Synthesis of a 3′-Fluoro-3′-deoxytetrose Adenine Phosphonate

Article abstract of DOI:10.1021/acs.joc.7b01482

A new synthetic route to a 3′-fluoro-3′-deoxytetrose adenine phosphonate has been developed. The synthesis starts from l-xylose and key steps include the stereospecific introduction of the phosphonomethoxy group and adenine. In addition, a regioselective

Full text of DOI:10.1021/acs.joc.7b01482

Article
pubs.acs.org/joc
Synthesis of a 3′-Fluoro-3′-deoxytetrose Adenine Phosphonate
Swarup De, Steven De Jonghe, and Piet Herdewijn*
Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium
S
* Supporting Information
ABSTRACT: A new synthetic route to a 3′-fluoro-3′-deoxytetrose adenine phosphonate has been developed. The synthesis
starts from L-xylose and key steps include the stereospecific introduction of the phosphonomethoxy group and adenine. In
addition, a regioselective fluorination reaction allows access to the desired 3′-fluoro-3′-deoxytetrose moiety. This methodology
allows the straightforward synthesis of a 3′-fluoro-3′-deoxytetrose adenine phosphonate and can be expanded toward the
synthesis of other types of 3′-fluoro nucleoside phosphonates.
properties of nucleoside phosphonates, we became interested in
the synthesis of a hybrid molecule, i.e., a 3′-fluoro-3′-
deoxyadenosine phosphonate (compound 1, Figure 1).
INTRODUCTION
■
The synthesis of modified nucleoside and nucleotide analogues
as antiviral agents is an ongoing research field.1 Among the
sugar modified analogues, the fluorinated congeners are a
prominent class.2 The best studied class of fluorinated
nucleoside analogues carries a fluorine at C-2′ of the sugar
moiety. A striking example is sofosbuvir that received marketing
approval for the treatment of hepatitis C virus infected
patients.3 The antiviral activity of nucleosides analogues with
a 3′-fluorine substituent at the carbohydrate moiety has been
described to a lesser extent. 3′-Fluoro-3′-deoxythymidine4 and
3′-fluoro-3′-deoxyadenosine5 are examples of this series of
antivirally active nucleoside analogues. An important class of
nucleoside analogues are the nucleoside phosphonates that are
chemically and metabolically stable mimics of the nucleoside
monophosphate.6 Hence, they can bypass the first, and often
rate-limiting step in the conversion of the nucleoside to the
pharmacologically active nucleoside triphosphate. The fact that
the phosphonate moiety is isopolar and isoelectronic with the
phosphate group allows the phosphonate to be phosphorylated
by kinases to afford the diphosphophosphonate analogue,
which acts as an analogue of the naturally occurring nucleoside
triphosphate. The improved stability results in a prolonged pool
of the nucleoside phosphonate inside the cell that is available
for metabolism to the biologically active species, ultimately
leading to long intracellular half-lives. As a result of these
properties, clinically approved antiviral phosphonates are used
in convenient once-daily antiviral treatment regimens. The
synthesis of nucleoside phosphonates with a fluorinated sugar
moiety has been hardly described in literature. An example is
2′-Fd4AP which is endowed with excellent activity against the
human immunodeficiency virus, a promising resistance profile
and minimal toxicity.7
Figure 1. A 3′-fluoro-3′-deoxytetrose adenine phosphonate.
Target molecule 1 possesses a fluorinated ribose sugar
moiety with two anomeric centers (a N-glycosidic bond with
adenine at the 1′-position and an O-glycosidic bond with
hydroxymethylphosphonate at 4′-position), both having the β-
configuration. Hence, key transformations in the synthetic
sequence will be the stereoselective introductions of the
phosphonomethoxy group and the nucleobase, as well as the
introduction of the fluorine with the correct stereochemistry.
For the synthesis of 3′-fluoro-3′-deoxyadenosine, two main
methods have been used in literature. Either a fluorinated sugar
moiety is synthesized first,5a,8 which is then coupled with a
nucleobase. Alternatively, an appropriate protected nucleoside
derivative with the 3′-hydroxyl group in the xylo configuration
is prepared, which is then fluorinated by DAST treatment.5b
Similar strategies were envisioned for the synthesis of 3′-fluoro-
3′-deoxytetrose adenine phosphonate 1. Retrosynthetic analysis
clearly demonstrated that compound 1 could become accessible
via these two major routes (Figure 2). The first route (Route 1)
Based on the broad spectrum antiviral activity profile of 3′-
fluoro-3′-deoxyadenosine and the favorable pharmacological
Received: June 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b01482
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Figure 2. Retrosynthetic analysis of compound 1.
a
Scheme 1. Synthetic Route toward Compound 1
a
Reagents and conditions: (a) NaH, TBAI, BnBr, dry THF, −78 °C to r.t., 5 h, 62%; (b) DAST, dry pyridine, dry CH2Cl2, −20 °C to r.t., 18 h, 56%;
(c) 50% TFA in H2O, 0 °C to r.t., 4 h, 100%; (d) Ac2O, dry pyridine, 0 °C to r.t., 14 h, 83%; (e) 1 M SnCl4 in CH2Cl2, N6-benzoyl adenine, dry
ACN, −20 °C to r.t., 4 h, 85%; (f) 1 M BCl3 in CH2Cl2, dry CH2Cl2, −78 to 0 °C, 3 h, 86%.
involves the synthesis of a fluorinated sugar moiety, derived
from a protected D-xylose derivate. The presence of a 2′-O-acyl
protecting group will allow the stereoselective introduction of
moiety, due to absence of anchimeric assistance because a 3′-
fluorine is present. Therefore, separation of both anomers will
be necessary. In an alternative way (which also has been applied
in the synthesis of 3′-fluoro-3′-deoxy-adenosine), a nucleoside
phosphonate with the xylo stereochemistry of the hydroxyl
group at 3′-position, is synthesized first, which is then
fluorinated in the last step affording target compound 1
(Route 2). The advantage of this approach is that the
nucleobase, as well as the phosphonomethoxy functionality
can be introduced in a stereoselective way, due to the presence
of 2′-O-acyl and 3′-O-acyl protecting groups, respectively. It
will avoid the (usually) tedious and time-consuming separations
of anomers. The phosphonylated sugar derivative is accessible
from a suitable protected D-ribose (route 2A) or L-ribose (route
2B) derivative. Due to the high costs of L-ribose, this will need
to be prepared from an appropriately protected L-xylose
derivative. As an anomeric acetate group at 4′-position is easily
accessible, the method of choice for insertion of the
the nucleobase (via Vorbruggen coupling),9 yielding a 3′-
̈
fluoro-3′-deoxyadenosine analogue. For the synthesis of
nucleoside analogues carrying a 4′-phosphonomethoxy moiety,
two major strategies are known. A first method uses a
regioselective and stereoselective electrophilic addition of a
phosphonomethoxy moiety to a furanoid glycal using N-
(phenylseleno)phthalimide or iodine bromide. This method-
ology has for example been applied for the synthesis of an
adenosine phosphonate10 and an inosine phosphonate11
analogue. Alternatively, a stereoselective (due to anchimeric
assistance of a 3′-O-acyl protecting group), Lewis acid-mediated
glycosidation of a phosphonate alcohol onto an anomeric
acetate has been used to synthesize nucleoside phosphonates.12
The latter method deemed to be useful for the synthesis of
compound 1. The main drawback of this strategy will be the
lack of stereoselectivity when inserting the phosphonate
B
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a
Scheme 2. Synthetic Route toward Compound 1
a
Reagents and conditions: (a) BnOH, SnCl4, dry ACN, −20 °C to r.t., 5 h; (b) 7 N NH3 in MeOH, r.t., 24 h, 64%; (c) 1,3-dichloro-1,1,3,3-
tetraisopropyldisiloxane, dry pyridine, 0 °C to r.t., 4 h, 89%; (d) BzCl, dry pyridine, 0 °C to r.t., 12 h, 91%; (e) BOMCl, DIPEA, dry CH2Cl2, reflux,
24 h, 92%; (f) Et3N·3HF, dry THF, r.t., 24 h, 48% (for 16), 94% (for 17); (g) MMTrCl, dry pyridine, r.t., 18 h, 96%; (h) BzCl, dry pyridine, 0 °C to
r.t., 16 h; (i) 80% AcOH, r.t., 4 h, 83% (over 2 steps) ; (j) DIB, TEMPO, ACN:H2O (1:1), 0 °C to r.t., 4.5 h, 91%; (k) Pb(OAc)4, dry pyridine, dry
THF, 35 °C, 20 h, 88%.
phosphonomethoxy group involves the Lewis-acid mediated
glycosylation, rather than the glycal approach.
under harsh reaction conditions. On the other hand, Lewis-acid
mediated debenzylation (using borontrichloride) afforded
compound 8 in excellent yield. Unfortunately, all attempts to
obtain the carboxylic acid derivative 9 from its corresponding
alcohol 8 using a variety of oxidizing agents (e.g., DIB/
TEMPO, PDC/DMF, CrO3/H2SO4, KMnO4, DMP/NaClO2)
failed, giving rise to unreacted starting material or decomposed
side products. The presence of the strongly electronegative
fluorine might explain the unreactivity of 8 or the instability of
product 9, arising from the strongly inductive effect of fluorine
(Scheme 1).
Synthesis of Compound 1 via a Phosphonylated
Sugar Derivative. Difficulties in oxidation of the primary
hydroxyl group of the 3′-fluoro-3′-deoxyadenosine analogue 8
(Scheme 1) forced us to explore another synthetic route, in
which first a phosphonylated sugar moiety was synthesized
(Figure 2, route 2). Reaction of β-D-ribofuranose 1,2,3,5-
tetraacetate 10 with benzyl alcohol under Lewis-acid catalyzed
RESULTS AND DISCUSSION
■
Attempted Synthesis of Compound 1 from a
Protected 3′-Fluoro-3′-deoxytetrose Adenine Deriva-
tive. Selective benzylation of the primary hydroxyl group of
1′,2′-O-isopropylidene-α-D-xylofuranose 2 afforded derivative 3
in good yield.13 To avoid selective protection and deprotection
sequences between the hydroxyl groups at 2′ and 3′-positions,
the 3′−OH group of compound 3 was converted to the
corresponding fluorine derivative 4 using the common
fluorinating agent diethylaminosulfur trifluoride (DAST) in a
moderate yield of 56%. Attempts to improve the yield of the
fluorination reaction by using other nucleophilic fluorinating
agents, such as deoxo-fluor or fluolead were unsuccessful.
Acidic deprotection of the isopropylidene moiety of 4 using
50% TFA in water, followed by acetylation of 5 using acetic
anhydride yielded a diastereomeric mixture of the diacetylated
analogue 6 in 83% yield over two steps. A stereoselective SnCl4
Vorbruggen conditions afforded 1′-O-benzyl-2′,3′,5′-tri-O-
̈
acetyl-β-D-ribofuranoside (11) in moderate yield (64%)
(Scheme 2).14 It was foreseen that the conversion from the
1′-O-benzyl group to its corresponding 1′-acetate will allow the
regioselective introduction of N6-benzoyl adenine, later on in
the synthesis. Removal of the O-acetyl protecting groups of 11
catalyzed Vorbruggen glycosylation of N6-benzoyl adenine with
̈
the 1′-O-,2′-O-acetyl sugar 6 afforded the protected 3′-fluoro-
3′-deoxyadenosine analogue 7 in good yield (85%). In order to
deprotect the benzyl group of derivative 6, different hydro-
genation conditions using a range of Pd-catalysts (including
10% Pd/C, 20% Pd(OH)2/C, Pd(OAc)2, and Pd-black) were
explored. None of these conditions were successful in
delivering compound 8. Either unreacted starting material
was recovered when mild reaction conditions were applied or
undesired side-products (that were not isolated) were formed
́
under modified Zemplen conditions (using a 7N NH3 solution
in methanol) afforded 1′-O-benzyl-β-D-ribofuranoside (12).
Simultaneous protection of the 3′- and 5′-hydroxyl groups of
ribofuranoside 12 using Markiewicz′s reagent (TIPDSCl2)
afforded disiloxane ribofuranoside 13 in 90% yield. The 2′-
benzoyl protected disiloxane ribofuranoside 14 was obtained in
C
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a
Scheme 3. Synthetic Route toward Compound 1
a
Reagents and conditions: (a) 5.4 M NaOMe in MeOH, MeOH, r.t., 1 h, 97%; (b) NaH, BnBr, dry THF, −20 °C to r.t., 19 h, 92%; (c) 50% TFA in
H2O, 0 °C to r.t., 4 h; (d) Ac2O, dry pyridine, 0 °C to r.t., 14 h, 90% (over 2 steps); (e) diisopropyl (hydroxymethyl)phosphonate, SnCl4, dry ACN,
−20 °C to r.t., 5 h, 80%; (f) 7 N NH3 in MeOH, r.t., 16 h, 96%; (g) Dess-Martin periodinane, dry CH2Cl2, −20 °C to r.t., 18 h; (h) NaBH4, 1:1
absolute EtOH: dry EtOAc, −50 °C to r.t., 5 h, 71% (over 2 steps); (i) Ac2O, dry pyridine, 0 °C to r.t., 14 h, 95%; (j) MEMCl, DIPEA, dry CH2Cl2,
reflux, 48 h, 86%; (k) TBDPSCl, imidazole, cat. DMAP, dry ACN, 60 °C, 48 h, 80%; (l) 10% Pd/C, H2, AcOH, EtOH: H2O (9:1), r.t., 20 h, 98%
(for 33), 95% (for 34); (m) (i) MMTrCl, DMAP, dry pyridine, 0 °C to r.t., 17 h,; (ii) BzCl, dry pyridine, 0 °C to r.t., 3 h, 85% (for 35, over 2 steps),
87% (for 36, over 2 steps); (n) 80% AcOH, r.t., 4 h, 84% (for 37), 85% (for 38); (o) DIB, TEMPO, ACN:H2O (1:1), 0 °C to r.t., 4.5 h, 96% (for
39), 93% (for 40); (p) Pb(OAc)4, dry pyridine, dry THF, 35 °C, 20 h, 90% (for 41), 75% (for 42); (q) 1 M SnCl4 in CH2Cl2, N6-benzoyl adenine,
dry ACN, 0 °C to r.t., 36 h, 45%.
excellent yield (91%) from its precursor 13. Benzoyl was
preferred as protecting group at 2′-position of 13, as a 2′-O-acyl
group allows the stereoselective glycosylation of the nucleobase.
However, during removal of the disiloxane protecting groups of
14, almost an equivalent amount of the 3′-benzoyl adduct was
observed along with the desired 2′-benzoyl ribofuranoside 16,
due to 2′↔3′ benzoyl migration, facilitated by basicity of the
fluoride anion. Both regioisomers were separated by silica gel
flash chromatography.
A similar problem was encountered during the protection of
the primary hydroxyl group of 16 as a monomethoxytrityl,
yielding a nonseparable mixture of regioisomers of 2′- and 3′-
benzoyl adducts. Therefore, we switched to a benzyloxymethyl
(BOM) group as an alternative, more stable and easily
removable protecting group for the 2′-hydroxyl group affording
compound 15. Subsequently, deprotection of the TIPDS group
of 15, followed by protection of the primary hydroxyl group,
afforded 18 in excellent yield. Benzoyl protection of 3′-hydroxyl
group of ribofuranoside 18, followed by 5′-MMTr removal by a
80% AcOH solution yielded 19 in good yield (83%) over two
steps. DIB-TEMPO mediated oxidation of the primary
hydroxyl group of 19 yielded its corresponding carboxylic
acid 20 in excellent yield (91%).15 Oxidative decarboxylation of
acid 20 via a modified Kochi reaction resulted into the 4′-
acetate derivative 21 as a mixture of α/β isomers.16
Unfortunately, efforts to obtain phosphonate 22 via a
Vorbruggen reaction of acetate 21 with hydroxymethyl
̈
phosphonic acid diisopropyl ester in the presence of different
Lewis acids, such as TMSOTf or SnCl4, at varying temperatures
were unsuccessful. At lower temperature, no reaction took
place, whereas at elevated temperatures or using prolonged
reaction times complex reaction mixture were obtained. This
might be caused by the instability of the starting material 21
due to the presence of two anomeric centers.
As the introduction of the phosphonate moiety on sugar
derivative 21 was not feasible (Scheme 2), an alternative
synthetic route, using L-xylose as starting material was explored
(Scheme 3) following route 2B of retrosynthetic analysis in
D
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a
Scheme 4. Synthesis of Compounds 1 and 49−51
a
Reagents and conditions: (a) 2 M NH3 in EtOH, 0 °C to r.t., 48 h, 44: 3%, 45: 42%, 46: 45%; (b) 7 N NH3 in MeOH, r.t., 48 h, 96%; (c) DAST,
dry pyridine, dry CH2Cl2, −20 °C to r.t., 6 h, 42% (from 45), 47% (from 46); (d) TMSBr, 2,6-lutidine, dry ACN, 0 °C to r.t., 24 h, 88%; (e) PhOH
and/or amino acid.HCl, Et3N, 2,2′-dithiodipyridine, PPh3, dry pyridine, 60 °C, 16 h, 57% (for 49), 54% (for 50), 42% (for 51).
