Efficient diastereoselective synthesis of a new class of azanucleosides: 2′-homoazanucleosides

Article abstract of DOI:10.1016/j.tet.2017.05.083

Azanucleosides, sugar-modified nucleoside analogues containing a 4′ nitrogen atom, have shown a lot of therapeutic potential, e.g. as anti-cancer and antiviral agents. We report the synthesis of a series of 2’-homoazanucleosides, in which the nucleobase is attached to the 2’-position of the pyrrolidine ring via a methylene linker. A suitable orthogonally protected iminosugar was synthesized by ring closing metathesis and dihydroxylation as key steps and further converted to a series of 8 nucleoside analogues through Mitsunobu reaction with suitably protected nucleobases. The 5′ position of the adenine analogue was then further derivatized with thiols to afford 2 additional compounds. The final compounds were evaluated for biological activity.

Full text of DOI:10.1016/j.tet.2017.05.083

Tetrahedron 73 (2017) 4307e4316
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient diastereoselective synthesis of a new class of azanucleosides:
20-homoazanucleosides
,
*
Jakob Bouton a, Kristof Van Hecke b, Serge Van Calenbergh a
a Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium
b XStruct, Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Azanucleosides, sugar-modified nucleoside analogues containing a 40 nitrogen atom, have shown a lot of
therapeutic potential, e.g. as anti-cancer and antiviral agents. We report the synthesis of a series of 2’-
homoazanucleosides, in which the nucleobase is attached to the 2’-position of the pyrrolidine ring via a
methylene linker. A suitable orthogonally protected iminosugar was synthesized by ring closing
metathesis and dihydroxylation as key steps and further converted to a series of 8 nucleoside analogues
through Mitsunobu reaction with suitably protected nucleobases. The 50 position of the adenine analogue
was then further derivatized with thiols to afford 2 additional compounds. The final compounds were
evaluated for biological activity.
Article history:
Received 28 April 2017
Received in revised form
24 May 2017
Accepted 27 May 2017
Available online 29 May 2017
Keywords:
Nucleoside
Azanucleoside
Homonucleoside
Iminosugar
© 2017 Elsevier Ltd. All rights reserved.
Transition state analogue
1. Introduction
The synthesis of azanucleosides is not trivial. The core imino-
sugar often requires a long multi-step synthesis, and attachment of
Azanucleosides, a class of sugar-modified nucleoside analogues
in which the 4’-oxygen of the ribose is replaced by a nitrogen atom,
have recently attracted considerable attention.1,2 The Immucillins, a
series of aza-sugar-C-nucleosides, show potential for the treatment
of leukemia, auto-immune disorders, bacterial infections, etc.3 The
pyrrolidine nitrogen atom allows these nucleosides to function as
transition state analogue inhibitors of several nucleoside-
processing enzymes such as human purine nucleoside phosphor-
ylase (PNP),4 5’-methylthioadenosine nucleosidase (MTAN) & 5’-
methylthioadenosine phosphorylase (MTAP).5 Due to the diverse
essential functions of these enzymes among several organisms and
species, inhibitors may exhibit various biological activities. The
most notable are inhibition of quorum sensing (through MTAN) and
anticancer activity (through MTAP and PNP).4,6,7 Other noteworthy
effects include antiparasitic and antibacterial activity.8e10 Immu-
cillin A (1), also shows broad-spectrum antiviral activity (Fig.1). It is
an RNA polymerase inhibitor and functions as a non-obligate chain
terminator. It is currently in clinical trials for the treatment of Ebola
virus infection under the name galidesivir®.11e13
the nucleobase poses a second challenge, due to the unstable hemi-
aminal linkage that would hydrolyze spontaneously upon contact
with water. Several strategies have been investigated to overcome
this liability. Apart from synthesizing C-nucleosides, where most of
the research has been focusing on, enhanced stability can also be
obtained by substituting the nitrogen. Chiacchio et al., for example,
reported an N-Boc-protected 3’-deoxyazaribonucleoside that dis-
plays highly potent anti-HCV activity in a replicon assay.14 A third
strategy is the synthesis of N-homoazanucleosides, in which a
methylene linker is inserted between the carbohydrate mimic and
the base. Although this formal insertion of a CH2 unit in the
glycosidic bond lengthens the separation between the base and the
pyrrolidine ring relative to that in the natural substrate, this bond is
likewise elongated in transition states. 1’-homoaza-adenosine 3 is
an inhibitor of protozoan nucleoside hydrolases, although less
potent than the corresponding C-nucleoside.15,16 Furthermore,
several second-generation Immucillins, for example the femto-
molar MTAP/MTAN inhibitor 2, also possess an extra methylene
linker between the pyrrolidine and the surrogate nucleobase.17e19
In addition, homonucleosides are resistant towards nucleases,
may still be phosphorylated by cellular enzymes and are able to pair
with natural nucleosides through Watson-Crick interactions.20 10-
21
* Corresponding author.
E-mail address: serge.vancalenbergh@ugent.be (S. Van Calenbergh).
ꢀ
Homonucleosides were recently reviewed by Wroblewski et al.
http://dx.doi.org/10.1016/j.tet.2017.05.083
0040-4020/© 2017 Elsevier Ltd. All rights reserved.

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J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
subsequently coupled with a variety of nucleobases. The desired 20-
C-hydroxymethyl iminosugar has, contrary to several of its ste-
reoisomers,22 not been reported yet. Its retrosynthesis comprises
ring-closing metathesis and subsequent dihyroxylation as key steps
(Fig. 2), based on the observation that this strategy has already been
successfully applied in the synthesis of a number of analogous
iminosugars.23
Several syntheses for the vinylglycinol precursor of 10 have been
reported,24,25 but we opted for the method of Van den Nieuwendijk
et al. using an Ellman tert-butylsulfinamide because of its 100%
enantiopurity.26,27 Rac-Solketal 12 was first protected as benzyl
ether, after which the isopropylidene acetal was hydrolyzed
(Scheme 1). Oxidative cleavage of the resulting diol and conden-
sation with (S)-tert-butanesulfinamide led to sulfinimine 14.
Addition of vinylmagnesium bromide resulted in a mixture of di-
astereoisomers in a 9:1 ratio in favor of the desired diastereoisomer
15, as determined by 1H NMR. We found that the addition of
hazardous AlMe3, as described by Van den Nieuwendijk et al., could
be omitted without a significant drop in diastereoselectivity. The
two diastereoisomers could be separated by column chromatog-
raphy, affording enantiopure 15. Removal of the sulfinamine chiral
auxiliary with HCl in MeOH and subsequent Boc-protection of the
resulting amine furnished 10 in 45% yield over 6 steps.
Fig. 1. Immucillin A (1), DADMe-Immucillin A (2), 10-N-homoazanucleoside (3), 20-N-
homoazanucleoside (4).
In this work we report the synthesis of a series of 2’-homo-
azanucleosides, regioisomers of the 1’-homoazanucleosides (e.g. 3),
in which the nucleobase is attached to the 2’-position of the pyr-
rolidine ring via a methylene linker. This transposition of the
nucleobase affords analogues with the same number of bonds be-
tween the nucleobase and carbons 20, 30 and 40 of the pyrrolidine
ring as in the natural nucleosides and therefore might more closely
mimic the spatial arrangements of natural nucleosides. A series of
2’-homo-azanucleosides was synthesized containing the natural
and some closely related nucleobases, as well as two 5’-thio ana-
logues, inspired by the potent methylthioadenosine-mimicking
aza-C-nucleosides (e.g. 2).
The second building block was synthesized from commercially
available 2-methylene-1,3-propanediol 17 (Scheme 2). Selective
monoprotection as TBS-ether and subsequent iodination yielded 11,
which required purification prior to use in the alkylation reaction
with 10 in order to get reproducible results.
Carbamate 10 was alkylated with 1.1 eq. of iodide 11 using so-
dium hydride as base (Scheme 3). Product 19 was then cyclized by
ring closing metathesis, which proceeded smoothly with only
1.5 mol% Grubbs II catalyst. Ring-closed product 20 was then
dihydroxylated with OsO4 to yield diastereomerically pure 21. The
stereocenter already present apparently provides enough stereo-
induction to have dihydroxylation selectively on the opposite face,
rendering the reaction stereospecific. The stereochemistry was
proven by X-ray analysis of compound 21 (see Supporting
Information), which shows the product to be the expected diaste-
reoisomer (Fig. 3). Isopropylidene protection of 21 was first tried
with 2,2-dimethoxypropane and catalytic TsOH, but resulted in
significant amounts of TBS-deprotected compound. This could be
2. Results and discussion
2.1. Scaffold synthesis
We envisioned a convergent synthetic approach wherein the
protected polyhydroxylated pyrrolidine scaffold is synthesized first,
Fig. 2. Retrosynthesis of the 20-N-homoazanucleoside scaffold. (FGI ¼ functional group interconversion, RCM ¼ ring closing metathesis).

