Diastereoselective Synthesis of C2′-Fluorinated Nucleoside Analogues Using an Acyclic Approach

Article abstract of DOI:10.1021/acs.joc.6b01845

Nucleoside analogues bearing a fluorine in the C2′-position have been synthesized by S_N2-like cyclizations of acyclic thioaminal precursors. This strategy provides access to two scaffolds, d-1′,2′-cis-thiofuranosides and d-1′,2′-trans-furanosides, which are difficult to generate using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto model C2-fluorinated dithioacetal substrates resulted in 1,2-syn diastereoselectivity, which is consistent with the C2-F and S-alkyl moiety being in close proximity. A new series of analogues bearing a C3′ all-carbon quaternary center along with a C2′-F atom have also been synthesized using this approach and are being investigated as potential antimetabolites.

Full text of DOI:10.1021/acs.joc.6b01845

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Article
Diastereoselective Synthesis of C2’-Fluorinated
Nucleoside Analogues using an Acyclic Approach
Starr Dostie, Michel Prévost, Philippe Mochirian, Kashif Tanveer, Nicholas
Andrella, Ariana Rostami, Guillaume Tambutet, and Yvan Guindon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01845 • Publication Date (Web): 13 Oct 2016
Downloaded from http://pubs.acs.org on October 14, 2016
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Diastereoselective Synthesis of C2’ꢀFluorinated Nucleoside
Analogues using an Acyclic Approach
†
,§
*,†
†
†
†
Starr Dostie , Michel Prévost , Philippe Mochirian , Kashif Tanveer , Nicholas Andrella ,
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†
†,‡
*,†,‡,§
Ariana Rostami , Guillaume Tambutet , and Yvan Guindon
†
Bioꢀorganic Chemistry Laboratory, Institut de Recherches Cliniques de Montréal (IRCM),
Montréal, Québec, H2W 1R7, Canada
‡
Department of Chemistry, Université de Montréal, Montréal, Québec, H3C 3J7, Canada
§
Department of Chemistry, McGill University, Montréal, Québec, H3A 2K6, Canada
yvan.guindon@ircm.qc.ca and michel.prevost@ircm.qc.ca
Abstract: Nucleoside analogues bearing a fluorine in the C2’ꢀposition have been synthesized by
SN2ꢀlike cyclizations of acyclic thioaminal precursors. This strategy provides access to two
scaffolds, Dꢀ1’,2’ꢀcis thiofuranosides and Dꢀ1’,2’ꢀtrans furanosides, that are difficult to generate
using the standard approach for nucleoside synthesis. The addition of silylated nucleobases onto
model C2ꢀfluorinated dithioacetal substrates resulted in 1,2ꢀsyn diastereoselectivity which is
consistent with the C2ꢀF and Sꢀalkyl moiety being in close proximity. A new series of analogues
bearing a C3’allꢀcarbon quaternary center along with a C2’ꢀF atom have also been synthesized
using this approach and are being investigated as potential antimetabolites.
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Introduction
Effective treatments against cancer and viral infections involve the administration of modified
nucleosides (NAs: nucleoside analogues) that act as inhibitors of tumor growth and viral
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replication. The synthesis of these molecules requires a stereocontrolled Nꢀglycosylation
reaction, which remains a challenge, especially when a fluorine atom is present at the C2’ꢀ
position. This structural feature is found in several important FDA approved anticancer (eg.
Clofarabine, Gemcitabine) and antiviral (eg. Sofosbuvir) agents. Two main approaches exist to
access these scaffolds involving either fluorination of natural nucleosides or nucleobase addition
2
,3
onto already fluorinated substrates. The first approach allows for the original configuration of
the glycosidic bond to be maintained and is limited to the natural pool of nucleosides.
Alternatively, nucleobase addition onto substrates already possessing a C2ꢀF group allows for
increased substrate diversity, but the stereochemistry of the glycosidic bond needs to be
controlled. Typically, a stereoselective 1’,2’ꢀcis relationship between the nucleobase and the
C2’ꢀF group in the furanoside series (A) is obtained through displacement of anomericꢀhalo
2,4
sugars (Scheme 1). However, to the best of our knowledge, no approach has been reported to
5
ꢀ7
provide high 1’,2’ꢀcis selectivity in the corresponding thiofuranoside (B) series.
Thioꢀ
scaffolds improve the pharmacokinetic profile of nucleoside analogues, as seen with TꢀAraC
8,9
versus AraC, for solid tumors.
Controlling the 1’,2’ꢀtrans stereochemistry (C) for C2’ꢀmonofluorinated NAs is also particularly
challenging due to the lack of possible C2ꢀneighboring group participation. Nucleobase addition
1
0ꢀ12
results in variable 1’,2’ꢀtrans selectivity,
and their synthesis often relies on fluorination of
1
3ꢀ15
preformed nucleoside analogues.
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Scheme 1. Standard approaches to synthesize NAs bearing a C2’ꢀF. This work addresses the
synthesis of two challenging scaffolds using the acyclic approach.
These synthetic challenges highlight the need for a novel approach to access such scaffolds
(Scheme 1). The acyclic methodology presented herein provides an efficient route for the
formation of 1’,2’ꢀtrans furanosides and 1’,2’ꢀcis thiofuranosides (Scheme 2). In the
development of this approach, it was determined that silylated nucleobases add to C2ꢀalkoxy
2
16,17
dithioacetals (R = OBn), with high 1,2ꢀsyn selectivity.
These acyclic 1,2ꢀsyn thioaminals
undergo two distinct and stereoselective intramolecular cyclizations. Displacement of the
activated thioether group with the C4ꢀhydroxy results in an inversion of the C1 stereocenter and
leads to Dꢀ1’,2’ꢀtrans NAs 3 (O4’ꢀC1 cyclization). Alternatively, displacement of a C4 leaving
group by the thioether inverts the C4 stereocenter while maintaining the stereochemistry of the
thioaminal providing Lꢀ1’,2’ꢀcisꢀ4ꢀthionucleosides 4 (S1’ꢀC4 cyclization).
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Scheme 2. Acyclic strategy for the synthesis NAs.
In this current work we report the applicability of this methodology to substrates bearing a C2’ꢀ
2
fluorine (R = F). This will provide a novel methodology to access C2’ꢀF nucleoside analogues
with an alkoxy group in C3’. In search of new antimetabolites that may serve as antiviral and/or
anticancer agents, our laboratory is developing a series of novel nucleoside analogues. In
particular, we are interested in those bearing an allꢀcarbon stereogenic quaternary center at C3’
18,19
along with fluorine atoms in the C2’ position.
suited for the efficient synthesis of these NAs.
The acyclic approach is particularly well
Results and Discussion
DFT and Experimental Model Study of Diastereoselective Dithioacetal Substitution. A
model substrate was examined to determine the stereoselective outcome of nucleobase additions
to dithioacetals with a C2ꢀstereogenic center containing a fluoride atom. Our proposed
mechanism for this substitution first involves the activation of a dithioacetal (5) with a halogen
20
(
X ) to generate interconverting halothioether intermediates (6a and 6b) that subsequently react
2
with the silylated nucleobase to generate 1,2ꢀsyn and 1,2ꢀanti thioaminals 7a and 7b (Scheme 3).
If the substitution steps (k and k ) are significantly slower than the epimerization (k ), the
2
3
1
stereochemical outcome of the substitution reaction is dependent on the difference in free energy
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between the preferred transition states leading to the 1,2ꢀsyn and 1,2ꢀanti products, as stated by
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the CurtinꢀHammett principle.
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Scheme 3. Proposed CurtinꢀHammett scenario for the substitution of halothioethers formed by
activation of dithioacetal 5.
Highlights of the Computational Model Study. Substitution of halothioethers was examined
by DFT calculations to determine the Gibbs free energies of the key transition states of our
2
3
mechanistic hypothesis. Quantum mechanical calculations were done in Gaussian 09.