Figure 2. It was reasoned that using this methodology, the
phosphonomethoxy side chain could be easily introduced as
only one anomeric center will be present. 1,2-O-isopropylidene-
α-L-ribofuranose 23 was prepared from L-xylose according to a
known procedure.17 The 5′-Bz protecting group was removed
with sodium methoxide to provide diol 24. The two remaining
free hydroxyl groups of 24 were protected as benzyl ethers
using a reported protocol18 furnishing compound 25. The 1′,2′-
O-isopropylidene moiety of 25 was smoothly cleaved by
treatment with a 50% TFA solution in water to furnish the vic-
diol intermediate, which was directly treated with acetic
anhydride in pyridine, without any purification, to provide
the 1′,2′-di-O-acetyl derivative 26 in excellent yield as an
formation of diastereomeric mixtures. A solvent mixture of
EtOAc-EtOH (1:1) was found to be optimal for stereoselective
reduction and L-arabinofuranoside 29 was obtained as a single
isomer (71% over two steps). It is well-known that solvents and
temperature play an important role in the stereoelectronic
effects of the ketone and the exclusive hydride attack from the
α-face, to obtain stereoselective product 29.19 It was foreseen
that an orthogonal protection−deprotection of 2′−OH was
essential for successive fluorination. Initial efforts for the
protection of 2′−OH of arabinofuranoside 29 as a MEM and
TBDPS protecting group were successful affording compounds
31 and 32, respectively, in good yields. However, didebenzy-
lation of TBDPS analogue 32 was problematic, as only the
monodebenzylated (5′-) product was isolated. In case of the
MEM protected analogue 31, cleavage of the benzyl protecting
groups went smoothly, affording compound 34. Selective
protection of the primary hydroxyl group of 34, followed by
protection of the secondary hydroxyl group as a benzoyl gave
36 in excellent yield. The primary hydroxyl group was
deprotected under acidic conditions and subsequently oxidized
to the corresponding carboxylic acid 40. Introduction of an
anomeric acetate group proceeded smoothly via a modified
Kochi reaction, affording compound 42. Unfortunately,
anomeric mixture of 1′-α/β isomers. Vorbruggen reaction
̈
between 26 and diisopropyl (hydroxymethyl)phosphonate in
the presence of SnCl4 yielded the protected phosphonate
derivative 27 exclusive as a 1′-β isomer. Deprotection of the 2′-
acetyl group of 27 was easily accomplished by treatment with a
7 N NH3 solution in MeOH affording phosphonate riboside 28
in excellent yield (96%).
Various strategies have been described for the conversion of
L-ribofuranoside to L-arabinofuranoside via inversion of
configuration of the hydroxyl group. Initial attempts by
Mitsunobu reaction with various carboxylic acids were
unsuccessful, as only unreacted starting material was isolated.
Therefore, an oxidation−reduction strategy to synthesize L-
arabinofuranoside 29 was applied. Several oxidizing agents have
been reported for the oxidation of the 2′−OH of ribofuranoside
28, but in our hands Dess-Martin periodinane (DMP) gave the
best yield (96%). For reduction of the resulting ketone by
NaBH4, solvents like EtOH, MeOH or EtOH-H2O resulted in
Vorbruggen N-glycosylation of N6-benzoyl adenine with the
̈
2′-O-MEM protected analogue 42 in the presence of various
Lewis acids (TMSOTf or SnCl4), resulted mainly in
decomposition. As an alternative, an acetyl protecting group
was selected for 2′−OH protection affording derivative 30 in
excellent yield. Removal of both benzyl groups of compound 30
by reductive hydrogenation with 10% Pd/C yielded the desired
diol 33 in excellent yield (98%). 5′-MMTr protection of the
E
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primary hydroxyl group of diol 33 followed by benzoyl
protection of the secondary hydroxyl group yielded the L-
arabino-phosphonate 35 in good yield (85%) over two steps.
Selective MMTr removal of 35 by 80% acetic acid and
oxidation of the resulting 5′-hydroxymethyl group of 37 by
treatment with bis(acetoxy)iodobenzene in the presence of a
catalytic amount of TEMPO furnished carboxylic acid 49 in
excellent yield (96%). Pb(OAc)4 mediated oxidative decarbox-
ylation via a modified Kochi reaction transformed acid 39 into
triphenylphosphine as activating agents and utilizing a mixture
of phenol and the appropriate amino acid ester in 42−57%
yield.7 Due to chirality of the phosphorus atom, compounds
49−50 were isolated as diastereomeric mixtures. To avoid this,
the synthesis of a symmetrical bisamidate (compound 51) was
also effected. Protection of 2′−OH group was not essential for
the coupling in our cases.
CONCLUSION
■
the acetate 41 as a mixture of α/β isomers. Vorbruggen
̈
In summary, the synthesis of the hitherto unknown 3′-fluoro-
3′-deoxytetrose adenine phosphonate 1 is accomplished with
an overall yield of 3% over 22 linear steps starting from L(−)-
xylose. Different synthetic roads were explored, and the
successful strategy started from a protected xylose derivative
with the unnatural L-configuration as chiral synthon giving
ultimately rise to a nucleoside phosphonate analogue with the
natural D-configuration. Highlights of the synthesis include the
stereoselective introduction of the phosphonomethoxy group
and the nucleobase. Moreover, access to the fluorinated ribose
moiety was possible via a regioselective fluorination of the 3′-
hydroxyl group, without protection of the 2′-hydroxyl group.
The route described enabled the preparation of 1, as well as its
phosphonoamidate prodrugs 49−51. Phosphonate 1 and
prodrugs 49−51 were screened both against DNA and RNA
viruses, but showed to be inactive.
glycosylation of N6-benzoyl adenine with acetate 41 in the
presence of SnCl4 led to the formation of the desired β-
nucleoside phosphonate 43 in moderate yield (55%).
Several reagents and reaction conditions, such as DBU in
benzene,20 Mg(OMe)2 in methanol,21 KCN in ethanol,22
guanidine in ethanol and dichloromethane,23 K2CO3 in
methanol and water,24 were screened for selective hydrolysis
of the acetyl protecting group and keeping the benzoyl groups
intact. None of these procedures gave exclusive formation of
44, but mixtures containing compounds 44, 45, and 46 were
formed, arising from cleavage of the protecting groups at 2′-
position of the sugar moiety and 6-position of the adenine part.
If milder reaction conditions were applied (2 M NH3 in
EtOH), the deprotected compounds 44, 45, 46 were isolated in
3, 42, and 45% yield, respectively (Scheme 4). Using a more
concentrated ammonia solution (7N NH3 in MeOH),
compound 46 was obtained directly from 43 in 96% yield.
However, 3′-fluorination of the dibenzoyl derivative 44 using
DAST did not furnish the desired fluorinated product 47, but
only led to cleavage of benzoyl groups affording a mixture of 45
and 46, probably via a benzylideneoxoniumyl-substituted
intermediate arising from 2′-benzoyl neighboring group
participation.25 Surprisingly, when the 2′,3′-dihydroxylated
analogue 45 was treated with DAST, a regioselective
fluorination of the 3′-hydroxyl group took place with
concomitant cleavage of the benzamide moiety of the adenine
nucleobase (due to strong basicity of fluoride ion), furnishing
fluoro nucleoside phosphonate ester 48 in 42% yield. Using a
similar fluorination protocol, unprotected derivative 46 was
converted to its desired 3′-fluoro analogue 48 in moderate yield
(47%) along with the unreacted starting nucleoside 46 (15%).
For both fluorination reactions, formation of a common side
product like 2′,3′-epoxy derivative (7−9%) and other
uncharacterized side products in small amounts were observed.
The regioselective 3′-fluorination was unambiguously deter-
mined from full structural analysis of 48 using 2D NMR
spectroscopy (H−COSY, HSQC, HMBC, ROESY; see
Supporting Information). The regioselectivity of 3′-fluorination
is presumably due to steric effects of dihydroxy compounds 45
and 46, where nucleophilic attack of fluoride ion at 3′-position
is sterically more favorable (downside with respect to adenine)
than at sterically hindered 2′-position (upside with respect to
adenine). The hydrolysis of di-isopropyl phosphonate ester 48
was carried out using trimethylsilyl bromide (TMSBr) and 2,6-
lutidine and the crude free phosphonate was purified by high-
performance liquid chromatography (HPLC) to provide
phosphonate diacid 1 as a triethylammonium salt in excellent
yield (88%). Because of their acidic properties, phosphonates
are predominantly present in their anionic form at physiological
pH, which has a negative impact on their antiviral activity.
Therefore, the synthesis of the corresponding phosphonoami-
date prodrugs was also effected. Protides 49−51 were prepared
from the phosphonate diacid 1 using 2,2′-dithiopyridine and
EXPERIMENTAL SECTION
■
General Information. For all reactions, either analytical grade or
anhydrous solvents were used. All moisture-sensitive reactions were
performed using oven-dried glassware (135 °C) under a nitrogen or
argon atmosphere. Reaction temperatures are reported as bath
temperatures. Precoated aluminum sheets (254 nm) were used for
TLC. Compounds were visualized with UV light (λ = 254 nm).
Products were purified by flash chromatography on ICN silica gel 63−
200, 60 Å. All final compounds were purified by preparative RP-HPLC
(Gemini 10 μm C18 110 Å, LC Column 250 × 21.2 mm, AXIA
column) using a gradient of H2O and CH3CN, or both containing 25
mmol TEAB as eluent buffer. 1H, 13C, 19F, and 31P NMR spectra were
recorded on Bruker Avance 300 MHz, 500 or 600 MHz spectrometers.
Final compounds were characterized using 2D NMR (H−COSY,
HSQC, HMBC, ROESY, and NOESY) techniques. For clarification,
numbering of NMR signals of protons and carbons for sugar and base
moieties are designated with and without a prime, respectively.
Chemical shifts were referenced to residual solvent signals at δ H/C
7.26/77.16 (CDCl3), 3.31/49.00 (CD3OD), D2O (4.79), 1.94/118.26
(CD3CN), and 2.50/39.52 (DMSO-d6) relative to TMS as internal
standard wherever applied. Coupling constants are stated in hertz
(Hz) and were directly obtained from the spectra. NMR splitting
patterns are designated as s (singlet), d (doublet), dd (doublet of
doublet), t (triplet), q (quartet), m (multiplet), br (broad), and
apparent (app). High-resolution mass spectra (HRMS) were obtained
on a quadruple orthogonal acceleration time-of-flight mass spec-
trometer (Synapt G2 HDMS, Waters, Milford, MA). Samples were
infused at 3 μL/min and spectra were obtained in positive (or
negative) ionization mode with a resolution of 15000 (fwhm) using
leucine enkephalin as lock mass.
5′-O-(Benzyl)-1′,2′-O-isopropylidene-D-xylofuranose (3). A solu-
tion of diol 2 (20 g, 100.2 mmol) in dry THF (200 mL) was added
dropwise to a stirred suspension of NaH (55% in mineral oil, 4.81 g,
110.2 mmol, washed with hexane to remove oil) in dry THF (250 mL)
at −78 °C under argon, and the resulting mixture was stirred at −78
°C for 30 min until the H2 gas liberation was complete.
Tetrabutylammonium iodide (19.42 g, 52.58 mmol) was added to
the reaction mixture followed by dropwise addition of benzyl bromide
(13.1 mL, 110.42 mmol). Then the reaction mixture was slowly
warmed to rt and left for stirring for 2.5 h at rt. The reaction mixture
F
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was cooled to 0 °C and quenched with a saturated NH4Cl solution and
diluted with water and the aqueous layer was extracted with EtOAc (3
× 300 mL). The combined organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo and the resulting crude residue was
purified by column chromatography on silica gel (gradient Hexane/
EtOAc, 9:1, v/v; 4:1, v/v; 3:2, v/v) to give 3 (18.27 g, 62%) as a sticky
mass (Rf = 0.48, 80% EtOAc in hexane). 1H NMR (300 MHz, CDCl3)
δ 7.37−7.28 (m, 5H, Ar-H OBn), 5.96 (d, J = 3.9 Hz, 1H, H-1′),
4.71−4.46 (m, 3H, CH2-OBn and H-2′), 4.26 (dd, J = 8.5, 4.9 Hz, 1H,
H-3′), 3.99 (d, J = 3.5 Hz, 1H, H-4′), 3.95−3.80 (m, 2H, H-5′ and H-
5″), 2.28 (br s, 1H, 3′-OH), 1.47 (s, 3H, CH3-isopropylidene), 1.31 (s,
3H, CH3-isopropylidene); 13C NMR (75 MHz, CDCl3) δ 137.2 (1C-
Bn), 128.7 (Ar−C), 128.2 (Ar−C), 127.8 (Ar−C), 112.0 (1C-
isopropyledene), 105.1 (C-1′), 82.8 (C-2′), 82.6 (C-4′), 80.2 (C-3′),
72.0 (CH2−OBn), 61.0 (C-5′), 26.9 (CH3-isopropyledene), 26.4
(CH3-isopropyledene); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C15H20O5 303.1203; Found 303.1203.
(2 x CH3−OAcβ), 21.2, 20.7 (2 x CH3−OAcα),); 19F NMR (470
MHz, CDCl3): δ −227.8 (app Hex, J = 46.4, 14.2 Hz, 0.33F, β-
isomer), −230.0 (app Hex, J = 46.4, 14.2 Hz, 0.33F, α-isomer));
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C16H19FO6 349.1058;
Found 349.1052.
(2′R,3′S,4′R,5′R)-2′-(6-Benzamido-9H-purin-9-yl)-5′-((benzyloxy)-
methyl)-4′-fluorotetrahydrofuran-3′-yl acetate (7). 1 M SnCl4 in
CH2Cl2 (14.15 mL, 14.15 mmol) was added dropwise to a stirred
mixture of 6 (2.1 g, 6.43 mmol) and N6-benzoyl adenine (1.85 g, 7.72
mmol) in anhydrous acetonitrile (60 mL) at −20 °C. The reaction
mixture was then slowly warmed to room temperature and stirred at
same temperature for 3 h. After completion, the reaction mixture was
cooled to 0 °C and quenched with saturated NaHCO3 solution.
Reaction mixture was diluted with EtOAc (200 mL) and milky aq.
layer was extracted with EtOAc (3 × 150 mL). Combined organic
layer was washed with brine, dried, concentrated in vacuo, and the
resulting crude residue was purified by column chromatography on
silica gel (gradient hexane/EtOAc, 4:1, v/v; 3:2, v/v; 1:4, v/v) to give
5′-O-(Benzyl)-1′,2′-O-isopropylidene-3′α-fluoro-D-ribofuranose
(4). To a stirred solution of 3 (5 g, 17.84 mmol) in a mixture of
anhydrous CH2Cl2 (160 mL) and anhydrous pyridine (30 mL) was
added DAST (10 mL, 75.63 mmol) at −20 °C. Then, the reaction
mixture was slowly warmed to rt and left stirring for 16 h at rt. After
completion, the reaction mixture was cooled to 0 °C and slowly
poured into an ice-cold saturated solution of NaHCO3 (500 mL) and
the aqueous layer was extracted with CH2Cl2 (3 × 200 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo and the resulting crude residue was purified by
column chromatography on silica gel (gradient hexane/EtOAc, 49:1,
v/v; 49:1, v/v; 9:1, v/v) to give 4 (2.82 g, 56%) as a colorless oil (Rf =
1
7 (2.76 g, 85%) as a white semisolid (Rf = 0.37, EtOAc). H NMR
(500 MHz, CDCl3) δ 9.22 (br s, 1H, NH), 8.78 (s, 1H, H-8), 8.36 (s,
1H, H-2), 8.02 (d, J = 7.6 Hz, 2H, o H-Bz), 7.59 (t, J = 7.4 Hz, 1H, p
H-Bz), 7.50 (app t, J = 7.8, 7.5 Hz, 2H, m H-Bz), 7.35−7.24 (m, 5H,
Ar−H OBn), 6.43 (s, 1H, H-1′), 5.56 (s, 1H, H-2′), 4.85−4.68 (m,
3H, CH2-OBn and H-5′), 4.59−4.53 (m, 2H, H-5″ and H-3′), 4.16 (d,
J = 4.0 Hz, 1H, H-4′), 2.18 (s, 3H, CH3-OAc); 13C NMR (125 MHz,
CDCl3): δ 169.6 (CO-OAc), 164.8 (CO-Bz), 152.9 (C-2), 151.6 (C-
4), 149.6 (C-6), 141.9 (C-8), 136.2 (ipso C- OBn), 133.7 (ipso C-Bz),
132.9 (p C-Bz), 128.9 (m C-Bz), 128.8, 128.6, 128.2 (Ar C-OBn),
128.0 (o C-Bz), 122.9 (C-5), 87.6 (C-1′), 81.3 (d, 1JC,F = 23.3 Hz, C-
1
2
3′), 81.1 (d, 5JC,F = 168.8 Hz, CH2−OBn), 79.9 (d, JC,F = 5.6 Hz, C-
0.49, 30% EtOAc in hexane). H NMR (300 MHz, CDCl3) δ 7.36−
4′), 79.9 (C-2′), 72.5 (C-5′), 20.9 (CH3−OAc); 19F NMR (470 MHz,
CDCl3): δ −228.9 (app Hex, J = 47.1, 14.3 Hz); HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C26H24FN5O5 506.1834; Found 506.1829.
-(2′R,3′S,4′R,5′R)-2-(6-Benzamido-9H-purin-9-yl)-4′-fluoro-5′-
(hydroxymethyl)tetrahydrofuran-3′-yl acetate (8). To a stirred
solution of 7 (2.7 g, 5.34 mmol) in anhydrous CH2Cl2 (54 mL)
was added 1 M BCl3 in CH2Cl2 (11.75 mL, 11.75 mmol) at −78 °C.