J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
4309
Scheme 1. Synthesis of (S)-O-benzyl-N-Boc-vinylglycinol 10. Reagents and conditions:
a) (i) BnBr, NaH, THF/DMF, 0 ꢀC to rt, 3 h; (ii) AcOH/H2O, rt, 24 h, 97% (2 steps); b) (i)
NaIO4, CH2Cl2/H2O, 0 ꢀC, 6 h; (ii) (S)-tert-butylsulfinamide, CuSO4, CH2Cl2, rt, overnight,
77% (2 steps); c) vinylMgBr, toluene, ꢁ78 ꢀC, 3 h, 71%; d) (i) HCl, MeOH, rt, 1.5 h; (ii) aq.
NaOH, rt, 94% (2 steps); e) Boc2O, Et3N, CH2Cl2, rt, 4 h, 90%.
Scheme 3. Synthesis of protected iminosugar scaffold 23. Reagents and conditions: a)
NaH, DMF, rt, 1 h, rt, 80%; b) 1.5 mol% Grubbs II, DCE, 50 ꢀC, 4 h; c) OsO4, NMO, acetone/
H2O, rt, overnight, 92%; d) 2-methoxypropene, CSA (cat.), THF, rt, 24 h, 98%; e) TBAF,
THF, rt, 1 h, 98%.
Scheme 2. Synthesis of 1-iodo-2-methylenepropanol 11. a) TBS-Cl, NaH, THF, rt, 2 h,
85%; b) I2, imidazole, PPh3, Et2O/MeCN, rt, 30 min, 48%.
circumvented by using 2-methoxypropene and 2 mol% cam-
phersulphonic acid (CSA), affording 22 in almost quantitative yield.
Final TBS-deprotection with TBAF provided the orthogonally pro-
tected central scaffold 23 in 43% yield over 5 steps from 10.
2.2. Nucleobase coupling and deprotection
Fig. 3. Molecular X-ray structure of 21, showing thermal displacement ellipsoids at the
50% probability level.
Introduction of the desired nucleobase in 23 was accomplished
by a Mitsunobu reaction. Two possible issues (i.e. the solubility of
the nucleobases in organic solvents and the alkylation site selec-
tivity) were avoided by prior protection of the nucleobases.28
We chose protecting groups that are cleavable under the same
conditions as the protecting groups on the pyrrolidine scaffold.
Adenine was protected as its N-6-Boc2 derivative, and almost
exclusively yielded the desired coupling product 24 (Scheme 4).29
N-3-BOM-protected uracil and thymine readily afforded 30 and
31.30 We first tried to deprotect the resulting nucleosides in 2 steps
using hydrogenolysis with Pd/C and subsequent acidic hydrolysis.
However, hydrogenolysis proved to be difficult and afforded only
small amounts of debenzylated product, presumably due to the

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J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
Scheme 4. Nucleobase alkylation and deprotection. Reagents and conditions: a) protected nucleobase, PPh3, DIAD, THF, dioxane or acetonitrile, 0 ꢀC to rt, overnight; b) i) Ms-Cl,
Et3N, CH2Cl2, 2 h, 0 ꢀC to rt; ii) protected nucleobase, K2CO3, 18-crown-6, DMF,
D
, overnight; c) i) BCl3, CH2Cl2, -78 ꢀC, 2 h; ii) MeOH, 5 min, ꢁ78 ꢀC to rt; iii) HCl, H2O; d) i) NaN3, DMF,
60 ꢀC, overnight; ii) Pd(OH)2, H2, EtOH, rt, 24 h, 74%; iii) conc. HCl, THF/H2O, reflux, 1 h; e) i) 7 N NH3 in MeOH, MeOH, rt, overnight, 98%; ii) BCl3, CH2Cl2, -78 ꢀC, 2 h, 53%; iii) HCl,
H2O.
coordinating effects of the different nitrogen atoms of the nucleo-
base to the palladium.31 Fortunately, deprotection with the Lewis
acid BCl3, provided the completely deprotected nucleosides in one
step.32 Purification by column chromatography and acidification
yielded the desired nucleoside analogues as their HCl salts.
The guanine and hypoxanthine analogues 28 and 29 were
synthesized from the corresponding 6-chloropurines. The chloride
was substituted for a hydroxy function during the BCl3-mediated
deprotection, by dropwise quenching with MeOH at low temper-
ature. Substitution can be avoided by adding Et3N prior to
quenching with MeOH.33
fashion, to afford 34. The chloride was then substituted with NaN3.
Reduction of the azide and simultaneous removal of the 50-O-
benzyl with Pd(OH)2 and H2, followed by acidic hydrolysis of the
remaining protecting groups afforded 7-deazadenine analogue 35.
5-Fluorouracil was introduced as its N-3-benzoyl protected deriv-
ative.34 Deprotection of 36 was realized in 2 steps: first basic
removal of the benzoyl group, then treatment with BCl3. Lastly,
substitution of the mesylate of 23 with N-4-acetylcytosine, affor-
ded an acceptable amount of N-1-alkylated 38.
The regiochemistry of the nucleobase alkylation reactions was
verified on the final compounds via NMR data, which were in
agreement with those found in literature.20,35e37 The deprotected
compounds were purified by column chromatography and con-
verted to the corresponding mono- or bis-HCl salts.38
Mitsunobu reaction of 23 with 7-deaza-6-chloropurine to syn-
thesize 34 was not possible due to the less acidic pyrrole NH. Hence,
23 was first mesylated and then substituted in a classical SN2

J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
4311
Kingdom) and used as received. NMR solvents were purchased
from Eurisotop (Saint-Aubin, France). Reactions were monitored by
TLC analysis using TLC aluminium sheets (MachereyeNagel, Alu-
gram Sil G/UV254) with detection by UV or by spraying with a
solution
of
(NH4)6Mo7O24
ꢂ
4H2O
(25
g/L)
and
(NH4)4Ce(SO4)4 ꢂ 2H2O (10 g/L) in H2SO4 (10%) followed by char-
ring or an aqueous solution of KMnO7 (20 g/L) and K2CO3 (10 g/L)
followed by charring. Silica gel column chromatography was per-
formed manually using Grace Davisil 60 Å silica gel (40e63 lm) or
automated using a Grace Reveleris X2 system and the corre-
sponding flash cartridges. High resolution spectra were recorded
with a Waters LCT Premier XE Mass spectrometer. 1H and 13C NMR
spectra were recorded with a Varian Mercury-300BB (300/75 MHz)
spectrometer. Chemical shifts are given in ppm (d) relative to tet-
ramethylsilane as an internal standard (1H NMR) or the NMR sol-
vent (13C NMR). In 19F NMR, signals have been referred to CDCl3 or
DMSO-d6 lock resonance frequency according to IUPAC referencing
with CFCl3 set to 0 ppm. Coupling constants are given in Hz. The
correct regiochemistry of the nucleobase alkylation reactions was
verified via HMBC NMR experiments of the final compounds. Op-
tical rotations were recorded on a PerkinElmer 241 polarimeter,
Scheme 5. 5’-derivatization of 24. Reagents and conditions: a) Pd(OH)2, H2, MeOH,
40 ꢀC, overnight, 56%; b) Ms-Cl, Et3N, CH2Cl2, 0 ꢀC to rt, 2 h; c) 4-chloro-thiophenol,
NaH, DMF, 50 ꢀC, 4 h, 97% or NaSMe, DMSO, 50 ꢀC, overnight; d) i) BCl3, CH2Cl2, -78 ꢀC,
2 h, ii) HCl, H2O.
using a sodium-vapor lamp (D-line;
l
¼ 589.3 nm).
4.2. Synthesis
2.3. 5’-derivatization
4.2.1. General procedure 1: mitsunobu reaction
Pd(OH)2-catalyzed hydrogenolysis of 24 yielded alcohol 40,
which was then converted to the mesylate and subsequently
substituted with sodium thiomethoxide or 4-chlorothiophenol to
yield 41 and 42, respectively (Scheme 5). Deprotection with BCl3
and HCl-salt formation yielded 43 and 44.