2
4,25
Geometry optimizations were performed with M06ꢀ2X
density functional using the 6ꢀ
effective core potential. Frequency
26,27
3
11+G** basis set in conjunction with LANLDZpd
calculations were done on all optimized geometries to allow characterizations of minima (no
imaginary frequencies) or transition structures (one imaginary frequency). The effect of the
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solvent was calculated with the polarizable continuum solvation model (PCM). Free energy
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9ꢀ31
corrections were performed using Truhlar’s quasiharmonic approximation.
The energy
barrier for the epimerization of 6a,b suggests a rapid equilibration between the syn and anti
iodothioethers (TSepi at 5.4 kcal/mol, Scheme 4). The substitution of these intermediates by the
nucleobase (silylated uracil used to simplify calculations) was found to preferably proceed
through an S 2ꢀlike mechanism involving TS A and D, the 1,2ꢀsyn and 1,2ꢀanti predictive
N
transition structures, respectively. The Gibbs free energy difference between these TS
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corresponds to 1.4 kcal/mol in THF at 0 C and thus an expected 13:1 diastereomeric ratio in
favor of the 1,2ꢀsyn thioaminal. This reaction pathway is similar to that previously reported for
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substitutions of C2ꢀalkoxy dithioacetals. It should be noted that all the different low energy
C1–C2 and C2–C3 conformations were examined at the ground state and transition state level.
Different leaving or attacking trajectories for iodide or the nucleophile were also screened.
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Furthermore, the S 1ꢀpathway was calculated to be prohibitively higher in energy.
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Scheme 4. Lowest 1,2ꢀsyn (TS A), 1,2ꢀanti (TS D) and epimerization transition structures at the
origin of the 1,2ꢀsyn inductions for coupling of silylated uracil onto dithioacetals in THF at 0 C.
o
(
Gibbs free energy in kcal/mol)
Both transition structures A and D have a C1ꢀC2 conformational preference orienting the C2ꢀ
o
fluoro atom and thioether moiety in close proximity to one another (FꢀCꢀCꢀS dihedral angle 15
o
in TS A and 17 in TS D). This conformational preference, which is also present in TS for the
epi
interconversion of halothioether species (6a and 6b), could be responsible for the particular
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providing electrostatic stabilization from the high electron density on the C2ꢀelectronegative
atom, this conformation allows for optimal σ(C2ꢀR) and σ(C2ꢀH) sigma donation to the π*(S−
C1) center at the transition state. This DFT study indicates that additions to C2ꢀfluoro
dithioacetals should furnish synthetically useful 1,2ꢀsyn inductions.
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Experimental Model Study. Substitution of model dithioacetals 8 and 10 with silylated thymine
was then investigated (Table 1). Diethylꢀdithioacetal 8 bearing an isopropyl group gave a
moderate 6:1 ratio in favor of the 1,2ꢀsyn diastereomer 9a when coupled with silylated thymine
o
in the presence of iodine at 0 C (entry 1). This is consistent with the selectivity obtained from
the DFT calculations assuming that the reaction is under kinetic control (Scheme 4). This
assumption was further confirmed by the fact that the selectivities measured at different reaction
o
o
o
temperatures (0 C, 25 C and 70 C) in THF (entries 1ꢀ3) follow Arrhenius’ equation with the
ratios remaining constant over time. However, a reaction mixture that reached completion at 25
o
1
C in DCM (full conversion and ratio were determined from H NMR of an aliquot of the
o
reaction mixture) with a 4.2:1 ratio of thioaminals was then heated at 70 C in DCM for several
days and resulted in a decreased 1.5:1.0 ratio (entry 4). This indicates that the reaction could be
reversible at higher temperatures in certain solvents providing a thermodynamic distribution of
products.
Table 1. Nucleobase Coupling on Model Substrates.
a
Entry
Conditions
T
Ratio (a:b) Yield (%)
o
b
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I2, 48h, THF
0 C
6.3:1
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I2, 48h, THF
25 C
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Me S(SMe)BF , 70h, THF
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Hg(OAc) , TMSOTf, 48h, THF 0 C
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Hg(OAc) , TMSOTf, 48h, THF 25 C
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Br , 16h, THF
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–20 C
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I2, 116h, THF
25 C
2:1
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a. Determined by H NMR spectroscopic analysis of crude mixtures. b. Starting material remaining in crude reaction
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mixture. c. Full conversion by H NMR.
o
When done at 0 C in DMSO opposed to THF (entries 5 versus 1), the reaction occurred faster
(
16 h versus 48 h) with similar selectivity. Different activating agents were also examined for the
substitution reaction. Addition to 8 provided comparable selectivity when activated with
Me S(SMe)BF (7:1, entries 6ꢀ7), as compared to I . Treatment with Hg(OAc) generated the
2
4
2
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corresponding acetate in situ, which was treated with TMSOTf and the nucleobase, to provide
the 1,2ꢀsyn diastereomer with similar selectivity (6:1, entries 8ꢀ9). The initial formation of
1
halothioether intermediates 6a,b (Scheme 3) is supported by H NMR studies. Upon addition of
o
bromine to dithioacetal 8 in d ꢀTHF at –20 C, two new species that display characteristic
8
chemical shifts corresponding to bromothioethers were rapidly formed in approximately a 1:1.4
ratio despite the 4:1 ratio of 1,2ꢀsyn and 1,2ꢀanti thioaminals 9a and 9b obtained (entry 10). This
supports the hypothesis that the substitution occurs through the proposed CurtinꢀHammett
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scenario as outlined in Scheme 3. With a secondary chain attached at C2 (dithioacetal 10), the
1,2ꢀsyn induction dropped significantly (2:1, Table 1, entry 11). This model study demonstrates
that nucleobase addition onto C2ꢀfluoro dithioacetals bearing a substituent in the C3ꢀposition
provides useful 1,2ꢀsyn inductions.
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Additions to C2ꢀFluoro, C3ꢀAlkoxy Dithioacetals. With the encouraging 1,2ꢀsyn induction
observed for model substrate 8, nucleobase coupling onto more complex dithioacetals was
investigated. The results with two acyclic dithioacetal scaffolds (2,3ꢀsyn 12 and 2,3ꢀanti 14) are
2
0
presented in Table 2. As previously observed with polyoxygenated dithioacetals, 2,3ꢀsyn
dithioacteal 12 provided high 1,2ꢀsyn dr (16:1) when coupled with silylated thymine in THF
(Table 2, entry 1). An important decrease in selectivity (2:1) was measured with 2,3ꢀanti
dithioacetal 14 (entry 5, Table 2).
Table 2. C2ꢀFluoro, C3ꢀAlkoxy Dithioacetals.
a
Entry
Conditions
T
Ratio (a:b) Yield (%)
o
b
1
2
3
4
I2, 48h, THF
I2, 48h, DCM
I2, 16h, DCM
I2, 16h, DMSO
25 C
16:1
12:1
1:1.4
20:1
70
62
50
o
25 C
o
70 C
o
b
0 C
60
o
5
6
7
8
9
I2, 48h, THF
I2, 48h, DMSO
25 C
2:1
3:1
4:1
5:1
6:1
89
73
57
o
0 C
o
Me S(SMe)BF , 48h, THF
25 C
2
4
o
c
Hg(OAc) , TMSOTf, 16h, THF
25 C
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2
o
c
Hg(OAc) , TMSOTf, 16h, DCM
25 C
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The selectivity measured at different reaction temperatures suggests that the nucleobase addition
is under kinetic control at room temperature (entries 1ꢀ3). Nucleobase addition in THF was not
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done at 0 C as the model substrate showed incomplete conversion at this temperature (Table 1,
entry 1). A lower selectivity in DCM versus THF was obtained (Table 2, entries 1 and 2) with a
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reversal of selectivity at 70 C (entries 2 and 3). This may be caused by an equilibration in DCM
allowing more of the thermodynamic 1,2ꢀanti product to be formed. This substitution reaction
o
o
could be performed at 0 C in DMSO opposed to 25 C in THF (entries 1 and 4 and entries 5 and
6
) with a slight increase in selectivity. Different activating agents were examined to perform the
o
substitution reaction with dithioacetal 14. Addition to 14 at 25 C provided an increase in
selectivity for the 1,2ꢀsyn isomer 15a with Me S(SMe)BF and Hg(OAc) /TMSOTf activating
2
4
2
agents (entries 7ꢀ9). The 1,2ꢀsyn:anti ratio for nucleobase coupling to 2,3ꢀanti dithioacetal 14
could therefore be improved with a variation of the activating agent and solvent from 2:1 to 6:1
(
entries 5 and 9) albeit with lower yields. Thus, both 1,2ꢀsyn thioaminal precursors with either a
2
,3ꢀsyn or anti relationship could be obtained with good diastereoselectivity.