Then the reaction mixture was slowly warmed to 0 °C over 2.5 h and
stirred at this temperature for 30 min. After completion, the reaction
mixture was cooled to −20 °C and quenched with dropwise addition
of saturated solution of NaHCO3 (150 mL). Aq. layer was extracted
with CH2Cl2 (3 × 200 mL). The combined organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo and the resulting
crude residue was purified by column chromatography on silica gel
(gradient CH2Cl2/MeOH, 100:0, v/v; 99:1, v/v; 49:1, v/v) to give 4
(1.91 g, 86%) as a white solid (Rf = 0.37, 10% MeOH in CH2Cl2), Mp:
7.29 (m, 5H, Ar-H OBn), 5.96 (d, J = 3.7 Hz, 1H, H-1′), 4.73−4.42
(m, 6H, CH2-OBn, H-2′, H-3′, H-5′ and H-5″), 4.01 (d, J = 3.3 Hz,
1H, H-4′), 1.50 (s, 3H, CH3-isopropylidene), 1.33 (s, 3H, CH3-
isopropylidene); 13C NMR (75 MHz, CDCl3) δ 137.3 (1C-Bn), 128.7
(Ar−C), 128.2 (Ar−C), 127.8 (Ar−C), 112.2 (1C-isopropylidene),
2
105.5 (C-1′), 82.4 (C-2′), 81.7 (d, JC,F = 5.4 Hz, C-4′), 80.2 (CH2−
1
OBn), 78.7 (d, JC,F = 23.5 Hz, C-3′), 72.1 (C-5′), 27.0 (CH3-
isopropylidene), 26.5 (CH3-isopropylidene); HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C15H19FO4 305.1160; Found 305.1159.
5′-O-(Benzyl)-1′,2′-diacetoxy-3′α-fluoro-α/β-D-ribofuranose (6).
To a stirred suspension of 4 (2.8 g, 9.92 mmol) in H2O (15 mL)
was added TFA (15 mL) at 0 °C and the solution was stirred at room
temperature for 4 h. Removal of the solvent in vacuo gave a residue
that was coevaporated with toluene (3×) to remove residual TFA. The
residue was redissolved in H2O and lyophilized to obtain the diol 5 as
a pale yellow solid (2.40 g, quan.), which was used directly in the
subsequent reaction without any purification (Rf = 0.27, 50% EtOAc in
hexane). HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C12H15FO4
265.0847; Found 265.0857.
1
180−182 °C. H NMR (300 MHz, CDCl3) δ 9.52 (br s, 1H, NH),
8.69 (s, 1H, H-8), 8.24 (s, 1H, H-2), 8.01 (d, J = 7.5 Hz, 2H, o H-Bz),
7.57 (t, J = 7.4 Hz, 1H, p H-Bz), 7.47 (app t, J = 7.8, 7.2 Hz, 2H, m H-
Bz), 6.94 (d, J = 9.2 Hz, 1H, 5′-OH), 5.98 (d, J = 1.6 Hz, 1H, H-1′),
5.35 (app t, J = 1.6 Hz 1H, H-2′), 5.00−4.93, 4.69−4.63 (m, 1H, H-
3′), 4.85−4.77 (m, 1H, H-4′), 4.51−4.42 (m, 2H, H-5′ and H-5″),
2.13 (s, 3H, CH3-OAc); 13C NMR (75 MHz, CDCl3): δ 169.7 (CO-
OAc), 164.7 (CO-Bz), 151.6 (C-2), 149.9 (C-4 and C-6), 142.8 (C-8),
132.9 (ipso C-Bz), 132.6 (p C-Bz), 128.4 (m C-Bz), 127.7 (o C-Bz),
123.3 (C-5), 89.6 (C-1′), 83.2 (C-2′), 81.6 (d, 2JC,F = 20.6 Hz, C-4′),
Acetic anhydride (10.2 mL) was added dropwise to a stirred
solution of compound 5 (2.4 g, 9.92 mmol) in anhydrous pyridine (22
mL) at 0 °C. The reaction mixture was then slowly warmed to room
temperature and the stirring was continued for 12 h. The volatiles were
removed in vacuo and residue was coevaporated with toluene (2×).
The resulting crude residue was purified by column chromatography
on silica gel (gradient hexane/EtOAc, 19:1, v/v; 9:1, v/v; 6:1, v/v) to
give 6 containing a mixture of two diastereomers (∼2:1) (2.8 g, 83%)
as a colorless liquid (Rf = 0.64, 50% EtOAc in hexane). 1H NMR (500
MHz, CDCl3) δ 7.34−7.26 (m, 5H, Ar-H OBn), 6.42 (d, J = 4.6 Hz,
0.67H, H-1′α), 6.18 (s, 0.33H, H-1′β), 5.27−5.24 (m, 1H, H-2′),
4.78−4.43 (m, 5H, CH2-OBn, H-3′ αβ, H-5′αβ and H-5″ αβ), 4.36
(dd, J = 6.6, 5.6 Hz, 0.67H, H-4′α), 4.36 (d, J = 5.6 Hz, 0.33H, H-4′β),
2.09, 2.07 (2 s, 2.33 H, 2 x βCH3-OAc), 2.06, 2.05 (2 s, 4.1H, 2 ×
CH3-αOAc); 13C NMR (125 MHz, CDCl3) δ 169.9, 169.8 (2 x CO-
βOAc), 169.9, 169.6 (2 x CO-αOAc), 138.5 (ipso C-Bn), 128.8, 128.4,
127.9 (Ar C-Bnα), 128.8, 128.3, 127.9 (Ar C-Bnβ), 99.7 (C-1′β), 93.9
(C-1′α), 82.4 (d, 1JC,F = 190.1 Hz, C-3′β), 81.8 (d, 1JC,F = 170.0 Hz, C-
1
3
81.5 (d, JC,F = 167.1 Hz, C-3′), 73.9 (d, JC,F = 7.7 Hz, C-5′), 20.3
(CH3−OAc); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C19H18FN5O5 416.1358; Found 416.1365.
1′-(Benzyloxy)-2′,3′,5′-triacetoxy-β-D-ribofuranose (11). SnCl4
(18.5 mL, 158.4 mmol) was added dropwise to a stirred mixture of
10 (42 g, 132 mmol) and BnOH (15.1 mL, 145.2 mmol) in anhydrous
acetonitrile (630 mL) at −20 °C. The reaction mixture was then
slowly warmed to room temperature and stirred at same temperature
for 4 h. After completion, the reaction mixture was cooled to −30 °C
and quenched with ice cooled saturated NaHCO3 solution. Reaction
mixture was diluted with cold EtOAc (1200 mL) and milky aq. layer
was extracted with cold EtOAc (3 × 600 mL). Combined organic layer
was washed with brine, dried, concentrated in vacuo, and the resulting
crude residue was purified by column chromatography on silica gel
1
2
3′α), 81.8 (d, JC,F = 170.0 Hz, C-3′α), 81.6 (C-5′β), 80.2 (d, JC,F
=
5.9 Hz, C-4′β), 79.6 (d, 2JC,F = 5.9 Hz, C-4′α), 79.5 (C-2′α), 77.6 (C-
2′β), 77.4 (C-5′α), 72.9 (CH2−OBnα), 72.3 (CH2−OBnβ), 21.4, 21.0
G
DOI: 10.1021/acs.joc.7b01482
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(gradient Hexane/EtOAc, 19:1, v/v; 9:1, v/v; 4:1, v/v) to give 11
(30.8 g, 64%) as a white semisolid (Rf = 0.47, 50% EtOAc in hexane).
1H NMR (300 MHz, CDCl3) δ 7.34−7.27 (m, 5H, Ar−H OBn), 5.40
16.45 mmol) in anhydrous CH2Cl2 (120 mL) was added BOM
chloride (5.70 mL, 41.11 mmol) followed by DIPEA (11.46 mL, 65.8
mmol) and the solution was refluxed for 24 h. Then, the reaction
mixture was cooled and quenched with a 5% NaHCO3 solution (300
mL). The aqueous layer was extracted with CH2Cl2 (3 × 200 mL).
The combined organic layers were washed with brine, dried,
concentrated in vacuo and the resulting crude residue was purified
by column chromatography on silica gel (gradient hexane/EtOAc,
99:1, v/v; 49:1, v/v; 24:1, v/v) to give 15 (9.12 g, 92%) as a colorless
liquid (Rf = 0.47, 20% EtOAc in hexane). 1H NMR (300 MHz,
CDCl3) δ 7.32−7.25 (m, 10H, Ar−H OBn and BOM), 4.92 (dd, J =
29.4, 6.7 Hz, 2H, OCH2O-BOM), 4.88 (s, 1H, H-1′), 4.63−4.56 (m,
3H, CH2-BOM and H-3′), 4.55 (dd, J = 87.6, 11.7 Hz, 2H, CH2-OBn),
4.19 (d, J = 4.4 Hz, 1H, H-2′), 4.10−4.00 (m, 2H, H-5′ and H-4′),
3.94−3.87 (m, 1H, H-5″), 1.08−0.85 (m, 28H, 4 x CH and 8 x
CH3-iPr); 13C NMR (75 MHz, CDCl3): 137.9 (ipso C- 1′OBn), 137.6
(ipso C- BOM), 128.4, 128.4, 128.0, 127.9, 127.8, 127.7 (Ar C-OBn
and BOM), 104.2 (C-1′), 94.4 (OCH2O-BOM), 81.4 (C-4′), 79.6 (C-
2′), 73.7 (C-3′), 69.6 (CH2−BOM), 69.0 (CH2-1′OBn), 64.3 (C-5′),
17.6, 17.4, 17.3, 17.2, 17.1, 13.4, 13.3, 12.9, 12.8 (4 x CH- iPr and 8 ×
(dd, J = 6.7, 5.0 Hz, 1H, H-3′), 5.56 (d, J = 4.9 Hz, 1H, H-2′), 5.08 (s,
1H, H-1′), 4.64 (dd, J = 75.4, 11.8 Hz, 2H, CH2-OBn), 4.40−4.29 (m,
2H, H-5′ and H-4′), 4.22−4.11 (m, 1H, H-5″), 2.09 (s, 3H, CH3-
OAc), 2.05 (s, 3H, CH3-OAc), 2.03 (s, 3H, CH3-OAc); 13C NMR (75
MHz, CDCl3): δ 170.7 (CO-OAc), 169.7 (CO-OAc), 169.6 (CO-
OAc), 136.9 (ipso C- OBn), 128.5, 128.0, 127.9 (Ar C-OBn), 104.3
(C-1′), 78.7 (C-4′), 74.9 (C-2′), 71.6 (C-3′), 69.5 (CH2−OBn), 64.5
(C-5′), 20.8, 20.7, 20.6 (3 x CH3−OAc); HRMS (ESI-TOF) m/z: [M
+Na]+ Calcd for C18H22O8 389.1207; Found 389.1209.
1′-(Benzyloxy)-β-D-ribofuranose (12). The compound 11 (26 g,
70.97 mmol) was dissolved in 7 N NH3 in MeOH (400 mL) and the
reaction mixture was stirred at room temperature in a sealed vessel for
24 h. The reaction mixture was concentrated under reduced pressure
and the resulting crude residue was purified by column chromatog-
raphy on silica gel (gradient CH2Cl2/MeOH, 49:1, v/v; 24:1, v/v;
23:2, v/v) to give 12 (15.2 g, 89%) as a white semisolid (Rf = 0.43,
15% MeOH in CH2Cl2). The NMR spectral data for 12 were identical
with those reported previously.14 HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C12H16O5 263.0890; Found 263.0891.
i
CH3- Pr); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C32H50O7Si2
625.2987; Found 625.2996.
2′-O-Benzoyl-1′-(benzyloxy)-β-D-ribofuranose (16). Et3N·3HF (5
mL, 15.33 mmol) was added to a stirred solution of compound 14 (3
g, 5.11 mmol) in anhydrous THF (45 mL) in a plastic flask. The
reaction mixture was then stirred at room temperature for 24 h. The
volatiles were removed in vacuo and residue was diluted with a
saturated NaHCO3 solution (100 mL). The aqueous layer was
extracted with EtOAc (3 × 150 mL). The combined organic layers
were washed with brine, dried, concentrated in vacuo and the resulting
crude residue was purified by column chromatography on silica gel
(gradient hexane/EtOAc, 9:1, v/v; 4:1, v/v; 3:2, v/v) to give 16 (0.85
g, 48%) as a white semisolid (Rf = 0.42, EtOAc). 1H NMR (300 MHz,
DMSO-d6) δ 8.02 (d, J = 7.6 Hz, 2H, o H-Bz), 7.68 (t, J = 7.4 Hz, 1H,
p H-Bz), 7.55 (app t, J = 7.8, 7.3 Hz, 2H, m H-Bz), 7.36−7.24 (m, 5H,
Ar−H OBn), 5.39 (d, J = 6.3 Hz, 1H, 3′-OH), 5.16−5.14 (m, 2H, H-
1′ and H-2′), 4.84 (t, J = 5.6 Hz, 1H, 5′-OH), 4.63 (dd, J = 83.1, 11.7
Hz, 2H, CH2-OBn), 4.33−4.24 (m, 1H, H-3′), 4.01−3.96 (m, 2H, H-
4′), 3.70−3.46 (m, 1H, H-5′ and H-5″); 13C NMR (75 MHz, DMSO-
d6): δ 165.1 (CO-Bz), 137.7 (ipso C- OBn), 133.5 (ipso C-Bz), 129.4
(p C-Bz), 128.7, 128.6, 128.4, 128.2 (Ar C-OBn and -Bz), 127.5 (o C-
Bz), 103.5 (C-1′), 84.0 (C-4′), 77.1 (C-2′), 69.4 (C-3′), 68.3 (CH2−
OBn), 62.4 (C-5′); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C19H20O6 367.1152; Found 367.1149.
3′,5′-O-Tetraisopropyldisiloxane-1′-(benzyloxy)-β-D-ribofuranose
(13). To a stirred suspension of 12 (12 g, 49.95 mmol) in anhydrous
pyridine (230 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisi-
loxane (15.32 mL, 47.95 mmol) at 0 °C and the solution was stirred at
room temperature for 4 h. Then, the reaction mixture was cooled and
quenched with a saturated NaHCO3 solution. The reaction mixture
was diluted with EtOAc (600 mL) and the aqueous layer was extracted
with EtOAc (3 × 400 mL). The combined organic layers were washed
with brine, dried, concentrated in vacuo, and the resulting crude
residue was purified by column chromatography on silica gel (gradient
Hexane/EtOAc, 99:1, v/v; 19:1, v/v; 9:1, v/v) to give 11 (21.7 g,
1
90%) as a colorless oil (Rf = 0.51, 30% EtOAc in hexane). H NMR
(300 MHz, CDCl3) δ 7.36−7.29 (m, 5H, Ar−H OBn), 5.03 (s, 1H, H-
1′), 5.40 (app t, J = 5.2 Hz, 1H, H-3′), 4.56 (dd, J = 74.5, 11.7 Hz, 2H,
CH2-OBn), 4.10−4.03 (m, 3H, H-5′, H-4′ and H-2′), 3.84−3.76 (m,
1H, H-5″), 3.00 (br s, 1H, 2′-OH), 1.09−1.01 (m, 28H, 4 x CH and 8
x CH3-iPr); 13C NMR (75 MHz, CDCl3): δ 136.9 (ipso C- OBn),
128.5, 128.2, 127.9 (Ar C-OBn), 105.4 (C-1′), 82.9 (C-4′), 76.0 (C-
2′), 75.2 (C-3′), 69.2 (CH2−OBn), 66.3 (C-5′), 17.6, 17.5, 17.4, 17.3,
17.1, 17.0, 16.9, 13.4, 12.9, 12.7 (4 x CH- iPr and 8 x CH3- iPr); HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C24H42O6Si2 505.2412; Found
505.2410.
3′,5′-O-Tetraisopropyldisiloxane-2′-O-benzoyl-1′-(benzyloxy)-β-
D-ribofuranose (14). To a stirred solution of 13 (4 g, 8.256 mmol) in
anhydrous pyridine (60 mL) was added benzoyl chloride (1.35 mL,
11.60 mmol) at 0 °C and the solution was stirred at room temperature
for 12 h. Then the reaction mixture was cooled and diluted with a
saturated NaHCO3 solution (150 mL). The aqueous layer was
extracted with EtOAc (3 × 200 mL). The combined organic layers
were washed with brine, dried, concentrated in vacuo, and the resulting
crude residue was purified by column chromatography on silica gel
(gradient Hexane/EtOAc, 99:1, v/v; 49:1, v/v; 97:3, v/v) to give 14
(4.42 g, 91%) as a colorless liquid (Rf = 0.60, 10% EtOAc in hexane).
