colourless oils.
13C NMR (100 MHz, CDCl3): δ 112.3 (Cq, i-Pr), 105.6 (C-1), 82.3 (C-2),
81.1 (C-3), 80.4 (C-4), 79.0 (C-2′), 75.4 (C-3′), 58.3 (C-1′), 27.0 (CH3, i-
Pr), 26.9 (C-5), 26.4 (CH3, i-Pr). HRMS: calcd. for C11H15BrO4 [M + Na]+
313.0046, found 313.0040.
5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-D-xylofuranose
(18): To a solution of 3-O-benzyl-1,2-O-isopropylidene-α-D-xylofuranose
(16,[13e] 785 mg, 2.8 mmol) in pyridine (17 mL), tosyl chloride (640 mg,
3.4 mmol) was added. The solution was left stirring at room temperature
and under nitrogen atmosphere for 16 h. It was then diluted with ethyl
acetate and washed with 2 M HCl soln. and water. The organic phase
was dried with anhydrous magnesium sulfate, filtered and the solvent
was evaporated under vacuum. The crude residue was dried under
vacuum and then it was dissolved in DMF (12 mL). To the resulting
solution and under nitrogen atmosphere, sodium azide (546 mg, 8.4
mmol) was added and the mixture was stirred at 80 ºC for 16 h. Then, the
mixture was diluted with diethyl ether and water was added. The phases
Data for 22:
= ‒ 17 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3):
20
 D

3
δ 7.65 (s, 1 H, H-5), 5.93 (d, 1 H, H-1′, J1′,2′ = 3.6), 4.78-4.69 (m, 3 H,
2
3
CH2OH, H-5ʹa, J5ʹa,5ʹb = 18.9, J4, 5ʹa = 8.4), 4.58 (d, 1 H, H-2′), 4.54-4.43
(m, 2 H, H-4′, H-5′b), 3.84 (d, 1 H, H-3′, 3J3′,4′ = 2.0), 3.63 (dt, 1 H, H-1′′a,
3
3
2J1ʹʹa,1ʹʹb
= 9.1, J1ʹʹa,2ʹʹa = =
3J1ʹʹa,2ʹʹb = 6.5), 3.41 (dt, 1H, H-1′′b, J1ʹʹb,2ʹʹa
3J1ʹʹb,2ʹʹb = 6.7), 1.63-1.49 (m, 2 H, H-2′′), 1.41 (s, 3 H, CH3, i-Pr), 1.36-1.16
3
(m, 21 H, CH3, i-Pr, H-3′′ to H-11′′), 0.86 (t, 3 H, CH3-12ʹʹ, J = 6.8). 13C
9
This article is protected by copyright. All rights reserved.

10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
NMR (100 MHz, CDCl3): δ 147.9 (C-4), 123.0 (C-5), 112.1 (Cq, i-Pr),
105.3 (C-1′), 82.6 (C-3′), 82.1 (C-3′), 79.2 (C-4′), 70.6 (C-1′′), 56.5
(CH2OH), 49.5 (C-5′), 32.0, 29.8, 29.8, 29.7, 29.7, 29.7, 29.5, 29.5, 26.3
(C-2′′ to C-10′′), 26.8, 26.2 (2 × CH3, i-Pr), 22.8 (C-11ʹʹ), 14.2 (C-3′′).
HRMS: calcd. for C23H41N3O5 [M + H]+ 440.3119, found 440.3125; calcd.
for [M + Na]+ 462.2938, found 462.2941.
(d, 1 H, H-b from CH2Ph), 4.11-3.96 (m, 5 H, 2 × CH2, 2 × Et, H-3′), 1.40
(s, 3 H, CH3, i-Pr), 1.32-1.20 (m, 9 H, 2 × CH3 from 2 × Et, CH3, i-Pr). 13
C
NMR (100 MHz, CDCl3): δ 136.9 (Cq, Ph), 134.3 (C-4), 133.0 (d, C-5,
3JC-5,P = 7.8), 128.8, 128.5, 128.1 (CH, Ph), 112.3 (Cq, i-Pr), 105.3 (C-1′),
82.2 (C-2′), 81.9 (C-3′), 79.7 (C-4′), 72.2 (CH2Ph), 64.3 (d, 2× CH2, 2× Et,
2JC,P = 5.9), 57.0 (d, CH2OP, 2JC,P = 4.9), 47.9 (C-5′), 26.8, 26.3 (2 × CH3,
3
i-Pr) 16.2 (d, 2 × CH3, 2 × Et, JC,P = 6.8). 31P NMR (162 MHz, CDCl3): δ
‒1.17. HRMS: calcd. for C22H32N3O8P [M
+
H]+ 498.2000, found
Data for 23:
= ‒ 25 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3): δ
20

 D
498.2010; calcd. for [M + Na]+ 520.1819, found 520.1830.
3
7.60 (s, 1 H, H-4), 5.92 (d, 1 H, H-1′, J1′,2′ = 3.5), 4.77-4.65 (m, 3 H,
CH2OH, H-5′a), 4.61-4.45 (m, 3 H, H-2′, H-4′, H-5′b, 2J5ʹa,5ʹb = 14.2, 3J4,5ʹb
=
3
2
8.6), 3.94 (d, 1 H, H-3′, J3′,4′ = 3.0), 3.63 (dt, 1 H, H-1′′a, J1ʹʹa,1ʹʹb = 9.1,
5-Deoxy-5-[4-(diethoxyphosphoryloxy)methyl-3-O-dodecyl-1H-1,2,3-
triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose (26): According to
the general procedure, the treatment of 5-deoxy-3-O-dodecyl-5-(4-
hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
3
3J1ʹʹa,2ʹʹa
= =
3J1ʹʹa,2ʹʹb = 6.6), 3.43 (dt, 1 H, H-1′′b, J1ʹʹb,2ʹʹa 3J1ʹʹb,2ʹʹb = 6.7),
1.60-1.49 (m, 2 H, CH2-2′′), 1.38 (s, 3 H, CH3, i-Pr), 1.34-1.16 (m, 21 H,
3
CH3, i-Pr, CH2-3′′ to CH2-11′′), 0.85 (t, 3 H, CH3-12ʹʹ, J = 6.5). 13C NMR
(100 MHz, CDCl3): δ = 137.2 (C-5), 133.6 (C-4), 112.5 (Cq, i-Pr), 105.2
(C-1′), 82.8 (C-3′), 82.1 (C-2′), 80.0 (C-4′), 70.8 (C-1′′), 52.6 (CH2OH),
47.9 (C-5ʹ), 32.0, 29.7, 29.7, 29.7, 29.5, 29.4, 26.3 (C-2′′ to C-10′′), 26.8,
26.2 (2 × CH3, i-Pr), 22.8 (C-11ʹʹ), 14.2 (C-2′′). HRMS: calcd. for
C23H41N3O5 [M + H]+ 440.3119, found 440.3130; calcd. for [M + Na]+
462.2938, found 462.2953.
xylofuranose (22, 50 mg, 0.11 mmol) with triethylamine (0.02 mL, 0.17
mmol) and diethyl phosphorochloridate (0.02 mL, 0.17 mmol) and
purification by column chromatography (EtOAc/Hexane, 1:2) afforded the
20
title compound (53 mg, 81%) as a colourless oil.
= ‒ 15 (c = 1, in
 D

CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H, H-5), 5.93 (d, 1 H, H-
1′, J1ʹ,2ʹ = 3.6), 5.18 (d, 2 H, CH2OP, JCH2,P = 8.8), 4.72 (dd, part A of
ABX system,1 H, H-5′a, J4ʹ,5ʹa = 7.5, J5ʹa,5ʹb = 17.5), 4.59 (d, 1 H, H-2′),
4.56-4.45 (m, 2 H, H-4′, H-5′b), 4.15-4.04 (m, 4 H, 2 × CH2, 2 × Et), 3.85
(d, 1 H, H-3′, J3ʹ,4ʹ = 2.4), 3.64 (dt, 1 H, H-1′′a, J1′′a,2′′a
3
3
3
2
General procedure for the phosphorylation of 3-O-protected 5-
(hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranoses with diethyl phosphorochloridate: To a solution of 5-
3
3
=
3J1′′a,2′′b = 6.5,
2J1′′a,1′′b = 9.2), 3.43 (dt, 1 H, H-1′′b, J1′′b,2′′a = 3J1′′b,2′′b = 6.6), 1.62-1.52 (m,
2 H, CH2-2′′), 1.42 (s, 3 H, CH3, i-Pr), 1.38-1.18 (m, 27 H , 2 × CH3, 2 × Et,
CH3, i-prop, CH2-3′′ to CH2-11′′), 0.90 (t, 3 H, CH3-12ʹʹ, 3J = 6.6). 13C
NMR (100 MHz, CDCl3): δ 143.4 (d, C-4, 3JC-4,P = 7.3), 124.8 (C-5), 112.2
(Cq, i-Pr), 105.4 (C-1′), 82.6 (C-3′), 82.2 (C-2′), 79.0 (C-4′), 70.7 (C-1′′),
3
(hydroxymethyl-1H-1,2,3-triazol-1-yl)-xylofuranose derivative
(0.14
mmol) in dichloromethane (3 mL) and under nitrogen atmosphere,
triethylamine (1.5 equiv.) was added. The reaction mixture was cooled to
0ºC and diethyl phosphorochloridate (1.5 equiv) and DMAP (catalytic
amount, one spatula point) were added. The reaction was stirred at room
temperature overnight. The solution was concentrated under vacuum
and the residue was purified by column chromatography.
2
2
64.1 (d, 2 × CH2, 2 × Et, JC,P = 5.9), 60.6 (d, CH2OP, JC,P = 5.2), 49.6
(C-5′), 32.1, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 26.3 (C-2′′ to C-10′′), 26.9,
3
26.3 (2 × CH3, i-Pr), 22.8 C-11′′), 16.2 (d, 2 × CH3, 2 × Et, JC,P = 6.8),
14.3 (C-12′′). 31P NMR (162 MHz, CDCl3): δ ‒1.13. HRMS: calcd. for
C27H50N3O8P [M + H]+ 576.3408, found 576.3405; calcd. for [M + Na]+
598.3228, found 598.3224.
3-O-Benzyl-5-deoxy-5-[4-(diethoxyphosphoryloxy)methyl-1H-1,2,3-
triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose (24): According to
the general procedure, the treatment of 3-O-benzyl-5-deoxy-5-(4-
hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranose (20, 50 mg, 0.14 mmol) with triethylamine (0.03 mL, 0.21
mmol) and diethyl phosphorochloridate (0.03 mL, 0.21 mmol) and
purification by flash column chromatography (EtOAc /Hexane, 1:2)
afforded the title compound (54 mg, 78%) as a colourless oil.
5-Deoxy-5-[5-(diethoxyphosphoryloxy)methyl-3-O-dodecyl-1H-1,2,3-
triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose (27): According to
the general procedure, the treatment of 5-deoxy-3-O-dodecyl-5-(5-
hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranose (23, 50 mg, 0.11 mmol) with triethylamine (0.02 mL, 0.17
mmol) and diethyl phosphorochloridate (0.02 mL, 0.17 mmol) and
= ‒ 20 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1
20