Diisopropylazodicarboxylate (2.3 eq.) was added dropwise to a
solution of triphenylphosphine (2.3 eq.) in THF, dioxane or aceto-
nitrile (indicated in individual procedures) at 0 ꢀC. After 15 min,
alcohol 23 was added and the reaction was allowed to warm to
room temperature. The appropriate protected nucleobase was
added and the reaction mixture stirred overnight. When TLC indi-
cated the disappearance of the starting material, the mixture was
concentrated in vacuo, absorbed onto celite® and purified by flash
column chromatography to afford the protected nucleoside
analogue.
2.4. Biological evaluation
The synthesized nucleosides were screened against a panel of
viruses (HSV-1, HSV-2, Vaccinia virus, Adenovirus-2, Human
Coronavirus) and microorganisms (Staphylococcus aureus, Escher-
ichia coli, Candida albicans, Trypanosoma brucei) in cell cultures, but
no activity was found in concentrations up to 64 mM. The effect on
signaling molecule (AI-2, AHL/CAI-1) production in Vibrio harveyi
4.2.2. General procedure 2: BCl3-mediated deprotection
BCl3 (1.0 M in CH2Cl2, 10 eq.) was added to a solution of pro-
tected nucleoside (0.1 M) in CH2Cl2 at ꢁ78 ꢀC. When TLC analysis
indicated disappearance of the starting material and the presence
of a single lower-running spot, MeOH (5 mL) was added dropwise
and the mixture warmed to room temperature. Then it was
concentrated in vacuo and co-evaporated with MeOH 3 times. The
residue was dissolved in MeOH, absorbed onto celite® and purified
by flash column chromatography (MeOH/NH4OH/CH2Cl2 20:1:79
and then 45:5:50).
was also investigated, but no activity was found in concentrations
up to 100 mM.
3. Conclusions
A convenient synthetic approach was developed to prepare a
series of 2’-homoazanucleosides. The unprecedented orthogonally
protected iminosugar scaffold was synthesized first, involving a
ring closing metathesis and dihyroxylation as key steps. All steps
proceeded in high yield, highlighting the practical use of this syn-
thesis. From this scaffold a series of 9 nucleoside analogues with
different nucleobases, as well as two 5’-thio modified adenine an-
alogues was synthesized. The nucleoside analogues were evaluated
broadly for antiviral, antibacterial, and antiprotozoal activity, but
failed to show activity.
4.2.3. General procedure 3: HCl-salt formation
The purified compound was dried under high vacuum over-
night, and dissolved in MeOH (10 mL). Concentrated HCl (0.5 mL)
was added, and the mixture concentrated in vacuo. The residue was
dissolved in 10 mL H2O, transferred to a separation funnel, and
washed with 2 ꢂ 5 mL CHCl3. The water phase was then lyophilized
overnight to afford the final nucleoside as its HCl salt.
4. Experimental section
4.2.4. 3-(benzyloxy)propane-1,2-diol (13)
Sodium hydride (60% wt. in mineral oil, 15.4 g, 117 mmol, 1.3 eq.)
was added portionwise to a solution of rac-solketal in a mixture of
DMF (50 mL) and THF (150 mL) at 0 ꢀC. When gas evolution had
ceased, benzyl bromide (23.9 g, 140 mmol, 1.2 eq.) was added
dropwise. After 3 h, TLC analysis (Hexanes/EtOAc 1:1) indicated
disappearance of the starting material. 150 mL water was added
and the mixture was extracted with 3 ꢂ 200 mL Et2O. The com-
bined organic layers were washed with brine, dried over Na2SO4
4.1. General
All reactions described were performed under argon atmo-
sphere and at ambient temperature unless stated otherwise. All
reagents and solvents were purchased from SigmaeAldrich (Die-
gem, Belgium), Acros Organics (Geel Belgium), TCI Europe (Zwijn-
drecht, Belgium) or Carbosynth Ltd (Compton Berkshire, United

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J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
and concentrated in vacuo. The residue was dissolved in AcOH/H2O
4:1 and stirred 24 h at room temperature. The mixture was
concentrated in vacuo, and purified by flash column chromatog-
raphy (hexanes/EtOAc, 7:3 and 0:10). The product was obtained as a
transparent oil in 97% yield (2 steps). 1H NMR (300 MHz, DMSO-d6)
J ¼ 10.4,1.2 Hz), 5.24 (1 H, dt, J ¼ 17.3, 1.5 Hz), 5.84 (1 H, ddd, J ¼ 17.1,
10.6, 6.0 Hz), 7.24e7.43 (5 H, m). 13C NMR (75 MHz, CDCl3)
ppm
53.8, 73.3, 75.1, 115.2, 127.7, 128.4, 137.9138.9. HRMS (ESI-TOF) m/z:
[MþH]þ Calculated for C11H16NOþ: 178.12319; found 178.1211.
d
d
ppm 3.30e3.42 (3 H, m), 3.47 (1 H, s), 3.64 (1 H, dt, J ¼ 16.1,
4.2.8. tert-butyl (S)-(1-(benzyloxy)but-3-en-2-yl)carbamate (10)
Et3N (6.01 mL, 43.1 mmol, 2.0 eq.) and Boc2O (6.44 mL,
28.0 mmol, 1.5 eq.) were added to a solution of 16 (3.82 g,
21.6 mmol) in CH2Cl2 (150 mL) at room temperature. After 4 h of
stirring, the mixture was transferred to a separation funnel. 70 mL
saturated NH4Cl solution was added and the mixture was extracted
with 3 ꢂ 100 mL CH2Cl2. The organic phases were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography (Hexanes/Et2O 9:1)
to afford 10 as a colourless oil in 90% yield. 1H NMR (300 MHz,
5.6 Hz), 4.49 (2 H, s), 4.52 (1 H, t, J ¼ 5.9 Hz), 4.69 (1 H, d, J ¼ 5.0 Hz),
7.21e7.42 (5 H, m). 13C NMR (75 MHz, DMSO-d6)
d ppm 62.9, 70.3,
71.7, 72.0, 127.0, 127.1, 127.9, 138.4. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C10H15Oþ3 : 183.10212; found 183.10184.
4.2.5. (S,E)-N-(2-(benzyloxy)ethylidene)-2-methylpropane-2-
sulfinamide (14)
3-(benzyloxy)propane-1,2-diol 13 (8.70 g, 47.7 mmol) was dis-
solved in CH2Cl2 (90 mL) and cooled to 0 ꢀC. A solution of NaIO4
(15.3 g, 71.6 mmol, 1.5 eq.) in H2O (90 mL) was added and the re-
action mixture was stirred for 6 h. The mixture was then trans-
ferred to a separation funnel and extracted with 3 ꢂ 150 mL CH2Cl2.
The organic phases were dried over Na2SO4 and concentrated in
vacuo under medium pressure at 35 ꢀC. The residue was dissolved
in CH2Cl2 after which anhydrous CuSO4 (15.2 g, 95.4 mmol, 2.0 eq.)
was added, followed by (S)-2-methyl-2-propane-sulfinamide
(6.94 g, 57.3 mmol, 1.2 eq). The reaction mixture was stirred over-
night, filtered over celite® and concentrated in vacuo. The residue
was purified by flash column chromatography (Hexanes/EtOAc 9:1
to 7:3) to afford 14 as a yellow oil in 77% yield. 1H NMR (300 MHz,
DMSO-d6)
d
ppm 1.36e1.44 (9 H, m), 3.46 (2 H, d, J ¼ 6.4 Hz),
4.13e4.28 (1 H, m), 4.50 (2 H, s), 5.09 (1 H, dt, J ¼ 10.5, 1.5 Hz), 5.18
(1 H, dt, J ¼ 17.6, 1.8 Hz), 5.74e5.91 (1 H, m), 6.48 (1 H, d, J ¼ 7.6 Hz),
7.19e7.42 (5 H, m). 13C NMR (75 MHz, DMSO-d6)
d ppm 27.8, 52.1,
71.5, 71.7, 77.4, 114.7, 126.8, 126.9, 127.6, 136.6, 138.1, 154.6. HRMS
(ESI-TOF) m/z: [MþH]þ Calculated for C16H24NOþ3 : 278.17517; found
278.1750.
