Synthesis of l -Deoxyribonucleosides from d -Ribose

Article abstract of DOI:10.1021/acs.joc.8b02002

The preparation of 2-deoxy-l-ribose derivatives or mirror image deoxyribonucleosides (l-deoxyribonucleosides) from d-ribose is reported. Starting from inexpensive d-ribose, an acyclic d-form carbohydrate precursor was synthesized to study a unique carbonyl translocation process. In this novel radical reaction, not only was the configuration of the sugar transformed from the d-form to the l-form, but also deoxygenation at the C(2) position of the sugar was successfully achieved. This is one of the most practical methods for converting a d-sugar to a 2-deoxy-l-sugar in a one-step reaction. To further identify the reaction product, radical reactions followed by treatment with 1,3-propanedithiol and then benzoylation were performed to afford a dithioacetal derivative. The stereochemistry and configuration of the 2-deoxy-l-ribose dithioacetal derivative were confirmed by its X-ray crystal structure. To further apply this methodology, a diethyl thioacetal derivative was formed, followed by selective benzoyl protection, and an NIS-initiated cyclization reaction to give the desired ethyl S-l-2-deoxyriboside, which can be used as a 2-deoxy-l-ribosyl synthon in the formal total synthesis of various l-deoxyribonucleosides, such as l-dT.