 D
3
purification by column chromatography (EtOAc/Hexane, 1:2) afforded the
H, H-5), 7.43-7.30 (m, 5 H, Ph), 5.97 (d, 1H, H-1′, J1′,2′ = 3.6), 5.16 (d, 2
H, CH2OP, 3JCH2,P = 8.8), 4.74 (d, part A of AB system, 1 H, H-a, CH2Ph,
2Ja,b = 11.7), 4.70-4.62 (m, 2 H, H-2′, H-5′a), 4.59-4.49 (m, 3 H, H-5′b, H-
4′, H-b from CH2Ph), 4.15-4.04 (m, 4 H, 2 × CH2, 2 × Et), 3.99 (d, 1 H, H-
3′, 3J3′,4′ = 2.2), 1.42 (s, 3 H, CH3, i-Pr), 1.35-1.27 (m, 9 H, 2 × CH3, 2 × Et,
CH3, i-Pr) ppm. 13C NMR (100 MHz, CDCl3): δ 143.4 (d, C-4, 3JC,P = 7.5),
136.9 (Cq, Ph), 128.9, 128.5, 128.1 (CH, Ph), 124.8 (C-5), 112.3 (Cq, i-
Prop), 105.4 (C-1′), 82.1 (C-2′), 81.6 (C-3′), 78.9 (C-4′), 72.1, (CH2, Bn),
20
title compound (61 mg, 93%) as a colourless oil.
= ‒ 10 (c = 1, in
 D

CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1 H, H-4), 5.92 (d, 1H, H-
3
1′ J1ʹ,2ʹ = 3.6), 5.29 (dd, part A of ABX system, 1 H, H-a from CH2OP,
2Ja,b = 13.2, JH-a,P = 9.2), 5.17 (dd, part B of ABX system, 1 H, H-b from
3
CH2OP, 3JH-b,P = 8.4), 4.73 (dd, 1 H, H-5′a, 3J4ʹ,5ʹa = 8.3, 2Ja,b = 19.3), 4.61-
4.50 (m, 3 H, H-2′, H-4′,H-5′b), 4.15-4.01 (m, 4 H, 2 × CH2, 2 × Et), 3.92
3
3
(d, 1 H, H-3′, J3ʹ,4ʹ = 2.1), 3.63 (dt, 1 H, H-1′′a, J1′′a,2′′a
2J1′′a,1′′b = 9.2), 3.44 (dt, 1 H, H-1′′b, J1′′b,2′′a = 3J1′′b,2′′b = 6.7), 1.64-1.49 (m,
=
3J1′′a,2′′b = 6.6,
3
2
2
64.1 (d, 2 × CH2, 2 × Et, JC,P = 5.9), 60.6 (d, CH2OP, JC,P = 5.1), 49.6
(C-5′), 26.9, 26.3 (2 × CH3, i-Pr), 16.1 (d, 2 × CH3, 2 × Et, 3JC,P = 6.9). 31
2 H, CH2-2′′), 1.41 (s, 3 H, CH3, i-Pr), 1.37-1.19 (m, 27 H , 2 × CH3, 2 × Et,
P
3
CH3, i-Pr, CH2-3ʹʹ to CH2-11′′), 0.87 (t, 3 H, CH3-12ʹʹ, J = 6.5). 13C NMR
NMR (162 MHz, CDCl3): δ = ‒ 1.15. HRMS: calcd. for C22H32N3O8P [M +
H]+ 498.2000, found 498.1995; calcd. for [M + Na]+ 520.1819, found
520.1814.
3
(100 MHz, CDCl3): δ 134.4 (C-4), 133.2 (d, C-5, JC-5,P = 7.8), 112.2 (Cq,
i-P), 105.3 (C-1′), 82.7 (C-3′), 82.2 (C-2′), 79.8 (C-4′), 70.7 (C-1′′), 64.4
2
(d, 2 × CH2, 2 × Et, JC,P = 5.9), 57.1 (d, CH2OP, 2JC,P = 5.1), 48.0 (C-5′),
32.1, 29.8, 29.8, 29.7, 29.6, 29.5, 26.4 (C-2′′ to C-10′′), 26.8, 26.3 (2 ×
CH3, i-Pr), 22.8 C-11′′), 16.2 (d, 2 × CH3, 2 × Et, 3JC,P = 6.8), 14.3 (C-12′′).
3-O-Benzyl-5-deoxy-5-[5-(diethoxyphosphoryloxy)methyl-1H-1,2,3-
triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose (25): According to
the general procedure, the treatment of 3-O-benzyl-5-deoxy-5-(5-
hydroxymethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranose (21, 50 mg, 0.14 mmol) with triethylamine (0.03 mL, 0.21
mmol) and diethyl phosphorochloridate (0.03 mL, 0.21 mmol) and
purification by flash column chromatography (EtOAc/hexane, 1:2)
afforded the title compound (47 mg, 68%) as a colourless oil.
31P NMR (162 MHz, CDCl3):
δ
‒ 1.13 ppm. HRMS: calcd. for
C27H50N3O8P [M + H]+ 576.3408, found 576.3405; calcd. for [M + Na]+
598.3228, found 598.3224.
5-(4-Aminomethyl-1H-1,2,3-triazol-1-yl)-3-O-benzyl-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranose (28) and 5-(5-aminomethyl-1H-
1,2,3-triazol-1-yl)-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-D-
xylofuranose (29): Obtained according to the general procedure for
thermal azide-alkyne cycloaddition, starting from 5-azido-3-O-benzyl-5-
deoxy-1,2-O-isopropylidene-α-D-xylofuranose (18, 600 mg, 1.97 mmol)
and propargylamine (0.25 mL, 3.93 mmol). The reaction was stirred for
= ‒ 23 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.70 (s, 1
20

 D
3
H, H-4), 7.42-7.28 (m, 5 H, Ph), 5.95 (d, 1 H, H-1′, J1ʹ,2ʹ = 3.6), 5.24 (dd,
1 H, part A of ABX system, H-a from CH2OP, Ja,b = 13.1, JH-a,P = 9.2)
2
3
3
5.11 (dd, part B of ABX system, 1 H, H-b from CH2OP, JH-b,P = 8.4),
4.76-4.55 (m, 5 H, H-a from CH2Ph, CH2-5′, H-2′, H-4′, 2Ja,b = 11.7), 4.50
10
This article is protected by copyright. All rights reserved.

10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
24 h. Purification by column chromatography (from EtOAc to
EtOAc/MeOH, 18:1) afforded the 1,4-disubstituted triazole 22 (20 mg,
3%) as a yellow oil and the 1,5-disubstituted regioisomer 29 (20 mg, 3%,
not isolated from 18), along with recovered 18 (480 mg, 80%).
in dichloromethane (5 mL) at 0 ºC and under nitrogen atmosphere,
diethyl phosphorochloridate (1.2 equiv.) was added. The mixture was
stirred at room temperature for 2 h. The solution was concentrated under
vacuum and the residue was subjected to column chromatography.
= ‒ 12 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3):
3-O-Benzyl-5-deoxy-5-[4-(diethoxyphosphoryl)aminomethyl-1H-
1,2,3-triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose
Obtained according to the general procedure, starting from 5-(4-
aminomethyl-1H-1,2,3-triazol-1-yl)-3-O-benzyl-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranose (28, 30 mg, 0.08 mmol) and diethyl
phosphorochloridate (0.01 mL, 0.1 mmol). Purification by column
20
Data for 28:

