Synthesis, Reactivity, and Stereoselectivity of 4-Thiofuranosides

Article abstract of DOI:10.1021/acs.joc.8b02536

Thiosugars, sugars that have their endocyclic oxygen substituted for a sulfur atom, have been used as stable bioisosteres of naturally occurring glycans because the thiosugar glycosydic linkage is supposed to be stabilized toward chemical and enzymatic hydrolysis. We have performed an in-depth investigation into the stability and reactivity of furanosyl thiacarbenium ions, by assessing all four diastereoisomeric thiofuranosides experimentally and computationally. We show that all furanosyl thiacarbenium ions react in a 1,2-cis-selective manner with triethylsilane, reminiscent of their oxo counterparts. The computed conformational space occupied by the thiacarbenium ions is strikingly similar to that of the corresponding furanosyl oxycarbenium ions, indicating that the stereoelectronic substituent effects governing the stability of furanosyl oxocarbenium ions and thiacarbenium ions are very similar. While the thio-ribo-furanose appears to be less reactive than its oxo counterpart, the thio-ara-, lyxo-, and xylo-furanosides appear to be more reactive than their oxygen equivalents. These differences are accounted for using the conformational preference of the donors and the carbocation intermediates. The lower reactivity of the thio-ribo furanosides in (Lewis) acid-mediated reactions and the similarity of the thia- and oxocarbenium ions make thio-ribo-furanosides excellent stabilized analogues of the naturally occurring ribo-furanose sugars.

Full text of DOI:10.1021/acs.joc.8b02536

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Article
Synthesis, reactivity and stereoselectivity of 4-thiofuranosides
Jerre M. Madern, Thomas Hansen, Erwin R. van Rijssel, Hans A. V. Kistemaker, Stefan van der
Vorm, Herman S. Overkleeft, Gijsbert A. van der Marel, Dmitri V. Filippov, and Jeroen D. C. Codée
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02536 • Publication Date (Web): 03 Jan 2019
Downloaded from http://pubs.acs.org on January 4, 2019
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The Journal of Organic Chemistry
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Synthesis, reactivity and stereoselectivity of 4-thiofuranosides
Jerre M. Madern, Thomas Hansen, Erwin R. van Rijssel, Hans A.V. Kistemaker, Stefan van der Vorm,
Herman S. Overkleeft, Gijsbert A. van der Marel, Dmitri V. Filippov*, Jeroen D. C. Codée*
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Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
[Activator]
TMSOTf
S
S
[Nucleo
TES-
OAc
phile]
OBn
OBn
S
d
D
OBn
experimental : ratio =
computational : ratio
Boltzmann
lation
DFT
popu
calculations
Conformational Energy Landscape
ABSTRACT: Thiosugars, sugars which have their endocyclic oxygen substituted for a sulfur atom have been used as stable
bioisosteres of naturally occurring glycans, because the thiosugar glycosydic linkage is supposed to be stabilized towards chemical
and enzymatic hydrolysis. We have performed an in-depth investigation into the stability and reactivity of furanosyl thiacarbenium
ions, by assessing all four diastereoisomeric thiofuranosides experimentally and computationally. We show that all furanosyl
thiacarbenium ions react in a 1,2-cis-selective manner with triethylsilane, reminiscent of their oxo-counterparts. The computed
conformational space occupied of the thiacarbenium ions is strikingly similar to that of the corresponding furanosyl oxycarbenium
ions indicating that the stereoelectronic substituent effects governing the stability of furanosyl oxocarbenium ions and thiacarbenium
ions are very similar. While the thio-ribo-furanose appears to be less reactive than its oxo-counterpart, the thio-ara-, lyxo- and xylo-
furanosides appear to be more reactive than their oxygen equivalents. These differences are accounted for using the conformational
preference of the donors and the carbocation intermediates. The lower reactivity of the thio-ribo furanosides in (Lewis) acid mediated
reactions and the similarity of the thia- and oxocarbenium ions make thio-ribo-furanosides excellent stabilized analogues of the
naturally occurring ribo-furanose sugars.
INTRODUCTION
Thiosugars, 4-thiofuranosides and 5-thiopyranosides, are sugars which have their endocyclic oxygen substituted for a sulfur atom.
These compounds have been found in nature, such as Salacinol (Figure 1, A), an anti-diabetes compound isolated from Salacia
reticulata that acts as a glycosidase inhibitor. Most thiosugars reported to date are man-made and they have been designed and
generated to function as mimics of their parent O-glycosides. As they are generally more stable towards both enzymatic1 and non-
enzymatic hydrolysis2, they may function as inhibitors for carbohydrate-processing enzymes. Indeed, the thiosugars and thio-
oligosaccharides reported to date are moderately active glycosidase inhibitors, with activity in the micro to millimolar range.3
Prominent 4-thiofuranosides that have been studied for their therapeutic potential owing to their increased chemical stability2,
include the 4’-thio analogues of DNA and RNA nucleotides (Figure 1, B) and they have shown antiviral4-5, antibiotic6 and
anticancer6-7 properties. The 4’-thio analogue of cADPR (Figure 1, C), which is resistant to enzymatic degradation, is a mimic of
the naturally occurring cADPR, an important mediator of intracellular Ca2+ signaling.8 Recently, the 4-thioribose nicotinamide
adenoside diphosphate (thio-NAD+, D) was introduced as a stabilized NAD+ analogue, allowing for crystallographic studies of
enzymes using this oft-used co-factor.9
______________________________________________
NH2
HO
NH2
NH2
N
N
N
N
N
N
OH OH
O
P
O
P
N
N
HO
N
OH
OH
N
O
S
O
O
O
N
O
N
OH
O
S
O
O
HO
S
N
HO
O
O
S
OSO3
P
OH OH
OH
O
H2N
O
R
P
OH
OH
Salacinol (A)
OH
O
O
O
4'-thio NAD+ (D)
4-thio Adenosine (B)
Cyclic 4'-thio ADPR (C)
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Figure 1. Examples of biologically relevant 4-thiofuranosides .
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To probe the stability and reactivity of thiosugars these substrates have been subjected to various studies. In 1963, Whistler and
Van Es described that methyl 5-thioxylopyranoside is hydrolyzed significantly faster than its O-counterpart10 and Bennet and co-
workers performed an extensive suite of KIE experiments to establish that xylo- and gluco-thiacarbenium ions are more stable than
the corresponding oxocarbenium ions in aqueous hydrolysis reactions.11-12 Experimental and theoretical evidence shows that sulfur
atoms stabilize an adjacent carbocation better than an oxygen atom.13 However, Jagannadham et al. determined that the
thermodynamically less stable, α-oxygen-stabilized, carbocation can form more rapidly than their thermodynamically more stable
α-sulfur-stabilized counterparts, as the intrinsic kinetic barrier to the formation of the oxocarbenium ion is smaller compared to the
formation of the thiacarbenium ion.14 The increased rate of hydrolysis of the thiopyranosides might be due to additional ring strain
of substituting an oxygen atom for a significantly bigger sulfur atom. In contrast, a study regarding the acid-catalyzed hydrolysis of
4-thio nucleosides has revealed a significant decrease in reactivity compared to the natural 4-oxo nucleosides2, which is more in
line with the reactivity of the acyclic benzylic substrates described by Jagannadham et al.14 To understand the stability and
reactivity of furanosyl thiacarbenium ions, in support of the use of 4-thiofuranosides as stabilized furanose analogues, we here
describe the synthesis of the full suite of diasteroisomeric thiofuranosides (thio-ribose, thio-arabinose, thio-xylose and thio-lyxose,
Scheme 1) and a study to map structure-reactivity-stereoselectivity relationships of these thiafuranosyl acetyl donors in Lewis-acid
mediated SN1-type substitution reactions. The putative ribosyl, arabinosyl, xylosyl and lyxosyl thiacarbenium ion intermediates
were investigated computationally following a computational method, we recently developed to establish the stability and reactivity
of fully decorated furanosyl oxocarbenium ions.15-16 In this method, which we built on the seminal work of Rhoad and co-orkers17,
the relative energy of furanosyl oxocarbenium ions is determined as a function of their overall shape. It was found that the low-
energy oxocarbenium ion conformers could accurately account for the stereoselectivity of addition reactions taking place on these
intermediates, thereby lending strong support for their intermediacy in the studied reactions. To investigate the reactivity/stability of
the related thiacarbenium ions and establish whether the stabilizing/destabilizing substituent effects that dictate the stability and
reactivity of furanosyl oxocarbenium ions are operational in thiacarbenium ions we here extend the method to 5-membered ring
thiacarbenium ions. It is found that these stereoelectronic effects indeed translate well to the thiacarbenium ions and the
stereoselectivity of reactions of thiafuranosyl donors in which these cations feature as product forming intermediates can be well
accounted for by the shape of the intermediate ions.