1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 2H, o H-Bz), 7.55
2′-O-Benzyloxymethyl-1′-(benzyloxy)-β-D-ribofuranose (17). A
similar synthetic protocol as the one used for the synthesis of 16
was employed for the synthesis of 17, starting from 15 (8.74 g, 14.49
mmol), Et3N·3HF (5.2 mL, 31.89 mmol) and anhydrous THF (80
mL) to obtain 17 (4.89 g, 94%) as a white solid (Rf = 0.4, EtOAc;
column chromatography gradient Hexane/EtOAc, 9:1, v/v; 4:1, v/v;
1
1:1, v/v), Mp: 56−58 °C. H NMR (300 MHz, DMSO-d6) δ 7.33−
7.27 (m, 10H, Ar−H OBn and BOM), 4.99 (d, J = 6.8 Hz, 1H, 3′-
OH), 4.97 (br s, 1H, H-1′), 4.84 (s, 2H, OCH2O-BOM), 4.72 (t, J =
5.8 Hz, 1H, 5′-OH), 4.58 (s, 2H, CH2-BOM), 4.55 (dd, J = 90.2, 11.7
Hz, 2H, CH2-OBn),), 4.10−4.04 (m, 1H, H-3′), 3.94 (d, J = 4.5 Hz,
1H, H-2′), 3.86−3.81 (m, 1H, H-4′), 3.62−3.38 (m, 2H, H-5′ and H-
5″); 13C NMR (75 MHz, DMSO-d6): δ 138.0 (ipso C- 1′OBn), 137.9
(ipso C- BOM), 128.2, 128.2, 127.7 127.6, 127.5, 127.4 (Ar C-OBn
and BOM), 104.4 (C-1′), 93.9 (OCH2O-BOM), 83.9 (C-4′), 79.6 (C-
2′), 70.4 (C-3′), 68.7 (CH2−BOM), 68.2 (CH2-1′OBn), 62.8 (C-5′);
[α]20D = −70.8° (c = 1, CH3OH); HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C20H24O6 383.1465; Found 383.1488.
(t, J = 7.4 Hz, 1H, p H-Bz), 7.42 (app t, J = 7.8, 7.3 Hz, 2H, m H-Bz),
7.35−7.27 (m, 5H, Ar−H OBn), 4.56 (d, J = 4.7 Hz, 1H, H-2′), 5.11
(s, 1H, H-1′), 4.74−4.70 (m, 1H, H-3′), 4.63 (dd, J = 70.7, 11.7 Hz,
2H, CH2-OBn), 4.16−4.08 (m, 2H, H-5′ and H-4′), 3.94−3.87 (m,
1H, H-5″), 1.09−0.81 (m, 28H, 4 × CH and 8 × CH3-iPr); 13C NMR
(75 MHz, CDCl3): δ 165.6 (CO-Bz), 137.3 (ipso C- OBn), 133.1 (ipso
C-Bz), 130.2 (p C-Bz), 129.9 (m C-Bz), 128.6, 128.4, 128.2 (Ar C-
OBn), 128.0 (o C-Bz), 103.6 (C-1′), 82.5 (C-4′), 77.5 (C-2′), 73.6 (C-
3′), 69.3 (CH2−OBn), 65.3 (C-5′), 17.6, 17.5, 17.4, 17.2, 17.1, 16.9,
5′-O-MMTr-2′-O-benzyloxymethyl-1′-(benzyloxy)-β-D-ribofura-
nose (18). To a stirred solution of 17 (3.73 g, 10.34 mmol) in
anhydrous pyridine (45 mL) was added MMTr chloride (3.84 g, 12.42
mmol) and the solution was stirred at room temperature for 18 h.
Then, the reaction mixture was diluted with CH2Cl2 (250 mL) and
washed with a 5% NaHCO3 solution (200 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 200 mL). The combined organic
layers were washed with brine, dried, concentrated in vacuo, and the
i
i
16.8, 13.4, 13.3, 12.9, 12.8 (4 x CH- Pr and 8 x CH3- Pr); HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C31H46O7Si2 587.2855; Found
587.2866.
3′,5′-O-Tetraisopropyldisiloxane-2′-O-benzyloxymethyl-1′-(benz-
yloxy)-β-D-ribofuranose (15). To a stirred solution of 13 (7.94 g,
H
DOI: 10.1021/acs.joc.7b01482
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The Journal of Organic Chemistry
Article
resulting crude residue was purified by column chromatography on
silica gel (gradient Hexane/EtOAc, 19:1, v/v; 17:3, v/v; 3:1, v/v) to
give 18 (6.3 g, 96%) as a pale-yellow sticky mass (Rf = 0.47, 50%
165.8 (CO-Bz), 137.3 (ipso C- OBn), 136.9 (ipso C- BOM), 133.6
(ipso C-Bz), 130.0 (p C-Bz), 128.6, 128.6, 128.5, 128.2, 128.1 (Ar C-
OBn, BOM and Bz), 127.9 (o C-Bz), 106.3 (C-1′), 94.9 (OCH2O-
BOM), 79.0 (C-4′), 78.7 (C-2′), 75.5 (C-3′), 70.1 (CH2−BOM), 69.9
(CH2-1′OBn); HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for
C27H26O8 496.1971; Found 496.1978.
1
EtOAc in hexane). H NMR (300 MHz, CDCl3) δ 7.52−7.18 (m,
22H, Ar−H OBn, BOM and MMTr), 6.79 (d, J = 8.9 Hz, 2H, m H-
Anisyl MMTr), 5.15 (s, 1H, H-1′), 4.892 (s, 2H, OCH2O-BOM), 4.63
(dd, J = 14.9, 12.0 Hz, 2H, CH2-BOM), 4.59 (dd, J = 88.9, 11.7 Hz,
2H, CH2-OBn), 4.34−4.27 (m, 1H, H-3′), 4.16−4.09 (m, 2H, H-2′
and H-4′), 3.75 (s, 3H, OCH3-MMTr), 3.38−3.21 (m, 2H, H-5′ and
H-5″), 2.52 (d, J = 8.2 Hz, 1H, 3′- OH); 13C NMR (75 MHz, CDCl3):
158.6 (p C-Anisyl MMTr), 144.6 (ipso C- MMTr), 137.5 (ipso C-
1′OBn), 137.3 (ipso C- BOM), 135.8 (ipso C- Anisyl MMTr), 128.6,
128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 126.9 (Ar C-OBn, BOM and
MMTr), 113.2 (m C-Anisyl MMTr), 104.8 (C-1′), 95.2 (OCH2O-
BOM), 86.4 (1C-MMTr), 83.4 (C-4′), 81.7 (C-2′), 72.0 (C-3′), 70.3
(CH2−BOM), 69.6 (CH2-1′OBn), 65.1 (C-5′), 55.3 (OCH3-MMTr);
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C40H40O7 655.2666;
Found 655.2690.
(3S,4R,5R)-2-Acetoxy-5-(benzyloxy)-4-((benzyloxy)methoxy)-
tetrahydrofuran-3-yl Benzoate (21). To a stirred solution of
compound 20 (1.83 g, 3.824 mmol) in anhydrous THF (50 mL)
was added anhydrous pyridine (1.11 mL, 13.77 mmol) and the
reaction mixture was flushed and degaussed with argon for 30 min.
Lead tetra acetate (2.88 g, 6.50 mmol) was then added to the degassed
reaction mixture in portions (2×). The reaction mixture was protected
from light and stirred for 20 h at 35 °C. The solid was filtered off
through a Celite pad and the filtrate was concentrated under reduced
pressure. The residue was diluted with ethyl acetate and the combined
organic layers were washed with saturated NaHCO3, brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (gradient
hexane/EtOAc, 19:1, v/v; 9:1, v/v; 17:3, v/v) to afford a
diastereomeric mixture (∼4:1) of compound 21 (1.66 g, 88%) as
3′-O-Benzoyl-2′-O-benzyloxymethyl-1′-(benzyloxy)-β-D-ribofura-
nose (19). To a stirred solution of 18 (3.7 g, 5.85 mmol) in anhydrous
pyridine (45 mL) was added benzoyl chloride (0.82 mL, 7.02 mmol)
at 0 °C and the solution was stirred at room temperature for 16 h.
Then, the reaction mixture was diluted with CH2Cl2 (250 mL) and
washed with a 5% NaHCO3 solution (200 mL). The aqueous layer
was extracted with CH2Cl2 (2 × 200 mL). The combined organic
layers were washed with brine, dried, concentrated in vacuo to give 5′-
O-MMTr-3′-O-benzoyl-2′-O-benzyloxymethyl-1′-(benzyloxy)-β-D-ri-
bofuranose (4.31 g, quan.) as a pale-yellow sticky mass (Rf = 0.58, 50%
EtOAc in hexane). The resulting crude residue was used for next step
without further purification.
A solution of the above crude of 5′-O-MMTr-3′-O-benzoyl-2′-O-
benzyloxymethyl-1′-(benzyloxy)-β-D-ribofuranose (4.31 g, 5.85 mmol)
in 80% AcOH (45 mL) was stirred at room temperature for 4 h. After
completion, the volatiles were removed in vacuo and residue was
coevaporated with toluene (2×). The resulting crude residue was
purified by column chromatography on silica gel (gradient hexane/
EtOAc, 9:1, v/v; 17:3, v/v; 4:1, v/v) to give 19 (2.25 g, 83% over two
steps) as a colorless sticky mass (Rf = 0.39, 50% EtOAc in hexane). 1H
NMR (300 MHz, CDCl3) δ 8.05 (d, J = 7.6 Hz, 2H, o H-Bz), 7.57 (t, J
= 7.4 Hz, 1H, p H-Bz), 7.43 (app t, J = 7.8, 7.3 Hz, 2H, m H-Bz),
7.35−7.20 (m, 10H, Ar−H OBn and BOM), 5.49 (t, J = 5.4 Hz, 1H,
H-3′), 5.20 (d, J = 1.5 Hz, 1H, H-1′), 4.78 (s, 2H, OCH2O-BOM),
4.68 (dd, J = 62.3, 11.7 Hz, 2H, CH2-BOM), 4.58−4.44 (m, 2H, CH2-
OBn, H-2′ and H-4′), 3.89−3.68 (m, 2H, H-5′ and H-5″), 2.04 (br s,
1H, 5′- OH); 13C NMR (75 MHz, CDCl3): 166.1 (CO-Bz), 137.5
(ipso C- OBn), 137.2 (ipso C- BOM), 133.5 (ipso C-Bz), 129.9 (p C-
Bz), 129.6, 128.7, 128.6, 128.5, 128.2, 128.1, 127.9 (Ar C-OBn, BOM
and Bz), 127.8 (o C-Bz), 106.1 (C-1′), 94.7 (OCH2O-BOM), 82.9 (C-
4′), 79.8 (C-2′), 73.3 (C-3′), 70.5 (CH2−BOM), 69.8 (CH2-1′OBn),
63.3 (C-5′); HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for C27H28O7
482.2178; Found 482.2164.
1
colorless sticky mass (Rf = 0.56, 40% EtOAc in hexane). H NMR
(300 MHz, CDCl3) δ 8.06, 8.01 (d, J = 7.4 Hz, 2H, o H-Bz), 7.57 (t, J
= 7.4 Hz, 1H, p H-Bz), 7.44 (app t, J = 7.8, 7.3 Hz, 2H, m H-Bz),
7.35−7.20 (m, 10H, Ar−H OBn and BOM), 6.62, 6.46 (d, J = 2.2 Hz,
1H, H-4′), 5.85−5.80, 5.57−5.52 (m, 1H, H-3′), 5.35 (d, J = 2.6 Hz,
1H, H-1′), 4.89 (d, J = 6.4 Hz, 1H, H-2′), 4.77−4.72 (m, 2H, OCH2O-
BOM), 4.68 (dd, J = 82.9, 11.7 Hz, 2H, CH2-BOM), 4.51 (dd, J =
33.1, 11.7 Hz, 2H, CH2-OBn), 2.10 (s, 3H, CH3-OAc); 13C NMR (75
MHz, CDCl3): 169.8 (CO-OAc), 165.6 (CO-Bz), 137.3 (ipso C-
OBn), 137.2 (ipso C- BOM), 133.6 (ipso C-Bz), 130.0 (p C-Bz), 128.6,
128.6, 128.5, 128.5, 128.1, 128.0 (Ar C-OBn, BOM and Bz), 127.9 (o
C-Bz), 107.2 (C-1′), 99.2 (C-4′), 94.6 (OCH2O-BOM), 78.8 (C-2′),
76.3 (C-3′), 70.4 (CH2−BOM), 69.8 (CH2-1′OBn), 21.2 (CH3-OAc);
HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for C28H28O8 510.2128;
Found 510.2139.
1′,2′-O-Isopropylidene-α-L-ribofuranose (24). To a stirred solution
of 23 (48 g, 163.1 mmol) in MeOH (500 mL) was added NaOMe
(5.4 M in MeOH, 36.3 mL, 196 mmol) at room temperature and the
solution was stirred 1 h at room temperature. The reaction was
quenched by the addition of solid NH4Cl and the reaction mixture was
diluted with diethyl ether. The solid was filtered off and washed with
diethyl ether. The filtrate was removed under reduced pressure, and
the resulting crude residue was purified via flash chromatography
(hexane/EtOAc, 1:1 to 1:2 v/v) to give the diol 24 (30 g, 97%) as a
white solid (Rf = 0.25, EtOAc), Mp: 86−88 °C. The NMR spectral
data for 24 were identical with those reported previously.18 mp 86−88
°C; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C8H14O5 213.0734;
Found 213.0734.
3′,5′-Di-O-benzyl-1′,2′-O-isopropylidene-α-L-ribofuranose (25). A
solution of diol 24 (28.51 g, 150 mmol) in dry THF (200 mL) was
added dropwise to a stirred suspension of NaH (55% in mineral oil,
16.35 g, 375 mmol) in dry THF (250 mL) at −20 °C under argon, and
the resulting mixture was stirred at 0 °C for 30 min, prior to addition
of benzyl bromide (44.6 mL, 375 mmol). Then, the reaction mixture
was slowly warmed to room temperature and left for stirring for 16 h
at same temperature. The reaction mixture was cooled to 0 °C and
quenched with a saturated NH4Cl solution. The reaction mixture was
diluted with EtOAc (500 mL) and the aqueous layer was extracted
with EtOAc (2 × 300 mL). The combined organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo and the resulting crude
residue was purified by column chromatography on silica gel (gradient
hexane/EtOAc, 19:1, v/v; 9:1, v/v; 4:1, v/v) to give 25 (54.4 g, 92%)
as a colorless oil (Rf = 0.70, 40% EtOAc in hexane). The NMR spectral
data for 25 were identical with those reported previously.18 HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C22H26O5 393.1673; Found
393.1672.
(2S,3S,4R,5R)-3-(Benzoyloxy)-5-(benzyloxy)-4-((benzyloxy)-
methoxy)tetrahydrofuran-2-carboxylic Acid (20). To a stirred
solution of 19 (2.0 g, 4.31 mmol) in a 1:1 ACN:H2O mixture (30
mL) were added iodosobenzene diacetate (3.05 g, 76.51 mmol)
followed by TEMPO (0.135 g, 0.861 mmol) at 0 °C and the mixture
was stirred at room temperature for 4.5 h. Upon completion, reaction
mixture was concentrated under reduced pressure and diluted with
H2O (50 mL). The aqueous layer was extracted with CHCl3 (3 × 100
mL) and the combined organic layers were washed with brine, dried
and concentrated in vacuo. The resulting crude residue was purified by
column chromatography on silica gel (gradient hexane/EtOAc, 9:1, v/
v; 4:1, v/v; 3:1, v/v) to give 20 (1.87 g, 91%) as a colorless sticky mass
1
(Rf = 0.38, 50% EtOAc in hexane). H NMR (300 MHz, CDCl3) δ
8.06 (d, J = 7.6 Hz, 2H, o H-Bz), 7.57 (t, J = 7.4 Hz, 1H, p H-Bz), 7.43
(app t, J = 7.8, 7.3 Hz, 2H, m H-Bz), 7.32−7.18 (m, 10H, Ar−H OBn
and BOM), 5.76 (t, J = 5.3 Hz, 1H, H-3′), 5.25 (s, 1H, H-1′), 4.89 (d,
J = 6.4 Hz, 1H, H-2′), 4.75 (dd, J = 9.0, 7.0 Hz, 2H, OCH2O-BOM),
4.72 (dd, J = 104.2, 11.6 Hz, 2H, CH2-BOM), 4.57−4.42 (m, 3H,
CH2-OBn and H-4′); 13C NMR (75 MHz, CDCl3): 174.8 (CO2H-4′),
3′,5′-Di-O-benzyl-1′,2′-diacetoxy-α/β-L-ribofuranose (26). Fol-
lowing a similar procedure as the one used for the synthesis of 5,
the diol 3,5-di-O-benzyl-α/β-L-ribofuranose was obtained as a pale
I
DOI: 10.1021/acs.joc.7b01482
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The Journal of Organic Chemistry
Article
yellow solid (Rf = 0.29, 50% EtOAc in hexane, 48.2 g, quan.), starting
from 25 (54 g, 146 mmol) and 1:1 H2O:TFA mixture (400 mL),
which was used directly in the subsequent reaction without any
purification.
the resulting suspension was stirred at room temperature for 18 h.
After completion, the reaction mixture was cooled to 0 °C and
quenched with water. The white solid was filtered off and washed with
CH2Cl2. The organic layer was washed with a 5% NaHCO3 solution
and brine, dried over Na2SO4, concentrated in vacuo to obtain 5′-di-O-
benzyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-oxo-L-β-ribofura-
nose (44 g, contains impurity from DMP) as colorless liquid (Rf =
0.32, EtOAc), which was used for next step without any further
purification. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H35O8P
507.2142; Found 507.2143.