 D
δ 7.61 (s, 1 H, H-5), 7.42-7.28 (m, 5 H, Ph), 5.95 (d, 1H, H-1′, 3J1′,2ʹ = 3.3),
4.76-4.58 (m, 3 H, H-2ʹ, H-a from CH2Ph, H-5ʹa), 4.57-4.43 (m, 3 H, H-4′,
H-b from CH2Ph, H-5ʹb), 4.07-3.93 (m, 3 H, CH2N, H-3′), 1.40 (s, 3 H,
CH3, i-Pr), 1.29 (s, 3H, CH3, i-Prop). 13C NMR (100 MHz, CDCl3): δ 146.9
(C-4), 137.0 (Cq, Ph), 128.8, 128.4, 128.1 (CH, Ph), 123.0 (C-5), 112.2
(Cq, i-Pr), 105.3 (C-1′), 82.1 (C-2′), 81.6 (C-3′), 79.0 (C-4′), 72.1 (CH2Ph),
49.4 (C-5′), 36.8 (CH2N), 26.8, 26.3 (2 × CH3, i-Pr). HRMS: calcd. for
C18H24N4O4 [M + H]+ 361.1870, found 361.1870; calcd. for C18H24N4O4 [M
+Na]+ 383.1690, found 383.1690.
(32):
chromatography (from EtOAc to EtOAc/MeOH, 25:1, then 18:1) afforded
20
the title compound (23 mg, 56%) as a colourless oil.
= ‒ 32 (c = 1,

 D
in CH2Cl2).1H NMR (400 MHz, CDCl3):
δ 7.56 (s, 1 H, H-5), 7.43-7.30
(m, 5 H, Ph), 5.99 (d, 1 H, H-1′, J1′,2′ = 3.6), 4.74 (d, 1 H, part A of AB
system, H-a from CH2Ph, Ja,b = 11.7), 4.70-4.60 (m, 2 H, H-2′, H-5′a),
3
2
NMR data for 29: 1H NMR (400 MHz, CDCl3): δ 7.56 (s, 1 H, H-4), 7.41-
7.28 (m, 5 H, Ph), 5.96 (d, 1H, H-1′, J1′,2ʹ = 3.7), 4.79-4.57 (m, 4 H, H-a
4.56-4.51 (m, 3 H, H-b from CH2Ph, H-4′, H-5′b), 4.19 (dd, 2 H, CH2NH,
3
3JCH2,P = 10.6, JCH2 NH
,
= 6.8), 4.13-3.95 (m, 5 H, H-3′, 2 × CH2, 2 × Et),
3
3.13 (dt, 1 H, NH, 2JNH,P = 10.2), 1.41 (s, 3 H, CH3, i-Pr), 1.34-1.18 (m, 9
H, CH3, i-Prop, 2 × CH3, 2 × Et). 13C NMR (100 MHz, CDCl3): δ 146.7 (d,
C-4, 3JC,P = 6.3), 136.9 (Cq, Ph), 128.9, 128.5, 128.1 (CH, Ph), 122.8 (C-
5), 112.2 (Cq, i-Prop), 105.4 (C-1′), 82.1 (C-3′), 81.7 (C-3′), 79.0 (C-4′),
from CH2Ph, H-2ʹ, H-4′, H-5ʹa), 4.55-4.43 (m, 2 H, H-b from CH2Ph, H-
5ʹb), 4.07 (d, 1 H, H-3′, 3J3ʹ,4ʹ = 3.1), 3.94 (s, 2 H, CH2N), 1.41 (s, 3 H, CH3,
i-Pr), 1.29 (s, 3 H, CH3, i-Pr).* 13C NMR (100 MHz, CDCl3): δ 139.3 (C-5),
137.0 (Cq, Ph), 132.4 (C-4), 128.8, 128.5, 128.1 (CH, Ph), 112.3 (Cq, i-
Pr), 105.2 (C-1′), 82.1 (C-2′), 82.0 (C-3′), 79.8 (C-4′), 72.1 (CH2Ph), 47.4
(C-5′), 35.0 (CH2N), 26.8, 26.3 (2 × CH3, i-Pr).*
2
71.9 (CH2Ph), 62.7 (d, 2 × CH2, 2 × Et, JC,P = 5.5), 49.6 (C-5′), 37.0
3
(CH2N), 26.8, 26.3 (2 × CH3, i-Pr), 16.3 (d, 2 × CH3, 2 × Et, JC,P = 7.0).
31P NMR (162 MHz, CDCl3): δ 8.19. HRMS: calcd. for C22H33N4O7P [M +
H]+ 497.2160, found 497.2173; calcd. for [M + Na]+ 519.1979, found
519.1997.
*Data extracted from the spectrum of a mixture containing 18/29.
5-(4-Aminomethyl-1H-1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-
isopropylidene-α-D-xylofuranose (30) and 5-(5-aminomethyl-1H-
1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-isopropylidene-α-D-
xylofuranose (31): Obtained according to the general procedure for
thermal azide-alkyne cycloaddition, starting from 5-azido-5-deoxy-3-O-
dodecyl-1,2-O-isopropylidene-α-D-xylofuranose (19, 600 mg, 1.56 mmol)
and propargylamine (0.2 mL, 3.12 mmol). The reaction was stirred for 16
h. Purification by column chromatography (from EtOAc to EtOAc/MeOH,
18:1) afforded the 1,4-disubstituted triazole 30 (140 mg, 20%) and the
1,5-disubstituted regioisomer 31 (140 mg, 20%) as yellow oils. Unreacted
19 was recovered (239 mg, 40%).
5-Deoxy-3-O-dodecyl-5-[4-(diethoxyphosphoryl)aminomethyl-1H-
1,2,3-triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose
(33):
Obtained according to the general procedure, starting from 5-(4-
aminomethyl-1H-1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-
isopropylidene-α-D-xylofuranose (30, 89 mg, 0.2 mmol) and diethyl
phosphorochloridate (0.04 mL, 0.24 mmol). Purification by flash column
chromatography (from EtOAc to EtOAc/MeOH, 28:1, then 22:1) afforded
20
the title compound (58 mg, 50%) as a colourless oil.
= ‒ 23 (c = 1,

 D
in CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H, H-5), 5.93 (d, 1 H,
H-1′, 3J1′,2′ = 3.6), 4.70 (dd, 1 H, H-5′a, 3J4ʹ,5ʹa = 8.3, 2J5ʹa,5ʹb = 18.9), 4.58 (d,
1 H, H-2′), 4.55-4.41 (m, 2 H, H-4′, H-5′b), 4.21 (dd, 2 H, CH2NH, 3JCH2,P
=
Data for 30:
= ‒ 45 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3): δ
20

 D
10.7, 3JCH2 NH
= 7.0), 4.14-3.97 (m, 4 H, 2 × CH2, 2 × Et), 3.85 (d, 1 H, H-
,
7.67 (s, 1 H, H-5), 5.93 (d, 1 H, H-1′, 3J1′,2′ = 3.6), 4.69 (dd, 1 H, part A of
ABX system, H-5′a, J4ʹ,5ʹa = 8.9, J5ʹa,5ʹb = 20.9) 4.58 (d, 1 H, H-2′), 4.56-
3, J3ʹ,4ʹ = 2.1), 3.63 (dt, 1 H, H-1′′a, 3J1′′a,2′′a = J1′′a,2′′b = 6.5, J1′′a,1′′b = 9.1),
3
3
2
3
2
3
3
2
3.42 (dt, 1 H, H-1′′b, J1′′b,2′′a = J1′′b,2′′b = 6.5), 3.18 (dt, 1 H, NH, JNH,P
=
3
4.42 (m, 2 H, H-5′b, H-4′), 4.04 (s, 2 H, CH2N), 3.85 (d, 1 H, H-3, J3ʹ,4ʹ
=
10.3), 1.61-1.50 (m, 2 H, CH2-2′′), 1.41 (s, 3 H, CH3, i-Pr), 1.37-1.15 (m,
27 H, CH3, i-Pr, 2 × CH3, 2 × Et, CH2-3′′ to CH2-11′′), 0.86 (t, 3 H, CH3-
12′′, 3J = 6.9). 13C NMR (100 MHz, CDCl3): δ 146.7 (d, C-4, 3JC-4,P = 6.2),
122.8 (C-5), 112.1 (Cq, i-Pr), 105.3 (C-1′), 82.7 (C-3′), 82.1 (C-2′), 79.1
2.4) 3.63 (dt, 1 H, H-1′′a, 3J1′′a,2′′a = 3J1′′a,2′′b = 6.7, 2J1′′a,1′′b = 9.1), 3.43 (dt, 1
H, H-1′′b, J1′′b,2′′a = 3J1′′b,2′′b = 6.6), 1.66-1.55 (m, 2 H, CH2-2′′), 1.38 (s, 3
3
H, CH3, i-Prop), 1.26-1.22 (m, 21 H, CH3, i-Pr, CH2-3′′ to CH2-11′′), 0.87
(t, 3 H, CH3-12ʹʹ, 3J = 6.9). 13C NMHz, CDCl3): δ 147.8 (C-4), 122.4 (C-5),
112.0 (Cq, i-Pr), 105.2 (C-1′), 82.5 (C-3′), 82.0 (C-2′), 79.0 (C-4′), 70.5
(C-1′′), 49.3 (C-5′), 36.9 (CH2N), 31.9, 29.7, 29.6, 29.6, 29.6, 29.4, 29.3,
26.2 (C-2′′ to C-10′′), 26.7, 26.1 (2 × CH3, i-Pr), 22.7 (C-11ʹʹ), 14.1 (C-12′′).
HRMS: calcd for C23H42N4O4 [M + H]+ 439.3279, found 439.3280.
2
(C-4′), 70.7 (C-1′′), 62.6 (d, 2 × CH2, 2 × Et, JC,P = 5.4), 49.6 (C-5′), 37.1
(CH2N), 32.0, 29.8, 29.8, 29.8, 29.7, 29.5, 29.5, 26.3 (CH2-3′′ to CH2-10′′)
26.9, 26.2 (2× CH3, i-Pr), 22.8 (CH2-10′′), 16.3 (d, 2 × CH3, 2 × Et, 3JC,P
=
7.1), 14.3 (C-12′′). 31P NMR (162 MHz, CDCl3): δ = 8.20. HRMS: calcd
for C27H51N4O7P [M + H]+ 575.3568, found 575.3572; calcd for [M + Na]+
597.3388, found 597.3390.
Data for 31:
= ‒ 10 (c = 1, in CH2Cl2).1H NMR (400 MHz, CDCl3): δ
20
 D