Synthesis of C2’ꢀF, C3’ꢀAlkoxy NAs. The thioaminal cyclization protocols previously
1
7
developed by our group with C2ꢀalkoxy intermediates, were next examined with the generated
,2ꢀsyn C2ꢀF substrates 13a and 15a.
1
1’,2’ꢀcis Nucleoside Synthesis. Deprotection of the C4ꢀTBS of 1,2ꢀsynꢀ2,3ꢀsyn thioaminal 13a
with subsequent mesylate installation provided thioaminal 17 (Scheme 5). A S1’ to C4
cyclization and dealkylation proceeded smoothly in 2,6ꢀlutidine to access the protected Dꢀ1’,2’ꢀ
cis thiofuranoside 18. The presence of the base (2,6ꢀlutidine) is proposed to facilitate sulfur
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32
dealkylation. The benzyl protecting groups were removed with BBr to provide the unprotected
3
5
Dꢀ1’,2’ꢀcis thiofuranoside SꢀFMAU.
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13
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15
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18
19
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25
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44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Synthesis of Dꢀ1’,2’ꢀcis thiofuranoside SꢀFMAU through S1’ꢀC4 cyclization of acyclic
thioaminal 13a.
1
’,2’ꢀtrans Nucleoside Synthesis. An O4’ꢀC1 cyclization of the 1,2ꢀsynꢀ2,3ꢀanti acyclic
thioaminal 15a was next examined to access Dꢀ1’,2’ꢀtrans furanosides. Removal of the C4ꢀTBS
silyl protecting group using HFꢀpyridine in THF resulted in 20. Activation of the ꢀStBu
functionality at C1 using the sulfonium salt Me S(SMe)BF resulted in the protected Dꢀ1’,2’ꢀ
2
4
trans furanoside 21 through an O4’ to C1 cyclization. The benzyl protecting groups were then
removed to furnish nucleoside analogue 22.
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Scheme 6. Synthesis of Dꢀ1’,2’ꢀtrans furanoside 22 through O4’ꢀC1 cyclization of acyclic thioaminal
15a.
Therefore, we have demonstrated that the acyclic 1,2ꢀsyn thioaminals bearing a C2ꢀfluoro group
can undergo the two modes of intramolecular S 2ꢀlike cyclization (S1’ꢀC4 and O4’ꢀC1)
N
providing two C2’ꢀF nucleoside scaffolds that are difficult to access using other strategies
(Scheme 1). In order to confirm that the S1′ꢀC4 cyclization proceeds with retention of
configuration at C1 and that the O4’ꢀC1 cyclization results in C1 inversion, the minor 1,2ꢀanti
thioaminals 13b and 15b were subjected to the cyclization conditions (Scheme 7).
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HF-
pyridine
Thy 69%
OBn OBn StBu
OBn OBn StBu
MsCl, NEt3
Thy 57%
2
3
1
TBSO
F
3b
OH
F
1
2
3
(1,2-anti-2,3-syn)
BnO
1'
OBn OBn StBu
S1'-C4
2,6-lutidine
Thy
S
F
4
10
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12
13
14
15
16
17
18
19
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21
22
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60
Thy
OMs F
OBn
24
25
D-1',2'-trans
OBn OBn StBu
OBn OBn StBu
HF-pyridine
THF, 71%
2
1
3
1
Thy
Thy
TBSO
F
4'OH 26
F
1
5b
(
1,2-anti-2,3-anti)
O4'-C1
Me S(SMe)BF , 64%
2
4
BnO
O
Thy
OBn
F
27
D-1',2'-cis
Scheme 7. Cyclization of 1,2ꢀanti thioaminals 13b and 15b
.
Cyclization of 1,2ꢀanti thioaminal 24 provided only the Dꢀ1′,2′ꢀtrans thionucleoside analogue 25
(>20:1). Silyl group deprotection of the minor 1,2ꢀantiꢀ2,3ꢀanti thioaminal 15b followed by an
O4’ꢀC1 cyclization provided Dꢀ1’,2’ꢀcis furanoside 27.
Additions to C2ꢀFluoro, C3ꢀQuaternary Center Dithioacetals. One of the advantages of the
acyclic strategy presented herein is that various functionalities can be incorporated onto the
acyclic thioaminal backbone allowing for the formation of novel nucleoside analogues. We are
interested in the synthesis and biological evaluation of scaffolds bearing a novel C3’ꢀall carbon
1
8
quaternary center (Figure 1). It is proposed that this stereogenic center may overcome some of
the potential resistance mechanisms of current anticancer and antiviral agents. The acyclic
approach is particularly well suited for the efficient synthesis of such substrates.
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Figure 1. Novel nucleoside analogues bearing a C2’ꢀfluoro and C3’ꢀquaternary center.
The key precursors to generate 1’,2’ꢀcis thiofuranosides bearing a C3’ꢀquaternary center and a
C2’ꢀF were obtained by allylation and subsequent methylation of (R)ꢀβꢀhydroxyꢀγꢀbutyrolactone
2
8 (Scheme 8).
Scheme 8. Synthesis of novel Dꢀ1’,2’ꢀcis thiofuranosides through a S1’ꢀC4 cyclization.
Reduction of the lactone 29 provided the acyclic triol, which was selectively benzoylated at the
two primary alcohol positions and protected with a TES group on the secondary C4ꢀOH
providing alkene 30. This terminal olefin was then converted to the corresponding aldehyde 31
through ozonolysis. Selective introduction of the C2ꢀfluoro group was accomplished using
3
3ꢀ35
MacMillan’s (S)ꢀimidazolidinone catalyst
and NFSI to provide the fluorinated aldehyde. The
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H NMR spectroscopic analysis of the unpurified C2ꢀF aldehyde indicated a 17:1 diastereomeric
ratio for the fluorination. Conversion into acyclic dithioacetal 32 was done using boron
trifluoride diethyl etherate and tꢀbutylthiol. Coupling of 32 with silylated thymine in the presence
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o
of iodine at 25 C, resulted in the selective formation of 1,2ꢀsyn thioaminal 33. Only one isomer
1
could be detected by H NMR. TES deprotection and mesylate installation followed by a S1’ꢀC4
cyclization and debenzoylation provided the novel Dꢀ1’,2’ꢀcis thiofuranoside 35.
Formation of Dꢀ1’,2’ꢀtrans furanosides was accomplished using a similar strategy to access
acyclic aldehyde 36 starting from (S)ꢀβꢀhydroxyꢀγꢀbutyrolactone (Scheme 9). Interestingly,
selective introduction (dr 17:1) of the C2ꢀfluoro group was accomplished with the (R)ꢀ
enantiomer of the imidazolidinone catalyst and NFSI to provide the C2ꢀF aldehyde, which was
converted into acyclic dithioacetal 37. Coupling with silylated thymine in the presence of iodine
resulted in the selective formation of 1,2ꢀsyn thioaminal 38. TBS deprotection followed by an
O4’ꢀC1 cyclization and debenzoylation provided the novel Dꢀ1’,2’ꢀtrans furanoside 41.