Following a similar procedure as the one used for the synthesis of 6,
compound 26 was obtained (Rf = 0.63, 50% EtOAc in hexane; column
chromatography gradient hexane/EtOAc, 9:1, v/v; 4:1, v/v; 3:1, v/v)
containing a mixture of two diastereomers (∼4:1) as a colorless foam
(54.5 g, 90% over two steps), starting from diol 3,5-di-O-benzyl-α/β-L-
ribofuranose (48.2 g, 146 mmol), acetic anhydride (143 mL) and
1
anhydrous pyridine (320 mL). H NMR (300 MHz, CDCl3) δ 7.34−
To a stirred solution of the above ketone (44 g, 78.7 mmol) in 1:1
absolute EtOH and anhydrous EtOAc mixture (500 mL), was added
NaBH4 (9.15 g, 236.1 mmol) in portions at −50 °C. The reaction
mixture was then slowly warmed to room temperature over 3 h and
stirred at same temperature for 2 h. After completion, the reaction was
quenched with dilute AcOH. Solvent was removed in vacuo and crude
residue was purified via flash column chromatography (gradient
Hexane/EtOAc, 3:1, v/v; 1:1, v/v; 3:7, v/v) to afford 29 (28.4 g, 71%
over two steps) as colorless liquid (Rf = 0.29, EtOAc). 1H NMR (300
MHz, CDCl3) δ 7.35−7.26 (m, 10H, Ar-H 2 × OBn), 5.02 (d, J = 4.5
Hz, 1H, H-1′), 4.80−4.59 (m, 4H, 2 x CH- iPr and CH2-OBn), 4.57−
4.46 (m, 2H, CH2-OBn), 5.30 (dd, J = 6.4, 4.6 Hz, 1H, H-2′), 4.26−
4.20 (dd, J = 11.7, 5.8 Hz, 1H, H-4′), 3.86 (app t, J = 6.2 Hz, 1H, H-
3′), 3.83 (ddd, J = 80.3 (2JH,P), 13.9, 8.7 Hz, 2H, -OCH2P), 3.55−3.52
(m, 2H, H-5′ and H-5″), 1.33−1.28 (m, 12H, 4 x CH3-iPr); 13C NMR
(75 MHz, CDCl3) δ 138.2 (ipso C-OBn), 138.1 (ipso C-OBn), 128.5,
7.23 (m, 10H, Ar-H 2 x OBn), 6.40 (d, J = 4.6 Hz, 0.2H, H-1′α), 5.31
(s, 0.8H, H-1′β), 5.30−5.13 (m, 1H, H-2′), 4.63−4.42 (m, 4H, 2 x
CH2-OBn), 4.34−4.25 (m, 1H, H-3′), 4.24−4.07 (m, 1H, H-4′),
3.70−3.38 (m, 2H, H-5′ and H-5″), 2.12, 2.10, 2.03, 1.93 (4 s, 6H, 2 x
CH3-OAc); 13C NMR (75 MHz, CDCl3) δ 170.1, 170.1, 170.0, 169.3
(2 x CO-OAC), 138.2, 137.8, 137.4 (2 x ipso C-Bn), 128.5, 128.5,
128.4, 128.3, 128.1, 128.1, 128.0, 127.9, 127.9, 127.8, 127.7, 127.6,
127.5 (Ar C-Bn), 98.5, 94.7 (C-1′), 83.4, 81.5 (C-4′), 76.5, 75.5 (C-
2′), 73.7, 73.6 (C-3′), 73.3, 73.1 (2 × CH2−OBn), 71.4, 69.2 (C-5′),
21.0, 20.8 (2 × CH3−OAc); HRMS (ESI-TOF) m/z: [M+Na]+ Calcd
for C23H26O7 437.1571; Found 437.1563.
3′,5′-Di-O-benzyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-ace-
toxy-β-L-ribofuranose (27). Following a similar procedure as the one
used for the synthesis of 11, compound 27 was obtained (Rf = 0.31,
90% EtOAc in hexane; column chromatography gradient Hexane/
EtOAc, 4:1, v/v; 3:2, v/v; 2:3, v/v) as a colorless liquid (57.6 g, 80%),
starting from 26 (54 g, 130.3 mmol), SnCl4 (35.2 mL, 300 mmol),
diisopropyl (hydroxymethyl)phosphonate (30.7 g, 156.4 mmol) and
anhydrous acetonitrile (800 mL), from −20 °C to room temperature
for 5 h. 1H NMR (300 MHz, CDCl3) δ 7.36−7.22 (m, 10H, Ar-H 2 ×
OBn), 5.30 (d, J = 4.4 Hz, 1H, H-2′), 5.07 (s, 1H, H-1′), 4.80−4.63
3
128.4, 127.9, 127.8 (Ar C-Bn), 103.1 (d, JC,P = 10.5 Hz, C-1′), 84.1
(C-3′), 81.2 (C-4′), 78.5 (C-2′), 73.4, 72.1 (2 x CH2−OBn), 72.0 (C-
2
i
1
5′), 71.6, 71.5 (d, JC,P = 6.6 Hz, 2 × 1C- Pr), 61.9 (d, JC,P = 170.5
Hz, -OCH2P), 24.2, 24.1 (d, JC,P = 3.3 Hz, 4 × CH3- Pr); 31P NMR
3
i
(121 MHz, CDCl3) δ = 19.4; [α]20 = +22.3° (c = 1, CH3OH);
D
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H37O8P 509.2299;
Found 509.2306.
i
(m, 2H, 2 x CH- Pr), 4.60−4.29 (m, 4H, 2 × CH2-OBn), 4.26−4.20
(m, 1H, H-4′), 4.13 (dd, J = 7.7, 4.4 Hz, 1H, H-3′), 3.76 (ddd, J = 73.5
(2JH,P), 13.8, 8.7 Hz, 2H, -OCH2P), 3.59 (dd, J = 10.5, 3.5 Hz, 1H, H-
5′), 3.49 (dd, J = 10.5, 5.9 Hz, 1H, H-5″), 2.11 (s, 3H, CH3-OAc),
1.36−1.27 (m, 12H, 4 x CH3-iPr); 13C NMR (75 MHz, CDCl3) δ
170.1 (CO-OAc), 138.1 (ipso C-OBn), 137.5 (ipso C-OBn), 128.5,
128.4, 128.1, 128.0, 127.7 (Ar C-Bn), 105.8 (d, 3JC,P = 11.8 Hz, C-1′),
80.8 (C-4′), 77.6 (C-3′), 73.8 (C-2′), 73.3, 73.1 (2 × CH2−OBn),
3′,5′-Di-O-benzyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-(β-
acetoxy)-L-β-ribofuranose (30). Following a similar procedure as the
one used for the synthesis of 6, compound 30 was obtained (Rf = 0.53,
EtOAc; column chromatography gradient hexane/EtOAc, 4:1, v/v;
3:2, v/v; 2:3, v/v) as a colorless liquid (28.8 g, 95%), starting from 29
(28 g, 55.06 mmol), pyridine (240 mL) and Ac2O (112 mL). 1H NMR
(300 MHz, CDCl3) δ 7.35−7.26 (m, 10H, Ar-H 2 x OBn), 5.23 (d, J =
4.5 Hz, 1H, H-1′), 5.00−4.95 (m, 1H, H-2′), 4.75−4.63 (m, 2H, 2 x
CH- iPr), 4.61−4.48 (m, 4H, 2 x CH2-OBn), 4.21−4.15 (m, 2H, H-4′
and H-3′), 3.72 (ddd, J = 88.0 (2JH,P), 13.8, 9.1 Hz, 2H, -OCH2P),
3.62−3.51 (m, 2H, H-5′ and H-5″), 2.07 (s, 3H, CH3-OAc), 1.32−
1.27 (m, 12H, 4 x CH3-iPr); 13C NMR (75 MHz, CDCl3) δ 170.2
(CO-OAc), 138.1 (ipso C-OBn), 137.8 (ipso C-OBn), 128.5, 128.4,
71.4, 71.3 (d, 2JC,P = 6.8 Hz, 2 × 1C- iPr), 70.9 (C-5′), 61.1 (d, 1JC,P
=
170.4 Hz, -OCH2P), 24.2, 24.1, 24.1, 24.0 (d, 3JC,P = 1.6 Hz, 4 x CH3-
iPr), 20.9 (CH3−OAc); 31P NMR (121 MHz, CDCl3) δ = 19.01;
[α]20 = −15.0° (c = 1, CH3OH); HRMS (ESI-TOF) m/z: [M+H]+
D
Calcd for C28H39O9P 551.2404; Found 551.2406.
3′,5′-Di-O-benzyl-1′-((diisopropoxyphosphoryl)methoxy)-β-L-ri-
bofuranose (28). The compound 27 (48 g, 87.2 mmol) was dissolved
in 7 N NH3 in MeOH (500 mL) and the reaction mixture was stirred
at room temperature in a sealed vessel for 16 h. The reaction mixture
was concentrated under reduced pressure and the resulting crude
residue was purified by column chromatography on silica gel (gradient
hexane/EtOAc, 3:1, v/v; 1:1, v/v; 3:7, v/v) to give 28 (42.8 g, 96.5%)
as a colorless foam (Rf = 0.28, EtOAc). 1H NMR (300 MHz, CDCl3) δ
7.36−7.25 (m, 10H, Ar-H 2 x OBn), 5.01 (s, 1H, H-1′), 4.73−4.63 (m,
3
127.9, 127.8, 127.7 (Ar C-Bn), 100.8 (d, JC,P = 12.7 Hz, C-1′), 81.5
(C-3′), 80.2 (C-4′), 79.0 (C-2′), 73.4, 72.4 (2 x CH2−OBn), 72.0 (C-
2
i
1
5′), 71.2, 71.1 (d, JC,P = 6.8 Hz, 2 × 1C- Pr), 61.4 (d, JC,P = 170.6
3
i
Hz, -OCH2P), 24.2, 24.1, 24.1, 24.0 (d, JC,P = 3.4 Hz, 4 x CH3- Pr),
20.7 (CH3−OAc); 31P NMR (121 MHz, CDCl3) δ = 18.8; [α]20
=
D
+77.0° (c = 1, CH3OH); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C28H39O9P 551.2404; Found 551.2411.
3′,5′-Di-O-benzyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-(β-
O-methoxyethoxymethyl)-L-β-ribofuranose (31). To a stirred sol-
ution of 29 (5.24 g, 10.3 mmol) in anhydrous CH2Cl2 (80 mL) were
added MEMCl (3.53 mL, 30.91 mmol) followed by DIPEA (10.76
mL, 61.8 mmol) and the resulting reaction mixture was refluxed for 48
h. Upon completion, the reaction mixture was cooled and diluted with
CH2Cl2 (300 mL) and washed with a saturated NaHCO3 solution
(150 mL). The organic layer was washed with brine, dried,
concentrated in vacuo and the resulting crude residue was purified
by column chromatography on silica gel (gradient hexane/EtOAc, 4:1,
v/v; 2:3, v/v; 1:4, v/v) to give 31 (5.28 g, 86%) as a white foam (Rf =
0.31, EtOAc). 1H NMR (300 MHz, CDCl3) δ 7.31−7.28 (m, 10H, Ar-
H 2 × OBn), 5.10 (d, J = 4.4 Hz, 1H, H-1′), 4.82 (dd, J = 26.5, 7.0 Hz,
2H, -OCH2O), 4.74−4.64 (m, 2H, 2 × CH- iPr), 4.63−4.47 (m, 4H, 2
× CH2-OBn), 4.33−4.27 (m, 1H, H-2′), 4.15−4.11 (m, 1H, H-4′),
4.07−4.03 (m, 1H, H-3′), 3.80−3.46 (m, 8H, H-5′, H-5″, OCH2P,
OCH2CH2OMe and OCH2CH2OMe), 3.37 (s, 3H, OCH3), 1.31−
i
4H, 2 × Pr−CH), 4.61−4.50 (m, 4H, 2 x CH2-OBn), 4.29−4.23 (m,
1H, H-4′), 4.12 (d, J = 4.7 Hz, 1H, H-2′), 4.05 (dd, J = 6.4, 4.8 Hz,
1H, H-3′), 3.76 (ddd, J = 82.9 (2JH,P), 13.7, 8.7 Hz, 2H, -OCH2P),
3.56−3.49 (m, 2H, H-5′, and H-5″), 3.03 (br s, 3′-OH), 1.31−1.25
(m, 12H, 4 × CH3-iPr); 13C NMR (75 MHz, CDCl3) δ 138.1 (ipso C-
OBn), 137.1 (ipso C-OBn), 128.6, 128.4, 128.2, 127.9, 127.6 (Ar−C),
108.2 (d, 3JC,P = 12.0 Hz, C-1′), 80.9 (C-4′), 79.2 (C-3′), 73.2 (C-2′),
73.1, 72.7 (2 × CH2−OBn), 71.5 (C-5′), 71.1, 71.0 (d, 2JC,P = 6.6 Hz,
2 × 1C- iPr), 61.2 (d, 1JC,P = 170.8 Hz, -OCH2P), 24.1, 24.1, 24.0, 23.9
3
i
(d, JC,P = 1.6 Hz, 4 × CH3- Pr); 31P NMR (121 MHz, CDCl3) δ =
19.5; [α]20 = −13.8° (c = 1, CH3OH); HRMS (ESI-TOF) m/z: [M
D
+H]+ Calcd for C26H37O8P 509.2299; Found 509.2302.
3′,5′-Di-O-benzyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-(β-
hydroxyl)-L-β-ribofuranose (29). To a stirred solution of 28 (40 g,
78.7 mmol) in anhydrous CH2Cl2 (800 mL) was carefully added solid
Dess-Martin periodinane reagent (91.7 g, 216.3 mmol) at −10 °C and
J
DOI: 10.1021/acs.joc.7b01482
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.24 (m, 12H, 4 x CH3-iPr); 13C NMR (75 MHz, CDCl3) δ 138.2,
137.6 (2 x ipso C-OBn), 128.5, 128.4, 128.0, 127.9, 127.7, 127.6 (Ar C-
Bn), 106.5 (d, 3JC,P = 12.4 Hz, C-1′), 95.7 (OCH2O), 80.6 (C-2′), 78.3
(30 mL). 1H NMR (300 MHz, DMSO-d6) δ 4.99−4.90 (m, 2H, H-1′
and 3′-OH), 4.78−4.69 (m, 2H, -OCH2O), 4.64−4.52 (m, 2H, 2 ×
CH-iPr), 4.03−3.96 (m, 1H, H-2′), 3.90−3.49 (m, 8H, H-4′, H-3′, H-
5′, H-5″, OCH2P and OCH2CH2OMe), 3.46 (t, J = 5.0 Hz, 2H,
OCH2CH2OMe), 3.24 (s, 3H, OCH3), 1.25−1.22 (m, 12H, 4 ×
CH3-iPr); 13C NMR (75 MHz, DMSO-d6) δ 105.8 (d, 3JC,P = 12.1 Hz,
C-1′), 94.7 (OCH2O), 84.1 (C-4′), 79.2 (C-3′), 71.2
(C-4′), 78.1 (C-3′), 73.2, 72.6 (2
× CH2−OBn), 71.6
2
(OCH2CH2OMe), 71.5 (OCH2CH2OMe), 71.1, 71.0 (d, JC,P = 6.6
i
1
Hz, 2 × 1C- Pr), 67.4 (C-5′), 61.2 (d, JC,P = 170.5 Hz, -OCH2P),
59.1 (OCH3), 27.1 (3 x CH3 tBu), 24.2, 24.1, 24.1, 24.0 (d, 3JC,P = 2.9
i
2
i
Hz, 4 x CH3- Pr); 31P NMR (121 MHz, CDCl3) δ = 19.4; HRMS
(OCH2CH2OMe), 70.5, 70.4 (d, JC,P = 6.3 Hz, 2 × 1C- Pr), 70.1
(C-2′), 66.6 (OCH2CH2OMe), 62.5 (C-5′), 60.6 (d, 1JC,P = 166.9 Hz,
-OCH2P), 58.2 (OCH3), 27.1 (3 x CH3 tBu), 23.9, 23.8 (d, 3JC,P = 3.8
Hz, 4 × CH3- iPr); 31P NMR (121 MHz, DMSO-d6) δ = 19.7; HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C16H33O10P 439.1704; Found
439.1687.
(ESI-TOF) m/z: [M+H]+ Calcd for C30H45O10P 597.2823; Found
597.2827.
3′,5′-Di-O-benzyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-(β-
O-TBDPS)-L-β-ribofuranose (32). To a stirred solution of 29 (1.5 g,
2.95 mmol) and imidazole (0.80 g, 11.8 mmol) in anhydrous
acetonitrile (30 mL) were added TBDPSCl (1.54 mL, 5.90 mmol)
followed by cat. DMAP (36 mg, 0.295 mmol) and the resulting
reaction mixture was heated at 60 °C for 48 h. Upon completion, the
reaction mixture was cooled to room temperature and volatiles were
concentrated in vacuo. The resulting reaction mixture was diluted with
a 5% NaHCO3 solution (150 mL) and the aqueous layer was extracted
with CH2Cl2 (3 × 200 mL). The combined organic layers were
washed with brine, dried, concentrated in vacuo and the resulting crude
residue was purified by column chromatography on silica gel (gradient
Hexane/EtOAc, 9:1, v/v; 4:1, v/v; 3:2, v/v) to give 32 (1.76 g, 80%)
as a colorless sticky mass (Rf = 0.52, 80% EtOAc in hexane). 1H NMR
(300 MHz, CDCl3) δ 7.76−7.18 (m, 20H, Ar-H 2 x OBn and 2 x Ph),
5′-MMTr-3′-Benzoyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-
(β-acetoxy)-L-β-ribofuranose (35). To a stirred solution of 33 (18.5 g,
49.96 mmol) in anhydrous pyridine (400 mL) were added DMAP
(0.122 g, 1 mmol) followed by MMTrCl (23.1 g, 74.93 mmol) at 0 °C
and the reaction mixture was stirred for 16 h at room temperature.