7.57 (s, 1 H, H-4), 5.92 (d, 1 H, H-1′, 3J1′,2′ = 3.5), 4.73-4.55 (m, 3 H, H-5′a,
H-4′, H-2′, 3J4′,5′a = 3.2, 2J5′a,5′b = 14.2), 4.45 (dd, part B of ABX system 1 H,
H-5′b, 3J4′,5′b = 7.9), 3.98 (s, 2 H, CH2N), 3.93 (d, 1 H, 3J3ʹ,4ʹ = 3.2), 3.64 (dt,
5-Deoxy-3-O-dodecyl-5-[5-(diethoxyphosphoryl)aminomethyl-1H-
1,2,3-triazol-1-yl]-1,2-O-isopropylidene-α-D-xylofuranose
(34):
Obtained according to the general procedure, starting from 5-(5-
aminomethyl-1H-1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-
isopropylidene-α-D-xylofuranose (31, 155 mg, 0.35 mmol) and diethyl
phosphorochloridate (0.06 mL, 0.42 mmol). Purification by flash column
3
2
1 H, H-1′′a, J1′′a,2′′a
=
3J1′′a,2′′b = 6.6, J1′′a,1′′b = 9.2), 3.44 (dt, 1 H, H-1′′b,
3J1′′b,2′′a = J1′′b,2′′b = 6.7), 1.63-1.49 (m, 2 H, CH2-2′′), 1.41 (s, 3 H, CH3, i-
Pr), 1.38-1.16 (m, 21 H, CH3, i-Prop, CH2-3′′ to CH2-11′′), 0.87 (t, 3 H,
CH3-12ʹʹ, 3J = 6.9). 13C NMR (100 MHz, CDCl3): δ 139.2 (C-5), 132.4 (C-
4), 112.2 (Cq, i-Pr), 105.3 (C-1′), 82.9 (C-3′), 82.2 (C-2′), 80.0 (C-4′), 70.7
(C-1′′), 47.5 (C-5′), 35.0 (CH2N), 32.1, 29.8, 29.8, 29.7, 29.5, 29.5, 26.3
(C-2′′ to C-10′′), 26.8, 26.2 (2 × CH3, i-Pr), 22.8 (C-11ʹʹ), 14.3 (C-12′′).
HRMS: calcd for C23H42N4O4[M + H]+ 439.3279, found 439.3280.
3
chromatography (from EtOAc to EtOAc/MeOH, 28:1, then 22:1) afforded
20
the title compound (105 mg, 52 %) as a colourless oil.
= ‒ 16 (c =

 D
1, in CH2Cl2).1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1 H, H-4), 5.92 (d,
1H, H-1′, 3J1′,2′ = 3.6), 4.73 (dd, part A of ABX system, 1 H, H-5′a, 3J4ʹ,5ʹa
=
2.8, 2J5′a,5′b =14.7), 4.62-4.50 (m, 2 H, H-2′, H-4′), 4.40 (dd, part B of ABX
system, 1 H, H-5′b, 3J4ʹ,5ʹb = 8.6), 4.29 (dt, 1 H, H-a from CH2NH, 3JH-a,NH
= 3JH-a,P = 9.5, Ja,b = 15.7), 4.17 (ddd, 1 H, H-b from CH2NH, 3JNH,Hb = 5.4,
3JH-b,P = 12.1), 4.11-3.89 (m, 4 H, 2 × CH2, 2 × Et, H-3ʹ, 3J3ʹ,4ʹ = 3.0), 3.64
General procedure for the N-phosphorylation of 3-O-protected 5-
(aminomethyl-1H-1,2,3-triazol-1-yl)-1,2-O-isopropylidene-α-D-
xylofuranoses with diethyl phosphorochloridate: To a solution of 5-
(aminomethyl-1H-1,2,3-triazol-1-yl) xylofuranose derivative (0.35 mmol)
2
3
3
(dt, 1 H, H-1′′a, J1′′a,1′′b = 9.2, J1′′a,2′′a = J1′′a,2′′b = 6.6), 3.57-3.38 (m, 2 H,
11
This article is protected by copyright. All rights reserved.

10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
2
3
H-1′′b, NH, 3J1′′b,2′ʹa = 3J1′′b,2′ʹb = 6.7, JNH,P = JH-a,NH = 9.5), 1.63-1.50 (m, 2
H, CH2-2′′), 1.38 (s, 3 H, CH3, i-Pr), 1.35-1.19 (m, 27 H, CH3, i-Pr, 2 ×
CH3, 2 × Et, CH2-3′′ to CH2-11′′), 0.86 (t, 3 H, CH3-12′′, J = 6.9). 13C NMR
(100 MHz, CDCl3): δ 136.5 (d, C-5, 3JC-5,P = 6.0), 133.5 (C-4), 112.3 (Cq,
i-Prop), 105.2 (C-1′), 82.9 (C-3′), 82.1 (C-2′), 80.0 (C-4′), 70.6 (C-1′′), 62.8,
11ʹʹ), 21.8 (CH2Br), 14.3 (C-12ʹʹ). HRMS: calcd for C23H40BrN3O4 [M +
H]+ 502.2275, found 502.2277.
Data for 38:
= ‒ 50 (c = 1, in CH2Cl2). 1H NMR (400 MHz, CDCl3):
20

 D
δ 7.67 (s, 1 H, H-4), 5.93 (d, 1 H, H-1′, 3J1′,2′ = 3.7), 4.80-4.67 (m, 2 H, H-
5′a, H-a from CH2Br), 4.65-4.47 (m, 4 H, H-2′, H-4′, H-5′b, H-b from
CH2Br), 3.94 (br. s, 1H, H-3′), 3.66 (dt, 1 H, H-1′′a, 3J1′′a,2′′a = 3J1′′a,2′′b = 6.5,
2
62.7 (2 d, 2 × CH2, 2 × Et, JC-P = 5.2), 47.9 (C-5′), 34.2 (CH2N), 32.0,
29.8, 29.7, 29.7, 29.5, 29.5, 26.3 (CH2-3′′ to CH2-10′′) 26.8, 26.2 (2 × CH3,
3
3
2J1′′a,1′′b = 9.1), 3.44 (dt, 1 H, H-1′′b, J1′′b,2′′a = 3J1′′b,2′′b = 6.6), 1.67-1.49 (m,
i-Pr), 22.8 (CH2-11′′), 16.30, 16.25 (d, 2 × CH3, 2 × Et, JC,P = 6.8), 14.2
(C-12′′). 31P NMR (162 MHz, CDCl3):
δ 7.83. HRMS: calcd for
2 H, CH2-2′′), 1.42 (s, 3 H, CH3, i-Pr), 1.37-1.19 (m, 21 H, CH3, i-Pr, CH2-
3′′ to CH2-11′′), 0.87 (t, 3 H, CH3-12′′, 3J = 6.9). 13C NMR (100 MHz,
CDCl3): δ = 133.4 (C-4)*, 112.2 (Cq, i-Pr), 105.3 (C-1′), 82.7 (C-3′), 82.2
(C-2′), 79.7 (C-4′), 70.7 (C-1′′), 47.8 (C-5′), 32.0, 29.8, 29.8, 29.7, 29.7,
29.5, 29.5, 27.0, 26.3 (C-2′′ to C-10′′), 26.8, 26.2 (2 × CH3, i-Pr), 22.8 (C-
11ʹʹ), 17.5 (CH2Br), 14.3 (C-12ʹʹ). *inferred from HSQC. HRMS: calcd for
C23H40BrN3O4 [M + H]+ 502.2275, found 502.2276.
C27H51N4O7P [M + H]+ 575.3568, found 575.3570; calcd for [M + Na]+
597.3388, found 597.3388.
3-O-Benzyl-5-(4-bromomethyl-1H-1,2,3-triazol-1-yl)-5-deoxy-1,2-O-
isopropylidene-α-D-xylofuranose
(35)
and
3-O-benzyl-5-(5-
bromomethyl-1H-1,2,3-triazol-1-yl)-5-deoxy-1,2-O-isopropylidene-α-
D-xylofuranose (36): Obtained according to the general procedure for
thermal azide-alkyne cycloaddition, starting from 5-azido-3-O-benzyl-5-
deoxy-1,2-O-isopropylidene-α-D-xylofuranose (18, 159 mg, 0.52 mmol)
and propargyl bromide (80 wt.% soln. in toluene, 0.12 mL, 1.04 mmol).
The reaction was stirred for 16 h. Purification by column chromatography
(EtOAc/cyclohexane, 1:6) afforded the 1,4-disubstituted triazole 35 (106
mg, 48%) as white crystals and the 1,5-disubstituted regioisomer 36 (4
mg, 2%) as yellowish oil.
General procedure for the Michaelis-Arbuzov reaction between 3-O-
protected
5-(bromomethyl-1H-1,2,3-triazol-1-yl)-1,2-O-
isopropylidene-α-D-xylofuranoses with triethyl phosphite: A solution
of 5-(bromomethyl-1H-1,2,3-triazol-1-yl)xylofuranose derivative (0.17
mmol) in triethyl phosphite (1.5 mL) was stirred at 110 ºC for 2 h. The
solution was concentrated under vacuum and the residue was subjected
to column chromatography.
20
Data for 35:
= ‒ 19 (c = 1, in CH2Cl2). m.p.: 122.2‒123.7 ºC. 1H
 D