Scheme 9. Synthesis of novel Dꢀ1’,2’ꢀtrans furanosides through an O4’ꢀC1 cyclization.
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It was envisioned that the C4ꢀdeprotected 1,2ꢀsyn thioaminal 39 could also be used to synthesize
1’,2’ꢀcis thiofuranosides of the Lꢀseries. The importance of Lꢀanalogues is highlighted by their
3
6,37
antiviral activity and reduced cytotoxicity as compared to their Dꢀenantiomers.
The synthesis
0
1
2
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7
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9
0
of novel Lꢀthiofuranosides was thus accomplished through installation of a mesylate at C4 of
acyclic thioaminal 39 followed by S1’ꢀC4 cyclization in the presence of 2,6ꢀlutidine and
debenzoylation (Scheme 10).
Scheme 10. Synthesis of novel Lꢀ1’,2’ꢀcis thiofuranosides through S1’ꢀC4 cyclization.
When the (S)ꢀimidazolidinone catalyst was used for the fluorination of aldehyde 36 (Scheme 11)
as opposed to the (R)ꢀimidazolidinone (Scheme 9), the fluorine could be introduced with the
opposite stereochemistry (dr 17:1) and converted to dithioacetal 43. Nucleobase coupling
provided the 1,2ꢀsyn thioaminal 44 in good yield and selectivity. Removal of the C4ꢀTBS
protecting group, O4’ꢀC1 cyclization and debenzoylation provided the αꢀ1’,2’ꢀtrans furanoside
1
8
46. Interest in this particular series stems from a potential dualꢀface activity of such scaffolds.
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Scheme 11. Synthesis of novel Dꢀ1’,2’ꢀtrans furanosides through an O4’ꢀC1 cyclization.
Preliminary Studies with different Nucleobases. Although the acyclic approach was optimized
with thymine, the synthesis of nucleoside analogues has also been examined with other
nucleobases. Preliminary unoptimized studies demonstrate that 6ꢀClꢀpurine can be
diastereoselectively (20:1) added to dithioacetal 12 providing acyclic thioaminal 47 in modest
yield (Table 3, entry 1). S1’ꢀC4 cyclization of the C4ꢀMs substrate provided the Dꢀ1’,2’ꢀcis
nucleoside analogue 48. Uracil, cytosine and adenine derivatives were coupled to dithioacetal 37
providing excellent diastereoselectively (20:1) and yields for the 1’,2’ꢀsyn thioaminals 49, 51 and
5
5 (entries 2ꢀ6). These substrates could be employed in the two modes of S 2ꢀlike cyclization
N
providing scaffolds 50ꢀ56.
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Table 3. Acyclic approach for the synthesis of nucleosides bearing different nucleobases.
Thioaminal
Formation
Yield
Cyclization Nucleoside
Entry
Nucleobase
Yield
Analogue
BnO
Nu
OBn OBn StBu
OBn OBn StBu
F
S
Nu
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1
StBu I , THF
Nu
2
TBSO
F
TBSO
F
OBn
12
1,2-syn
(one isomer observed)
1
6-Cl-purine
47, 44%
45%
48
2
3
Uracil(TMS)2
49, 86%
51, 81%
73%
48%
50
52
4
N -BzCytosine(TMS)
2
4
5
*
*
Uracil(TMS)2
49, 86%
51, 81%
55, 84%
91%
57%
40%
53 (R=H)
54 (R=Bz)
56 (R=Bz)
4
N -BzCytosine(TMS)
2
6
6-Cl-purine
*Nucleobase coupling conditions repeated.
These novel nucleoside analogues bearing a C2’ꢀF and a C3’ꢀall carbon quaternary center as well
as their prodrugs are currently being tested as potential anticancer and antiviral agents.
Conclusions. Nucleobase coupling onto acyclic dithioacetals bearing a C2ꢀF maintains
preference for 1,2ꢀsyn stereocontrol. The stereoselective silylated nucleobase addition is
proposed to occur through a S 2ꢀlike mechanism where the C2ꢀF and Sꢀalkyl moiety are in close
N
proximity to one another in both the major TS A (1,2ꢀsyn) and minor TS D (1,2ꢀanti). Access to
two NA scaffolds that are difficult to synthesize using standard approaches, namely, 1’,2’ꢀtrans
furanosides and 1’,2’ꢀcis thiofuranosides bearing a fluorine in the C2’ꢀposition is possible using
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our acyclic strategy. The acyclic methodology is well suited to access a novel series of substrates
in which high diastereoselective fluorination, high 1,2ꢀsyn control for thioaminal formation and
efficient intramolecular S 2ꢀlike cyclization provides NAs with a C2`ꢀF and a C3`ꢀall carbon
N
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37
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47
48
49
50
51
52
53
54
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quaternary center that are being investigated as potential antimetabolites.
Experimental Section
General Comments. All reactions requiring anhydrous conditions were carried out under an
atmosphere of nitrogen or argon in flameꢀdried glassware using standard syringe techniques. All
anhydrous solvents were dried with 4 Å molecular sieves prior to use. The 4 Å molecular sieves
o
(
1–2 mm beads) were activated by heating at 180 C for 48 hours under vacuum prior to adding
to new bottles of solvent purged with argon. Commercially available reagents were used as
received. Flash chromatography was performed on silica gel 60 (0.040 – 0.063 mm) using forced
flow (flash chromatography) of the indicated solvent system or an automated flash purification
system. Analytical thinꢀlayer chromatography (TLC) was carried out on preꢀcoated (0.25 mm)
silica gel aluminum plates. Visualization was performed with U.V. short wavelength and/or
1
revealed with ammonium molybdate or potassium permanganate solutions. H NMR spectra
were recorded at room temperature on a 500 MHz NMR spectrometer. The data are reported as
follows: chemical shift in ppm referenced to residual solvent (CDCl δ 7.26 ppm), multiplicity (s
3
=
singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, t = triplet,
td = triplet of doublets, m = multiplet, app = apparent), coupling constants (Hz), and integration.
1
13
The large J values (greater than 18 Hz) result from HꢀF coupling. C NMR spectra were
recorded at room temperature using 125 MHz. The data are reported as follows: chemical shift
in ppm referenced to residual solvent (CDCl δ 77.16 ppm). The large J values (greater than 18
3
1
3
Hz) result from CꢀF coupling. Infrared spectra were recorded on a FTIR spectrophotometer on
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5
5
6
ꢀ1
a NaCl support and signals are reported in cm . Mass spectra were recorded through
electrospray ionization (ESI) positive ion mode. A Q exactive mass analyzer was used for
HRMS measurements. Optical rotations were measured at room temperature from the sodium D
0
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9
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0
line (589 nm) using CDCl as solvent unless otherwise noted and calculated using the formula:
3
[α] =(100)α /(ℓ·(c)), where c = (g of substrate/100 ml of solvent) and ℓ = 1 dm.
D
obs
38
Preparation of silylated nucleobases
To a suspension of the nucleobase in HMDS (2.7 eq.) under inert atmosphere was added
o
(
NH ) SO (0.1 eq.). The reaction mixture was refluxed at 180 C until a clear solution was
4
2
4
o
obtained (typically three hours). Upon cooling to 25 C, the solution was placed under high
vacuum for ~1 hour to remove excess HMDS. A solution of the silylated nucleobase was made
in the corresponding solvent (0.60 ꢀ 0.90 M).