4.2.9. 2-(((tert-butyldimethylsilyl)oxy)methyl)prop-2-en-1-ol (18)
Sodium hydride (60% wt. in mineral oil, 0.800 g, 20.0 mmol, 1.0
eq.) was dispersed in dry THF (70 mL). 2-methylene-1,3-
propanediol (1.67 mL, 20.0 mmol, 1.0 eq.) in dry THF (10 mL) was
added dropwise. A precipitate was formed. After 45 min, TBS-Cl
(3.01 g, 20.0 mmol, 1.0 eq.) was added. After 2 h of stirring,
100 mL H2O was added and the mixture was extracted with
3 ꢂ 100 mL EtOAc. The combined organic fractions were washed
with brine, dried over Na2SO4 and concentrated in vacuo. Purifi-
cation by flash column chromatography (0e15% EtOAc in hexanes)
yielded 18 as a colourless oil in 85%. 1H NMR (300 MHz, CDCl3)
CDCl3)
d
ppm 1.13 (9 H, s), 4.32 (2 H, dd, J ¼ 3.4, 1.0 Hz), 4.55 (2 H, s),
7.26e7.38 (5 H, m), 8.05 (1H, t, J ¼ 3.2 Hz). 13C NMR (75 MHz, CDCl3)
d
ppm 22.4, 56.9, 71.2, 73.3, 127.8, 128.0, 128.5, 137.2, 166.7. HRMS
(ESI-TOF) m/z: [MþH]þ Calculated for C13H20O2Sþ: 254.12148;
found 254.1209.
4.2.6. (S)-N-((S)-1-(benzyloxy)but-3-en-2-yl)-2-methylpropane-2-
sulfinamide (15)
Compound 14 (9.28 g, 36.6 mmol, 1.0 eq.) was dissolved in dry
toluene and cooled to ꢁ78 ꢀC. Vinylmagnesium bromide (1.0 M in
THF, 54.9 mL, 54.9 mmol,1.5 eq.) was added dropwise (0.5 mL/min).
After 3 h, 7 mL of a saturated solution of Na2SO4 in H2O was added
slowly and the mixture was warmed to room temperature. The
mixture was further dried over Na2SO4 and concentrated in vacuo.
The residue was purified twice by column chromatography (5e25%
EtOAc in hexanes) to afford diastereomerically pure 15 as a yellow
oil in 71% yield.
d
ppm 0.05e0.12 (6 H, m), 0.87e0.96 (9 H, m), 2.08 (1 H, br. s.), 4.17
(2 H, s), 4.21e4.27 (2 H, m), 5.05e5.15 (2 H, m). 13C NMR (75 MHz,
CDCl3)
d
ppm ꢁ5.5, 18.3, 25.6, 25.8, 64.6, 65.1, 111.1, 147.4. HRMS
(ESI-TOF) m/z: [MþH]þ Calculated for C11H16NOþ: 203.14629; found
203.1462.
4.2.10. tert-butyl((2-(iodomethyl)allyl)oxy)dimethylsilane (11)
Compound 18 (3.456 g, 17.08 mmol) was dissolved in Et2O/
MeCN 4:1 (200 mL). PPh3 (6.27 g, 23.9 mmol,1.4 eq.), and imidazole
(1.63 g, 23.9 mmol, 1.4 eq.) were added, followed by I2 (6.07 g,
23.9 mmol, 1.4 eq.). A white precipitate started to form. After
30 min, TLC analysis indicated completion of the reaction, and
100 mL 2 M Na2S2O3 solution was added. The mixture was
extracted 3 times with 100 mL Et2O, washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by flash
column chromatography (100% hexanes and 10% EtOAc in hexanes)
to afford 11 as an orange oil in 48% yield. 1H NMR (300 MHz, CDCl3)
1H NMR (300 MHz, DMSO-d6)
d ppm 1.07e1.20 (9 H, m), 3.46
(1 H, dd, J ¼ 9.7, 6.4 Hz), 3.50 (1 H, dd, J ¼ 9.7, 6.4 Hz), 3.79e3.97
(1 H, m), 4.51 (2 H, s), 4.92 (1 H, d, J ¼ 6.2 Hz), 5.14 (2 H, dt, J ¼ 10.5,
1.2 Hz), 5.28 (2 H, dt, J ¼ 17.3, 1.8 Hz), 5.78 (1 H, ddd, J ¼ 17.0, 10.5,
7.0 Hz), 7.24e7.46 (5 H, m). 13C NMR (75 MHz, DMSO-d6)
d ppm
22.4, 55.0, 57.1, 72.0, 72.5, 116.9, 127.4, 127.5, 128.2, 137.2, 138.2.
HRMS (ESI-TOF) m/z: [MþH]þ Calculated for C15H24O2Sþ:
282.15278; found 282.1521.
d
ppm 0.07e0.16 (6 H, m), 0.93 (9 H, s), 3.96 (2 H, s), 4.31 (2 H, s),
4.2.7. (S)-1-(benzyloxy)but-3-en-2-amine (16)
5.20 (1 H, d, J ¼ 1.5 Hz), 5.32 (1 H, d, J ¼ 0.6 Hz). 13C NMR (75 MHz,
10 mL concentrated HCl was added to a solution of 15 (18.7 g,
66.4 mmol) in MeOH at room temperature. After 90 min, TLC
analysis indicated completion of the reaction and the mixture was
concentrated in vacuo. The residue was purified by column chro-
matography (Hexanes/EtOAc 1:1 to remove a higher-running im-
purity and then CH2Cl2/MeOH 9:1 to elute the title compound as its
HCl salt). The purified HCl salt was then dissolved in 200 mL 0.5 M
NaOH solution and extracted with 3 ꢂ 100 mL CH2Cl2. The organic
phases were dried over Na2SO4 and concentrated in vacuo to give
the title compound as a yellow oil in 94% yield. 1H NMR (300 MHz,
CDCl3)
d
ppm ꢁ5.4, 5.7, 18.3, 25.9, 63.9,113.3, 145.8. HRMS (ESI-TOF)
m/z: [MþH]þ Calculated for C10H22IOSiþ: 313.04791; found
313.0478.
4.2.11. tert-butyl (S)-(1-(benzyloxy)but-3-en-2-yl)(2-(((tert-
butyldimethylsilyl)oxy)methyl)allyl)carbamate (19)
NaH (60% in mineral oil, 0.309 g, 7.74 mmol, 1.3 eq.) was added
to an ice-cold solution of compound 10 (1.65 g, 5.95 mmol) in DMF
(25 mL). After 30 min, a solution of compound 11 (2.60 g,
8.33 mmol, 1.4 eq.) in DMF (5 mL) was added and the mixture
warmed to room temperature. After 1 h, TLC analysis (Hexanes/
EtOAc 8:2) indicated completion of the reaction. 50 mL water was
CDCl3)
d
ppm 1.48 (2 H, br. s), 3.31 (1 H, dd, J ¼ 9.1, 7.9 Hz), 3.51 (1 H,
dd, J ¼ 9.1, 4.1 Hz), 3.63 (1 H, br. s.), 4.56 (2 H, s), 5.11 (1 H, dt,

J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
4313
added and the mixture was extracted with 3 ꢂ 50 mL Et2O. The
combined organic phases were dried over MgSO4, concentrated in
vacuo and purified by flash column chromatography (0e10% Et2O in
hexanes). The product was retrieved in 80% yield as a colourless oil.
(5 H, m). 13C NMR (75 MHz, DMSO-d6, 80 ꢀC)
d
ppm ꢁ5.9, 17.5, 25.3,
26.9, 27.6, 27.6, 54.1, 64.3, 68.3, 72.1, 78.5, 111.0, 126.9, 127.0, 127.8,
137.7, 152.9. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for
C
27H45NO6Siþ: 508.30889; found 508.3120.