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___________________________________________
Scheme 1. The four studied 4-thiofuranosyl donors.
OBn OBn
BnO
OBn
S
S
OAc
AcO
OBn OBn
2
L-lyxosyl donor ( )
1
D-ribosyl donor ( )
OBn
S
OBn
OBn
BnO
S
OAc
AcO
OBn
D-xylosyl donor ( )
OBn
L-arabinosyl donor ( )
3
4
___________________________________________
RESULTS AND DISCUSSION
The four required 4-thiofuranosyl donors ribose 1, lyxose 2, arabinose 3 and xylose 4 were synthesized following the method
reported by Minakawa et al. as depicted in Scheme 2.18 The synthesis of the 4-thio ribosyl donor 1 started from D-ribose to afford,
after standard protecting group manipulations, 2,3,5-tri-O-benzyl ribose 7 in 88% yield over three steps. Reduction of the lactol
with sodium borohydride in methanol yielded the corresponding ribitol of which both hydroxyl functionalities were mesylated to
provide dimesylate 9. To generate the thio-ribofuranosyl donor 1 a double inversion of the C-4-mesylate was required. To this end,
both mesylates in 9 were substituted by bromines in a Finkelstein-type reaction. Next, a second substitution and concomitant ring
closure were effected by a SN2 substitution using sodium sulfide in DMF at 100 °C to give thioether 11 in 63% over three steps.
These last two reactions required specific attention, as epimerization can occur on both the C3 and C4 position leading to the
formation of a mixture of stereoisomers (See SI for more information). To deliver the required acetyl donor 1, thioether 11 was
oxidized with m-CPBA, to give the corresponding sulfoxide, which was transformed through a Pummerer rearrangement in donor 1
in 81% yield over two steps. Dimesylate 9 was also used for the construction of the 4-thio lyxofuranosyl donor 2. To this end, 9
was exposed to the sodium sulfide substitution/ring closure conditions to provide 4-thio L-lyxitol 13. This compound was then
oxidized, to give, after a Pummerer rearrangement, the 4-thio lyxosyl donor 2. The 4-thio-L-arabinosyl and 4-thio-L-xylosyl donors
3 and 4 were synthesized using similar transformations starting from commercially available L-arabinose in similar overall yields
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(Scheme 2). With the synthesized 4-thio pentofuranosyl donors (1, 2, 3, 4) in hand, the glycosylation reactions were undertaken. All
reactions were carried out in dry DCM using TMSOTf as an activator and triethylsilane-d (TES-d) as a nucleophile. This
nucleophile was used as we have previously shown that it can faithfully report on the stereoselectivity of SN1-type substitution
reactions on glycofuranosyl oxocarbenium ions.15-16 Of note, the use of allyl trimethyl silane (TMS-All) as a nucleophile in
combination with donor 1 provided the 1-allyl-4-thioribofuranoside with identical selectivity.
1
2
3
4
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Scheme 2. Synthesis of 4-thiofuranosyl donors.
7
8
1. DCM,
m-CPBA
2. Ac2O
OBn
BnO
BnO
DMF, Na2S
S
S
OAc
9
BnO
Br
63% (over 4
steps)
D-ribose
81% (over
2 steps)
Br OBn
10
11
12
13
14
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OBn OBn
OBn OBn
10
1. MeOH, AcCl
11
88% (over
3 steps)
1
(ribo)
2. DMF, BnBr, NaH
3. H2O, HCOOH
2-butanone, LiBr
1. DCM,
m-CPBA
2. Ac2O
OBn OBn
S
OBn OBn
S
OBn
1. MeOH, NaBH4
2. DCM, MsCl, Et3N
BnO
OBn
OBn
O
DMF, Na2S
OH
AcO
BnO
OMs
43% (over 3
steps)
31% (over
2 steps)
OMs OBn
OBn OBn
13
2
(lyxo)
7
9
1. DCM,
m-CPBA
2. Ac2O
OBn
S
OBn
OBn
DMF, Na2S
OBn
S
OBn
AcO
L-arabinose
BnO
Br
50% (over 4
steps)
51% (over
2 steps)
Br OBn
OBn
1. MeOH, AcCl
2. DMF, BnBr, NaH
3. H2O, HCOOH
OBn
66% (over
3 steps)
21
20
3
(ara)
2-butanone, LiBr
1. DCM,
m-CPBA
2. Ac2O
OBn
O
OBn
OBn
1. MeOH, NaBH4
2. DCM, MsCl, Et3N
OBn
DMF, Na2S
OBn
S
OBn
S
HO
BnO
BnO
BnO
OMs
OAc
47% (over 3
steps)
42% (over
2 steps)
OMs OBn
17
OBn
OBn
(xylo)
19
23
4
___________________________________________
The results of the glycosylation reactions are summarized in Table 1, alongside the results previously obtained for the O-
furanosides for comparison. We first probed the reaction of ribo-donor 1 and found that a relatively high activation temperature was
required (-30 oC with respect to a reaction temperature of -78 oC, for its oxo-counterpart). Upon reaction with triethylsilane-d the
1,2-cis addition product was formed selectively (α:β = 91:9). Next the other three donors similarly probed to deliver the results depicted
in Table 1 and from these it becomes apparent that the stereoselectivities of the reactions of the 4-thiofuranosyl donors parallel those
obtained with the O-furanosides, but the reactions of the thiodonors are all slightly less selective. In all cases the 1,2-cis-products
are formed selectively and only the 4-thioxylosyl donor 4 provides a significant amount of the trans-product.
_______________________________________________
Table 1. Results of the substitution reaction of TES-d with the 4-oxo and 4-thiofuranosides.
X
X
OAc
D
TES-d, TMSOTf
BnO
BnO
X = O, S
DCM
OBn
BnO
OBn
BnO
X = O
X = S
α:β ratio
(exp.)a,b
α:β ratio
(comp.)
α:β ratio
(exp.)c,b
Riboside
>98:2
<2:98
85:15
<2:98
94:6
2:98
91:9
8:92
Arabinoside
Xyloside
68:32
0:100
69:31
3:97
Lyxoside
aReagents and conditions: 2 eq. TES-d, 1.3 eq. TMSOTf, -78 °C, 7 days. bThe α:β-ratio was established by NMR spectroscopy. cReagents and conditions: 2
eq. TES-d, 1.3 eq. TMSOTf, -30 °C, 10 days.
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We then set out to investigate the furanosyl thiacarbenium ions using the computational approach we recently used to determine the
relative energy of all furanosyl oxocarbenium ion conformers.15 To this end we calculated the energies associated with 81 pre-fixed
ring conformations for the thiacarbenium ions. We did so for each of the three C4-C5 rotamers, having the C-5-OMe group in a tg,
gg or gt position (see Figure 2B). Using Gaussian 03, employing the B3LYP hybrid functional and the 6-311G(d,p) basis set, the
structures of these (3 x 81 = 243) conformers were optimized and their relative energy calculated. The energies obtained from the
DFT calculations were corrected for solvation in DCM by a polarized continuum model (PCM) and subsequently a Gibbs free
energy correction was applied at the temperature of the respective experimental glycosylation. The energies of all conformations
were then plotted as a polar contour plot on the pseudo-rotational circle (which describes the complete conformational space of a
five-membered ring as a function of the phase angle (P) and puckering amplitude (τm)19, with isoenergetic values as the contour
lines, resulting in the Conformational Energy Landscape (CEL) map (For more information see Supplementary Information).