Compounds from Table 1:
(
2ꢀfluoroꢀ3ꢀmethylbutaneꢀ1,1ꢀdiyl)bis(ethylsulfane) (8)
Isovaleraldehyde (1.0 ml, 9.3 mmol, 1.0 eq.) was added to a solution of (R)ꢀ5ꢀbenzylꢀ2,2,3,ꢀ
3
9
trimethylimidazolidinꢀ4ꢀone dichloroacetic acid salt (0.64 g, 1.9 mmol, 0.20 eq.), and NFSI
o
(
4.4 g, 14.0 mmol, 1.5 eq.) in THF:iPrOH(10%) (31.0 ml, 0.30 M) at –20 C. The reaction
o
mixture was stirred for 16 hours at 0 C. To verify that the reaction was complete, an aliquot was
diluted with ether, filtered through a pad of silica gel, quenched with Me S, washed with a
2
saturated solution of NaHCO , extracted with Et O and dried with MgSO . Due to the volatility
3
2
4
of the C2ꢀF aldehyde, the diethyl ether was removed by a stream of air. Directly to the reaction
o
mixture at 0 C was added ethanethiol (2.8 ml, 37.3 mmol, 4.0 eq.) and conc. HCl (6.0 ml, 74.6
o
mmol, 8.0 eq.). The reaction was stirred for 72 hours at 25 C followed by addition of NEt (5
3
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ml) and dilution with Et O (40 ml). A saturated solution (40 ml) of NaHCO was added and the
2
3
aqueous layer was extracted with diethyl ether (3 × 20 ml). The combined organic layers were
washed with brine, dried over MgSO , filtered and concentrated in vacuo. Purification by flash
4
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chromatography (Hexanes/EtOAc, 95:5), provided 8 as a colorless oil (1.1 g, 54%): R = 0.50
f
(Hexanes/EtOAc, 95:5); Formula : C H FS ; MW : 210.3756 g/mol ; IR (neat) ν 2965,
max
9
19
2
−1
1
2
928, 2873 cm ; H NMR (500 MHz, CDCl ) δ 4.34 (ddd, J = 47.2, 6.2, 5.4 Hz, 1H), 3.93 (dd,
3
J = 22.6, 5.2 Hz, 1H), 2.82 – 2.65 (m, 4H), 2.35 – 2.23 (m, 1H), 1.27 (t, J = 7.4Hz, 3H), 1.27 (t, J
1
3
=
7.4Hz, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H) ppm; C NMR (125 MHz,
CDCl ) δ 101.1 (d, J = 180.8 Hz), 52.8 (d, J = 22.2 Hz), 30.7 (d, J = 20.4 Hz), 25.0 (d, J = 2.5
3
Hz), 24.8 (d, J = 1.1 Hz), 19.0 (d, J = 6.7 Hz), 16.9 (d, J = 4.9 Hz), 14.59, 14.57 ppm ; HRMS
+
calcd for C H FS Na [M+Na ] : 233.0804, found: 233.0797 (ꢀ3.3 ppm). Since we were only
9
19
2
interested in the diastereoselectivity for the coupling of the nucleobase to the dithioacetal, the
enantioselectivity for introduction of the fluorine was not determined.
(2ꢀfluoroꢀ3ꢀphenylpropaneꢀ1,1ꢀdiyl)bis(ethylsulfane) (10)
Hydrocinnamaldehyde (0.30 ml, 2.3 mmol, 1.0 eq.) was added to a solution of (R)ꢀ5ꢀbenzylꢀ
3
9
2,2,3ꢀtrimethylimidazolidinꢀ4ꢀone dichloroacetic acid salt (0.16 g, 0.45 mmol, 0.20 eq.), and
o
NFSI (1.1 g, 3.4 mmol, 1.5 eq.) in THF:iPrOH(10%) (7.0 ml, 0.30 M) at –20 C. The reaction
o
mixture was stirred for 16 hours at 0 C. To verify that the reaction was complete, an aliquot was
diluted with ether, filtered through a pad of silica gel, quenched with Me S, washed with a
2
saturated solution of NaHCO , extracted with Et O and dried with MgSO . Due to the volatility
3
2
4
of the C2ꢀF aldehyde, the diethyl ether was removed by a stream of air. Directly to the reaction
o
mixture at 0 C was added ethanethiol (0.67 ml, 9.1mmol, 4.0 eq.) and conc. HCl (1.5 ml, 18.2
o
mmol, 8.0 eq.). The reaction was stirred for 16 hours at 25 C followed by addition of NEt (2
3
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ml) and dilution with Et O (10 ml). A saturated solution (10 ml) of NaHCO was added and the
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aqueous layer was extracted with diethyl ether (3 × 10 ml). The combined organic layers were
washed with brine, dried over MgSO , filtered and concentrated in vacuo. Purification by flash
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chromatography (Hexanes/EtOAc, 95:5), provided 10 as a colorless oil (0.19 g, 32%): R = 0.32
f
(Hexanes/EtOAc, 95:5); Formula : C H FS ; MW : 258.4184 g/mol ; IR (neat) ν 2963,
1
3
19
2
max
−1
1
2
926, 2869 cm ; H NMR (500 MHz, CDCl ) δ 7.38 – 7.25 (m, 5H), 4.99 – 4.85 (m, 1H), 3.92
3
(dd, J = 18.3, 4.4 Hz, 1H), 3.22 (ddd, J = 20.4, 14.1, 5.5 Hz, 2H), 2.83 – 2.69 (m, 4H), 1.33 –
1
3
1
9
.26 (m, 6H) ppm ; C NMR (125 MHz, CDCl ) δ 136.9 (d, J = 3.6 Hz), 129.6, 128.7, 126.9,
3
6.8 (d, J = 181.9 Hz), 53.8 (d, J = 21.8 Hz), 38.8 (d, J = 21.5 Hz), 25.63, 25.61, 14.64, 14.61
+
ppm ; HRMS calcd for C H FS Na [M+Na ] : 281.0804, found: 281.0802 (ꢀ0.73 ppm). Since
13
19
2
we were only interested in the diastereoselectivity for the coupling of the nucleobase to the
dithioacetal, the enantioselectivity for introduction of the fluorine was not determined.
General Procedure A:
o
To a solution of the corresponding C2ꢀF dithioacetal in anhydrous solvent at 0 C were added
silylated nucleobase and the activating agent. The reaction mixture was stirred until complete by
TLC. In certain cases, additional silylated thymine and activating agent were added in order for
the reaction to go to completion. A saturated solution (1 ml) of Na S O (with I or Br ) or
2
2
3
2
2
NaHCO (with Hg(OAc) /TMSOTf or Me S(SMe)BF ) was added and the aqueous layer was
3
2
2
4
extracted with ethyl acetate (3 × 5 ml). The combined organic layers were washed with brine,
dried over MgSO , filtered and concentrated in vacuo.