1H NMR (300 MHz, DMSO-d6, 80 ꢀC)
d ppm 0.05 (6 H, s), 0.89 (9 H,
s), 1.39 (9 H, s), 3.65 (2 H, ddd, J ¼ 29.9, 9.7, 7.0 Hz), 3.79 (2 H, dd,
J ¼ 16.7, 6.7 Hz), 4.08 (2 H, s), 4.41 (1 H, d, J ¼ 6.7 Hz), 4.48 (2 H, dd,
J ¼ 11.7, 3.5 Hz), 4.99 (2 H, s), 5.11e5.19 (2 H, m), 5.82e6.00 (1 H, m),
4.2.15. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-
hydroxymethyl-3,4-isopropylidene-pyrrolidine-1-carboxylate (23)
TBAF (1.0 M in THF, 10.8 mL, 10.77 mmol, 1.2 eq.) was added to a
solution of 22 (4.56 g, 8.98 mmol, 1.0 eq.) in THF. After 1 h, TLC
analysis showed completion of the reaction. The mixture was
concentrated in vacuo, and the residue purified by flash column
chromatography (0e30% EtOAc in hexanes) to afford 23 in 98%
7.22e7.42 (5 H, m). 13C NMR (75 MHz, DMSO-d6,, 80 ꢀC)
d
ppm ꢁ5.9,
17.5, 25.3, 27.6, 47.2, 58.2, 63.5, 70.0, 71.7, 78.6, 108.9, 116.4, 126.8,
127.6, 134.8, 137.9, 145.4, 154.3. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C26H44NO4Siþ: 462.30342; found 462.3055.
yield as a colourless oil. 1H NMR (300 MHz, DMSO-d6, 80 ꢀC)
d ppm
4.2.12. tert-butyl (S)-2-((benzyloxy)methyl)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-2,5-dihydro-1H-pyrrole-1-
carboxylate (20)
1.33 (3 H, s), 1.34 (3 H, s), 1.39 (9 H, s), 3.33 (1 H, d, J ¼ 12.3 Hz),
3.49e3.61 (6 H, m), 4.04 (1 H, t, J ¼ 5.8 Hz), 4.48 (1 H, s), 4.51 (2 H, s),
4.84 (1 H, t, J ¼ 5.8 Hz), 7.23e7.42 (5 H, m). 13C NMR (75 MHz,
Compound 19 (6.60 g, 14.3 mmol) was dissolved in dry degassed
1,2-dichloroethane (10 mL). The reaction was warmed to 50 ꢀC and
Grubbs II catalyst (0.121 g, 0.143 mmol, 1 mol%) in 2 mL DCE was
added. After 1 h of stirring, a second portion of Grubbs II catalyst
(0.060 g, 0.071 mmol, 0.5 mol%) in 2 mL DCE was added. After 3
more hours, TLC analysis indicated that most of the starting ma-
terial reacted and further progression of the reaction had ceased.
The reaction mixture was concentrated in vacuo and the residue
purified by flash column chromatography (0e10% Et2O in hexanes).
The obtained material was not pure enough for NMR analysis and
was used as such in the next reaction. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C24H40NO4Siþ: 434,27012; found 434.2725.
DMSO-d6, 80 ꢀC)
d ppm 27.0, 27.6, 27.7, 54.0, 62.8, 63.2, 67.9, 72.0,
78.4, 83.9, 110.8, 126.9, 127.7, 137.8, 153.0. HRMS (ESI-TOF) m/z:
[MþH]þ Calculated for C21H32NOþ6 : 394.22242; found 394.2132.
4.2.16. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-9-
methyl-N-6-bis-tert-butyloxycarbonyl-adenine)-3,4-
isopropylidene-pyrrolidine-1-carboxylate (24)
Compound 23 (0.596 g, 1.51 mmol) was subjected to general
procedure 1, using N-6-Boc2-adenine as nucleobase and THF as
solvent. The residue was purified by flash column chromatography
(5 / 40% EtOAc in hexanes) to afford 24 as a white foam in 65%
yield. 1H NMR (300 MHz, DMSO-d6, 80 ꢀC)
d ppm 1.00 (3 H, s), 1.30
(3 H, s), 1.37 (9 H, s), 1.38 (18 H, s), 3.58 (2 H, dd, J ¼ 12.6, 2.9 Hz),
3.62e3.70 (2 H, m), 4.61 (2 H, dd, J ¼ 12.0, 2.9 Hz), 4.69 (2 H, s), 4.75
(1 H, s), 7.21e7.46 (5 H, m), 8.47 (1 H, s), 8.82 (1 H, s). 13C NMR
4.2.13. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-3,4-dihydroxypyrrolidine-1-
carboxylate (21)
(75 MHz, DMSO-d6, 80 ꢀC)
d ppm 21.1, 26.5, 26.9, 27.3, 27.6, 46.6,
To a stirred solution of 20 (4.70 g, 10.8 mmol, 1.0 eq.) in acetone/
water (3:1, 100 mL was added K2OsO4$2H2O (0.041 g, 0.11 mmol,
0.01 eq.), followed by NMO monohydrate (2.13 g, 15.7 mmol, 1.5
eq.). The mixture was stirred overnight, after which Na2SO3 (3.96 g,
31.4 mmol, 3.0 eq.) was added and the mixture stirred for another
hour. The mixture was concentrated in vacuo to remove the
acetone, diluted with water (50 mL) and extracted with 3 ꢂ 100 mL
EtOAc. The organic phases were washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash
column chromatography (0e40% EtOAc in hexanes) to afford 21 in
70% yield as a white solid. 1H NMR (300 MHz, DMSO-d6, 80 ꢀC).
55.6, 63.5, 69.0, 72.4, 78.8, 82.7, 111.7, 127.1, 127.2, 127.8, 137.7, 147.2,
149.0, 149.4, 151.1, 152.7, 153.2. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C36H51N6O9þ: 711,37121; found 711.3737.
4.2.17. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-9-
methyl-6-chloropurine)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (25)
Compound 23 (0.261 g, 0.66 mmol) was subjected to general
procedure 1, using 6-chloropurine as nucleobase and THF as sol-
vent. The residue was purified by flash column chromatography
(10e40% EtOAc in hexanes) to afford 25 as a white powder in 58%
d
ppm 0.05 (6 H, s), 0.87 (9 H, s), 1.39 (9 H, s), 3.24 (1 H, d,
yield. 1H NMR (300 MHz, DMSO-d6, 80 ꢀC)
d ppm 1.03 (3 H, s), 1.31
J ¼ 12.3 Hz), 3.40 (1 H, d, J ¼ 11.4 Hz), 3.43e3.57 (3 H, m), 3.65 (1 H,
dd, J ¼ 10.0, 1.8 Hz), 3.90 (1 H, dd, J ¼ 9.8, 4.0 Hz), 4.20 (2 H, br. s.),
4.50 (2 H, s), 4.68 (1 H, br. s.), 7.17e7.39 (5 H, m). 13C NMR (75 MHz,
(3 H, s),1.37 (9 H, s), 3.52e3.68 (4 H, m), 4.03 (1 H, t, J ¼ 3.8 Hz), 4.58
(2 H, dd, J ¼ 12.3, 3.8 Hz), 4.69 (2 H, s), 4.74 (1 H, s), 7.23e7.42 (5 H,
m), 8.55 (1 H, s), 8.77 (1 H, s). 13C NMR (75 MHz, DMSO-d6, 80 ꢀC)
DMSO-d6, 80 ꢀC).
d
ppm ꢁ6.0, 17.4, 25.3, 27.8, 52.9, 61.9, 63.0, 67.6,
d ppm 27.4, 28.1, 28.5, 47.8, 56.4, 64.4, 69.9, 73.2, 79.7, 110.0, 112.7,
71.1, 72.2, 76.0, 77.9,126.6,126.7,127.6,138.3,153.6. HRMS (ESI-TOF)
m/z: [MþH]þ Calculated for C24H40NO4Siþ: 468.27759; found
468.2796.
127.9, 128.0, 128.0, 128.7, 138.5, 152.8. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C26H33ClN5Oþ5 : 530.21648; found 530.2158.
4.2.18. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-9-
methyl-2-amino-6-chloropurine)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (26)
Compound 23 (0.300 g, 0.76 mmol) was subjected to general
procedure 1, using 2-amino-6-chloropurine as base and 1,4-
dioxane as solvent. The residue was purified by flash column
chromatography (10e45% EtOAc in hexanes), but 26 could not be
separated from Mitsunobu byproducts. The residue was used as
such in the next reaction. HRMS (ESI-TOF) m/z: [MþH]þ Calculated
for C26H34N6Oþ5 : 545.22738; found 545.2316.