Figure 2 depicts the pseudo-rotational circle (A) with a set of canonical ring conformations as well as the studied C4-C5 rotamers
(B). Table 2 presents the so-obtained CEL maps for both diastereoisomeric sets of furanosyl thiacarbenium ions and oxocarbenium
ions. The CEL maps show that the thiacarbenium ions adopt structures that are very similar to their oxocarbenium ion counterparts
and the minimal energy conformers can be found on the 3E - E3 axis. The presence of the 4-S ring atom does influence the amount
of puckering of the 5-membered ring going from an approximate puckering of 25° for the oxocarbenium ions to approximately 35°
for the thiacarbenium ions, as a result of the larger bond length for the C-S bonds. The maps of the thiacarbenium ions overall show
a steeper energy landscape.
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OMe
H
A
B
O
H
H
O
O5

3E
gg

O5
H
H
O
H
gt
H
H
E3
O
H

O5
MeO
O
tg
C
O
O
Nu
Nu
Nu
Nu
H
3
H
4
outside attack
inside attack
H
O
H
H
O
O
4
Nu
3
H
4
3
4
O
O
E3
3E
2
1
2
1
3
H
3
H
H
Nu
4
H
H
O
4
inside attack
outside attack
3
H
Nu
Nu
O
O
Nu
Nu
Figure 2. A) Pseudorotational circle B) The C4-C5 rotamers in Newman projection C) Th two-conformer model as advanced by
Woerpel and co-workers.
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________________________________________________
Table 2. The conformational energy landscapes of the 4-oxo furanosyl carbenium ions and 4-thio thiacarbenium ions.
1
2
3
X = O
X = S
Lowest energy conformer (X = S)
4
5
6
7
8
9
O
3E
X
MeO
MeO
OMe
Riboside
E3
O
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∆GTDCM
0
+1.4
(kcal/mol)a
X
MeO
MeO
OMe
Arabinoside
∆GTDCM
0.1
0
(kcal/mol)a
X
MeO
MeO
OMe
Xyloside
∆GTDCM
+0.9
+1.4
(kcal/mol)a
X
MeO
MeO
OMe
Lyxoside
∆GTDCM
+0.2
+0.2
(kcal/mol)a
T
a
∆GDCM represents the relative energy difference between the lowest energy conformer from the given diastereoisomer with respect to the energy of
the most stable conformer of the full suite of diastereoisomers.
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Looking at the individual stereoisomers, the CEL map of the ribofuranosyl thiacarbenium shows a clear minimum for the E3
envelope. This structure (see Table 2) places all substituent in a position that allows for maximum stabilization of the thiacarbenium
ion. As empirically established by Woerpel and co-workers20-24 and supported by previous computational studies15-16, 25-28, an
oxocarbenium ion is best stabilized by an equatorial OMe-substituent at C2 to allow for electron density donation by the axial C2-
H2 bond, while the electron density of the ether group at C3 is nearest and most stabilizing to the electron depleted anomeric center
when placed axially. The same holds true for the C5-OMe, that is positioned closest to the positive charge, when taking up the
axial-gg-orientation in the E3 envelope. The CEL maps reveal that the stereoelectronic “stability rules” that play a decisive role in
determining the stability and reactivity of furanosyl oxocarbenium ions, equally apply to thiacarbenium ions. A minor population of
the ribosyl thiacarbenium ion adopting a 3E conformation (∆GDT CM = 1.3 kcal/mol) can be found. Assuming that the E3
thiacarbenium ion is preferentially attacked on the α-face and the 3E structure on the opposite β-side, the Boltzmann-weighed
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population of both families of conformers predicts a 94:6 α/β selectivity, which closely matches the ratio obtained in the experiment
(91:9).
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2
3
4
5
6
7
8
9
The CEL maps of the arabinosyl and lyxosyl thiacarbenium ion show a clear preference for the 3E conformer. Nucleophilic attack
on this arabinosyl 3E conformer leads to the selective formation of the β-arabinose anomer, corresponding well with the
experimental findings. Similarly, the lyxosyl 3E conformer is stereoselectively attacked to provide the all-cis product. In line with
the furanosyl oxocarbenium ion series, the lyxose configured thiacarbenium shows the strongest preference for a single conformer,
which translates into the highest stereoselectivity in the substitution reactions. For the xylofuranosyl thiacarbenium ion two minima
are found on the CEL map, matching the situation for the xylofuranosyl oxocarbenium ion. The difference in energy of the two
minima is smaller in the case of the thiacarbenium ion with respect to the oxocarbenium ions and this translates into lower
stereoselectivity of thiofuranosyl donor 4 in the substitution reaction. The Boltzmann-weighed relative population of the E3 and 3E
conformers predicts a poorly selective glycosylation event, which is closely matched in the experiment. Overall there is very good
agreement between the stereoselectivity that is theoretically predicted based on the CEL maps, in combination with Woerpel’s
inside attack model and the stereoselectivity obtained experimentally (Table 1). This shows that the relative energy difference
between the transition states leading to the products is relatively well approximated using the difference in ground state energy of
the thiacarbenium ion conformers, and that a Curtin-Hammett kinetic scenario, in which the lowest energy transition state is
reached from a higher energy ground state species, plays a very minor role. The correlation between the reaction stereoselectivity
and the thiacarbenium ion structure strongly indicates the thiacarbenium ions to be the product forming reactive intermediates in
these reactions.
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Finally, we investigated the difference in reactivity between the C4-S and C4-O donors in a set of direct competition glycosylation
experiments (Table 3). In the first set of experiments, the 4-S-ribosyl and 4-O-ribosyl15 donors, 1 and 29, were mixed and exposed
to reaction conditions, in which the quantity of the activator (TMSOTf) or acceptor (TES-d) was varied to investigate whether
either of the two substrates is activated more easily or if the resulting oxo- or thiacarbenium ion intermediate is more reactive
towards nucleophiles (Table 3, entries 1-3). All experiments showed that the 4-thio ribofuranosyl donor reacts more slowly than its
4-oxo counterpart. For all other furanosides, the 4-thio-donors reacted faster and only the 1-D-products derived from these donors
were formed. The striking difference in relative reactivity may be explained by the relative stability of the intermediate thia- and
oxo carbenium ions. In Table 2 the relative energy difference between the different diasteroisomeric CEL maps is depicted. The
difference in energy between the lowest energy conformer of the individual diastereoisomers with respect to the most stable
diasteroisomeric oxocarbenium ion is: ∆GDT CM ribo = 0 kcal/mol; ∆GDT CM ara = 0.1 kcal/mol; ∆GTDCM xylo = 0.9 kcal/mol; ∆GTDCM
lyxo = 0.2 kcal/mol. Thus, in the oxo-series, the ribose oxocarbenium is most stable, closely followed by the arabinose and lyxose
ions, with the xylose oxocarbenium ion clearly being least stable. The situation is rather different in the thio-series. Here the order
of stability is: arabinose (∆GTDCM Ara = 0 kcal/mol) > lyxose (∆GDT CM lyxo = 0.2 kcal/mol) > ribose (∆GTDCM ribo = 1.4 kcal/mol) ~
xylose (∆GTDCM xylo = 1.4 kcal/mol). In this case the ribo-thiacarbenium ion appears to be one of the least stable of the series.
Overall this data suggests that the formation of the ribo-thiacarbenium ion when compared to the formation of the corresponding
oxocarbenium ion is relatively difficult, providing an explanation for the relatively low reactivity of donor 1 with respect to donor
29.