4
1ꢀ(1ꢀ(ethylthio)ꢀ2ꢀfluoroꢀ3ꢀmethylbutyl)ꢀ5ꢀmethylpyrimidineꢀ2,4(1H,3H)ꢀdione (9a and 9b)
Following general procedure A, silylated thymine (0.90 ml, 0.63 mmol, 3.0 eq. of a 0.71 M
solution in DCM), and Br (22 µl, 0.42 mmol, 2.0 eq.) were added to a solution of 8 (44 mg, 0.21
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o
1
mmol) in anhydrous THF (2.0 ml, 0.10 M) and stirred at –20 C. H NMR spectroscopic analysis
of the unpurified product indicated the formation of a 3.5:1 mixture of 1,2ꢀsyn and anti
diastereomers. Purification by flash chromatography (Hexanes/EtOAc, 70:30) did not allow
separation of the diastereomers and provided a mixture of 9a and 9b (39 mg, 67%) as a white
foam: R = 0.30 (Hexanes/EtOAc, 70:30) ; Formula : C H FN O S ; MW : 274.3549 g/mol ;
10
11
12
13
14
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16
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59
60
f
12 19
2
2
−1
1
IR (neat) νmax 3183, 2967, 1686 cm ; H NMR (500 MHz, CDCl ) δ 8.89 (s, 1H, isomer a),
3
8
.87 (s, 1H, isomer b), 7.68 (s, 1H, isomer a), 7.51 (s, 1H, isomer b), 6.09 – 5.94 (m, 2H, isomer
a & b), 4.38 (ddd, J = 46.9, 7.6, 3.9 Hz, 1H, isomer b), 4.23 (ddd, J = 48.7, 9.4, 1.6 Hz, 1H,
isomer a), 2.66 – 2.54 (m, 2H, isomer b), 2.51 (q, J = 7.4 Hz, 2H, isomer a), 2.20 – 2.08 (m, 1H,
isomer a), 1.96 (s, 6H, isomer a & b), 1.90 – 1.78 (m, 1H, isomer b), 1.28 (t, J = 7.4 Hz, 3H,
1
3
isomer a), 1.28 (t, J = 7.3Hz, 3H, isomer b), 1.06 – 0.99 (m, 12H, isomer a & b) ppm ; C NMR
(
125 MHz, CDCl ) δ 163.7 (isomer a), 163.6 (isomer b), 151.5 (isomer b), 151.1 (isomer a),
3
138.0 (d, J = 5.0 Hz, isomer a), 137.8 (d, J = 6.6 Hz, isomer b), 111.9 (isomer b), 111.3 (isomer
a), 101.0 (d, J = 180.6 Hz, isomer a), 99.1 (d, J = 52.8 Hz, isomer b), 61.1 (d, J = 19.3 Hz,
isomer a), 59.3 (d, J = 22.0 Hz, isomer b), 30.9 (d, J = 19.1 Hz, isomer a), 30.3 (d, J = 19.6 Hz,
isomer b), 25.2 (isomer b), 24.9 (isomer a), 18.5 (d, J = 4.8 Hz, isomer a), 18.4 (d, J = 10.1 Hz,
isomer b), 17.8 (d, J = 8.6 Hz, isomer a), 17.5 (d, J = 6.5 Hz, isomer b), 14.7 (isomer b), 14.6
(
isomer a), 12.83 (isomer b), 12.76 (isomer a) ppm ; HRMS calcd for : C H FN O SNa
12 19 2 2
+
[
M+Na ] : 297.1043, found: 297.1047 (1.07 ppm).
1
1
ꢀ(1ꢀ(ethylthio)ꢀ2ꢀfluoroꢀ3ꢀphenylpropyl)ꢀ5ꢀmethylpyrimidineꢀ2,4(1H,3H)ꢀdione (11a and
1b)
Following general procedure A, silylated thymine (0.70 ml, 0.45 mmol, 3.0 eq. of a 0.71 M
solution in DCM), and I (76 mg, 0.30 mmol, 2.0 eq.) were added to a solution of 10 (39 mg,
2
o
1
0
.15 mmol) in anhydrous THF (1.5 ml, 0.10 M) and stirred at 25 C. H NMR spectroscopic
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analysis of the unpurified product indicated the formation of a 2.3:1 mixture of 1,2ꢀsyn and anti
diastereomers. Purification by flash chromatography (Hexanes/EtOAc, 70:30) did not allow
separation of the diastereomers and provided a mixture of 11a and 11b (25 mg, 52%) as a white
foam: R = 0.19 (Hexanes/EtOAc, 70:30); Formula : C H FN O S ; MW : 322.3977 g/mol ;
0
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8
9
0
f
16 19
2
2
−
1
1
IR (neat) νmax 3183, 3027, 1692 cm ; H NMR (500 MHz, CDCl ) δ 8.57 (s, 1H, isomer b),
3
8.50 (s, 1H, isomer a), 7.61 (s, 1H, isomer a), 7.48 (s, 1H, isomer b), 7.33 – 7.17 (m, 10H,
isomer a & b), 5.94 (dd, J = 24.0, 4.0 Hz, 1H, isomer b), 5.81 (dd, J = 29.2, 1.9 Hz, 1H, isomer
a), 4.96 – 4.80 (m, 2H, isomer a & b), 3.24 (td, J = 13.9, 8.1 Hz, 1H, isomer a), 3.09 – 2.95 (m,
2H, isomer a & b), 2.91 – 2.79 (m, 1H, isomer b), 2.59 – 2.46 (m, 4H, isomer a & b), 1.93 (s,
3H, isomer b), 1.90 (s, 3H, isomer a), 1.27 (t, J = 7.2 Hz, 3H, isomer b), 1.26 (t, J = 7.3Hz, 3H,
1
3
isomer a) ppm ; C NMR (125 MHz, CDCl ) δ 163.5 (isomer a), 163.4 (isomer b), 151.4
3
(isomer b), 150.9 (isomer a), 137.7 (d, J = 4.8 Hz, isomer a), 137.4 (d, J = 4.6 Hz, isomer b),
135.4 (d, J = 1.6 Hz, isomer b), 135.3 (d, J = 6.0 Hz, isomer a), 129.4 (isomer b), 129.2 (isomer
a), 128.9 (isomer a), 128.8 (isomer b), 127.4 (isomer a), 127.3 (isomer b), 112.0 (isomer b),
111.5 (isomer a), 96.9 (d, J = 181.5 Hz, isomer a), 95.1 (d, J = 183.0 Hz, isomer b), 62.3 (d, J =
19.7 Hz, isomer a), 61.1 (d, J = 17.1 Hz, isomer b), 39.4 (d, J = 21.3 Hz, isomer a), 38.8 (d, J =
21.0 Hz, isomer b), 25.4 (isomer b), 25.1 (isomer a), 14.7 (isomer a & b), 12.8 (isomer b), 12.7
+
(
isomer a) ppm; HRMS calcd for : C H FN O SNa [M+Na ] : 345.1043, found: 345.1045
16 19
2
2
(0.47 ppm).
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Compounds from Table 2:
Synthesis of Dithioacetal 12
(–)ꢀ(3S,4R,5S)ꢀ4ꢀ(benzyloxy)ꢀ5ꢀ((benzyloxy)methyl)ꢀ3ꢀfluorotetrahydrofuranꢀ2ꢀol (S1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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38
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
40ꢀ42
To a solution of the known glycal
derived from Lꢀxylose (1.75 g, 5.9 mmol, 1.0 eq.) in 10:1
DMF: H O (30 ml, 0.18 M) was added Selectfluor (3.1 g, 8.8 mmol, 1.5 eq.). The reaction
2
o
mixture was stirred at 25 C for 16 hours and concentrated. Purification by flash chromatography
(
Hexanes/EtOAc, 70:30), provided the C2ꢀfluorinated lactol S1 (0.77 g, 39%): R = 0.27
f
2
5
(Hexanes/EtOAc, 70:30) ; [α]
–5 (c 0.9, CDCl ) ; Formula : C H FO ; MW : 332.3714
3 19 21 4
D
−1
1
g/mol ; IR (neat) νmax 3419, 2920, 2861 cm ; H NMR (500 MHz, CDCl ) δ 7.40 – 7.24 (m,
3
20H), 5.56 – 5.48 (m, 1H), 5.30 (appt, J = 12.8 Hz, 1H), 4.97 (dd, J = 52.3, 2.6 Hz, 1H), 4.93 (dt,
J = 52.0, 3.2 Hz, 1H), 4.74 – 4.47 (m, 7H), 4.41 (dd, J = 9.6, 4.3 Hz, 1H), 4.27 (tdd, J = 18.0,
5
.5, 3.0 Hz, 2H), 4.09 (d, J = 11.9 Hz, 1H), 3.78 – 3.64 (m, 4H), 3.23 (d, J = 5.5 Hz, 1H) ppm
1
3
OH signals missing possibly due to exchange in CDCl ; C NMR (125 MHz, CDCl ) δ 138.3,
3
3
1
1
1
6
37.51, 137.48, 137.2, 128.8, 128.71, 128.70, 128.5, 128.4, 128.20, 128.16, 128.1, 128.0, 127.9,
27.83, 127.81, 101.2 (d, J = 34.2 Hz), 99.1 (d, J = 185.5 Hz), 96.0 (d, J = 17.3 Hz), 93.9 (d, J =
90.2 Hz), 81.2 (d, J = 24.6 Hz), 80.7, 80.5, 80.2 (d, J = 3.2 Hz), 74.1, 73.8, 73.3, 73.0, 68.52,
+
8.49 ppm ; HRMS calcd for : C H FO Na [M+Na ] : 355.1316, found: 355.1320 (1.05 ppm).