3-O-Benzyl-5-deoxy-5-[4-(diethylphosphono)methyl-1H-1,2,3-triazol-
1-yl]-1,2-O-isopropylidene-α-D-xylofuranose (39): Obtained according
to the general procedure, starting from 3-O-benzyl-5-(4-bromomethyl-1H-
1,2,3-triazol-1-yl)-5-deoxy-1,2-O-isopropylidene-α-D-xylofuranose (35, 80
mg, 0.19 mmol) and triethyl phosphite (1.5 mL). Purification by column
chromatography (EtOAc/hexane, 1:3) afforded the title compound (75 mg,
NMR (400 MHz, CDCl3): δ 7.57 (s, 1 H, H-5), 7.42-7.30 (m, 5 H, Ph),
5.97 (d, 1 H, H-1′, J1′,2′ = 3.7), 4.73 (d, part A of AB system, 1 H, H-a
3
2
3
from CH2Ph, Ja,b = 11.8), 4.70-4.59 (m, 2 H, H-2′, H-5′a, J4ʹ,5′a = 7.4,
2J5′a,5′b = 17.1), 4.57-4.42 (m, 5 H, H-4′, H-5′b, CH2Br, H-b from CH2Ph),
3.97 (d, 1 H, H-3′, J3′,4′ = 2.7), 1.42 (s, 3 H, CH3, i-Pr), 1.30 (s, 3 H, CH3, i-
Pr). 13C NMR (100 MHz, CDCl3): δ 144.6 (C-4), 136.8 (Cq, Ph), 128.8,
128.5, 128.1 (CH, Ph), 124.0 (C-5), 112.2 (Cq, i-Prop), 105.3 (C-1′), 82.0
(C-2′), 81.5 (C-3′), 78.8 (C-4′), 72.0 (CH2Ph), 49.5 (C-5′), 26.8, 26.3 (2 ×
CH3, i-Pr), 21.7 (CH2Br). HRMS: calcd for C18H22BrN3O4 [M + H]+
424.0866, found 424.0867.
20
1
83%) as a colourless oil.
= ‒ 33 (c = 1, in CH2Cl2). H NMR (400


D
MHz, CDCl3): 7.64 (d, 1 H, H-5, 4J = 2.1), 7.43-7.29 (m, 5 H, Ph), 5.98 (d,
3
1 H, H-1′, J1′,2ʹ = 3.7), 4.72 (d, 1 H, part A of AB system, H-a, CH2Ph,
2Ja,b = 11.6), 4.68-4.60 (m, 2 H, H-2ʹ, H-5′a, J5ʹa,5ʹb = 13.3, J4ʹ,5ʹa = 7.7),
4.57-4.46 (m, 3 H, H-4ʹ, H-5′b, H-b from CH2Ph), 4.14-4.01 (m, 4 H, 2 ×
CH2, 2× Et), 3.97 (d, 1 H, H-3′, 3J3ʹ,4ʹ = 2.5), 3.38-3.21 (m, 2 H, CH2P, 2Ja,b
= 20.5, 2JH-a,P = 15.8, 2JH-b,P = 16.0), 1.41 (s, 3 H, CH3, i-Pr), 1.33-1.21 (m,
9 H, CH3, i-Pr, 2 × CH3, 2 × Et). 13C NMR (100 MHz, CDCl3): δ 138.5 (d,
C-4, 2JC-4,P = 7.1), 136.9 (Cq, Ph), 128.8, 128.4, 128.0 (CH, Ph), 123.9 (d,
2
3
20
Data for 36:
= ‒ 26 (c = 1, in CH2Cl2). 1H NMR (400 MHz, CDCl3):
 D

δ 7.65 (s, 1 H, H-4), 7.43-7.29 (m, 5 H, Ph) 5.97 (d, 1H, H-1ʹ, 3J1′,2′ = 3.7),
2
4.75 (d, part A of AB system, 1 H, H-a from CH2Ph, Ja,b = 11.8), 4.71-
4.56 (H-2ʹ, H-4ʹ, CH2-5ʹ, H-a from CH2Br), 4.54-4.42 (m, 2 H, H-b from
3
C-5, JC-5,P = 4.1), 112.2 (Cq, i-Pr), 105.3 (C-1′), 82.0 (C-2′), 81.6 (C-3′),
2
3
2
CH2Ph, H-b from CH2Br, Ja,b = 12.1), 4.07 (d, 1 H, H-3ʹ, J3ʹ,4ʹ = 2.6),
1.41 (s, 3 H, CH3, i-Pr), 1.30 ( s, 3 H, CH3, i-Pr). 13C NMR (100 MHz,
CDCl3): δ 136.0 (C-5), 134.2 (Cq, Ph), 134.0 (C-4), 128.9, 128.5, 128.1
(CH, Ph), 112.3 (Cq, i-Pr), 105.3 (C-1′), 82.2 (C-2′), 81.8 (C-3′), 79.6 (C-
4′), 72.2 (CH2Ph), 47.8 (C-5′), 26.8, 26.3 (2 × CH3, i-Pr), 17.5 (CH2Br).
78.9 (C-4′), 71.9 (CH2Ph), 62.49, 62.45 (2 d, 2 × CH2, 2 × Et, JC,P = 6.5),
49.5 (C-5′), 26.8, 26.3 (2 × CH3, i-Pr), 24.3 (d, CH2P, 1JC,P = 142.6), 16.5
3
(d, 2 × CH3, 2 × Et, JC,P = 6.0). 31P NMR (162 MHz, CDCl3): δ 24.87.
HRMS: calcd for C22H32N3O7P [M + H]+ 482.2051, found 482.2063; calcd
for C22H32N3O7P [M + Na]+ 504.1870, found 504.1873.
5-(4-Bromomethyl-1H-1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-
isopropylidene-α-D-xylofuranose (37) and 5-(5-bromomethyl-1H-
1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-isopropylidene-α-D-
xylofuranose (38): Obtained according to the general procedure for
thermal azide-alkyne cycloaddition, starting from 5-azido-5-deoxy-3-O-
dodecyl-1,2-O-isopropylidene-α-D-xylofuranose (19, 300 mg, 0.78 mmol)
and propargyl bromide (80 wt.% soln. in toluene, 0.17 mL, 1.56 mmol).
The reaction was stirred for 48 h. Purification by column chromatography
(EtOAc/cyclohexane, 1:7) afforded the 1,4-disubstituted triazole 35 (227
mg, 58%) as and the 1,5-disubstituted regioisomer 36 (20 mg, 5%) as
yellowish oils.
5-Deoxy-5-[4-(diethylphosphono)methyl-1H-1,2,3-triazol-1-yl]-3-O-
dodecyl-1,2-O-isopropylidene-α-D-xylofuranose
(40):
Obtained
according to the general procedure, starting from 5-(4-bromomethyl-1H-
1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-isopropylidene-α-D-
xylofuranose (37, 85 mg, 0.17 mmol) and triethyl phosphite (1.5 mL).
Purification by column chromatography (EtOAc/hexane, 1:3) afforded the
20
title compound (91 mg, 96%) as a colourless oil.
= ‒ 14 (c = 1, in

 D
1
4
CH2Cl2). H NMR (400 MHz, CDCl3) : δ 7.71 (d, 1 H, H-5, J = 1.6), 5.94
3
(d, 1 H, H-1′, J1′,2′ = 3.6), 4.71 (dd, 1 H, part A of ABX system, H-5′a,
3J4′,5′a = 7.9, 2J5′a,5′b = 17.5), 4.59 (d, 1 H, H-2′), 4.56-4.46 (m, 2 H, H-4′, H-
3
5′b), 4.17-4.03 (m, 4 H, 2 × CH2, 2 × Et), 3.84 (d, 1 H, H-3ʹ, J3′, 4′ = 2.5),
3.64 (dt, 1 H, H-1′′a, J1′′a,2′′a = J1′′a,2′′b = 6.6, J1′′a,1′′b = 9.0), 3.50-3.23 (m,
3
3
2
3 H, H-1′′b, CH2P, J1′′b,2′′a = 3J1′′b,2′′b = 6.6, Ja,b (CH2P) = 20.5, 2JH-a,P = 15.7,
2JH-b,P = 15.9), 1.66-1.52 (m, 2 H, CH2-2′′), 1.43 (s, 3 H, CH3, i-Pr), 1.39-
1.17 (m, 27 H, CH3, i-Pr, CH2-3′′ to CH2-11′′, 2 × CH3, 2 × Et), 0.88 (t, 3
H, CH3-12ʹʹ, 3J = 6.9). 13C NMR (100 MHz, CDCl3): δ = 138.48 (d, C-4,
3
2
20
D
Data for 37:
= ‒ 12 (c = 1, in CH2Cl2). 1H NMR (400 MHz, CDCl3):