______________________________________________
Table 3. Results of the substitution reaction of TES-d with the 4-oxo and 4-thiofuranosides. Competition experiments screening the
reactivity of 4-oxo pentofuranosyl donors relative to 4-thio pentofuranosyl donors
Entry
O-donor
S-donor
Acceptor
Activator
Conditions
-30 °C, 2 days
-30 °C, 2 days
-30 °C, 2 days
-30 °C, 2 days
-30 °C, 2 days
-30 °C, 2 days
Product ratioa
S:O
1
2
3
4
5
6
29
(1 eq.)
1
TES-d
(2 eq.)
TMSOTf
(2 eq.)
1:4
1:4
(1 eq.)
29
(1 eq.)
1
TES-d
(1 eq.)
TMSOTf
(2 eq.)
(1 eq.)
29
(1 eq.)
1
TES-d
(2 eq.)
TMSOTf
(1 eq.)
1:3.5
1:0
(1 eq.)
31
(1 eq.)
2
TES-d
(1 eq.)
TMSOTf
(2 eq.)
(1 eq.)
33
(1 eq.)
3
TES-d
(1 eq.)
TMSOTf
(2 eq.)
1:0
(1 eq.)
35
(1 eq.)
4
TES-d
(1 eq.)
TMSOTf
(2 eq.)
1:0
(1 eq.)
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aThe product ratio was established by NMR spectroscopy and isolated mass of products.
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CONCLUSIONS
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In conclusion, we have performed an in-depth investigation into the stability/reactivity of furanosyl thiacarbenium ions, assessing
all four diastereoisomeric thiofuranosides experimentally and computationally to show that all furanosyl thiacarbenium ions react in
a 1,2-cis-selective manner. There is a clear correlation to the stereoselectivity of 4-oxofuranosides, with the cationic intermediates
taking up similar structures. From these results it can be concluded that the substitution reactions follow similar reaction paths.
Interestingly, differences in relative reactivity were observed for the reactivity of the 4-thio donors with respect to their oxo-
counterparts. While the ribo-configured 4-thio furanose is less reactive than the corresponding 4-O-furanoside, the other three
diastereoisomeric 4-thio donors are more reactive than the parent 4-oxofuranosides. The relative reactivity of the ribo-furanosides
thus follows the reactivity difference observed for the acyclic benzylic thia/oxocarbenium ions studied by Jagannadham et al.14
while the reactivity of the arabino-, xylo- and lyxo-species are in line with the relative reactivity of 5-thio/oxo pyranosides. The
similar but lower reactivity of 4-thioribofuranosides supports their use as stable and close mimics of the naturally occurring
ribofuranosides. Finally, the results presented here show that the model for rationalizing the stereoselectivity of addition reactions
to oxocarbenium ions can be extended to other non-typical glycosyl carbocations, providing further support for the model and the
relevance of the reactive intermediates.
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The Journal of Organic Chemistry
Experimental Section
General
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7
8
9
All solvents used under anhydrous conditions were stored over 4Å molecular sieves, except for methanol which was stored over 3Å
molecular sieves. Solvents used for workup and column chromatography were of technical grade from Sigma Aldrich and used
directly. Unless stated otherwise, solvents were removed by rotary evaporation under reduced pressure at 40 °C. Reactions were
monitored by TLC‐analysis using Merck 25 DC plastikfolien 60 F254 with detection by spraying with 20% H2SO4 in EtOH,
(NH4)6Mo7O24·4H2O (25 g/L) and (NH4)4Ce(SO4)4·2H2O (10 g/L) in 10% sulfuric acid or by spraying with a solution of ninhydrin
(3 g/L) in EtOH / AcOH (20/1 v/v), followed by charring at approx. 150 °C. Column chromatography was performed on Fluka
silicagel (0.04 – 0.063 mm) or by automation using a Biotage® Isolera™ Spektra Four machine. For LC-MS analysis a JASCO
HPLC‐system (detection simultaneously at 214 and 254 nm) equipped with an analytical C18 column (4.6 mmD × 50 mmL, 3μ
particle size) in combination with buffers A: H2O, B: MeCN and C: 0.5% aq. TFA and coupled to a PE/SCIEX API 165 single
quadruple mass spectrometer (Perkin-Elmer) was used, unless stated otherwise. Alternatively a Thermo Finnigan LCQ Advantage
MAX ion-trap mass spectrometer with an electrospray ion source coupled to Surveyor HPLC system (Thermo Finnegan) was used
with the same analytical column. High resolution mass spectra were recorded by direct injection (2 μL of a 2 μM solution in
water/acetonitrile; 50/50; v/v and 0.1% formic acid) on a mass spectrometer (Thermo Finnigan LTQ Orbitrap) equipped with an
electrospray ion source in positive mode (source voltage 3.5 kV, sheath gas flow 10, capillary temperature 250 °C) with resolution R
= 60000 at m/z 400 (mass range m/z = 150‐2000) and dioctylpthalate (m/z = 391.2842) as a “lock mass”. The high resolution mass
spectrometer was calibrated prior to measurements with a calibration mixture (Thermo Finnigan). 1H‐ and 13C‐NMR spectra were
measured on a Bruker AV‐400 (400 MHz) or a Bruker DMX‐600 (600 MHz) and all individual signals were assigned using 2D-NMR
spectroscopy. Chemical shifts are given in ppm (δ) relative to TMS (0 ppm) and coupling constants are given in Hz. Optical rotations
were measured in CHCl3 or methanol at a concentration of 10 mg/mL at 25 °C. Stereoisomers were, when possible, separated by
silica gel column chromatography for analytical purposes.
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Synthesis and Characterization
Methyl α,β-D-ribofuranoside (5)
D-ribose (15.0 g, 100 mmol) was dissolved in methanol (250 ml). The solution was cooled to 0 oC and
sulfuric acid (0.27 ml, 5 mmol) was slowly added. The reaction mixture was stirred for 24 hours at 4 oC.
The reaction was quenched upon the addition of sodium bicarbonate. The reaction mixture was filtered,
concentrated in vacuo and used in the next step without further purification. Rf = 0.25
(CHCl3:EtOAc:MeOH 63:25:12).
HO
O
OMe
OH OH
Methyl 2,3,5-tri-O-benzyl-α,β-D-ribofuranoside (6)
Crude 5 (100 mmol) was dissolved in DMF (400 ml), cooled to 0 oC and sodium hydride (350 mmol,
BnO
O
8.40 g, 60% in mineral oil) was slowly added. After hydrogen gas formation stopped benzyl bromide
(350 mmol, 41.6 ml) was slowly added and the reaction mixture was stirred at room temperature for 5
hours. The reaction was quenched by the addition of ice. The reaction mixture was diluted with EtOAc
and washed with water and brine. The organic layer was dried (MgSO4), concentrated in vacuo and used
OMe
OBn OBn
in the next step without further purification. Rf = 0.35 (EtOAc:pentane 5:95).
2,3,5-tri-O-benzyl-α,β-D-ribose (7)
o
Crude 6 (100 mmol) dissolved in formic acid (800 ml) and water (200 ml) and stirred at 60 C for 18
hours. The reaction mixture was diluted with diethyl ether and the organic layer was washed with water,
aq. NaHCO3 (sat.), dried (MgSO4), concentrated in vacuo and column chromatography (pentane: EtOAc,
95/5 – 70/30) yielded the title compound (36.2 g, 86.2 mmol, 86% over three steps). Spectroscopic data
was in agreement with literature.15
BnO
O
OH
OBn OBn
(2S,3R,4R)-2,3,5-tri-O-benzyl-pentane-1,4-diol (8)
Compound 7 (21.5 mmol) was dissolved in methanol (110 ml) and sodium borohydride (43 mmol, 1.63
OBn
g) was added in small portions over a period of 30 minutes at 0 oC. The reaction was then stirred for 1
hour at room temperature after which the solvent was removed in vacuo. The residue was dissolved in
EtOAc and washed with water, brine, dried (MgSO4) and concentrated in vacuo and used in the next
step without further purification. Rf = 0.55 (EtOAc:pentane 40:60).