After completion, the reaction mixture was again cooled to 0 °C and
benzoyl chloride (8.70 mL, 74.93 mmol) was added slowly to the same
reaction vessel. The reaction mixture was then stirred at room
temperature for 2 h. The volatiles were removed in vacuo and the
reaction mixture was quenched with a 5% NaHCO3 solution (500
mL). The aqueous layer was extracted with EtOAc (3 × 400 mL) and
the combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
resulting crude residue was purified via flash column chromatography
(gradient hexane/EtOAc, 4:1, v/v; 3:2, v/v; 2:3, v/v) to afford 35
(31.7 g, 85% over two steps) as a colorless foam (Rf = 0.59, EtOAc).
The resulting crude residue was used for next step without any further
i
4.83−4.69 (m, 2H, 2 x CH- Pr), 4.61−4.50 (m, 4H, 2 x CH2-OBn),
4.30 (dd, J = 6.9, 4.1 Hz, 1H, H-2′), 4.14 (d, J = 4.4 Hz, 1H, H-1′),
4.11−4.06 (m, 1H, H-3′), 4.01 (dd, J = 12.2, 6.0 Hz, 1H, H-4′), 3.61−
3.51 (m, 2H, H-5′ and H-5″), 3.58 (ddd, J = 155.0 (2JH,P), 13.2, 10.4
Hz, 2H, -OCH2P), 1.35−1.29 (m, 12H, 4 x CH3-iPr), 1.09 (s, 9H, tBu-
TBDPS); 13C NMR (75 MHz, CDCl3) δ 138.3, 138.2 (2 × ipso C-
OBn), 136.3, 136.0 (Ar C-Bn), 133.6, 133.0 (2 × ipso C-Ph TBDPS),
130.0, 129.9, 128.5, 128.4, 128.3, 127.9, 127.9, 127.8, 127.8, 127.7,
1
purification. H NMR (300 MHz, CDCl3) δ 8.04−6.74 (m, 19H, Ar
H-Bz and MMTr), 5.75−5.66 (m, 1H, H-3′), 5.41−5.21 (s, 2H, H-1′
and H-2′), 4.78−4.41 (m, 3H, 2 × CH- iPr and H-4′), 4.09−3.37 (m,
7H, -OCH2P, OCH3-MMTr, H-5′ and H-5″), 2.06 (s, 3H, CH3-OAc),
1.35−1.25 (m, 12H, 4 × CH3-iPr); 31P NMR (121 MHz, CDCl3) δ =
18.6; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C41H47O11P
769.2748; Found 769.2755.
3
127.6 (Ar C-Bn and TBDPS), 102.1 (d, JC,P = 15.1 Hz, C-1′), 84.7
(C-3′), 80.1 (C-4′), 78.7 (C-2′), 73.4, 72.9 (2 × CH2−OBn), 72.7 (C-
2
i
1
5′), 71.1, 71.0 (d, JC,P = 6.6 Hz, 2 × 1C- Pr), 61.4 (d, JC,P = 172.9
Hz, -OCH2P), 27.1 (3 × CH3 tBu), 24.3, 24.2 (d, JC,P = 3.4 Hz, 4 ×
3
CH3- Pr), 19.2 (1 C-tBu); 31P NMR (121 MHz, CDCl3) δ = 19.5;
i
5′-MMTr-3′-Benzoyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-
(β-O-methoxyethoxymethyl)-L-β-ribofuranose (36). Following a
similar procedure as the one used for the synthesis of 35, compound
36 was obtained (Rf = 0.75, 10% MeOH in CH2Cl2; column
chromatography gradient CH2Cl2/MeOH, 100:0, v/v; 99.5:0.5, v/v;
99:1, v/v) as a colorless sticky mass (0.95 g, 87%), starting from 36
(0.57 g, 1.369 mmol), MMTrCl (0.64 g, 2.053 mmol), BzCl (0.24 mL,
2.053 mmol), DMAP (3.5 mg, 0.027 mmol), and dry pyridine (15
mL). 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H, o H-Bz),
7.58 (t, J = 7.4 Hz, 1H, p H-Bz), 7.47−7.14 (m, 14H, Ar−H OBz and
MMTr), 6.77 (d, J = 8.9 Hz, 2H, m H-Anisyl MMTr), 5.36 (dd, J =
6.5, 5.1 Hz, 1H, H-3′), 5.24 (s, 1H, H-1′), 4.78−4.62 (m, 4H,
-OCH2O and 2 × CH-iPr), 4.50−4.44 (m, 2H, H-2′ and H-4′), 3.91−
3.26 (m, 14H, -OCH2P, OCH3-MMTr, OCH2CH2OMe, H-5′, H-5″,
OCH2CH2OMe and OCH3-MEM), 1.33−1.26 (m, 12H, 4 x CH3-iPr);
13C NMR (75 MHz, CDCl3) δ 165.7 (CO-Bz), 158.7 (p C-Anisyl
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C42H55O8Psi 747.3476;
Found 747.3468.
1′-((Diisopropoxyphosphoryl)methoxy)-2′-(β-acetoxy)-L-β-ribo-
furanose (33). To a stirred solution of 30 (28 g, 50.8 mmol, 1 equiv)
and glacial AcOH (0.58 mL, 10.2 mmol) in EtOH/H2O (9:1, 300 mL,
degassed with argon), was added 10% Pd/C (11.2 g, 0.4 eq. w/w) and
evacuation was then carried out with hydrogen atmosphere replace-
ments (3×). The reaction mixture was stirred at room temperature for
20 h under an atmospheric pressure of hydrogen. After completion of
the reaction, the catalyst was removed by filtration through a Celite
pad and washed with EtOH. The filtrate was concentrated under
reduced pressure and the crude residue was purified via flash column
chromatography (gradient CH2Cl2/MeOH, 99:1, v/v; 49:1, v/v; 97:3,
v/v) to afford 33 (18.51 g, 98%) as a colorless foam (Rf = 0.42, 10%
1
MeOH in CH2Cl2). H NMR (600 MHz, CDCl3) δ 5.15 (d, J = 4.8
Hz, 1H, H-1′), 4.83 (dd, J = 8.4, 4.7 Hz, 1H, H-2′), 4.80−4.72 (m, 2H,
2 × CH- iPr), 4.68 (dd, J = 8.3, 7.4 Hz, 1H, H-3′), 3.93−3.91 (m, 1H,
H-4′), 3.89−3.77 (m, 3H, H-5′ and-OCH2P), 3.68−3.65 (m, 1H, H-
5″), 2.11 (s, 3H, CH3-OAc), 1.35−1.32 (m, 12H, 4 x CH3-iPr); 13C
NMR (150 MHz, CDCl3) δ 171.2 (CO-OAc), 100.8 (d, 3JC,P = 8.8 Hz,
MMTr), 144.4 (ipso C- MMTr), 135.5 (ipso C- Anisyl MMTr), 133.4
(ipso C-Bz), 130.5, 129.9,129.6, 128.5, 128.5, 127.9, 127.0 (Ar C-OBz
and MMTr), 113.2 (m C-Anisyl MMTr), 106.9 (d, 3JC,P = 10.5 Hz, C-
1′), 95.6 (OCH2O), 86.6 (1C-MMTr), 80.5 (C-4′), 78.7 (C-2′), 74.3
2
(C-3′), 71.6 (OCH2CH2OMe), 71.3, 71.1 (d, JC,P = 6.6 Hz, 2 × 1C-
2
1
iPr), 67.3 (OCH2CH2OMe), 65.0 (C-5′), 61.8 (d, JC,P = 168.5 Hz,
C-1′), 82.9 (C-4′), 79.8 (C-2′), 72.1, 71.6 (d, JC,P = 6.7 Hz, 2 × 1C-
1
iPr), 70.7 (C-3′), 62.9 (d, JC,P = 172.3 Hz, -OCH2P), 61.3 (C-5′),
-OCH2P), 59.0 (OCH3-MEM), 55.2 (OCH3-MMTr), 24.2, 24.2, 24.1
3
i
3
i
24.3, 24.1, 24.0, 23.8 (d, JC,P = 3.9 Hz, 4 × CH3- Pr), 20.8 (CH3−
OAc); 31P NMR (202 MHz, CDCl3) δ = 20.0; [α]20D = +90.0° (c = 1,
CH3OH); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H27O9P
371.1465; Found 371.1464.
(d, JC,P = 3.8 Hz, 4 x CH3- Pr); 31P NMR (121 MHz, CDCl3) δ =
18.9; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C43H53O12P
815.3167; Found 815.3174.
3′-Benzoyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-(β-ace-
toxy)-L-β-ribofuranose (37). A solution of compound 35 (31 g, 41.5
mmol) in 80% AcOH (400 mL) was stirred at room temperature for 4
h. After completion, the volatiles were removed in vacuo and residue
was coevaporated with toluene (2×). The resulting crude residue was
purified by column chromatography on silica gel (Rf = 0.55, 10%
MeOH in CH2Cl2; gradient CH2Cl2/MeOH, 100:0, v/v; 99:1, v/v;
1′-((Diisopropoxyphosphoryl)methoxy)-2′-(β-O-methoxyethoxy-
methyl)-L-β-ribofuranose (34). Following a similar procedure as the
one used for the synthesis of 33, compound 34 was obtained (column
chromatography gradient CH2Cl2/MeOH, 99:1, v/v; 49:1, v/v; 24:1,
v/v) as a colorless sticky mass (0.57 g, 95%), starting from 31 (0.86 g,
1.441 mmol), 10% Pd/C (0.35 g, 0.4 eq. w/w) and MeOH:H2O 49:1
K
DOI: 10.1021/acs.joc.7b01482
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The Journal of Organic Chemistry
Article
98.5:1.5, v/v) to give 37 (16.54 g, 84%) as a colorless foam. 1H NMR
(500 MHz, CDCl3) δ 8.03 (d, J = 7.8 Hz, 2H, o H-Bz), 7.59 (t, J = 7.4
Hz, 1H, p H-Bz), 7.45 (app t, J = 7.8, 7.4 Hz, 2H, m H-Bz), 5.74 (dd, J
= 6.6, 5.3 Hz, 1H, H-3′), 5.31−5.30 (m, 1H, H-1′), 5.26 (dd, J = 6.6,
4.9 Hz, 1H, H-2′), 4.86−4.73 (m, 2H, 2 × CH-iPr), 4.36 (br s, 1H, 5′-
OH), 4.18−4.16 (m, 1H, H-4′), 3.95−3.80 (m, 4H, -OCH2P, H-5′ and
1′), 4.69−4.55 (m, 5H, -OCH2O, H-4′ and 2 x CH- iPr), 4.28 (d, J =
4.9 Hz, 1H, H-2′), 3.96 (ddd, J = 75.1 (2JH,P), 13.8, 8.2 Hz, 2H,
-OCH2P), 3.56−3.40 (m, 2H, OCH2CH2OMe), 3.34−3.31 (m, 2H
OCH2CH2OMe), 3.17 (s, 3H, OCH3), 1.27−1.24 (m, 12H, 4 x
CH3-iPr); 13C NMR (75 MHz, DMSO-d6) δ 171.7 (CO2H-4′), 165.0
(CO-Bz), 133.7 (ipso C-Bz), 129.3 (p C-Bz), 128.9 (m C-Bz), 128.8 (o
H-5″), 2.09 (s, 3H, CH3-OAc), 1.38−1.33 (m, 12H, 4 × CH3-iPr); 13
C
C-Bz), 106.1 (d, JC,P = 12.6 Hz, C-1′), 94.5 (OCH2O), 78.8 (C-4′),
3
NMR (125 MHz, CDCl3) δ 170.3 (CO-OAc), 165.9 (CO-Bz), 133.4
(ipso C-Bz), 129.8 (p C-Bz), 129.1 (m C-Bz), 128.4 (o C-Bz), 101.2
77.5 (C-2′), 74.9 (C-3′), 70.8 (OCH2CH2OMe), 70.5, 70.4 (d, 2JC,P
=
6.2 Hz, 2 × 1C- iPr), 66.6 (OCH2CH2OMe), 60.4 (d, 1JC,P = 165.5 Hz,
3
3
(d, JC,P = 9.8 Hz, C-1′), 82.8 (C-4′), 77.5 (C-2′), 75.3 (C-3′), 71.9,
-OCH2P), 57.9 (OCH3), 23.8, 23.7, 23.6, 23.5 (d, JC,P = 3.8 Hz, 4 x
2
i
1
CH3-iPr); 31P NMR (121 MHz, DMSO-d6) δ = 19.2; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C23H35O12P 535.1939; Found
535.1934.
71.4 (d, JC,P = 6.6 Hz, 2 × 1C- Pr), 63.1 (d, JC,P = 171.3 Hz,
3
-OCH2P), 62.9 (C-5′), 24.1, 23.9, 23.9, 23.8 (d, JC,P = 3.8 Hz, 4 x
CH3- iPr), 20.5 (CH3−OAc); 31P NMR (202 MHz, CDCl3) δ = 19.4;
[α]20D = +109.4° (c = 1, CH3OH); HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C21H31O10P 475.1727; Found 475.1730.
(3′R,4′R,5′R)-3′-(Benzoyloxy)-5′-((diisopropoxyphosphoryl)-
methoxy)tetrahydrofuran-2′,4′-diyl diacetate (41). Following a
similar procedure as the one used for the synthesis of 21, a
diastereomeric mixture (∼3:1) of compound 41 was obtained (Rf =
0.42, EtOAc; column chromatography gradient Hexane/EtOAc, 4:1,
v/v; 3:2, v/v; 2:3, v/v) as a colorless liquid (15.09 g, 90%), starting
from 39 (16.3 g, 33.4 mmol), Pb(OAc)4 (25.15 g, 56.7 mmol),
anhydrous pyridine (9.72 mL, 120.1 mmol) and anhydrous THF (400
mL). 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.7 Hz, 2H, o H-Bz),
7.61 (t, J = 7.4 Hz, 1H, p H-Bz), 7.47 (app t, J = 7.8, 7.5 Hz, 2H, m H-
Bz), 6.54−6.26 (m, J = 2.5 Hz, 1H, H-4′), 5.78−5.59 (dd, J = 5.0, 2.5
Hz, 1H, H-3′), 5.48−5.42 (m, 1H, H-2′), 5.38−5.19 (m, 1H, H-1′),
3′-Benzoyl-1′-((diisopropoxyphosphoryl)methoxy)-2′-(β-O-me-
thoxyethoxymethyl)-L-β-ribofuranose (38). Following a similar
procedure as the one used for the synthesis of 37, compound 38
was obtained (Rf = 0.36, 5% MeOH in CH2Cl2; column
chromatography gradient CH2Cl2/MeOH, 100:0, v/v; 99:1, v/v;
49:1, v/v) as a colorless liquid (0.51 g, 85%), starting from 36 (0.92 g,
1
1.369 mmol) and 80% acetic acid (15 mL). H NMR (300 MHz,
CDCl3) δ 8.03 (d, J = 7.7 Hz, 2H, o H-Bz), 7.57 (t, J = 7.4 Hz, 1H, p
H-Bz), 7.44 (app t, J = 7.8, 7.5 Hz, 2H, m H-Bz), 5.52 (dd, J = 6.7, 4.9
Hz, 1H, H-3′), 5.14 (s, 1H, H-1′), 4.88−4.71 (m, 4H, -OCH2O and 2
i
i
x CH- Pr), 4.52 (d, J = 4.9 Hz, 1H, H-2′), 4.46−4.41 (m, 1H, H-4′),
4.79−4.71 (m, 2H, 2 x CH- Pr), 4.07−3.66 (m, 2H, -OCH2P), 2.17,
4.00−3.34 (m, 8H, -OCH2P, OCH2CH2OMe, H-5′, H-5″ and
OCH2CH2OMe), 3.33 (s, 3H, OCH3), 1.39−1.33 (m, 12H, 4 x
CH3-iPr); 13C NMR (75 MHz, CDCl3) δ 165.9 (CO-Bz), 133.4 (ipso
C-Bz), 129.8 (p C-Bz), 129.7 (m C-Bz), 128.6 (o C-Bz), 107.7 (d, 3JC,P
= 7.9 Hz, C-1′), 95.9 (OCH2O), 83.3 (C-4′), 80.0 (C-2′), 71.9 (C-3′),
72.2, 71.5 (d, 2JC,P = 6.6 Hz, 2 × 1C- iPr), 71.6 (OCH2CH2OMe), 67.4
2.14 (s, 3H, CH3-4′OAc), 2.13, 1.99 (s, 3H, CH3-2′OAc), 1.37−1.34
(m, 12H, 4 x CH3-iPr); 13C NMR (75 MHz, CDCl3) δ 170.1 (CO-
4′OAc), 168.7 (CO-3′OAc), 165.1 (CO-Bz), 133.4 (ipso C-Bz), 129.6
(p C-Bz), 129.5 (m C-Bz), 128.2 (o C-Bz), 101.5, 98.5 (d, 3JC,P = 12.4
Hz, C-1′), 97.9, 90.4 (C-4′), 79.1, 76.0 (C-2′), 72.6, 72.3 (C-3′), 71.0,
2
i
1
70.9 (d, JC,P = 6.5 Hz, 2 × 1C- Pr), 62.1, 61.7 (d, JC,P = 170.9 Hz,
1
3
i
(OCH2CH2OMe), 63.0 (d, JC,P = 172.4 Hz, -OCH2P), 61.4 (C-5′),
-OCH2P), 23.7, 23.6 (d, JC,P = 3.7 Hz, 4 x CH3- Pr), 20.5 (CH3-
4′OAc), 20.2 (CH3-2′OAc); 31P NMR (121 MHz, CDCl3) δ = 17.7;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C22H31O11P 525.1496;
Found 525.1485.