3
δ 7.71 (s, 1 H, H-5), 5.95 (d, 1 H, H-1ʹ, J1′,2′ = 3.7), 4.71 (m, 1 H, H-5′a,
3J4ʹ,5′a = 2.2, J5′a,5′b = 12.3), 4.63-4.43 (m, 5 H, H-2′, H-4′, H-5′b, CH2Br),
3.84 (d, 1 H, H-3′, 3J3′,4′ = 2.7), 3.64 (dt, 1 H, H-1′′a, 3J1′′a,2′′a = 3J1′′a,2′′b = 6.5,
2
2JC-4,P = 7.2), 123.9 (d, C-5, JC-5,P = 3.4), 112.1 (Cq, i-Pr), 105.3 (C-1′),
3
3
2J1′′a,1′′b = 9.2), 3.41 (dt, 1 H, H-1′′b, J1′′b,2′′a = 3J1′′b,2′′b = 6.7), 1.62-1.50 (m,
82.5 (C-3′), 82.1(C-2′), 79.0 (C-4′), 70.6 (C-1′′), 62.53, 62.51 (2 d, 2 ×
2 H, CH2-2′′), 1.43 (s, 3 H, CH3, i-Pr), 1.39-1.16 (m, 21 H, CH3, i-Pr, CH2-
3′′ to CH2-11′′), 0.87 (t, 3 H, CH3-12ʹʹ, 3J = 6.9). 13C NMR (100 MHz,
CDCl3): δ 144.7 (C-4), 124.1 (C-5), 112.2 (Cq, i-Pr), 105.4 (C-1′), 82.6
(C-3′), 82.1 (C-2′), 78.9 (C-4′), 70.7 (C-1′′), 49.6 (C-5′), 32.1, 29.8, 29.8,
29.7, 29.5, 29.5, 26.3 (C-2′′ to C-10′′), 26.9, 26.2 (2 × CH3, i-Pr), 22.8 (C-
2
CH2, 2 × Et, JC,P = 6.6), 49.4 (C-5′), 32.0, 29.8, 29.8, 29.7, 29.7, 29.5,
29.5, 26.3 (C-2′′ to C-10′′), 26.9, 26.2 (2 × CH3, i-Pr), 24.3 (d, CH2P, 1JC,P
3
= 142.6), 22.8 (C-11ʹʹ), 16.5 (d, 2 × CH3, 2 × Et, JC,P = 6.0), 14.3 (C-12ʹʹ).
12
This article is protected by copyright. All rights reserved.

10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
31P NMR (162 MHz, CDCl3):
δ
24.91 ppm. HRMS: calcd for
1,2-Di-O-acetyl-5-deoxy-5-[4-(diethylphosphono)methyl-1H-1,2,3-
C27H50N3O7P [M + H]+ 560.3459, found 560.3462.
triazol-1-yl]-3-O-dodecyl-α-D-xylofuranose
(43-α,β):
Obtained
according to the general procedure starting from 5-deoxy-5-[4-
(diethylphosphono)methyl-1H-1,2,3-triazol-1-yl]-3-O-dodecyl-1,2-O-
isopropylidene-α-D-xylofuranose (40, 109 mg, 0.195 mmol). Purification
by column chromatography (EtOAc/hexane, 6:1) afforded the title
compound (80 mg, 68%, two steps, anomeric mixture, α/β ratio, 1:0.5) as
a colourless oil. 1H NMR (400 MHz, CDCl3): δ 7.63, 7.62 (2 d, 1.4 H, H-5
α, H-5 β, 4J = 2.1, 4J = 1.6), 6.44 (d, 1 H, H-1ʹα, 3J1ʹ,2ʹ(α) = 4.4), 6.14 (s, 0.4
H, H-1ʹβ), 5.26-5.21 (m, 1.5 H, H-2ʹα, H-2ʹβ), 4.81-4.65 (m, 2.8 H, H-5ʹa α,
H-5ʹa β, H-4ʹα, H-4ʹβ), 4.58-4.49 (m, H-5ʹb β), 4.44 (dd, 1 H, part B of
5-Deoxy-5-[5-(diethylphosphono)methyl-1H-1,2,3-triazol-1-yl]-3-O-
dodecyl-1,2-O-isopropylidene-α-D-xylofuranose
(41):
Obtained
according to the general procedure, starting from 5-(5-bromomethyl-1H-
1,2,3-triazol-1-yl)-5-deoxy-3-O-dodecyl-1,2-O-isopropylidene-α-D-
xylofuranose (38, 90 mg, 0.18 mmol) and triethyl phosphite (1.5 mL).
Purification by column chromatography (EtOAc/hexane, 1:3) afforded the
20
title compound (76 mg, 76%) as a colourless oil.
= ‒ 18 (c = 1, in

 D
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.66 (br.s, 1 H, H-4), 5.90 (d, 1 H,
H-1′, 3J1′,2′ = 3.6), 4.67 (dd, part A of ABX system, 1 H, H-5′a, 3J4ʹ,5ʹa = 7.0,
2J5ʹa,5ʹb = 17.8), 4.61-4.46 (m, 3 H, H-2′, H-4′, H-5′b), 4.16-3.99 (m, 4 H, 2
× CH2, 2 × Et), 3.88 (d, 1 H, H-3′, 3J3′,4′ = 2.2), 3.61 (dt, 1 H, part A of ABX
3
ABX system, H-5ʹb α, J4ʹ,5ʹb (α) = 8.3, 2J5ʹa,5ʹb(α) = 14.1), 4.19-4.05 (m, 7 H,
H-3ʹα, H-3ʹβ, 2 × CH2, 2 × Et, α, β), 3.79-3.59 (m, 1.4 H, H-1′′a, α, β,
3
2
3J1′′a,2′′a = J1′′a,2′′b = 6.4, J1′′a,1′′b = 9.0), 3.54-3.41 (m, 1.4 H, H-1′′b, α, β),
3.40-3.25 (m, 2.8 H, CH2P, α, β, Ja,b (CH2P) = 19.6, 2JH-a,P = 16.1, 2JH-b,P
=
2
3
3
2
system, H-1′′a, J1′′a,2′′a = J1′′a,2′′b = 6.7, J1′′a,1′′b = 9.0), 3.54-3.36 (m, 2 H,
H-1′′b, H-a from CH2P, 3J1′′b,2′′a = 3J1′′b,2′′b = 6.6, JH-a,P = 16.3), 3.29 (dd, H-
2
16.1), 2.15, 2.11, 2.06 (3 s, 5.4 H, CH3, Ac, α, β), 1.63-1.54 (m, 2.8 H,
CH2-2′′, α, β),1.41-1.21 (m, 33.6 H, CH2-3′′ to CH2-11′′, 2 × CH3, 2 × Et, α,
b from CH2P, Ja,b (CH2P) = 21.2, 2JH-b,P = 16.3), 1.63-1.48 (m, 2 H, CH2-2′′),
2
3
β), 0.88 (t, 4.2 H, CH3-12ʹʹ, α, β, J = 6.7).13C NMR (100 MHz, CDCl3): δ
1.44-1.16 (m, 30 H, 2 × CH3, i-Pr, CH2-3′′ to CH2-11′′, 2 × CH3, 2 × Et),
169.9, 169.6, 169.5, 169.2 (CO, Ac, α, β), 138.5 (d, C-4 α, 2JC-4,P (α) = 7.1),
138.4 (d, C-4 β, 2JC-4,P (β) = 6.6), 124.3 (C-5 β, 3JC-5,P (β) = 3.9), 124.1 (C-5
3
0.88 (t, 3 H, CH3-12ʹʹ, J = 6.9). 13C NMR (100 MHz, CDCl3): δ 134.0 (d,
3
C-4, JC-4,P = 4.3), 129.4 (d, C-5, 2JC-5,P = 7.4), 112.1 (Cq, i-Pr), 105.2 (C-
3
α, JC-5,P (α) = 4.2), 99.7 (C-1ʹ β), 94.0 (C-1ʹ α), 81.4 (C-4ʹ β), 80.6, 80.1
1ʹ), 82.8 (C-3ʹ), 82.1 (C-2ʹ), 80.1 (C-4ʹ), 70.6 (C-1′′), 62.76, 62.73 (2 d, 2 ×
2
(C-3ʹ α, C-3ʹ β), 78.9 (C-2ʹ β), 78.2 (C-4ʹ α), 76.4 (C-2ʹ α), 71.4, 70.9
CH2, 2 × Et, JC,P = 6.5), 47.5 (C-5ʹ), 32.0, 29.7, 29.7, 29.5, 29.5, 26.3
2
(CH2-1ʹʹ, α, β), 62.51, 62.48 (2 d, 2 × CH2, 2 × Et, α, β, JC,P = 6.7, 2JC,P
=
(C-2′′ to C-10′′), 26.8, 26.2 (2 × CH3, i-Pr), 22.8 (C-11ʹʹ), 21.9 (d, CH2P,
3
1JC,P = 144.1), 16.5 (d, 2 × CH3, 2 × Et, JC,P = 6.0), 14.2 (C-12ʹʹ). 31
P
6.5), 51.1, 50.1 (C-5ʹ, α, β), 32.0, 29.8, 29.7, 29.7, 29.6, 29.6, 29.5, 29.5,
1
29.4, 26.2, 26.1 (C-2′′ to C-10′′, α, β), 24.18, 24.13 (CH2P, α, β, JC,P
=
NMR (162 MHz, CDCl3): δ 22.21. HRMS: calcd for C27H50N3O7P [M +
H]+ 560.3459, found 560.3479; calcd for C27H50N3O7P [M + Na]+
582.3279, found 582.3295.
143.0), 22.8 (C-11ʹʹ, α, β), 21.2, 20.9, 20.8, 20.6 (CH3, Ac, α, β), 16.4 (d,
2 × CH3, 2 × Et, α, β, 3JC,P = 6.0), 14.2 (C-12ʹʹ, α, β). 31P NMR (162 MHz,
CDCl3): δ 24.85. HRMS: calcd for C28H50N3O9P [M + H]+ 604.3357,
found 604.3362; calcd for C28H50N3O9P [M + Na]+ 626.3177, found
626.3179.
General procedure for TFA-mediated acetonide hydrolysis in 1,2-O-
isopropylidene xylofuranose 5-(triazolyl)methyl phosphonates
followed by acetylation:
A
solution of 3-O-protected 1,2-O-
General procedure for N-glycosylation of uracil with 1,2-O-acetyl
xylofuranose 5-(triazolyl)methyl phosphonates: To a suspension of
uracil (0.15 mmol, 2 equiv. relatively to the glycosyl acetate) in anhydrous
acetonitrile (1.5 mL), N,O-bis(trimethylsilyl)acetamide (BSA, 3 equiv.)
was added and the mixture was stirred at room temperature for 20 min,
whereupon a clear solution of the silylated derivative was obtained. A
solution of 1,2-O-acetyl xylofuranose 5-(triazolyl)methyl phosphonate (0.1
mmol) in anhydrous acetonitrile (1.5 mL) was added to the previous
solution, followed by dropwise addition of trimethylsilyl triflate (TMSOTf,
6.5 equiv.). The mixture was stirred under microwave irradiation (150 W,
P max = 250 Psi) at 65 ºC for 45 min. It was then diluted with
dichloromethane and neutralized with satd. aq. NaHCO3 solution. The
aqueous phase was extracted with dichloromethane (3x) and the
combined organic phases were washed with brine and dried with
anhydrous MgSO4. After filtration and concentration under vacuum, the
residue was subjected to column chromatography.
isopropylidene xylofuranose 5-(triazolyl)methyl phosphonate (0.1 mmol)
in aqueous trifluoroacetic acid (1.5 mL) was stirred at room temperature
for 2 h. The solvents were co-evaporated with toluene. The residue was
dried under vacuum and was then treated with pyridine (2 mL) and acetic
anhydride (1.5 mL). The mixture was stirred at room temp. for 90 min.
The solvents were co-evaporated with toluene and the residue was
subjected to column chromatography.
1,2-Di-O-acetyl-3-O-benzyl-5-deoxy-5-[4-(diethylphosphono)methyl-
1H-1,2,3-triazol-1-yl]-α,β-D-xylofuranose (42-α,β): Obtained according
to the general procedure starting from 3-O-benzyl-5-deoxy-5-[4-
(diethylphosphono)methyl-1H-1,2,3-triazol-1-yl]-1,2-O-isopropylidene-α-
D-xylofuranose (39, 50 mg, 0.1 mmol).
Purification by column
chromatography (EtOAc/hexane, 6:1) afforded the title compound (28 mg,
51%, two steps, anomeric mixture, α/β ratio, 1:0.5) as a colourless oil.
1H NMR (400 MHz, CDCl3): δ 7.63, 7.62 (2 d, 1.5 H, H-5 α, H-5 β), 7.42-
3
7.29 (m, 7.5 H, Ph), 6.44 (d, 1 H, H-1ʹα, J1ʹ,2ʹ(α) = 4.5), 6.15 (s, 0.5 H, H-
1-{2-O-Acetyl-3-O-benzyl-1,5-dideoxy-5-[4-
1ʹβ), 5.32-5.27 (m, 1.5 H, H-2ʹα, H-2ʹβ), 4.82 (d, 0.5 H, part A of AB
2
(diethoxyphosphono)methyl-1H-1,2,3-triazol-1-yl]-α-D-xylofuranos-1-
yl}uracil (44): Obtained according to the general procedure, starting
from 1,2-di-O-acetyl-3-O-benzyl-5-deoxy-5-[4-(diethylphosphono)methyl-
1H-1,2,3-triazol-1-yl]-α,β-D-xylofuranose (42-α,β, 50 mg, 0.095 mmol)
and uracil (17 mg, 0.152 mmol) and using BSA (0.07 mL, 0.297 mmol)
and TMSOTf (0.12 mL, 0.644 mmol). Purification by flash column
system, H-a from CH2Ph, β, Ja,b(β ) = 11.8), 4.75-4.63 (m, 4 H, H-a from
CH2Ph, α, H-5ʹa α, H-5ʹa β, H-4ʹα, H-4ʹβ), 4.61-4.51 (m, 2 H, H-b from
CH2Ph, α, H-b from CH2Ph, β, H-5ʹb β), 4.46 (dd, 1 H, part B of ABX
3
2
system, H-5ʹb α, J4ʹ,5ʹb (α) = 7.7, J5ʹa,5ʹb(α) = 13.8), 4.25 (m, 1 H, H-3ʹα,
3J2ʹ,3ʹ (α) = 3.7, 3J3ʹ,4ʹ (α) = 5.1), 4.15-4.01 (m, 6.5 H, H-3ʹβ, 2 × CH2, 2 × Et,
2
2
2
α, β), 3.38-3.21 (m, 3 H, CH2P, α, β, Ja,b (CH2P) = 18.0, JH-a,P = 16.3, JH-
b,P = 15.8), 2.13, 2.10 (2 s, 3 H, CH3, 2 × Ac, β), 2.07, 2.03 (2 s, 6 H, CH3,
2 × Ac, α), 1.28 (t, 9 H, 2 × CH3, 2 × Et, α, β, 3J = 7.0). 13C NMR (100
MHz, CDCl3): δ 169.8, 169.7, 169.6, 169.3 (CO, Ac, α, β), 138.6 (d, C-4,
α, β, 2JC-4,P = 6.9), 137.0, 136.8 (Cq, Ph, α, β), 128.8, 128.8, 128.5, 128.4,
chromatography (EtOAc/MeOH, from 24:1 to 18:1) afforded the title
20
compound (20 mg, 36%) as a colorless oil.
= + 6 (c = 1, in CH2Cl2).