BnO
OH
OH OBn
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(2S,3S,4R)-2,3,5-tri-O-benzyl-pentane-1,4-dimesylate (9)
Page 10 of 16
1
2
3
4
5
Crude 8 (21.5 mmol) was dissolved in DCM (110 ml) and triethylamine (86 mmol, 12.0 ml) was
added. Mesyl chloride (64.5 mmol, 5.0 ml) was slowly added at -20 oC and the reaction was stirred
for 30 minutes after which it was quenched upon addition of ice. The organic layer was washed with
water, aq. NaHCO3 (sat.), brine, dried (MgSO4), concentrated in vacuo and used in the next step
without further purification. Rf = 0.60 (EtOAc:pentane 30:70).
OBn
BnO
OMs
OMs OBn
6
7
8
(2R,3S,4S)-2,3,5-O-tri-benzyl-1,4-dibromopentane (10)
9
Crude 9 (38.4 mmol), co-evaporated with toluene to remove traces of water, was dissolved in dry 2-
OBn
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butanone (130 ml). Lithium bromide (384 mmol, 33.4 g) was added and the reaction was refluxed for 16
Br hours. The reaction mixture was diluted with EtOAc and washed with water, aq. NaHCO3 (sat.) and
brine. The organic layer was dried (MgSO4), concentrated in vacuo and used in the next step without
further purification. Rf = 0.55 (EtOAc:pentane 5:95).
BnO
Br OBn
1,4-Anhydro-2,3,5-O-tri-benzyl-4-thio-D-ribitol (11)
Crude 10 (38.4 mmol) and sodium sulfide nonahydrate (46.1 mmol, 11.1 g) were dissolved in DMF (130 ml).
BnO
S
The reaction mixture was stirred at 100 oC for 30 minutes. The residue was dissolved in EtOAc, washed with
water, brine, dried (MgSO4) and concentrated in vacuo. Column chromatography (pentane: EtOAc, 99/1 –
93/7) yielded the title compound (24.0 mmol, 10.1 g, 63% over 4 steps). 1H NMR (600 MHz, CDCl3) δ: 7.59
– 7.13 (m, 15H), 4.64 – 4.38 (m, 6H), 3.99 (ddd, J = 6.9, 5.4, 3.4 Hz, 1H), 3.93 (dd, J = 4.8, 3.5 Hz, 1H), 3.67
OBn OBn
(td, J = 6.6, 4.6 Hz, 1H), 3.45 (AB, J = 10.0, 6.5 Hz, 2H), 3.00 (AB, J = 10.7, 6.8 Hz, 1H), 2.84 (AB, J = 10.7, 5.4 Hz, 1H); 13C{1H}
NMR (151 MHz, CDCl3) δ 138.0, 137.9, 137.9, 128.3, 128.3, 128.2, 127.8, 127.6, 127.6, 127.5, 127.5, 80.8, 79.5, 72.9, 71.8, 71.7,
71.6, 47.0, 30.5; IR (neat): 3029, 2932, 2857, 1496, 1453, 1112, 1070, 1027, 732, 694 cm-1;
HRMS (ESI) m/z: [M + Na] + Calcd for C26H28O3SNa 443.1644; Found 443.1651.
[α]D 20(c=2, DCM): +64.6; Rf = 0.35 (EtOAc:pentane 5:95). Spectroscopic data was in agreement with literature.29
1,4-Anhydro-2,3,5-tri-O-benzyl-4-sulfoxide-D-ribitol (12)
Compound 11 (15.7 mmol, 6.61 g) was dissolved in DCM (100 ml) and m-CPBA (17.3 mmol, 3.00 g) was
O
S
o
BnO
added at -40 C. The reaction mixture was stirred for 1 hour. The reaction mixture was quenched by the
addition of aq. Na2S2O3 (sat.) and the organic layer was washed with aq. NaHCO3 (sat.). The organic layer
was dried (MgSO4), concentrated in vacuo and used in the next step without further purification.
Rf = 0.05 (EtOAc:pentane 30:70).
OBn OBn
1-O-Acetyl-2,3,5-tri-O-benzyl-4-thio-α,β-D-ribofuranose (1)
Crude 12 (15.7 mmol) was dissolved in acetic anhydride (100 ml) and stirred at 100 oC for 3 hours. The
BnO
S
reaction mixture was concentrated in vacuo and column chromatography (pentane: EtOAc, 90/10 –
80/20) yielded the title compound (11.3 mmol, 5.4 g, 72% over two steps). 1H NMR (500 MHz, CDCl3)
δ: 7.44 – 7.14 (m, 15H), 6.21 (d, J = 4.7 Hz, 1H), 5.97 (d, J = 2.0 Hz), 4.78 – 4.39 (m, 6H, CH2 Bn),
4.11 (dd, J = 4.1, 2.2 Hz, 1H), 4.07 (dd, J = 3.5, 2.0 Hz, 1H), 4.05 – 4.00 (m, 1H), 3.98 (dd, J = 8.4, 3.5
OAc
OBn OBn
Hz, 1H), 3.88 – 3.82 (m, 1H), 3.81 – 3.72 (m, 2H), 3.59 (AB, J = 9.8, 6.9 Hz, 1H), 3.39 (AB, J = 10.0, 5.4 Hz, 1H), 3.31 (AB, J =
10.0, 7.7 Hz, 1H), 2.12 (s, 3H), 2.02 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ: 171.0, 169.9, 138.4, 138.2, 137.82, 137.8, 137.7,
137.7, 128.5, 128.5, 128.5, 128.4, 128.3, 128.0, 128.0, 127.9, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 81.3, 81.2, 80.9, 80.6, 79.9,
77.0, 73.2, 72.9, 72.9, 72.8, 72.2, 72.1, 72.0, 71.7, 71.5, 48.5, 47.9, 21.5, 21.2; IR (neat): 3064, 3030, 2939, 2865, 1733, 1496, 1454,
1366, 1265, 1225, 1102, 1027, 1016, 957, 731, 695 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for C28H30O5SNa 501.1706; Found
501.1700. Rf = 0.40 (EtOAc:pentane 15:85).
1,4-Anhydro-2,3,5-O-tri-benzyl-4-thio-L-lyxitol (13)
Crude 9 (12.1 mmol, 6.98 g) and sodium sulfide nonahydrate (13.3 mmol, 3.18 g) were dissolved in DMF (120
OBn OBn
ml). The reaction mixture was stirred at 100 oC for 2 hours. The mixture was dissolved in EtOAc, washed with
water, brine, dried (MgSO4) and concentrated in vacuo. Column chromatography (pentane: EtOAc, 99/1 – 93/7)
yielded the title compound (5.2 mmol, 2.2 g, 43% over 3 steps). 1H NMR (400 MHz, CDCl3) δ: 7.38 – 7.22 (m,
OBn
S
15H), 4.86 (d, J = 11.7 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 4.53 (m, 4H), 4.20 (dd, J = 4.1, 2.8 Hz, 1H), 4.10 – 3.99 (m, 1H), 3.90
(dd, J = 8.4, 7.0 Hz, 1H), 3.64 – 3.50 (m, 2H), 3.06 (t, J = 9.4 Hz, 1H), 2.91 (dd, J = 9.8, 6.1 Hz, 1H); 13C{1H} NMR (101 MHz,
CDCl3) δ: 138.7, 138.2, 128.6, 128.5, 128.4, 127.9, 127.8, 127.8, 127.7, 127.5, 83.6, 78.9, 73.7, 73.4, 72.3, 70.3, 45.8, 30.5; IR (neat):
3087, 3062, 3029, 2931, 2859, 1496, 1453, 1360, 1207, 1086, 1068, 1027, 732, 695 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for
C26H28O3SNa 443.1644; Found 443.1658. [α]D 20(c=1, DCM): -7.0; Rf = 0.30 (EtOAc:pentane 5:95). Spectroscopic data was in
agreement with literature.18
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1
1,4-Anhydro-2,3,5-tri-O-benzyl-4-sulfoxide-L-lyxitol (14)
2
3
4
5
6
7
Compound 13 (4.4 mmol, 1.84 g) was dissolved in DCM (45 ml) and m-CPBA (4.8 mmol, 0.83 g) was added
at -40 oC. The reaction mixture was stirred for 1 hour. The reaction mixture was quenched by the addition of
aq. Na2S2O3 (sat.) and the organic layer was washed with aq. NaHCO3 (sat.). The organic layer was dried
(MgSO4), concentrated in vacuo and used in the next step without further purification. Rf = 0.05
(EtOAc:pentane 30:70).