4.2.14. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(((tert-
butyldimethylsilyl)oxy)methyl)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (22)
Camphersulphonic acid (0.029 g, 0.125 mmol, 0.02 eq.) was
added to a solution of 21 (2.94 g, 6.28 mmol, 1.0 eq.) in THF
(180 mL). 2-methoxypropene (5.80 mL, 62.8 mmol, 10.0 eq.) was
added and the mixture was stirred for 24 h 200 mL Et3N was added
and the mixture was concentrated in vacuo. The residue was puri-
fied by flash column chromatography (0e20% EtOAc in hexanes) to
afford 22 as a colourless oil in 98% yield. 1H NMR (300 MHz, DMSO-
d6, 80 ꢀC)
d
ppm 0.04 (6 H, s), 0.88 (9 H, s), 1.33 (3 H, s), 1.34 (3 H, s),
4.2.19. (2R,3R,4R)-2-((hydroxy)methyl)-4-(N-9-methyladenine)-
3,4-dihydroxy-pyrrolidine (27)
1.39 (9 H, s), 3.31 (1 H, d, J ¼ 12.3 Hz), 3.46e3.61 (3 H, m), 3.70 (2 H,
s), 4.04 (1 H, dd, J ¼ 6.4, 4.4 Hz), 4.48 (1 H, s), 4.50 (2 H, s), 7.20e7.43
Compound 24 (0.143 g, 0.20 mmol) was subjected to general

4314
J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
procedure 2 and general procedure 3. white powder, 85% yield (2
steps). 1H NMR (300 MHz, D2O)
steps). 1H NMR (300 MHz, D2O)
d
ppm 3.39 (1 H, d, J ¼ 13.2 Hz), 3.50
d
ppm 3.28 (1 H, d, J ¼ 12.9 Hz), 3.55
(1 H, d, J ¼ 13.2 Hz), 3.67 (1 H, ddd, J ¼ 9.1, 5.9, 2.8 Hz), 3.80e4.01
(1 H, d, J ¼ 12.9 Hz), 3.69 (1 H, ddd, J ¼ 9.1, 5.6, 3.5 Hz), 3.86 (1 H, dd,
J ¼ 12.6, 5.6 Hz), 3.98 (1 H, dd, J ¼ 12.7, 3.4 Hz), 4.26 (1 H, d,
J ¼ 9.1 Hz), 4.46 (2 H, s), 8.08 (1 H, s), 8.09 (1 H, s). 13C NMR (75 MHz,
(3 H, m), 4.14 (1 H, d, J ¼ 14.9 Hz), 4.19 (1 H, d, J ¼ 9.1 Hz), 5.81 (1 H,
d, J ¼ 7.9 Hz), 7.59 (1 H, d, J ¼ 7.9 Hz). 13C NMR (75 MHz, D2O)
d ppm
51.6, 51.7, 57.8, 61.9, 72.2, 77.3, 101.4, 147.9, 152.5, 166.7. HRMS (ESI-
D2O)
d
ppm 47.3, 51.5, 57.7, 62.3, 72.2, 77.0, 117.7, 142.9, 148.9, 151.7,
TOF) m/z: [MþH]þ Calculated for C33H42N3Oþ8 : 258,10845; found
154.6. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for C11H17N6O3þ:
258.1086. ½a 2D1
ꢃ
: þ68:9ꢀ ðc ¼ 0:10; H2OÞ.
281.13567; found 281.1374. ½a D21
ꢃ
: þ28:9ꢀ ðc ¼ 0:18; H2OÞ.
4.2.25. (2R,3R,4R)-2-((hydroxy)methyl)-4-(N-1-methylthymine)-
3,4-dihydroxy-pyrrolidine (33)
4.2.20. (2R,3R,4R)-2-(hydroxymethyl)-4-(N-9-
methylhypoxanthine)-3,4-dihydroxy-pyrrolidine (28)
Compound 31 was subjected to general procedure 2 and general
Compound 25 (0.094 g, 0.177 mmol) was subjected to general
procedure 3. light yellow powder, 37% yield (3 steps). 1H NMR
procedure 2 and general procedure 3. White powder, 44% yield. 1H
(300 MHz, D2O)
d
ppm 1.85 (3 H, s), 3.39 (1 H, d, J ¼ 12.9 Hz), 3.49
NMR (300 MHz, D2O)
d
ppm 3.33 (1 H, d, J ¼ 12.9 Hz), 3.54e3.72
(1 H, d, J ¼ 13.2 Hz), 3.67 (1 H, ddd, J ¼ 9.0, 5.6, 3.5 Hz), 3.81e4.14
(2 H, m), 3.83 (1 H, dd, J ¼ 12.9, 5.6 Hz), 3.95 (1 H, dd, J ¼ 12.6,
3.2 Hz), 4.30 (1 H, d, J ¼ 9.1 Hz), 4.66 (2 H, m, J ¼ 1.0 Hz), 8.28 (1 H,
(4 H, m), 4.18 (1 H, d, J ¼ 9.1 Hz), 7.44 (1 H, d, J ¼ 1.0 Hz). 13C NMR
(75 MHz, D2O)
d ppm 11.3, 51.3, 51.6, 57.8, 61.9, 72.1, 77.3, 110.5,
s), 8.81 (1 H, br. s.). 13C NMR (75 MHz, D2O)
d
ppm 48.7, 51.4, 57.6,
143.7, 152.5, 166.8. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for
62.3, 72.3, 76.3, 148.0, 155.9. (3 quaternary carbons missing). HRMS
C
11H18N3Oþ5 :
272,12410;
found
272.1245.
(ESI-TOF) m/z: [MþH]þ Calculated for C11H16N5Oþ4 : 282.11968;
½
a 2D1
ꢃ
: þ64:6ꢀ ðc ¼ 0:43; H2OÞ.
found 282.1188. ½a D21
ꢃ
: þ27:2ꢀ ðc ¼ 0:31; H2OÞ .
4.2.26. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(4-chloro-
7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3,4-isopropylidene-
pyrrolidine-1-carboxylate (34)
4.2.21. (2R,3R,4R)-2-(hydroxymethyl)-4-(N-9-methylguanine)-3,4-
dihydroxy-pyrrolidine (29)
Compound 26 was subjected to general procedure 2 and general
Compound 23 (0.524 g, 1.33 mmol, 1.0 eq.) and DMAP (0.024 g,
0.2 mmol, 0.1 eq.) were dissolved in CH2Cl2 (15 mL) and cooled to
procedure 3. White solid, 11% yield (3 steps). 1H NMR (300 MHz,
D2O)
d
ppm 3.36 (1 H, d, J ¼ 13.2 Hz), 3.58e3.71 (2 H, m), 3.84 (1 H,
0
ꢀC. Et3N (0.279 mL, 2.00 mmol, 1.5 eq.) and Ms-Cl (0.155 mL,
dd, J ¼ 12.9, 5.6 Hz), 3.96 (1 H, dd, J ¼ 12.6, 3.5 Hz), 4.29 (1 H, d,
2.0 mmol, 1.5 eq.) were added and the mixture was stirred for 2 h
25 mL saturated NaHCO3 solution was added, and the mixture was
extracted with 3 ꢂ 50 mL CH2Cl2. The combined organic phases
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was dissolved in 7 mL DMF and added to a
previously stirred (30 min) mixture of 6-chloro-7-deazapurine
(0.511 g, 3.33 mmol, 2.5 eq.) and NaH (60% wt. in mineral oil,
0.106 g, 2.66 mmol, 2.0 eq.). The temperature was raised to 85 ꢀC
and the mixture stirred overnight. The mixture was filtered over
celite®, rinsed with EtOAc and transferred to a separation funnel.
30 mL saturated NaHCO3 solution was added and the mixture was
extracted with 3 ꢂ 50 mL EtOAc. The organic phases were dried
over Na2SO4, concentrated in vacuo and purified by flash column
chromatography (10e50% EtOAc in hexanes) to yield 34 as a col-
ourless oil in 14% yield (2 steps). 1H NMR (300 MHz, DMSO-d6,
J ¼ 9.1 Hz), 4.52 (2 H, d, J ¼ 2.6 Hz), 8.88 (1 H, br. s.). 13C NMR
(75 MHz, D2O) d ppm 48.6, 51.5, 57.6, 62.2, 72.2, 76.1, 155.2, 155.4. (3
quaternary carbons missing). HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C11H17N6O4þ: 297.13058; found 297.1295.
½
a 2D1
ꢃ
: þ64:3ꢀ ðc ¼ 0:25; H2OÞ.