3
i
59.1 (OCH3), 24.3, 24.2, 24.0, 23.9 (d, JC,P = 3.7 Hz, 4 × CH3- Pr);
31P NMR (121 MHz, CDCl3) δ = 19.9; HRMS (ESI-TOF) m/z: [M
+Na]+ Calcd for C23H37O11P 543.1966; Found 543.1950.
(3′R,4′S,5′R)-2′-Acetoxy-5′-((diisopropoxyphosphoryl)methoxy)-
4′-((2′-methoxyethoxy)methoxy)tetrahydrofuran-3′-yl Benzoate
(42). Following a similar procedure as the one used for the synthesis
of 21, a diastereomeric mixture (∼49:1) of compound 42 was obtained
(Rf = 0.22, EtOAc; column chromatography gradient Hexane/EtOAc,
4:1, v/v; 1:1, v/v; 1:9, v/v) as a colorless sticky mass (0.231 g, 75%),
starting from 40 (0.30 g, 0.561 mmol), Pb(OAc)4 (0.423 g, 0.954
mmol), anhydrous pyridine (0.1 mL, 1.234 mmol) and anhydrous
THF (8 mL). 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J = 7.7 Hz, 2H,
o H-Bz), 7.60 (t, J = 7.4 Hz, 1H, p H-Bz), 7.46 (app t, J = 7.8, 7.5 Hz,
2H, m H-Bz), 6.42 (d, J = 2.3 Hz, 1H, H-4′), 5.50 (dd, J = 4.9, 2.4 Hz,
1H, H-3′), 5.42−5.30 (m, 1H, H-1′), 4.89−4.71 (m, 4H, -OCH2O and
2 x CH- iPr), 4.57 (dd, J = 4.9, 2.4 Hz, 1H, H-2′), 3.87 (ddd, J = 75.0
(2JH,P), 13.5, 8.9 Hz, 2H, -OCH2P), 3.73−3.55 (m, 2H, -
OCH2CH2OMe), 3.51−3.43 (m, 2H, -OCH2CH2OMe), 3.33 (s,
3H, OCH3-MEM), 2.13 (s, 3H, CH3-OAc), 1.37−1.34 (m, 12H, 4 ×
CH3-iPr); 13C NMR (75 MHz, CDCl3) δ 169.4 (CO-OAc), 165.3
(CO-Bz), 133.5 (ipso C-Bz), 129.7 (p C-Bz and m C-Bz), 128.4 (o C-
Bz), 108.3 (d, 3JC,P = 12.6 Hz, C-1′), 98.9 (C-4′), 95.6 (OCH2O), 78.3
( 2′R , 3′R , 4 ′R, 5 ′R) -4 ′-Aceto xy-3′- ( b en z o y l o x y ) - 5′-
((diisopropoxyphosphoryl)methoxy)tetrahydro-furan-2′-carboxylic
Acid (39). Following a similar procedure as the one used for the
synthesis of 20, compound 39 was obtained (Rf = 0.29, 10% MeOH in
CH2Cl2; column chromatography gradient CH2Cl2/MeOH, 99:1, v/v;
49:1, v/v; 24:1, v/v) as a pale-yellow sticky mass (16.3 g, 96%),
starting from 37 (16.5 g, 34.78 mmol), iodosobenzene diacetate
(24.64 g, 76.51 mmol), TEMPO (1.63 g, 10.43 mmol) and 1:1
ACN:H2O mixture (300 mL). 1H NMR (300 MHz, DMSO-d6) δ 8.02
(d, J = 7.8 Hz, 2H, o H-Bz), 7.69 (t, J = 7.4 Hz, 1H, p H-Bz), 7.55 (app
t, J = 7.8, 7.4 Hz, 2H, m H-Bz), 5.94 (dd, J = 6.6, 5.4 Hz, 1H, H-3′),
5.37 (d, J = 4.3 Hz, 1H, H-1′), 5.19 (dd, J = 6.6, 4.3 Hz, 1H, H-2′),
4.65−4.56 (m, 3H, H-4′ and 2 x CH- iPr), 3.95 (ddd, J = 79.6 (2JH,P),
13.9, 7.9 Hz, 2H, -OCH2P), 2.01 (s, 3H, CH3-OAc), 1.27−1.21 (m,
12H, 4 × CH3-iPr); 13C NMR (75 MHz, DMSO-d6) δ 171.4 (CO2H-
4′), 169.5 (CO-OAc), 164.8 (CO-Bz), 133.7 (ipso C-Bz), 129.5 (p C-
Bz), 128.9 (m C-Bz), 128.7 (o C-Bz), 100.4 (d, 3JC,P = 12.6 Hz, C-1′),
77.4 (C-4′), 76.8 (C-2′), 76.5 (C-3′), 70.5, 70.4 (d, 2JC,P = 6.2 Hz, 2 ×
1C- iPr), 60.6 (d, 1JC,P = 165.5 Hz, -OCH2P), 23.8, 23.7, 23.6, 23.5 (d,
3JC,P = 3.8 Hz, 4 × CH3- iPr), 20.3 (CH3−OAc); 31P NMR (121 MHz,
2
(C-2′), 75.9 (C-3′), 71.4 (OCH2CH2OMe), 71.3, 71.1 (d, JC,P = 6.5
i
1
DMSO-d6) δ = 18.6; [α]20 = +69.7° (c = 1, CH3OH); HRMS (ESI-
Hz, 2 × 1C- Pr), 67.3 (OCH2CH2OMe), 62.4 (d, JC,P = 170.1 Hz,
D
3
TOF) m/z: [M+H]+ Calcd for C21H29O11P 489.1520; Found
489.1519.
-OCH2P), 58.8 (OCH3), 24.0, 23.9, 23.8 (d, JC,P = 3.7 Hz, 4 x CH3-
iPr), 20.9 (CH3−OAc); 31P NMR (121 MHz, CDCl3) δ = 18.1;
(2′R,3′R,4′S,5′R)-3′-(Benzoyloxy)-5′-((diisopropoxyphosphoryl)-
methoxy)-4′-((2′-methoxyethoxy)methoxy)tetrahydrofuran-2′-car-
boxylic Acid (40). Following a similar procedure as the one used for
the synthesis of 20, compound 40 was obtained (Rf = 0.28, 10%
MeOH in CH2Cl2; column chromatography gradient CH2Cl2/MeOH,
99:1, v/v; 49:1, v/v; 19:1, v/v) as a colorless sticky mass (0.49 g, 93%),
starting from 38 (0.51 g, 0.98 mmol), iodosobenzene diacetate (0.35 g,
2.16 mmol), TEMPO (0.031 g, 0.20 mmol) and 1:1 ACN:H2O
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C24H37O12P 571.1915;
Found 571.1915.
(2′R,3′R,4′R,5′R)-4′-Acetoxy-2′-(6-benzamido-9H-purin-9-yl)-5′-
((diisopropoxyphosphoryl)methoxy)tetrahydrofuran-3′-yl Benzoate
(43). 1 M SnCl4 in CH2Cl2 (89.6 mL, 89.6 mmol) was added slowly to
a stirred suspension of 41 (15 g, 29.85 mmol) and 6-benzoyl adenine
(10.71 g, 44.8 mmol) in anhydrous acetonitrile (440 mL) at 0 °C. The
reaction mixture was then stirred at room temperature for 36 h. Upon
completion, the reaction mixture was cooled to 0 °C and quenched
with a saturated NaHCO3 solution. The reaction mixture was diluted
with EtOAc (800 mL) and the milky aqueous layer was extracted with
1
mixture (10 mL). H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J = 7.7
Hz, 2H, o H-Bz), 7.69 (t, J = 7.4 Hz, 1H, p H-Bz), 7.55 (app t, J = 7.8,
7.5 Hz, 2H, m H-Bz), 5.52 (t, J = 5.53 Hz, 1H, H-3′), 5.28 (s, 1H, H-
L
DOI: 10.1021/acs.joc.7b01482
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
EtOAc (3 × 600 mL). The combined organic layers were washed with
brine, dried, concentrated in vacuo, and the crude residue was purified
by flash column chromatography on silica gel (gradient CH2Cl2/
MeOH/, 100:1, v/v; 99:1, v/v; 49:1, v/v) to give 43 (11.2 g, 55%) as a
Spectral data for 46: H NMR (600 MHz, CD3OD) δ 8.36 (s, 1H,
H-8), 8.21 (s, 1H, H-2), 6.09 (d, J = 5.8 Hz, 1H, H-1′), 5.17 (d, J = 4.4
Hz, 1H, H-4′), 4.80−4.74 (m, 2H, 2 × CH- iPr), 4.71 (dd, J = 8.0, 5.8
Hz, 1H, H-2′), 4.23 (dd, J = 8.0, 4.4 Hz, 1H, H-3′), 3.94 (ddd, J = 56.2
(2JH,P), 13.8, 9.5 Hz, 2H, -OCH2P), 2.17 (s, 3H, CH3-OAc), 1.38−1.35
(m, 12H, 4 × CH3-iPr); 13C NMR (150 MHz, CD3OD) δ 157.4 (C-
4), 154.1 (C-2), 151.0 (C-6), 140.7 (C-8), 119.9 (C-5), 105.4 (d, 3JC,P
= 13.1 Hz, C-4′), 87.7 (C-1′), 79.7 (C-2′), 77.2 (C-3′), 73.6, 73.5 (d,
2JC,P = 6.8 Hz, 2 × CH- iPr), 63.4 (d, 1JC,P = 170.9 Hz, -OCH2P), 24.3,
24.2 (d, 3JC,P = 3.4 Hz, 4 × CH3- iPr); 31P NMR (202 MHz, CD3OD)
1
pale-yellow semisolid (Rf = 0.59, 10% MeOH in CH2Cl2). H NMR
(600 MHz, CDCl3) δ 9.20 (br s, 1H, NH), 8.75 (s, 1H, H-8), 8.62 (s,
1H, H-2), 8.03, 7.97 (2d, J = 7.6 Hz, 2H, 2 × o H-Bz), 7.61, 7.59 (2t, J
= 7.4 Hz, 2H, 2 x p H-Bz), 7.53, 7.45 (2app t, J = 7.8, 7.5 Hz, 4H, 2 x
m H-Bz), 6.56 (d, J = 4.0 Hz, 1H, H-1′), 6.18 (dd, J = 7.8, 5.0 Hz, 1H,
H-2′), 5.60 (d, J = 4.5 Hz, 1H, H-4′), 5.49 (dd, J = 7.7, 4.5 Hz, 1H, H-
3′), 4.83−4.76 (m, 2H, 2 x CH- iPr), 3.84 (ddd, J = 111.2 (2JH,P), 13.7,
9.6 Hz, 2H, -OCH2P), 2.17 (s, 3H, CH3-OAc), 1.38−1.35 (m, 12H, 4
x CH3-iPr); 13C NMR (150 MHz, CDCl3) δ 170.0 (CO-OAc), 165.5
(CO-OBz), 164.7 (CO-NHBz), 153.1 (C-2), 152.2 (C-4), 149.7 (C-
δ = 19.6; [α]20 = +19.6° (c = 1, CH3OH); HRMS (ESI-TOF) m/z:
D
[M+H]+ Calcd for C16H26N5O7P 432.1642; Found 432.1643.
Alternatively, compound 46 was obtained starting from 43 in 96%
yield using 7 N NH3 in MeOH at room temperature for 48 h.
Diisopropyl ((((2′R,3′S,4′S,5′R)-5′-(6-Amino-9H-purin-9-yl)-3′-flu-
oro-4′-hydroxytetrahydrofuran-2′-yl)oxy)methyl)phosphonate
(48). To a stirred solution of 45 (3.77 g, 7.04 mmol) in a mixture of
anhydrous CH2Cl2 (112 mL) and anhydrous pyridine (17 mL) was
added DAST (6.92 mL, 52.38 mmol) at −20 °C. Then the reaction
mixture was slowly warmed to room temperature and left for stirring at
same temperature for 5 h. After completion, the reaction mixture was
cooled to 0 °C and slowly poured into an ice-cold saturated solution of
NaHCO3 (140 mL) and the aqueous layer was extracted with CH2Cl2
(3 × 200 mL). Due to partial solubility of the compound in water, the
aqueous layer was lyophilized and the resulting solid was washed with
10% MeOH in CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered and concentrated in vacuo. The resulting crude
residue was purified by column chromatography on silica gel (gradient
CH2Cl2/MeOH, 49:1, v/v; 24:1, v/v; 16:1, v/v) to give 48 (1.28 g,
42%) as an off white solid, Mp: 80−82 °C (Rf = 0.27, 10% MeOH in
6), 141.7 (C-8), 134.1, 133.9 (2 × ipso C-Bz), 132.9, 130.1, 129.9,
3
128.9, 128.7, 128.2, 128.0 (Ar C-Bz), 122.6 (C-5), 101.9 (d, JC,P
=
=
2
11.7 Hz, C-4′), 83.9 (C-1′), 78.4 (C-2′), 74.9 (C-3′), 71.7 (d, JC,P
i
1
6.8 Hz, 2 × CH- Pr), 62.9 (d, JC,P = 171.3 Hz, -OCH2P), 24.2, 24.1
(d, JC,P = 3.4 Hz, 4 x CH3- Pr), 20.6 (CH3−OAc); 31P NMR (202
3
i
MHz, CDCl3) δ = 17.3; [α]20 = −23.1° (c = 1, CH3OH); HRMS
D
(ESI-TOF) m/z: [M+H]+ Calcd for C32H36N5O10P 682.2272; Found
682.2280.
(2′R,3′R,4′S,5′R)-2′-(6-Benzamido-9H-purin-9-yl)-5′-
((diisopropoxyphosphoryl)methoxy)-4′-hydroxytetrahydrofuran-3′-
yl Benzoate (44), Diisopropyl ((((2′R,3′R,4′R,5′R)-5′-(6-Benzamido-
9H-purin-9-yl)-3′,4′-dihydroxytetrahydrofuran-2′-yl)oxy)methyl)-
phosphonate (45), and Diisopropyl ((((2′R,3′R,4′R,5′R)-5′-(6-
Amino-9H-purin-9-yl)-3′,4′-dihydroxytetrahydrofuran-2′-yl)oxy)-
methyl)phosphonate (46). The compound 43 (11.5 g, 16.87 mmol)
was dissolved in 2 M NH3 in EtOH (102 mL) at 0 °C and the reaction
mixture was stirred at room temperature for 48 h in a sealed vessel.
The reaction mixture was concentrated under reduced pressure (bath
temp 10 °C) and the resulting crude residue was purified by column
chromatography on silica gel (gradient CH2Cl2/MeOH/, 97:3, v/v;
24:1, v/v; 23:2, v/v) to give 44 (0.32 g, 3%, white foam, Rf = 0.69, 12%
MeOH in CH2Cl2), 45 (3.78 g, 42%, white semisolid, Rf = 0.49, 12%
MeOH in CH2Cl2), and 46 (3.26 g, 45%, white solid, Rf = 0.28, 12%
1
CH2Cl2). H NMR (600 MHz, CDCl3) δ 8.45 (s, 1H, H-8), 8.01 (s,
1H, H-2), 6.40 (d, J = 6.4 Hz, 1H, H-1′), 5.49 (d, J = 27.0 Hz, 1H, H-
2′), 5.25 (d, J = 8.3 Hz, 1H, H-4′), 5.13 (dd, J = 52.7 (2JH,F), 3.6 Hz,
i
1H, H-3′), 4.85−4.67 (m, 2H, 2 × CH- Pr), 3.76 (ddd, J = 167.9
(2JH,P), 13.1, 10.2 Hz, 2H, -OCH2P), 1.47−1.16 (m, 12H, 4 ×
CH3-iPr); 13C NMR (150 MHz, CDCl3) δ 154.8 (C-4), 153.4 (C-2),
149.2 (C-6), 139.6 (C-8), 118.1 (C-5), 105.1 (dd, J = 29.1 (2JC,F), 11.7
(3JC,P) Hz, C-4′), 93.6 (d, 1JC,F = 187.1 Hz, C-3′), 87.2 (C-1′), 75.4 (d,
2JC,F = 15.4 Hz, C-2′), 72.2, 71.7 (2d, 2JC,P = 6.3 Hz, 2 × CH- iPr), 61.5
1
MeOH in CH2Cl2; Mp: 71−73 °C). Spectral data for 44: H NMR
(300 MHz, CDCl3) δ 9.45 (br s, 1H, NH), 8.78 (s, 1H, H-8), 8.74 (s,
1H, H-2), 7.98, 7.97 (2d, J = 7.7 Hz, 2H, 2 × o H-Bz), 7.56, 7.55 (2t, J
= 7.4 Hz, 2H, 2 x p H-Bz), 7.45, 7.40 (2app t, J = 7.8, 7.5 Hz, 4H, 2 x
m H-Bz), 6.48 (d, J = 4.6 Hz, 1H, H-1′), 6.07 (dd, J = 6.6, 4.6 Hz, 1H,
H-2′), 5.88 (br s, 1H, 3′-OH), 5.42 (d, J = 4.4 Hz, 1H, H-4′), 4.84−
1
3
(d, JC,P = 175.4 Hz, -OCH2P), 24.4, 24.2, 24.0 (d, JC,P = 3.7 Hz, 4 x
CH3- iPr); 19F NMR (470 MHz, CDCl3) δ = −211.5; 31P NMR (202
MHz, CDCl3) δ = 17.6; [α]20D = +3.8° (c = 1, CH3OH); HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C16H25FN5O6P 434.1599; Found
434.1596.