OBn
BnO
O
S
OBn
8
9
1-O-Acetyl-2,3,5-tri-O-benzyl-4-thio-α,β-L-lyxofuranose (2)
Crude 14 (4.4 mmol) was dissolved in acetic anhydride (30 ml) and stirred at 100 oC for 5 hours. The
reaction mixture was concentrated in vacuo and column chromatography (pentane: EtOAc, 90/10 –
80/20) yielded the title compound (1.34 mmol, 0.64 g, 31% over two steps). 1H NMR (400 MHz, CDCl3)
δ: 7.45 – 7.24 (m, 15H), 6.01 (d, J = 3.7 Hz, 1H), 4.73 – 4.45 (m, 6H), 4.31 – 4.28 (m, 1H), 4.27 – 4.21
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OBn OBn
S
OBn
AcO
(m, 1H), 4.10 (t, J = 3.5 Hz, 1H), 4.00 – 3.91 (m, 3H), 3.78 (dt, J = 7.9, 5.6 Hz, 1H), 3.69 (dd, J = 9.2, 7.9 Hz, 1H), 3.62 – 3.47 (m,
2H), 2.09 (s, 3H), 2.04 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ: 138.3, 138.1, 137.8, 128.7, 128.5, 128.5, 128.5, 128.3, 128.1,
127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 127.5, 84.5, 84.2, 80.7, 79.5, 78.6, 76.0, 73.6, 73.5, 73.4, 72.7, 72.5, 71.2, 69.7, 46.5, 46.3,
21.5, 21.2; IR (neat): 3078, 3064, 3030, 2923, 2864, 1735, 1496, 1453, 1366, 1309, 1224, 1094, 1061, 1016, 957, 910, 733, 695 cm-
1; HRMS (ESI) m/z: [M + Na] + Calcd for C28H30O5SNa 501.1706; Found 501.1714. Rf = 0.45 (EtOAc:pentane 15:85).
Methyl α,β-L-arabinofuranoside (15)
L-arabinose (100 mmol, 15.0 g) was dissolved in methanol (250 ml). The solution was cooled to 0 oC
OH
OH
and sulfuric acid (5 mmol, 0.27 ml) was slowly added. The reaction mixture was stirred for 4 nights at
room temperature. The reaction was quenched upon the addition of sodium bicarbonate. The reaction
mixture was filtered, concentrated in vacuo and used in the next step without further purification. Rf =
0.30 (CHCl3:EtOAc:MeOH 63:25:12).
O
MeO
OH
Methyl 2,3,5-tri-O-benzyl-α,β-L-arabinofuranoside (16)
Crude 15 (100 mmol) was dissolved in DMF (350 ml), cooled to 0 oC and sodium hydride (350 mmol,
OBn
O
OBn
14.0 g, 60% in mineral oil) was slowly added. After hydrogen gas formation stopped benzyl bromide
(350 mmol, 41.6 ml) was slowly added and the reaction mixture was stirred at room temperature for 3
hours. The reaction was quenched by the addition of ice. The reaction mixture was diluted with diethyl
ether and washed with water and brine. The organic layer was dried (MgSO4), concentrated in vacuo
MeO
OBn
and used in the next step without further purification. Rf = 0.25 (EtOAc:pentane 5:95).
2,3,5-tri-O-benzyl-α,β-L-arabinose (17)
Crude 16 (100 mmol) was dissolved in formic acid (800 ml) and water (200 ml) and stirred at 60 oC for
OBn
O
OBn
18 hours. The reaction mixture was extracted with DCM and the organic layer was washed with water,
aq. NaHCO3 (sat.), dried (MgSO4), concentrated in vacuo. Column chromatography (pentane: EtOAc,
95/5 – 70/30) yielded the title compound (27.2 g, 65.6 mmol, 66% over three steps). Spectroscopic data
was in agreement with literature.15
HO
OBn
(2S,3S,4S)-2,3,5-tri-O-benzyl-pentane-1,4-diol (18)
Compound 17 (64.0 mmol, 26.9 g) was dissolved in methanol (320 ml) and sodium borohydride (134
OBn
mmol, 5.1 g) was added in small portions over a period of 30 minutes at 0 oC. The reaction was then
stirred for 1.5 hour at room temperature after which the solvent was removed in vacuo. The residue
was dissolved in EtOAc and washed with water, brine, dried (MgSO4) and concentrated in vacuo and
used in the next step without further purification. Rf = 0.45 (EtOAc:pentane 40:60).
BnO
OH
OH OBn
(2S,3R,4S)-2,3,5-tri-O-benzyl-pentane-1,4-dimesylate (19)
Crude 18 (64 mmol) was dissolved in DCM (300 ml) and triethylamine (256 mmol, 36.0 ml) was
OBn
added. Mesyl chloride (192 mmol, 15.0 ml) was slowly added at -20 oC and the reaction was stirred
for 30 minutes after which it was quenched upon addition of ice. The organic layer was washed with
water, aq. NaHCO3 (sat.), brine, dried (MgSO4), concentrated in vacuo and used in the next step
without further purification. Rf = 0.45 (EtOAc:pentane 30:70).
BnO
OMs
OMs OBn
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(2R,3R,4R)-2,3,5-O-tri-benzyl-1,4-dibromopentane (20)
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5
6
7
8
Crude 19 (27.2 mmol), co-evaporated with toluene to remove traces of water, was dissolved in dry 2-
butanone (100 ml). Lithium bromide (226 mmol, 19.6 g) was added and the reaction was refluxed for
20 hours. The reaction mixture was diluted with EtOAc and washed with water, aq. NaHCO3 (sat.) and
brine. The organic layer was dried (MgSO4), concentrated in vacuo and used in the next step without
further purification. Rf = 0.60 (EtOAc:pentane 5:95).
OBn
BnO
Br
Br OBn
9
1,4-Anhydro-2,3,5-O-tri-benzyl-4-thio-L-arabitol (21)
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19
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26
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Crude 20 (27.2 mmol) and sodium sulfide nonahydrate (24.9 mmol, 6.0 g) were dissolved in DMF (220 ml).
OBn
S
OBn
The reaction mixture was stirred at 100 oC for 30 minutes. The residue was dissolved in EtOAc washed with
water, brine, dried (MgSO4) and concentrated in vacuo. Column chromatography (pentane: EtOAc, 99/1 – 93/7)
yielded the title compound (13.6 mmol, 5.7 g, 50% over 4 steps). 1H NMR (400 MHz, CDCl3) δ: 7.39 – 7.22
(m, 15H), 4.61 (s, 2H), 4.54-4.45 (m, 4H), 4.19 (q, J = 4.6 Hz, 1H), 4.11 (t, J = 3.7 Hz, 1H), 3.68 (dd, J = 8.9,
OBn
7.6 Hz, 1H), 3.61 – 3.44 (m, 2H), 3.07 (dd, J = 11.3, 5.1 Hz, 1H), 2.90 (dd, J = 11.4, 4.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3)
δ: 138.3, 138.2, 138.0, 128.6, 128.5, 128.5, 128.0, 127.9, 127.8, 127.8, 127.7, 85.2, 73.2, 72.5, 72.0, 71.6, 49.1, 33.3; IR (neat): 3087,
3063, 3029, 2932, 2861, 1496, 1362, 1207, 1093, 1070, 1028, 735, 696 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for C26H28O3SNa
443.1644; Found 443.1656. [α]D 20(c=0.5, DCM): +9.7; Rf = 0.45 (EtOAc:pentane 5:95). Spectroscopic data was in agreement with
literature.30
1,4-Anhydro-2,3,5-tri-O-benzyl-4-sulfoxide-L-arabitol (22)
Compound 21 (1.73 mmol, 0.73 g) was dissolved in DCM (15 ml) and m-CPBA (1.91 mmol, 0.33 g) was added
at -40 oC. The reaction mixture was stirred for 2 hours. The reaction mixture was quenched by the addition of
aq. Na2S2O3 (sat.) and the organic layer was washed with aq. NaHCO3 (sat.). The organic layer was dried
(MgSO4), concentrated in vacuo and used in the next step without further purification. Rf = 0.05 (EtOAc:pentane
30:70).