4.2.22. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-3-
benzyloxymethyluracil)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (30)
Compound 23 (0.253 g, 0.64 mmol) was subjected to general
procedure 1, using in N-3-BOM-uracil as nucleobase and THF as
solvent. The residue was purified by flash column chromatography
(10e45% EtOAc in hexanes), affording 30 as a colourless oil in 52%
yield. 1H NMR (300 MHz, DMSO-d6, 80 ꢀC)
d ppm 1.25 (3 H, s), 1.32
(3 H, s), 1.38 (9 H, s), 3.44 (1 H, d, J ¼ 12.3 Hz), 3.59 (2 H, d,
J ¼ 4.7 Hz), 3.66 (1 H, d, J ¼ 12.6 Hz), 3.97e4.26 (4 H, m), 4.55 (2 H,
s), 4.61 (2 H, s), 4.68 (1 H, s), 5.39 (2 H, s), 5.71 (1 H, d, J ¼ 8.0 Hz),
7.20e7.38 (10 H, m), 7.54 (1 H, d, J ¼ 8.0 Hz). 13C NMR (75 MHz,
80 ꢀC)
d ppm 1.08 (3 H, s), 1.31 (3 H, s), 1.36 (9 H, s), 3.45e3.67 (4 H,
m), 3.98e4.06 (1 H, m), 4.50e4.75 (5 H, m), 6.66 (1 H, d, J ¼ 3.5 Hz),
7.25e7.39 (4 H, m), 7.65 (1 H, d, J ¼ 3.5 Hz), 8.62 (1 H, s). 13C NMR
(75 MHz, DMSO-d6, 80 ꢀC)
d ppm 27.4, 28.2, 28.5, 48.8, 56.3, 64.3,
DMSO-d6, 80 ꢀC)
d
ppm 22.5, 27.6, 28.3, 28.5, 51.6, 56.2, 64.2, 69.6,
69.7, 73.1, 79.6, 85.7, 99.1,112.6,117.1,127.9,128.0,128.7,133.0,138.5,
150.8, 151.3, 151.8, 153.6. HRMS (ESI-TOF) m/z: [MþH]þ Calculated
for C27H33ClN4Oþ5 : 529.22123; found 529.2209.
70.7, 71.7, 73.1, 79.6, 100.6, 112.5, 127.7, 127.8, 127.9, 127.9, 128.6,
128.6,138.6,146.6,152.4,153.6,162.6. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C33H42N3O8þ: 608.29665; found 608.2994.
4.2.27. (2R,3R,4R)-2-((hydroxy)methyl)-4-(4-amino-7H-pyrrolo
[2,3-d]pyrimidin-7-yl)methyl)-3,4-dihydroxy-pyrrolidine (35)
4.2.23. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-3-
benzyloxymethylthymine)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (31)
Compound 23 (0.275 g, 0.70 mmol) was subjected to general
procedure 1, using N-3-BOM-thymine as nucleobase and THF as
solvent. The residue was purified by flash column chromatography
(10e45% EtOAc in hexanes), but 31 could not be separated from
Mitsunobu byproducts. The residue was used as such in the next
reaction. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for C34H44N3O8þ:
622.31230; found 622.3138.
NaN3 (0.029 g, 0.45 mmol, 3.0 eq.) was added to a solution of
compound 34 (0.080 g, 0.15 mmol, 1.0 eq.) in 5 mL DMF. The so-
lution was warmed to 85 ꢀC and stirred for 24 h 10 mL water was
added, and the mixture was extracted with 3 ꢂ 25 mL EtOAc. The
organic phases were dried over Na2SO4, concentrated in vacuo and
purified by flash column chromatography (5e40% EtOAc in hex-
anes). The residue was dissolved in 5 mL EtOH, Pd(OH)2 (0.016 g,
20% wt.) was added and the reaction mixture was stirred under H2
atmosphere for 24 h. The mixture was filtered over celite®,
concentrated in vacuo, and used crude in the next reaction. The
residue was dissolved in a mixture of THF & H2O (1:1, 4 mL) and
1 mL concentrated HCl was added. After 1 h of stirring, the mixture
was concentrated in vacuo and purified by flash column chroma-
tography (MeOH/NH4OH/CH2Cl2 20:1:9 and 45:5:55). The residue
4.2.24. (2R,3R,4R)-2-((hydroxy)methyl)-4-(N-1-methyluracil)-3,4-
dihydroxy-pyrrolidine (32)
Compound 30 (0.177 g, 0.29 mmol) was subjected to general
procedure 2 and general procedure 3. white powder, 32% yield (3

J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
4315
was then subjected to general procedure 3 to afford 35 in 54% yield
(3 steps) as a white solid. 1H NMR (300 MHz, D2O)
ppm 3.23 (1 H,
J ¼ 15.5 Hz), 4.16e4.25 (2 H, m), 6.16 (1 H, d, J ¼ 7.6 Hz), 7.79 (1 H, d,
d
J ¼ 7.9 Hz). 13C NMR (75 MHz, D2O)
d ppm 51.6, 52.4, 57.7, 61.9, 72.2,
d, J ¼ 12.9 Hz), 3.54 (1 H, d, J ¼ 13.2 Hz), 3.67 (1 H, ddd, J ¼ 9.0, 5.6,
3.2 Hz), 3.83 (1 H, dd, J ¼ 12.9, 5.6 Hz), 3.95 (1 H, dd, J ¼ 12.6,
3.2 Hz), 4.22 (1 H, d, J ¼ 9.1 Hz), 4.52 (2 H, d, J ¼ 3.2 Hz), 6.81 (1 H, d,
J ¼ 3.8 Hz), 7.37 (1 H, d, J ¼ 3.5 Hz), 8.23 (1 H, s). 13C NMR (75 MHz,
76.9, 94.3, 149.3, 150.3, 159.5. HRMS (ESI-TOF) m/z: [MþH]þ
Calculated for C10H17N4O4þ: 257,12444; found 257.1256.
½
a 2D1
ꢃ
: þ50:8ꢀ ðc ¼ 0:21; H2OÞ.
D2O)
d
ppm 48.4, 51.5, 57.7, 62.1, 72.0, 77.6, 101.5, 101.8, 129.3, 141.7,
4.2.32. tert-butyl (2R,3R,4R)-2-((hydroxy)methyl)-4-(N-9-methyl-
N-6- bis-tert-butyloxycarbonyl -adenine)-3,4-isopropylidene-
pyrrolidine-1-carboxylate (40)
147.2, 150.6. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for
C
12H18N5Oþ3 :
280.14042;
found
280.1403. ½a 2D1
ꢃ
: þ36:0ꢀ ðc ¼ 0:10; H2OÞ.
Pd(OH)2 (0.107 g, 20% wt.) was added to a solution of compound
24 (0.537 g, 0.76 mmol) in MeOH. The reaction mixture was
warmed to 40 ꢀC and stirred under H2 atmosphere for 3 days. The
mixture was filtered over celite®, concentrated in vacuo, and puri-
fied by flash column chromatography (10e50% EtOAc in hexanes)
to afford 40 as a white foam in 56% yield. 1H NMR (300 MHz, DMSO-
4.2.28. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-3-
benzoyl-5-fluorouracil)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (36)
Compound 23 (0.281 g, 0.71 mmol) was subjected to general
procedure 1, using N-3-benzoyl-5-fluorouracil as nucleobase and
MeCN as solvent. The residue was purified by flash column chro-
matography (5e40% EtOAc in hexanes), but 36 could not be sepa-
rated from Mitsunobu byproducts. The residue was used as such in
the next reaction. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for
d6, 80 ꢀC)
d ppm 1.02 (3 H, s), 1.30 (3 H, s), 1.35e1.41 (27 H, m), 3.57
(2 H, s), 3.60e3.69 (2 H, m), 3.92 (1 H, t, J ¼ 4.1 Hz), 4.67e4.81 (3 H,
m), 4.93 (1 H, t, J ¼ 5.0 Hz), 8.51 (1 H, s), 8.84 (1 H, s). 13C NMR
(75 MHz, DMSO-d6, 80 ꢀC)
d 26.6, 26.9, 27.3, 27.7, 46.9, 55.8, 60.5,
65.4, 78.6, 82.7, 111.6, 127.2, 147.1, 149.0, 149.4, 151.1, 152.8, 153.2.
HRMS (ESI-TOF) m/z: [MþH]þ Calculated for C29H45N6Oþ9 :
621,32426; found 621.3249.
C
32H37FN3Oþ8 : 610.22592; found 610.2605.