1
9
21
4
(+)ꢀ(2S,3R,4R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀfluorohexꢀ5ꢀenꢀ2ꢀol (S2)
To a solution of dry methyltriphenylphosphonium bromide (2.5 g, 6.9 mmol, 3.0 eq., dried with
o
benzene and left 16 hours under high vacuum) in anhydrous THF (13.0 ml, 0.55 M) at 0 C was
added potassium bis(trimethylsilyl) amide (14.0 ml, 6.9 mmol, 3.0eq. of a 0.5 M solution in
o
o
toluene). The reaction mixture was stirred at 25 C for 2 hours. Upon cooling to 0 C, S1 (0.77 g,
2
.3 mmol, 1.0 eq.) as a solution in anhydrous THF (8.0 ml, 0.30 M) was added and stirred for 3
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5
6
o
hours at 0 C. Silica gel (1.2 g) was added and the reaction was concentrated to remove THF.
The crude mixture was dissolved in diethyl ether (30.0 ml) and passed through a pad of silica
gel. Purification by flash chromatography (Hexanes/EtOAc, 80:20), provided S2 (0.58 g, 76%)
0
1
2
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4
5
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8
9
0
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0
25
as a colorless oil: R = 0.34 (Hexanes/EtOAc, 80:20) ; [α]
+23 (c 0.9, CDCl ) ; Formula :
3
f
D
−
1
1
C H FO ; MW : 330.3994 g/mol ; IR (neat) ν 3392, 3027, 2850 cm ; H NMR (500 MHz,
20
23
3
max
CDCl ) δ 7.38 – 7.25 (m, 10H), 6.02 – 5.91 (m, 1H), 5.50 – 5.45 (m, 1H), 5.36 (d, J = 10.7 Hz,
3
1
H), 5.15 (appdt, J = 48.4, 6.6 Hz, 1H), 4.84 (d, J = 11.2 Hz, 1H), 4.57 (d, J = 11.3 Hz, 1H), 4.49
(
appq, J = 11.9 Hz, 2H), 3.91 – 3.84 (m, 1H), 3.66 (ddd, J = 15.3, 6.6, 2.8 Hz, 1H), 3.56 – 3.44
13
(
m, 2H), 2.28 (d, J = 7.4 Hz, 1H) ppm ; C NMR (125 MHz, CDCl ) δ 138.2, 138.1, 133.2 (d, J
3
= 18.9 Hz), 128.61, 128.57, 128.4, 128.1, 128.02, 127.98, 119.6 (d, J = 12.2 Hz), 94.7 (d, J =
1
71.8 Hz), 80.1 (d, J = 20.5 Hz), 75.0 (d, J = 2.7 Hz), 73.6, 71.2, 69.8 (d, J = 5.9 Hz) ppm ;
+
HRMS calcd for C H FO Na [M+Na ] : 353.1523, found: 353.1529 (1.55 ppm).
2
0
23
3
(–)ꢀ(((2S,3R,4R)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀfluorohexꢀ5ꢀenꢀ2ꢀyl)oxy)(tertꢀbutyl)dimethylsilane
S3)
(
o
To a solution of S2 (1.6 g, 4.7 mmol, 1.0 eq.) in anhydrous DCM (10 ml, 0.50 M) at 0 C was
added 2,6ꢀlutidine (1.4 ml, 11.8 mmol, 2.5 eq.) and TBSOTf (1.7 ml, 7.1 mmol, 1.5 eq.). The
o
reaction was stirred for 5 hours at 0 C. A saturated solution (5 ml) of NH Cl was added and the
4
aqueous layer was extracted with dichloromethane (3 × 10 ml). The combined organic layers
were washed with brine, dried over MgSO , filtered and concentrated in vacuo. Purification by
4
flash chromatography (Hexanes/EtOAc, 95:5), provided S3 (1.74 g, 83%) as a colorless oil: R =
f
25
0
.53 (Hexanes/EtOAc, 95:5) ; [α]
–11 (c 1.1, CDCl ) ; Formula : C H FO Si ; MW :
D 3 26 37 3
−
1
1
4
44.6624 g/mol ; IR (neat) νmax 2925, 2855 cm ; H NMR (500 MHz, CDCl ) δ 7.39 – 7.27
3
(
m, 10H), 6.05 – 5.94 (m, 1H), 5.43 – 5.38 (m, 1H), 5.28 (d, J = 10.7 Hz, 1H), 5.25 – 5.12 (m,
1H), 4.70 (dd, J = 27.0, 11.7 Hz, 2H), 4.52 (apps, 2H), 4.05 (ddd, J = 6.5, 4.9, 3.4 Hz, 1H), 3.73
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(
dd, J = 10.1, 3.2 Hz, 1H), 3.59 – 3.53 (m, 1H), 3.49 (dt, J = 24.1, 4.4 Hz, 1H), 0.89 (s, 9H), 0.06
1
3
(s, 3H), 0.01 (s, 3H) ppm ; C NMR (125 MHz, CDCl ) δ 138.6, 138.5, 134.4 (d, J = 19.7 Hz),
3
1
28.5, 128.4, 128.1, 127.82, 127.79, 127.6, 117.8 (d, J = 12.2 Hz), 92.6 (d, J = 173.7 Hz), 81.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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59
60
(
d, J = 18.5 Hz), 74.3 (d, J = 1.1 Hz), 73.5, 72.22 (d, J = 4.1 Hz), 72.16 (d, J = 3.2 Hz), 26.1,
+
18.3, ꢀ4.1, ꢀ4.7 ppm ; HRMS calcd for C H FO SiNa [M+Na ] : 467.2388, found: 467.2396
2
6
37
3
(1.6 ppm).