OBn
O
OBn
S
OBn
1-O-Acetyl-2,3,5-tri-O-benzyl-4-thio-α,β-L-arabinofuranose (3)
Crude 22 (1.73 mmol) was dissolved in acetic anhydride (15 ml) and stirred at 100 oC for 3 hours. The
OBn
S
OBn
reaction mixture was concentrated in vacuo and column chromatography (pentane: EtOAc, 90/10 –
80/20) yielded the title compound (0.88 mmol, 0.42 g, 51% over two steps). 1H NMR (400 MHz, CDCl3)
δ: 7.41 – 7.23 (m, 15H), 6.11 (d, J = 4.0 Hz, 1H), 6.02 (d, J = 3.0 Hz, 1H), 4.86 – 4.50 (m, 6H), 4.30
(dd, J = 5.2, 3.1 Hz, 1H), 4.27 – 4.12 (m, 2H), 4.07 (dd, J = 6.5, 5.2 Hz, 1H), 3.81 (q, J = 6.4 Hz, 1H),
AcO
OBn
3.77 – 3.68 (m, 2H), 3.59 – 3.39 (m, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ: 138.4, 138.0, 137.6, 128.6, 128.6, 128.5, 128.5, 128.1,
128.1, 128.0, 128.0, 127.9, 127.9, 127.8, 127.8, 88.9, 86.1, 84.7, 83.9, 82.1, 74.8, 73.6, 73.3, 73.3, 73.2, 72.9, 72.8, 72.7, 71.0, 49.5,
45.4, 21.5, 21.3. IR (neat): 3088, 3063, 3031, 2926, 2863, 1793, 1496, 1453, 1367, 1226, 1098, 1074, 1017, 734, 695 cm-1; HRMS
(ESI) m/z: [M + Na] + Calcd for C28H30O5SNa 501.1706; Found 501.1713. Rf = 0.25 (EtOAc:pentane 10:90). Spectroscopic data was
in agreement with literature.31
1,4-Anhydro-2,3,5-O-tri-benzyl-4-thio-D-xylitol (23)
Crude 20 (10.4 mmol) and sodium sulfide nonahydrate (10.5 mmol, 2.5 g) were dissolved in DMF (40 ml).
OBn
S
BnO
o
The reaction mixture was stirred at 100 C for 4 hours. The residue was dissolved in EtOAc, washed with
water and brine, dried (MgSO4) and concentrated in vacuo. Column chromatography (pentane: EtOAc, 99/1
– 93/7) yielded the title compound (4.9 mmol, 2.0 g, 47% over 3 steps). 1H NMR (400 MHz, CDCl3) δ: 7.37
– 7.23 (m, 15H), 4.61 – 4.45 (m, 6H), 4.14 (m, 2H), 3.89 – 3.79 (m, 2H), 3.68 – 3.57 (m, 1H), 3.11 (dd, J =
OBn
11.4, 4.4 Hz, 1H), 2.85 (dd, J = 11.5, 2.3 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ: 138.3, 138.2, 138.1, 128.6, 128.5, 128.5,
127.9, 127.9, 127.9, 127.8, 127.7, 127.7, 83.1, 73.4, 72.8, 71.4, 69.4, 48.1, 33.2; IR (neat): 3087, 3062, 3030, 2935, 2860, 1497, 1453,
1392, 1361, 1313, 1271, 1207, 1087, 1070, 1027, 733, 695; HRMS (ESI) m/z: [M + Na] + Calcd for C26H28O3SNa 443.1644; Found
443.1657. [α]D 20(c=1, DCM): +52.2; Rf = 0.60 (EtOAc:pentane 10:90).
1,4-Anhydro-2,3,5-tri-O-benzyl-4-sulfoxide-D-xylitol (24)
Compound 23 (4.8 mmol, 2.0 g) was dissolved in DCM (40 ml) and m-CPBA (5.3 mmol, 0.9 g) was added
O
S
BnO
at -40 oC. The reaction mixture was stirred for 2 hours. The reaction mixture was quenched by the addition
of aq. Na2S2O3 (sat.) and the organic layer was washed with aq. NaHCO3 (sat.). The organic layer was dried
BnO
OBn
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(MgSO4), concentrated in vacuo and used in the next step without further purification. Rf = 0.05 (EtOAc:pentane 30:70).
1-O-Acetyl-2,3,5-tri-O-benzyl-4-thio-α,β-D-xylofuranose (4)
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3
4
5
6
7
8
9
Crude 24 (4.8 mmol) was dissolved in acetic anhydride (30 ml) and stirred at 80 oC for 16 hours. The
OBn
BnO
reaction mixture was concentrated in vacuo and column chromatography (pentane: EtOAc, 90/10 –
80/20) yielded the title compound (2.0 mmol, 0.96 g, 42% over two steps). 1H NMR (400 MHz, CDCl3)
δ: 7.37-7.24 (m, 15H), 6.07 (d, J = 4.5 Hz, 1H), 5.94 (d, J = 2.7 Hz, 1H), 4.80 – 4.54 (m, 6H), 4.39 –
4.25 (m, 2H), 4.29 – 4.12 (m, 2H), 3.98 – 3.83 (m, 1H), 3.79 (dd, J = 9.6, 4.7 Hz, 1H), 3.74 – 3.64 (m,
S
OAc
OBn
3H), 3.53 (dd, J = 9.6, 7.5 Hz, 1H), 2.09 (s, 3H), 2.00 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ: 138.3, 138.2, 138.2, 137.9, 137.8,
137.8, 128.6, 128.5, 128.5, 128.4, 128.0, 128.0, 127.9, 127.9, 127.8, 127.8, 127.8, 127.7, 127.7, 127.7, 127.7, 86.6, 83.3, 83.1, 82.1,
81.6, 73.7, 73.5, 73.5, 73.2, 72.7 72.5, 71.0, 69.8, 48.1, 42.1, 21.4, 21.2; IR (neat): 3063, 3031, 2927, 2863, 1738, 1496, 1454, 1367,
1227, 1093, 1017, 932, 735, 696 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for C28H30O5SNa 501.1706; Found 501.1713. Rf = 0.45
(EtOAc:pentane 10:90). Spectroscopic data was in agreement with literature.32
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1-Deutero-2,3,5-tri-O-benzyl-4-thio-D-ribitol (25)
Donor 1 (0.10 mmol, 0.046 g), dried by co-evaporating with dry toluene (3x), was dissolved in dry DCM
(3.22 ml) and stirred with freshly activated 3 Å molecular sieves at room temperature for 1 hour under
argon to remove traces of water. The solution was then cooled to -78 oC and TES-d (0.19 mmol), dissolved
in DCM (0.38 ml), was added followed by the addition of TMSOTf (0.12 mmol), dissolved in DCM (0.24
ml). Next, the reaction mixture was stirred on -30 oC for 10 days and quenched by the addition of TEA (0.5
BnO
S
D
OBn OBn
ml). The reaction mixture was filtered through a path of celite and concentrated in vacuo. Column chromatography (pentane: EtOAc,
1
99/1 – 93/7) yielded the title compound (0.029 g, 0.07 mmol, 72%, α:β = 91 : 9). H NMR (400 MHz, CDCl3) δ: 7.37 – 7.23 (m,
15H), 4.64-4.46 (m, 6H), 4.02 (dd, J = 5.4, 3.5 Hz, 1H), 3.95 (t, J = 4.0 Hz, 1H), 3.68 (td, J = 6.4, 4.4 Hz, 1H), 3.54 – 3.41 (m, 2H),
3.02 (d, J = 6.8 Hz, 0.09H), 2.87 (d, J = 5.3 Hz, 0.91H); 13C{1H} NMR (101 MHz, CDCl3) δ: 138.2, 138.2, 138.1, 128.5, 128.4, 128.1,
127.8, 127.8, 81.0, 79.7, 73.1, 72.0, 72.0, 71.9, 47.3, 30.5 (t); IR (neat): 3088, 3064, 3030, 2924, 2863, 1497, 1454, 1362, 1207, 1107,
1046, 1027, 763, 697 cm-1; HRMS (ESI) m/z: [M + Na]+ Calcd for C26H27DO3SNa 444.1720; Found 444.1720. [α]D 20(c=0.5, DCM):
+28.2.