 D
1H NMR (400 MHz, CDCl3): δ 9.21 (br. s, 1 H, NH), 7.65 (d, 1 H, H-5′′, 4J
= 1.7), 7.60 (d, 1 H, H-6, 3J5,6 = 8.2), 7.43-7.28 (m, 5 H, Ph), 6.12 (s, 1 H,
H-1′), 5.67 (br.d, 1 H, H-5), 5.18 (s, 1 H, H-2′), 4.78 (d, 1 H, part A of AB
system, H-a from CH2Ph, 2Ja,b= 11.5), 4.74-4.56 (m, 3 H, CH2-5′, H-b
from CH2Ph, 2J5ʹa,5ʹb = 14.3, 3J4ʹ,5ʹa = 5.0, 3J4ʹ,5ʹb = 7.4), 4.50 (ddd, 1 H, H-4′),
4.15-4.02 (m, 4 H, 2 × CH2, 2 × Et), 3.83 (d, 1 H, H-3′, 3J3′,4′ = 3.1), 3.38-
3.21 (m, 2 H, CH2P, 2Ja,b (CH2P) = 19.2, 2JH-a,P = 16.3, 2JH-b,P = 16.0), 2.13 (s,
3 H, CH3, Ac), 1.31-1.21 (m, 6 H, 2 × CH3, 2 × Et). 13C NMR (100 MHz,
CDCl3): δ 169.8 (CO, Ac), 163.0 (C-4), 150.1 (C-2), 140.1 (C-6), 138.8 (d,
3
128.1, 128.1 (CH, Ph, α, β), 124.1 (C-5 α, JC-5,P (α) = 3.9), 124.0 (C-5 β,
3JC-5,P (β) = 4.3), 99.7 (C-1ʹ β), 94.1 (C-1ʹ α), 81.7 (C-4ʹ β), 80.0, 80.0 (C-3ʹ
α, C-3ʹ β), 79.1 (C- 2ʹ β), 78.2 (C-4ʹ α), 76.5 (C-2ʹ α), 72.5, 72.2 (CH2Ph, α,
2
2
β), 62.52, 62.50 (2 d, 2 × CH2, 2 × Et, α, β, JC,P = 6.7, JC,P = 6.2), 50.6,
1
50.1 (C-5ʹ, α, β), 24.29, 24.26 (CH2P, α, β, JC,P = 142.8), 21.3, 21.0 ,
20.9, 20.6 (CH3, Ac, α, β), 16.5 (d, 2 × CH3, 2 × Et, α, β, 3JC,P = 6.0). 31
P
NMR (162 MHz, CDCl3): δ 24.79. HRMS: calcd for C23H32N3O9P [M +
H]+ 526.1949, found 526.1959; calcd for C23H32N3O9P [M + Na]+
548.1768, found 548.1774.
2
C-4′′, JC-4′′,P = 6.8) 136.0 (Cq, Ph), 129.0, 128.9, 128.7 (CH, Ph), 123.9
(C-5′′, 3JC-5′′,P = 3.8), 103.2 (C-5), 88.9 (C-1′), 80.8 (C-4′), 79.8 (C-3′), 79.6
(C-2′), 72.2 (CH2Ph), 62.61, 62.57 (2 d, 2 × CH2, 2 × Et, 2JC,P = 6.6), 48.9
13
This article is protected by copyright. All rights reserved.