(–)ꢀ(((2S,3R,4S)ꢀ1,3ꢀbis(benzyloxy)ꢀ5,5ꢀbis(tertꢀbutylthio)ꢀ4ꢀfluoropentanꢀ2ꢀyl)oxy)(tertꢀ
butyl)dimethylsilane (12)
o
To a solution of S3 (1.74 g, 3.9 mmol, 1.0 eq.) in DCM (150 ml, 0.026 M) at –78 C was
bubbled O under vacuum until the solution turned pale blue (about 20 minutes). The reaction
3
was then purged with nitrogen to remove excess ozone. After addition of NEt (1.1 ml, 7.8
3
o
mmol, 2.0 eq.), the reaction was warmed to 25 C for 30 minutes. A 1 N HCl solution (20 ml)
was added and the aqueous layer was extracted with dichloromethane (3 × 50 ml). The combined
organic layers were washed with brine, dried over MgSO , filtered and concentrated in vacuo. To
4
o
the crude C2ꢀF aldehyde in anhydrous DCM (40 ml, 0.10 M) at –60 C was added tBuSH (1.8
ml, 15.7 mmol, 4.0 eq.) and BF3
•
OEt (1.3 ml, 9.8 mmol, 2.5 eq.). The reaction was stirred at –60
2
o
o
C for five hours. NEt (2.2 ml, 15.7 mmol, 4.0 eq.) was added and stirring at –60 C was
3
maintained for 15 minutes. A saturated solution (10 ml) of NaHCO was added and the aqueous
3
layer was extracted with dichloromethane (3 × 20 ml). The combined organic layers were
washed with brine, dried over MgSO , filtered and concentrated in vacuo. Purification by flash
4
chromatography (Hexanes/EtOAc, 90:10), provided 12 (1.85 g, 78%) as a colorless oil: R = 0.48
f
2
5
(Hexanes/EtOAc, 90:10) ; [α]
–1.9 (c 1.3, CDCl ) ; Formula : C H FO S Si ; MW :
3 33 53 3 2
D
−1
1
6
08.9874 g/mol ; IR (neat) νmax 2958, 2925, 2861 cm ; H NMR (500 MHz, CDCl ) δ 7.38 –
3
7
.23 (m, 10H), 4.77 – 4.63 (m, 3H), 4.50 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.35
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(
dd, J = 8.5, 7.0 Hz, 1H), 4.20 – 4.11 (m, 2H), 3.80 (d, J = 10.4 Hz, 1H), 3.57 – 3.51 (m, 1H),
1
3
1
.39 (s, 9H), 1.37 (s, 9H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H) ppm ; C NMR (125 MHz,
CDCl ) δ 138.9, 138.6, 128.44, 128.35, 127.8, 127.73, 127.69, 127.5, 92.0 (d, J = 187.5 Hz),
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0
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8.4 (d, J = 17.1 Hz), 73.5, 73.4, 72.7 (d, J = 7.0 Hz), 72.0, 47.4 (d, J = 24.6 Hz), 46.0, 45.5,
32.1 (d, J = 2.0 Hz), 31.9, 26.1, 18.4, ꢀ4.2, ꢀ4.4 ppm ; HRMS calcd for C H FO S SiNa
3
3
53
3 2
+
[
M+Na ] : 631.3082, found: 631.3087 (0.91 ppm).
Synthesis of Dithioacetal 14
(+)ꢀ(2R,3R,4S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀfluorohexꢀ5ꢀenꢀ2ꢀol (S4)
To a solution of dry methyltriphenylphosphonium bromide (1.6 g, 4.5 mmol, 3.0 eq., dried with
o
benzene and left 16 hours under high vacuum) in anhydrous THF (8.0 ml, 0.55 M) at 0 C was
added potassium bis(trimethylsilyl) amide (9.0 ml, 4.5 mmol, 3.0eq. of a 0.5 M solution in
o
o
toluene). The reaction mixture was stirred at 25 C for 2 hours. Upon cooling to 0 C, the starting
4
3
lactol derived from Dꢀarabinose (0.50 g, 1.5 mmol, 1.0 eq.) as a solution in anhydrous THF
o
(5.0 ml, 0.30 M) was added and stirred for 3 hours at 0 C. Silica gel (0.80 g) was added and the
reaction was concentrated to remove THF. The crude mixture was dissolved in diethyl ether
(30.0 ml) and passed through a pad of silica gel. Purification by flash chromatography
(Hexanes/EtOAc, 70:30), provided S4 (0.39 g, 78%) as a colorless oil: R = 0.59
f
2
5
(Hexanes/EtOAc, 70:30); [α]
+58 (c 1.4, CDCl ) ; Formula : C H FO ; MW : 330.3932
3 20 23 3
D
−1
1
g/mol ; IR (neat) νmax 3468, 2925, 2860 cm ; H NMR (500 MHz, CDCl ) δ 7.38 – 7.25 (m,
3
1
0H), 6.09 (dddd, J = 17.5, 13.4, 10.7, 6.9 Hz, 1H), 5.47 (ddd, J = 17.4, 2.5, 1.3 Hz, 1H), 5.39
(d, J = 10.7 Hz, 1H), 5.34 – 5.21 (m, 1H), 4.80 (d, J = 11.3 Hz, 1H), 4.56 – 4.48 (m, 3H), 3.84
(ddd, J = 14.1, 8.3, 2.7 Hz, 1H), 3.71 (ddd, J = 14.0, 7.1, 4.5 Hz, 1H), 3.67 – 3.63 (m, 1H), 3.60
1
3
(dd, J = 9.5, 5.6 Hz, 1H), 2.42 (d, J = 5.9 Hz, 1H) ppm; C NMR (125 MHz, CDCl ) δ 138.2,
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37.9, 132.3 (d, J = 19.9 Hz), 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 120.0 (d, J = 12.2 Hz),
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5.1 (d, J = 168.6 Hz), 80.1 (d, J = 21.1 Hz), 74.3 (d, J = 2.6 Hz), 73.6, 70.7 (d, J = 1.4 Hz), 69.9
+
(d, J = 8.1 Hz) ppm ; HRMS calcd for C H FO Na [M+Na ] : 353.1523, found: 353.1525
2
0
23
3
10
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(
0.54 ppm).
(+)ꢀ(((2R,3R,4S)ꢀ1,3ꢀbis(benzyloxy)ꢀ4ꢀfluorohexꢀ5ꢀenꢀ2ꢀyl)oxy)(tertꢀbutyl)dimethylsilane
(S5)
o
To a solution of S4 (0.80 g, 2.4 mmol, 1.0 eq.) in anhydrous DCM (5.0 ml, 0.50 M) at 0 C was
added 2,6ꢀlutidine (0.70 ml, 6.0 mmol, 2.5 eq.) and TBSOTf (0.85 ml, 3.6 mmol, 1.5 eq.). The
o
reaction was stirred for 3 hours at 25 C. A saturated solution (2 ml) of NH Cl was added and the
4
aqueous layer was extracted with dichloromethane (3 × 10 ml). The combined organic layers
were washed with brine, dried over MgSO , filtered and concentrated in vacuo. Purification by
4
flash chromatography (Hexanes/EtOAc, 90:10), provided S5 (0.96 g, 89%) as a colorless oil: Rf
2
5
=
0.25 (Hexanes/EtOAc, 95:5) ; [α]
+5.9 (c 1.1, CDCl ) ; Formula : C H FO Si ; MW :
D 3 26 37 3
−
1
1
444.6541 g/mol ; IR (neat) νmax 2954, 2929, 2857 cm ; H NMR (500 MHz, CDCl ) δ 7.40 –
3
7
.23 (m, 10H), 6.08 (dddd, J = 17.1, 15.1, 10.8, 6.2 Hz, 1H), 5.50 – 5.44 (m, 1H), 5.38 (d, J =
10.8 Hz, 1H), 5.29 – 5.15 (m, 1H), 4.73 (d, J = 11.3 Hz, 1H), 4.65 (d, J = 11.3 Hz, 1H), 4.52
(apps, 2H), 3.96 – 3.91 (m, 1H), 3.85 (ddd, J = 12.9, 5.9, 4.4 Hz, 1H), 3.67 (dd, J = 9.5, 3.1 Hz,
1
3
1
H), 3.59 (dd, J = 10.0, 5.1 Hz, 1H), 0.91 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H) ppm ; C NMR
(125 MHz, CDCl ) δ 138.5, 138.4, 133.1 (d, J = 18.7 Hz), 128.44, 128.40, 128.1, 127.9, 127.72,
3
1
27.67, 119.2 (d, J = 12.3 Hz), 93.7 (d, J = 169.0 Hz), 81.4 (d, J = 22.7 Hz), 74.3 (d, J = 1.7 Hz),
7
3.4, 72.0 (d, J = 6.5 Hz), 71.8 (d, J = 2.0 Hz), 26.1, 18.3, ꢀ4.0, ꢀ4.7 ppm ; HRMS calcd for
+
C H FO SiNa [M+Na ] : 467.2388, found: 467.2383 (ꢀ1.1 ppm).
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