Following this similar synthetic protocol, 48 was also obtained (0.97
g, 47%) starting from 46 (2.06 g, 4.775 mmol), DAST (3.79 mL, 28.65
mmol), anhydrous pyridine (9.2 mL), and anhydrous CH2Cl2 (60
mL).
((((2′R,3′S,4′S,5′R)-5′-(6-Amino-9H-purin-9-yl)-3′-fluoro-4′-hy-
droxytetrahydrofuran-2′-yl)oxy)methyl)phosphonic Triethylammo-
nium Salt (1). To a stirred solution of 48 (1.52 g, 3.51 mmol) in dry
acetonitrile (35 mL) were added 2,6-lutidine (6.54 mL, 56.16 mmol)
followed by TMSBr (3.71 mL, 28.08 mmol) at 0 °C and the reaction
mixture was then stirred at room temperature for 24 h. Upon
completion, the reaction mixture was cooled to 0 °C and quenched
with a 1 M TEAB buffer. The volatiles were removed in vacuo and the
residue was diluted with water and lyophilized. The crude product was
purified first by column chromatography on silica gel (gradient
IPA:H2O:Et3N, 20:1:1, v/v/v; 15:1:1, v/v/v; 10:1:1, v/v/v), then by
preparative RP-HPLC (linear gradient, 2−95% 25 mmol TEAB in
CH3CN and 25 mmol TEAB in H2O). The collected eluates were
freeze-dried repeatedly until constant mass to afford compound 1
i
4.68 (m, 3H, H-3′ and 2 x CH- Pr), 3.91 (ddd, J = 40.6 (2JH,P), 13.8,
8.6 Hz, 2H, -OCH2P), 1.35−1.28 (m, 12H, 4 × CH3-iPr); 13C NMR
(75 MHz, CDCl3) δ 166.0 (CO-OBz), 165.0 (CO-NHBz), 152.9 (C-
2), 151.9 (C-4), 149.7 (C-6), 142.2 (C-8), 133.8 (ipso C-Bz), 132.7,
130.1, 128.8, 128.6, 128.5, 128.0 (Ar C-Bz), 122.6 (C-5), 104.2 (d,
3JC,P = 9.7 Hz, C-4′), 84.8 (C-1′), 81.2 (C-2′), 75.2 (C-3′), 72.0, 71.9
2
i
1
(d, JC,P = 5.2 Hz, 2 × CH- Pr), 63.3 (d, JC,P = 170.7 Hz, -OCH2P),
24.1, 24.1, 24.0 (d, 3JC,P = 3.4 Hz, 4 × CH3- iPr); 31P NMR (121 MHz,
CDCl3) δ = 18.1; [α]20 = +11.9° (c = 1, CH3OH); HRMS (ESI-
D
TOF) m/z: [M+H]+ Calcd for C30H34N5O9P 640.2167; Found
640.2189.
Spectral data for 45: 1H NMR (600 MHz, CDCl3) δ 9.28 (br s, 1H,
NH), 8.68 (s, 1H, H-8), 8.53 (s, 1H, H-2), 7.98 (d, J = 7.4 Hz, 2H, o
H-Bz), 7.55 (t, J = 7.1 Hz, 2H, p H-Bz), 7.46 (app t, J = 7.4, 7.1 Hz,
4H, m H-Bz), 6.25 (d, J = 5.4 Hz, 1H, H-1′), 6.11 (br s, 1H, 2′- OH),
5.15 (d, J = 3.9 Hz, 1H, H-4′), 5.10 (br s, 1H, 3′- OH), 5.01 (app t, J =
6.7 Hz, 1H, H-2′), 4.74−4.61 (m, 2H, 2 × CH- iPr), 4.39 (br s, 1H, H-
3′), 3.82 (ddd, J = 118.0(2JH,P), 13.3, 8.7 Hz, 2H, -OCH2P), 1.31−1.91
(m, 12H, 4 × CH3-iPr); 13C NMR (150 MHz, CDCl3) δ 164.9 (CO-
Bz), 152.7 (C-2), 152.0 (C-4), 149.1 (C-6), 142.0 (C-8), 133.3 (ipso
C-Bz), 132.7 (p C-Bz), 128.7 (m C-Bz), 127.9 (o C-Bz), 122.3 (C-5),
103.9 (d, 3JC,P = 12.4 Hz, C-4′), 86.4 (C-1′), 78.6 (C-2′), 76.4 (C-3′),
1
(1.70 g, 88% over) as a white solid, Mp: 79−81 °C. H NMR (500
MHz, D2O) δ 8.39 (s, 1H, H-8), 8.19 (s, 1H, H-2), 6.27 (d, J = 6.5 Hz,
1H, H-1′), 5.46 (d, J = 9.5 Hz, 1H, H-4′), 5.19 (dd, J = 55.0 (2JH,F), 3.7
Hz, 1H, H-3′), 5.16 (ddd, J = 25.3 (1JH,F), 6.8, 3.6 Hz, 1H, H-2′), 3.73
(ddd, J = 86.8 (2JH,P), 12.9, 9.3 Hz, 2H, -OCH2P); 13C NMR (125
MHz, D2O) δ 155.1 (C-4), 152.4 (C-2), 148.9 (C-6), 139.7 (C-8),
118.0 (C-5), 105.8 (dd, J = 29.5 (2JC,F), 13.1 (3JC,P) Hz, C-4′), 92.5 (d,
2
i
1
72.1, 72.0 (d, JC,P = 6.8 Hz, 2 × CH- Pr), 62.6 (d, JC,P = 172.5 Hz,
-OCH2P), 23.9, 23.9, 23.8 (d, JC,P = 3.4 Hz, 4 x CH3- iPr); 31P NMR
3
(202 MHz, CDCl3) δ = 18.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
2
for C23H30N5O8P 536.1905; Found 536.1904.
1JC,F = 182.8 Hz, C-3′), 85.9 (C-1′), 73.9 (d, JC,F = 16.0 Hz, C-2′),
M
DOI: 10.1021/acs.joc.7b01482
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
64.2 (d, JC,P = 157.7 Hz, -OCH2P); 19F NMR (470 MHz, D2O) δ =
(OCH2CH2-isopentyl), 26.1, 26.0 (2 × CH-isopentyl), 22.9, 22.8, 22.8,
22.7 (4 x CH3-isopentyl); 19F NMR (470 MHz, CD3OD) δ = −212.2,
−212.3 (2m); 31P NMR (202 MHz, CD3OD) δ = 23.4, 22.6; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C30H42FN6O9P 681.2807; Found
681.2822.
−210.5 (Oct); 31P NMR (202 MHz, D2O) δ = 14.2; [α]20D = +3.7° (c
= 1, CH3OH); ξ: 15.0 × 10−3 cm2. mol−1 (λ = 260 nm); HRMS (ESI-
TOF) m/z: [M-H]− Calcd for C10H13FN5O6P 348.0515; Found
348.0519.
Dipropyl 2,2′-((((((2′R,3′S,4′S,5′R)-5′-(6-Amino-9H-purin-9-yl)-3′-
fluoro-4′-hydroxytetrahydrofuran-2′-yl)oxy)methyl)phosphoryl)bis-
(azanediyl))(2S,2′S)-bis(3-phenylpropanoate) (51). A similar syn-
thetic protocol as the one used for the synthesis of 49 was employed
for the synthesis of 51, starting from ditriethylammonium salt of 1
(117.4 mg, 0.213 mmol) and L-phenylalanine propyl ester HCl salt
(311.3 mg, 1.277 mmol), Et3N (0.36 mL, 2.56 mmol) in dry pyridine
(1.8 mL) and 2,2′-dithiodipyridine (329 mg, 1.49 mmol), PPh3 (415
mg, 1.49 mmol) in anhydrous pyridine (1 mL) to obtain 51 as white
powder (65.1 mg, 42%, white solid, Rf = 0.46, 10% MeOH in CH2Cl2;
Isopropyl (((((2′R,3′S,4′S,5′R)-5′-(6-Amino-9H-purin-9-yl)-3′-fluo-
ro-4′-hydroxytetrahydrofuran-2′-yl)oxy)methyl)(phenoxy)-
phosphoryl)-L-alaninate (49). To a stirred suspension of ditriethy-
lammonium salt of 1 (100.4 mg, 0.182 mmol) and L-alanine isopropyl
ester HCl salt (54 mg, 0.322 mmol) in dry pyridine (1.5 mL), were
added PhOH (76 mg, 0.804 mmol) followed by Et3N (0.27 mL, 1.93
mmol) at room temperature. The reaction mixture was then stirred at
60 °C under nitrogen for 15−20 min. In a separate flask The 2,2′-
dithiodipyridine (294 mg, 1.333 mmol) and PPh3 (250 mg, 0.897
mmol) were added in anhydrous pyridine (0.5 mL) and the resultant
mixture was stirred at room temperature for 10−15 min to give a clear
light yellow solution. The solution was then added to the solution of 1
at 60 °C and the combined mixture stirred for 16 h at 60 °C. The
volatiles were removed in vacuo and the residue was dissolved in
EtOAc. Organic layer was washed with saturated NaHCO3 solution
(2×), brine, dried over Na2SO4, filtered and concentrated under
reduced pressure. The resulting crude residue was purified first by
column chromatography on silica gel (gradient CH2Cl2/MeOH, 99:1,
v/v; 49:1, v/v; 24:1, v/v) and further by preparative HPLC (linear
gradient, 5−95% CH3CN in H2O) to provide 49 (56 mg, 57%, white
powder, Rf = 0.43, 10% MeOH in CH2Cl2) as a mixture of P(R) and
1
Mp: 72−74 °C). H NMR (500 MHz, CD3OD) δ 8.24 (s, 1H, H-8),
8.21 (s, 1H, H-2), 7.24−7.11 (m, 5H, Ar-H OPh), 6.15 (d, J = 7.3 Hz,
1H, H-1′), 5.16 (ddd, J = 26.8 (1JH,F), 7.4, 3.5 Hz, 1H, H-2′), 5.03 (d, J
= 9.5 Hz, 1H, H-4′), 4.88 (dd, J = 52.6 (2JH,F), 3.4 Hz, 1H, H-3′),
4.19−4.14 (m, 1H. CH-Phe), 4.12−3.96 (m, 5H. CH-Phe and 2 ×
OCH2-nPr), 3.24 (ddd, J = 129.3 (2JH,P), 13.2, 7.3 Hz, 2H, -OCH2P),
3.07−2.74 (m, 4H, 2 × CH2-Phe), 1.70−1.56 (m, 4H, 2 ×
OCH2CH2-nPr), 0.95−0.87 (m, 6H, 2 x CH3-nPr), 1.19 (d, J = 6.2
Hz, 6H, 2 x CH3-iPr); 13C NMR (125 MHz, CD3OD) δ 174.5 (2d,
3JC,P = 6.8 Hz, 2 × CO-Phe), 157.4 (C-4), 154.4 (C-2), 151.0 (C-6),
141.7 (C-8), 138.3, 138.2 (2 x ipsoC-Ph), 130.8, 130.6, 129.5, 129.4,
128.0, 127.9 (Ar C-Ph), 120.6 (C-5), 106.4 (dd, J = 29.9 (2JC,F), 13.1
1
P(S) isomers (approx 1:1). H NMR (500 MHz, CD3OD) δ 8.36,
1
(3JC,P) Hz, C-4′), 94.2 (d, JC,F = 184.4 Hz, C-3′), 88.6 (C-1′), 73.8
8.29 (2s, 1H, H-8), 8.21 (s, 1H, H-2), 7.37−7.18 (m, 5H, Ar-H OPh),
6.29, 6.27 (2d, J = 6.8 Hz, 1H, H-1′), 5.42, 5.37 (2d, J = 9.5 Hz, 1H,
H-4′), 5.18−5.11 (m, 1H, H-2′), 5.10−4.97 (m, 1H, H-3′), 4.96−4.91
(m, 1H. CH-iPr), 4.21−4.03 (m, 2H, -OCH2P), 4.02−3.95 (m, 1H.
CH-Ala), 1.28, 1.25 (2d, J = 7.1 Hz, 3H. CH3-Ala), 1.19 (d, J = 6.2 Hz,
6H, 2 x CH3-iPr); 13C NMR (125 MHz, CD3OD) δ 174.8, 174.5 (CO-
Ala), 157.4 (C-4), 154.2 (C-2), 151.3, 151.2 (C-6), 140.7 (C-8), 130.8,
126.3, 122.0, 121.9, 121.8, 121.7 (Ar C-OPh), 120.2 (C-5), 107.1,
107.0 (2dd, J = 30.8 (2JC,F), 10.3 (3JC,P) Hz, C-4′), 94.2, 94.1 (2d, 1JC,F
= 180.6 Hz, C-3′), 88.2, 88.1 (C-1′), 74.9, 74.8 (2d, 2JC,F = 17.2 Hz, C-
(2d, 2JC,F = 16.1 Hz, C-2′), 68.0, 67.9 (2 x OCH2-nPr), 64.9 (d, 1JC,P
=
139.6 Hz, -OCH2P), 55.9, 55.5 (2 × CH2−Phe), 23.0, 22.9 (2 ×
OCH2CH2-nPr), 10.8, 10.7 (2 × CH3-nPr); 19F NMR (470 MHz,
CD3OD) δ = −212.8 (oct); 31P NMR (202 MHz, CD3OD) δ = 22.2;
[α]20 = −8.4° (c = 1, CH3OH); HRMS (ESI-TOF) m/z: [M+H]+
D
Calcd for C34H43FN7O8P 728.2967; Found 728.2969.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01482.
■
S
1
2′), 70.2 (CH-iPr), 64.8, 64.7 (2d, JC,P = 158.5 Hz, -OCH2P), 51.1,
2
51.0 (2d, JC,P = 13.0 Hz, CH-Ala), 21.9, 21.8 (CH3-iPr), 21.0, 20.4
3
(2d, JC,P = 5.0 Hz, CH3-iPr); 19F NMR (470 MHz, CD3OD) δ =
1H, 13C, 19F, 31P NMR, and HRMS spectra of
intermediates and final compounds (PDF)
−212.2, −212.40 (2Hex); 31P NMR (202 MHz, CD3OD) δ = 23.3,
22.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H28FN6O7P
539.1814; Found 539.1814.
Diisopentyl (((((2′R,3′S,4′S,5′R)-5′-(6-Amino-9H-purin-9-yl)-3′-flu-
oro-4′-hydroxytetrahydrofuran-2′-yl)oxy)methyl)(phenoxy)-
phosphoryl)-L-aspartate (50). A similar synthetic protocol as the one
used for the synthesis of 49 was employed for the synthesis of 50,
starting from ditriethylammonium salt of 1 (80.3 mg, 0.146 mmol)
and L-aspartic acid diisopentyl ester HCl salt (80.1 mg, 0.258 mmol),
PhOH (61 mg, 0.643 mmol), Et3N (0.22 mL, 1.55 mmol) in dry
pyridine (1.2 mL) and 2,2′-dithiodipyridine (235 mg, 1.07 mmol),
PPh3 (200 mg, 0.718 mmol) in anhydrous pyridine (0.4 mL) to obtain
50 (54 mg, 54%, white powder, Rf = 0.46, 10% MeOH in CH2Cl2) as a
mixture of P(R) and P(S) isomers (approx 1:1). 1H NMR (500 MHz,
CD3OD) δ 8.35, 8.29 (2s, 1H, H-8), 8.21, 8.21 (2s, 1H, H-2), 7.36−
7.17 (m, 5H, Ar-H OPh), 6.28, 6.27 (2d, J = 6.4 Hz, 1H, H-1′), 5.43,
5.36 (2d, J = 9.5 Hz, 1H, H-4′), 5.19−5.11 (m, 1H, H-2′), 5.10−4.94
(m, 1H, H-3′), 4.39−4.31 (m, 1H, CH-Asp), 4.25−3.95 (m, 6H,
-OCH2P and 2 × OCH2-isopentyl), 2.79−2.59 (m, 2H, CH2-Asp),
1.65−1.57 (m, 2H, 2 x CH-isopentyl), 1.48−1.42 (m, 4H, 2 x
OCH2CH2-isopentyl), 0.89−0.85 (m, 12H, 4 x CH3-isopentyl), 1.19
(d, J = 6.2 Hz, 6H, 2 x CH3-iPr); 13C NMR (125 MHz, CD3OD) δ
AUTHOR INFORMATION
Corresponding Author
*E-mail: piet.herdewijn@kuleuven.be
ORCID
Steven De Jonghe: 0000-0002-3872-6558
Piet Herdewijn: 0000-0003-3589-8503
Notes
■
The authors declare no competing financial interest.
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