1-Deutero-2,3,5-tri-O-benzyl-4-thio-L-lyxitol (26)
Donor 2 (0.17 mmol, 0.080 g), dried by co-evaporating with dry toluene (3x), was dissolved in dry DCM
OBn OBn
(5.3 ml) and stirred with freshly activated 3 Å molecular sieves at room temperature for 1 hour under argon
OBn
S
o
to remove traces of water. The solution was then cooled to -78 C and TES-d (0.34 mmol), dissolved in
D
DCM (0.68 ml), was added followed by the addition of TMSOTf (0.22 mmol), dissolved in DCM (0.44
ml). Next, the reaction mixture was stirred on -30 oC for 10 days and quenched by the addition of TEA (0.5 ml). The reaction mixture
was filtered through a path of celite and concentrated in vacuo. Column chromatography (pentane: EtOAc, 99/1 – 93/7) yielded the
title compound (0.028 g, 0.07 mmol, 41%, α:β = 3 : 97). 1H NMR (400 MHz, CDCl3) δ: 7.39 – 7.22 (m, 15H), 4.86 (d, J = 11.7 Hz,
1H), 4.68 (d, J = 11.8 Hz, 1H), 4.57 (s, 2H), 4.49 (s, 2H), 4.20 (dd, J = 4.0, 2.9 Hz, 1H), 4.03 (dd, J = 6.1, 2.9 Hz, 1H), 3.99 – 3.82
(m, 1H), 3.63 – 3.50 (m, 2H), 3.04 (dd, J = 10.3, 3.7 Hz, 0.07H), 2.89 (d, J = 6.1 Hz, 0.93H); 13C{1H} NMR (101 MHz, CDCl3) δ:
138.8, 138.3, 138.2, 128.6-127.5, 83.6, 78.9, 73.7, 73.4, 72.3, 70.3, 45.8, 30.2 (t); IR (neat): 3066, 3033, 2922, 2860, 1454, 1269,
1112, 1027, 738, 698, 668 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for C26H27DO3SNa 444.1720; Found 444.1720. [α]D 20(c=1,
DCM): +1.0.
1-Deutero-2,3,5-tri-O-benzyl-4-thio-L-arabitol (27)
Donor 3 (0.16 mmol, 0.075 g), dried by co-evaporating with dry toluene (3x), was dissolved in dry DCM
OBn
S
(5.3 ml) and stirred with freshly activated 3 Å molecular sieves at room temperature for 1 hour under
argon to remove traces of water. The solution was then cooled to -78 oC and TES-d (0.32 mmol), dissolved
in DCM (0.64 ml), was added followed by the addition of TMSOTf (0.21 mmol), dissolved in DCM (0.42
ml). Next, the reaction mixture was stirred on -30 oC for 10 days and quenched by the addition of TEA
(0.5 ml). The reaction mixture was filtered through a path of celite and concentrated in vacuo. Column
OBn
D
OBn
chromatography (pentane: EtOAc, 99/1 – 93/7) yielded the title compound (0.046 g, 0.11 mmol, 68%, α:β = 8 : 92). 1H NMR (400
MHz, CDCl3) δ: 7.37-7.23 (m, 15H), 4.61 (s, 2H), 4.58 – 4.43 (m, 4H), 4.22 – 4.14 (m, 1H), 4.11 (t, J = 3.7 Hz, 1H), 3.68 (dd, J =
8.9, 7.5 Hz, 1H), 3.56 (td, J = 7.3, 6.8, 3.4 Hz, 1H), 3.50 (dd, J = 8.9, 6.2 Hz, 1H), 3.06 (d, J = 5.1 Hz, 0.91H), 2.89 (d, J = 4.2 Hz,
0.09H); 13C{1H} NMR (101 MHz, CDCl3) δ: 138.3, 138.2, 138.0, 128.8-127.7, 85.1, 73.2, 72.6, 72.0, 71.6, 49.1, 33.0 (t); IR (neat):
3088, 3063, 3029, 2926, 2858, 1496, 1454, 1361, 1208, 1093, 1073, 1028, 736, 697 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for
C26H27DO3SNa 444.1720; Found 444.1716. [α]D 20(c=1, DCM): +2.1.
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1-Deutero-2,3,5-tri-O-benzyl-4-thio-D-xylitol (28)
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5
6
7
8
9
Donor 4 (0.09 mmol, 0.043 g), dried by co-evaporating with dry toluene (3x), was dissolved in dry DCM
OBn
S
BnO
(3.0 ml) and stirred with freshly activated 3 Å molecular sieves at room temperature for 1 hour under argon
D
o
to remove traces of water. The solution was then cooled to -78 C and TES-d (0.18 mmol), dissolved in
DCM (0.36 ml), was added followed by the addition of TMSOTf (0.12 mmol), dissolved in DCM (0.24
ml). Next, the reaction mixture was stirred on -30 oC for 10 days and quenched by the addition of TEA (0.5
OBn
ml). The reaction mixture was filtered through a path of celite and concentrated in vacuo. Column chromatography (pentane: EtOAc,
99/1 – 93/7) yielded the title compound (0.023 g, 0.06 mmol, 61%, α:β = 69 : 31). 1H NMR (400 MHz, CDCl3) δ: 7.40 – 7.16 (m,
15H), 4.61 – 4.42 (m, 6H), 4.23 – 4.06 (m, 2H), 3.90 – 3.78 (m, 2H), 3.62 (q, J = 3.9 Hz, 1H), 3.10 (d, J = 4.4 Hz, 0.69H), 2.84 (d, J
= 2.0, 0.31H); 13C{1H} NMR (101 MHz, CDCl3) δ: 138.3, 138.2, 138.1, 128.7-127.7, 83.0, 73.4, 72.8, 71.2, 69.4, 48.1, 32.9 (t); IR:
3089, 3064, 3031, 2925, 2860, 1496, 1454, 1362, 1207, 1098, 1073, 1028, 735, 697 cm-1; HRMS (ESI) m/z: [M + Na] + Calcd for
C26H27DO3SNa 444.1720; Found 444.1715. [α]D 20(c=0.5, DCM): +21.1.
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Associated Content
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Supporting Information: Supplementary data on the optimization of the synthetic procedures, NMR spectra, procedure for computing CEL
maps, detailed description of the CEL-maps and supplementary computational data.
.
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Author Information
Corresponding Author
*E-mail: jcodee@chem.leidenuniv.nl
*E-mail: filippov@lic.leidenuniv.nl
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Notes
The authors declare no competing financial interest.
Acknowledgements
The Netherlands Organization for Scientific Research (NWO) is acknowledged for financial support.
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