10.1002/cplu.202000424
ChemPlusChem
FULL PAPER
1
(C-5′), 24.1 (CH2P, JC,P = 142.7), 20.9 (CH3, Ac), 16.5 (d, 2 × CH3, 2 ×
V = 913.99(18) Å3, Z = 2, μ = 0.110 mm–1; space group was P 21. A total
of 6749 reflection intensities were collected up to 2θmax = 25°; for
structure refinement 2583 independent reflections with I > 4σ(I) were
used. The final Rfactor was 0.0372 and Rw = 0.0753.
Et, JC,P = 6.0).31P NMR (162 MHz, CDCl3): δ 24.78. HRMS: calcd for
C25H32N5O9P [M + H]+ 578.2010, found 578.2011; calcd for C25H32N5O9P
[M + Na]+ 600.1830, found 600.1830.
3
1-{2-O-Acetyl-1,5-dideoxy-5-[4-(diethoxyphosphono)methyl-1H-
1,2,3-triazol-1-yl]-3-O-dodecyl-α-D-xylofuranos-1-yl}uracil
Computational Details
(45):
Obtained according to the general procedure, starting from 1,2-di-O-
acetyl-5-deoxy-5-[4-(diethylphosphono)methyl-1H-1,2,3-triazol-1-yl]-3-O-
dodecyl-α-D-xylofuranose (43-α,β, 45 mg, 0.074 mmol) and uracil (13 mg,
0.12 mmol) and using BSA (0.06 mL, 0.24 mmol) and TMSOTf (0.09 mL,
0.50 mmol). Purification by flash column chromatography (EtOAc/MeOH,
All DFT calculations were perfomed with Gaussian 09.[31] Using three-
dimensional structures of 12-a and 12-b built using Pymol,[30] the
geometries were optimized using the PBE1PBE functional, also known
as PBE0,[39] along with the standard 6-311G** basis set for all elements.
Solvent effects (toluene or chloroform) were taken into account using a
polarizable continuum model described by the SMD variation of the
integral equation formalism variant (IEFPCM),[40] as implemented in
Gaussian09. Frequency calculations were performed to characterize the
stationary points, all corresponding to true minima. The optimized
structures of 12-a (toluene, chloroform) were compared with the
experimental X-ray structure with Pymol by pair-fitting the non-hydrogen
atoms, yielding RMSD values of 0.093 Å and 0.096 Å, respectively.
from 24:1 to 18:1) afforded the title compound (8 mg, 16%) as colorless
oil.
= + 5 (c = 1, in CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 8.69 (br.
20
 D

4
3
s, 1 H, NH), 7.70 (d, 1 H, H-5′′, J = 1.7), 7.63 (d, 1 H, H-6, J5,6 = 8.2),
6.10 (s, 1 H, H-1′), 5.76 (br.d, 1 H, H-5), 5.09 (s, 1 H, H-2′), 4.80 (d, 1 H,
part A of AB system, H-5′a, 3J4ʹ,5ʹa = 4.7, 2J5aʹ,5ʹb = 14.3), 4.64 (d, 1 H, part
3
B of AB system, H-5′b, J4ʹ,5ʹb = 7.6), 4.52 (ddd, 1 H, H-4′), 4.16-4.02 (m,
4 H, 2 × CH2, 2 × Et), 3.95 (d, 1 H, H-3′, 3J3′,4′ = 3.2), 3.74 (dt, 1 H, H-1′′ʹa,
2
3
3J1′′ʹa,2ʹ′′a
= =
3J1ʹ′ʹa,2′′ʹb = 6.6, J1′ʹ′a,1′ʹ′b = 9.3), 3.52 (dt, 1 H, H-1ʹʹʹb, J1ʹ′′b,2ʹ′′a
2
2
3J1′ʹ′b,2ʹ′′b = 6.6), 3.39-3.23 (m, 2 H, CH2P, Ja,b (CH2P) = 19.9, JH-a,P = 15.9,
2JH-b,P = 15.8), 2.12 (s, 3 H, CH3, Ac), 1.63-1.52 (m, 2 H, CH2-2′′ʹ), 1.37-
1.17 (m, 24 H, CH2-3′′′ to CH2-11′′′, 2 × CH3, 2 × Et), 0.87 (t, 3 H, CH3-
12′′′, 3J = 6.9). 13C NMR (100 MHz, CDCl3): δ 169.6 (CO, Ac), 162.7 (C-4),
Acknowledgements
3
150.0 (C-2), 140.2 (C-6), 138.8 (C-4′′), 123.8 (C-5′′, JC-5′′,P = 4.1), 103.1
The authors thank ‘Fundacão para a Ciência e Tecnologia’
(FCT) for funding through the FCT Investigator Program - grant
numbers IF/01488/2013 (N.M.X) and IF/00069/2014 (P.J.C), the
exploratory projects IF/01488/2013/CP1159/CT0006 (N.M.X.)
and IF/00069/2014/CP1216/CT0006 (P.J.C.), and the projects
(C-5), 89.0 (C-1′), 81.0 (C-4′), 80.9 (C-3′), 79.5 (C-2′), 70.9 (C-1′′′), 62.60,
2
62.57 (2 d, 2 × CH2, 2 × Et, JC,P = 6.5), 48.8 (C-5′), 32.0, 29.8, 29.8,
1
29.7, 29.5, 29.5, 26.4 (C-2′′′ to C-10′′′), 24.2 (d, CH2P, JC,P = 143.5),
3
22.8 (C-11′′′), 20.9 (CH3, Ac), 16.5 (d, 2 × CH3, 2 × Et, JC,P = 6.1), 14.3
(C-12′′′). 31P NMR (162 MHz, CDCl3): δ 24.79. HRMS: calcd for
C30H50N5O9P [M + H]+ 656.3419, found 656.3434; calcd for C30H50N5O9P
[M + Na]+ 678.3238, found 678.3254.
UIDB/00100/2020,
UIDP/00100/2020
(CQE),
UID/MULTI/04046/2019, UIDB/04046/2020, UIDP/04046/2020
(BioISI) and UID/MULTI/00612/2013, UID/MULTI/00612/2019
(Centro de Química e Bioquímica). Financial support from
FCT/MCTES, Programa Operacional Regional de Lisboa
(Lisboa 2020), Portugal 2020, FEDER/FN, and the European
Union under Project No. 28455 (LISBOA-01-0145-FEDER-
028455, PTDC/QUI-QFI/28455/2017) is also acknowledged.
Crystal structure determination: X-Ray diffraction data were collected
at 296 K on a Bruker AXS-KAPPA D8 QUEST diffractometer using
graphite monochromated Mo-Kα radiation (λ
=
0.71073Å). All
nonhydrogen atoms were refined anisotropically whereas the hydrogen
atoms were placed in calculated positions and allowed to refine riding on
the parent atom on compounds 12-a and 20 while in compound 35 were
located from the electron density map and allowed to refine freely. All the
structures were solved by direct methods with Bruker SHELXTL[34] and
refined by full-matrix least-squares on F2 using SHELXL 2017/1,[35] both
programs included in WINGX version 2018.3.[36] Graphics were made
with MERCURY 4.3.1[37] and PLATON[38] was used for determination of
hydrogen bond interactions. Deposition Numbers 2004694 (for 12),
2004693 (for 20), and 2004692 (for 35), contain the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
Keywords: cycloaddition • N-glycosylation •
nucleoside/nucleotide analogs • phosphate bioisosteres •
triazole moiety
[1]
[2]
[3]
a) L. P. Jordheim, D. Durantel, F. Zoulim and C. Dumontet, Nat. Rev.
Drug Discov. 2013, 12, 447–464; b) J. Shelton, X. Lu, J. A.
Hollenbaugh, J. H. Cho, F. Amblard, R. F. Schinazi, Chem. Rev.
2016, 116, 14379-14455; c) W. B. Parker, Chem. Rev. 2009, 109,
2880–2893.
a) V. L. Damaraju, S. Damaraju, J. D. Young, S. A. Baldwin, J. Mackey,
M. B. Sawyer, C. E. Cass, Oncogene 2003, 22, 7524–7536; b) J.
Zhang, F. Visser, K. M. King, S. A. Baldwin, J. D. Young, C. E. Cass,
Cancer Metastasis Rev. 2007, 26, 85–110; (c) K. D. Ibarra, J. K.
Pfeiffer, J. Virol. 2009, 83, 4538–4547.
Data for 12: Colourless monocrystals for X-ray studies were obtained
from crystallization with ethyl acetate. Crystal data: orthorhombic; space
group P 21 21 21, a = 5.4925(4), b = 10.0614(8), c = 21.3348(16) Å; V =
1179.01(15) Å3, Z = 4, μ = 0.110 mm–1. A total of 10880 reflection
intensities were collected up to 2θmax = 25°; for structure refinement 2583
independent reflections with I > 4σ(I) were used. The final Rfactor was
0.0317and Rw = 0.0705.
a) C. M. Galmarini, M. L. Clarke, L. Jordheim, C. L. Santos, E. Cros, J.
R. Mackey, C. Dumontet, BMC Pharmacol. 2004, 4, 8; b) O. H.
Temmink, I. V. Bijnsdorp, H.-J. Prins, N. Losekoot, A. D. Adema, K.
Smid, R. J. Honeywell, B. Ylstra, P. P. Eijk, M. Fukushima, G. J. Peters,
Mol Cancer Ther. 2010, 9, 1047-1057; c) M. I. Besecker, C. L. Furness,
D.M. Coen, A.Griffiths, J. Virol. 2007, 81, 8356–8360.
Data for 20: Colourless monocrystals for X-ray studies were obtained.
Crystal data: orthorhombic; a = 8.8217(16), b = 11.0251(18), c =
19.290(3) Å; V = 1876.2(5) Å3, Z = 4, μ = 0.110 mm–1; space group was
P 21 21 21. A total of 7630 reflection intensities were collected up to
2θmax = 21°; for structure refinement 3473 independent reflections with I
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Entry for the Table of Contents
The synthesis of novel 3ʹ/5ʹ-isonucleosides and related prospective nucleotide or sugar diphosphate mimetics containg a triazole unit
as a nucleobase surrogate or as a potential phosphate group bioisostere is described. The synthetic methodologies employed 3-O-
propargyl or 5-azido xylofuranoses as precursors and included the azide-alkyne cycloaddition, N/O-phosphorylation, the Staudinger
reaction, the Arbuzov reaction or N-glycosylation as key steps.
16
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