4.2.29. (2R,3R,4R)-2-((hydroxy)methyl)-4-(N-1-methyl-5-
fluorouracil)-3,4-dihydroxy-pyrrolidine (37)
4.2.33. tert-butyl (2R,3R,4R)-2-((methylthio)methyl)-4-(N-9-
methyl-N-6-bis-tert-butyloxycarbonyl -adenine)-3,4-
isopropylidene-pyrrolidine-1-carboxylate (41)
Compound 36 (0.075 g, 0.12 mmol) was dissolved in 3 mL
MeOH. A 7 N solution of NH3 in MeOH (2 mL) was added and the
mixture was stirred overnight. The mixture was concentrated in
vacuo and purified by flash column chromatography (10e40%
EtOAc in hexanes). The residue was subjected to general procedure
2 and general procedure 3. White powder, 52% yield. 1H NMR
Compound 40 (0.119 g, 0.19 mmol, 1.0 eq.) and DMAP (0.002 g,
0.02 mmol, 0.1 eq.) were dissolved in CH2Cl2 (4 mL) and cooled to
0
ꢀC. Et3N (0.040 mL, 0.29 mmol, 1.5 eq.) and Ms-Cl (0.022 mL,
0.29 mmol, 1.5 eq.) were added and the mixture was stirred for 1 h
10 mL saturated NaHCO3 solution was added, and the mixture was
extracted with 3 ꢂ 25 mL CH2Cl2. The combined organic phases
were dried over Na2SO4, and concentrated in vacuo. The residue
was dissolved in DMSO (4 mL), NaSMe (0.043 g, 0.61 mmol, 3.2 eq.)
was added and the temperature was raised to 50 ꢀC. After 5 h of
stirring, TLC analysis indicated completion of the reaction. The re-
action mixture was diluted with EtOAc (50 mL), washed with
2 ꢂ 15 mL saturated NaHCO3 solution and 15 mL of brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (15e60% EtOAc in hexanes) to afford
a mixture of 2 products, 41 and mono-Boc-protected 41. The
mixture of these two compounds was used in the next reactions.
HRMS (ESI-TOF) m/z: [MþH]þ Calculated for C30H47N6O8Sþ:
(300 MHz, D2O)
d
ppm 3.39 (1 H, d, J ¼ 13.2 Hz), 3.49 (1 H, d,
J ¼ 12.9 Hz), 3.67 (1 H, ddd, J ¼ 8.9, 5.6, 3.1 Hz), 3.80e4.16 (5 H, m),
4.19 (1 H, d, J ¼ 9.1 Hz), 7.80 (1 H, d, J ¼ 5.9 Hz). 13C NMR (75 MHz,
D2O) d ppm 51.6, 51.8, 57.8, 61.9, 72.1, 77.2, 131.6, 132.0, 138.6, 141.7,
151.0, 159.9. 19F NMR (282 MHz, D2O)
d
ppm ꢁ168.09. HRMS (ESI-
TOF) m/z: [MþH]þ Calculated for C10H15FN3Oþ5 : 276.09903; found
276.0985. ½a 2D1
ꢃ
: þ77:9ꢀ ðc ¼ 0:12; H2OÞ.
4.2.30. tert-butyl (2R,3R,4R)-2-((benzyloxy)methyl)-4-(N-1-
methyl-N-4-acetylytosine)-3,4-isopropylidene-pyrrolidine-1-
carboxylate (38)
Compound 23 (0.275 g, 0.70 mmol, 1.0 eq.) and DMAP (0.08 g,
0.07 mmol, 0.1 eq.) were dissolved in CH2Cl2 (8 mL) and cooled to
0
ꢀC. Et3N (0.146 mL, 1.05 mmol, 1.5 eq.) and Ms-Cl (0.081 mL,
651.31706; found 651.3173. Calculated for
551.26518; found 551.2678.
C
25H39N6O6Sþ:
1.05 mmol, 1.5 eq.) were added and the mixture was stirred for 1 h
25 mL saturated NaHCO3 solution was added, and the mixture was
extracted with 3 ꢂ 50 mL CH2Cl2. The combined organic phases
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was dissolved in 6 mL DMF. N-4-acetylcytosine
(0.129 g, 0.84 mmol, 1.2 eq.), K2CO3 (0.145 g, 1.05 mmol, 1.5 eq.)
and 18-crown-6 (0.030 mL, 0.14 mmol, 0.2 eq.) were added and the
mixture was warmed to 75 ꢀC. After 18 h, the mixture was filtered
over celite® and purified by flash column chromatography (0e5%
MeOH in CH2Cl2) to afford 38. 38 could not be obtained pure
enough for NMR analysis and was used as such in the next re-
actions. HRMS (ESI-TOF) m/z: [MþH]þ Calculated for C27H37N5O7þ:
529.26568; found 529.2678.
4.2.34. tert-butyl (2R,3R,4R)-2-(4-chloro-phenylthiomethyl)-4-(N-
9-methyl-N-6- bis-tert-butyloxycarbonyl -adenine)-3,4-
isopropylidene-pyrrolidine-1-carboxylate (42)
Compound 40 (0.120 g, 0.19 mmol, 1.0 eq.) and DMAP (0.002 g,
0.02 mmol, 0.1 eq.) were dissolved in CH2Cl2 (4 mL) and cooled to
0
ꢀC. Et3N (0.040 mL, 0.29 mmol, 1.5 eq.) and Ms-Cl (0.022 mL,
0.29 mmol, 1.5 eq.) were added and the mixture was stirred for 1 h
10 mL saturated NaHCO3 solution was added, and the mixture was
extracted with 3 ꢂ 25 mL CH2Cl2. The combined organic phases
were washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was used crude in the next reaction. The residue
was dissolved in 3 mL DMF and added to a previously stirred
(30 min) mixture of 4-chloro-thiophenol (0.082 g, 0.57 mmol, 3.0
eq.) and NaH (60% wt. in mineral oil, 0.019 g, 0.48 mmol, 2.5 eq.) in
2 mL DMF. The mixture was stirred overnight and concentrated in
vacuo. The residue was dissolved in CH2Cl2 (25 mL), washed with
saturated Na2CO3 solution (10 mL) and brine (10 mL), dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash
column chromatography (10 / 50% EtOAc in hexanes) to afford 42
4.2.31. (2R,3R,4R)-2-((hydroxy)methyl)-4-(N-1-methylcytosine)-
3,4-dihydroxy-pyrrolidine (39)
Compound 38 (0.098 g, 0.185 mmol) was subjected to general
procedure 2 and general procedure 3. Off-white solid, 15% (2 steps).
1H NMR (300 MHz, D2O)
d
ppm 3.39 (1 H, d, J ¼ 13.2 Hz), 3.50 (1 H,
d, J ¼ 13.2 Hz), 3.65 (1 H, ddd, J ¼ 11.8, 5.6, 3.1 Hz), 3.83 (1 H, dd,
J ¼ 12.7, 5.7 Hz), 3.96 (1 H, dd, J ¼ 12.7, 3.4 Hz), 4.03 (1 H, d,

4316
J. Bouton et al. / Tetrahedron 73 (2017) 4307e4316
as a colourless oil in 97% yield (2 steps). HRMS (ESI-TOF) m/z:
[MþH]þ Calculated for C35H48ClN6O8Sþ: 747,29374; found
747.2935.
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1H NMR (300 MHz, D2O)
3.10e3.26 (2 H, m), 3.75 (1 H, d, J ¼ 8.8 Hz), 4.30 (2 H, s), 8.04 (1 H,
s), 8.06 (1 H, s). 13C NMR (75 MHz, D2O)
ppm 14.9, 35.9, 49.1, 52.8,
d ppm 2.09 (3 H, s), 2.58e2.88 (3 H, m),
d
60.6, 77.4, 78.2,117.7, 142.8,149.0, 152.2,155.2. HRMS (ESI-TOF) m/z:
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4.2.36. (2R,3R,4R)-2-(4-chloro-phenylthiomethyl)-4-(N-9-
methyladenine)-3,4-dihydroxy-pyrrolidine (44)
Compound 42 was dissolved in a mixture of THF and H2O (1/1,
4 mL) and 1 mL concentrated HCl was added. After 4 h of stirring,
the mixture was concentrated in vacuo and the residue purified by
flash column chromatography (MeOH/NH4OH/CH2Cl2 0:0:100 to
20:1:79). The residue was then subjected to general procedure 3 to
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ppm 33.0, 47.6, 51.2, 60.0, 75.2, 76.7,
d ppm 3.20e3.34 (2 H, m), 3.47e3.71 (3 H, m), 4.17 (1 H, d,
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407.1063. ½a 2D1
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: þ75:1ꢀ ðc ¼ 0:28; H2OÞ.
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.05.083.