Full text of DOI:10.1021/acs.joc.8b02002

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Article
Synthesis of L-Deoxyribonucleosides from D-Ribose
Wei-Syun Song, Si-Xian Liu, and Che-Chien Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02002 • Publication Date (Web): 26 Nov 2018
Downloaded from http://pubs.acs.org on November 26, 2018
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Synthesis of L-Deoxyribonucleosides from D-Ribose
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Wei-Syun Song, Si-Xian Liu, Che-Chien Chang*
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Department of Chemistry, Fu Jen Catholic University.; 510, Zhongzheng Rd., Xinzhuang Dist., New
Taipei City, 24205 Taiwan.; E-mail:080686@mail.fju.edu.tw
[TOC graphic]
O
HN
HO
OPG
5
OH
5
5
O
N
1
glycosylation
1
O
2
O
O
RS
OH
2
2
HO OH
OPG
2-deoxy-L-ribosyl synthon
OH
D-ribose
L-dT
Abstract:
The preparation of 2-deoxy-L-ribose derivatives or mirror image deoxyribonucleosides (L-
deoxyribonucleosides) from D-ribose is reported. Starting from inexpensive D-ribose, an acyclic D-
form carbohydrate precursor was synthesized to study a unique carbonyl translocation process. In this
novel radical reaction, not only was the configuration of the sugar transformed from the D-form to the
L-form, but also deoxygenation at the C(2) position of the sugar was successfully achieved. This is
one of the most practical methods for converting a D-sugar to a 2-deoxy-L-sugar in a one-step reaction.
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To further identify the reaction product, radical reactions followed by treatment with 1,3-
propanedithiol and then benzoylation were performed to afford a dithioacetal derivative. The
stereochemistry and configuration of the 2-deoxy-L-ribose dithioacetal derivative were confirmed by
its X-ray crystal structure. To further apply this methodology, a diethyl thioacetal derivative was
formed, followed by selective benzoyl protection, and an NIS-initiated cyclization reaction to give the
desired ethyl S-L-2-deoxyriboside, which can be used as a 2-deoxy-L-ribosyl synthon in the formal
total synthesis of various L-deoxyribonucleosides, such as L-dT.
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Introduction
L-Deoxysugars are less abundant in nature compared to their mirror image isomers, D-
deoxysugars.1 Among all of the L-deoxysugars, 2-deoxy-L-ribose is obviously an important
carbohydrate, because it could be used as the starting material for the synthesis of many biological
important molecules.2 2-Deoxy-L-ribose also serves as the sugar backbone for preparing unnatural L-
DNA, which could be used in studies of nucleic acid recognition with natural D-DNA.3 Moreover,
modified L-deoxyribonucleosides, such as L-FMAU (Clevudine), L-dT (Telbivudine), and val-L-dC
(Valtorcitabine), are promising antitumor or antiviral drugs.4 These modified L-deoxyribonucleosides
all contain 2-deoxy-L-ribose as their sugar components. It is noteworthy that, even 2-deoxy-L-ribose
itself has been reported to inhibit the growth of tumor cells through its ability to regulate the action of
thymidine phosphorylase (TP).5 Because of such biological importance, a number of synthetic
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methods for preparing 2-deoxy-L-sugar derivatives and L-deoxyribonucleosides have been reported.6-8
Although the synthesis of derivatives of 2-deoxy-L-sugar derivatives and L-deoxyribonucleosides
from less abundant L-sugars has been reported,6 the use of inexpensive D-sugars as starting materials
in their synthesis would be a more practical approach.7 However, preparing L-sugars from inexpensive
D-sugars is complex and involves multiple steps, since all of the stereocenters in the molecule would
need to be changed to the opposite configuration. To produce the L-form of a 2-deoxy sugar would
then require the selective deoxygenation of the C-2 hydroxy group. Lastly, it would be necessary to
convert the 2-deoxy-L-ribose into a suitable 2-deoxy-L-ribosyl sugar donor for glycosylation reactions
with nucleobases, and to eventually produce the desired L-deoxyribonucleosides, as shown in Scheme
1.
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O
HN
H
O
O
H
HO
OH
OH
5
5
5
O
N
OH
OH
OH
OH
H
HO
HO
HO
H
H
2
L
2
1
1
O
O
O
H
H
H
H
HO
OH
2
2
2
D
OH
HO
OH
OH
5
5
D-ribose
2-deoxy-L-ribose
L-dT
Scheme 1 Stereochemical configurations of D-ribose, 2-deoxy-L-ribose, and L-dT.
A unique radical process involving carbonyl translocation was developed recently in this
laboratory,9 as shown in Scheme 2. This carbonyl translocation process was used to transform
inexpensive D-sugars into rare L-deoxysugars.10 However, an early attempt to prepare 2-deoxy-L-
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ribose from a D-hexitol met with only partial success.10c The inefficiency associated with this synthesis
of the radical precursor and the fact that the corresponding alcohol (L-2-deoxyribitol) was produced,
rather than 2-deoxy-L-ribose itself prompted us to develop a more practical methodology. A practical
synthetic approach that starts from a simple D-sugar and ends with the formation of the mirror image
deoxyribonucleosides, L-deoxyribonucleosides, would be highly attractive for organic chemists
because of the potential biological properties of such compounds.
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O
BzO
carbonyl
translocation
BzO
O
n
R
R
R = H or CH3
n = 1 or 2
Br
n
Scheme 2 Radical cyclization followed by fragmentation of a carbonyl compound.
Retrosynthetic plan
Herein, we report on an efficient synthetic methodology for converting a simple D-sugar to a deoxy-
L-nucleoside. In our retrosynthetic plan, a 2-deoxy-L-ribosyl sugar synthon could be used to prepare
various L-deoxyribonucleosides. This 2-deoxy-L-ribosyl sugar synthon was envisioned to arise from
the selective cyclization reaction of a dithioacetal derivative, which can be directly generated using
our previously developed carbonyl translocation process. Using this radical process, it is possible to
transform a D-ribose derivative into a 2-deoxy-L-ribose derivative in a one-step reaction. The radical
precursor could be prepared from the commercially available D-ribose, as shown in Scheme 3.
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The Journal of Organic Chemistry
O
N
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2
3
4
5
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8
RS
SR
OR
HN
5
dithioacetal
nucleobase
cyclization
H
RO
HO
RO
H
H
H
2
L
OH
O
5
RS
O
2
O
OR
2
5
OH
2-deoxy-L-ribosyl
sugar synthon
9
L-deoxyribonucleoside
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O
5
O
OR
carbonyl
translocation
Fischer
HO
5
2
H
OR
OR
2
OR
OR
OR
Br
O
2
180o
RO
OH
2
H
RO
L
D
HO OH
RO
5
O
5
2-deoxy-L-ribose
derivative
D-ribose
D-ribose
derivative
Scheme 3 Retrosynthetic plan.
Results and Discussion
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The inexpensive D-ribose was used as the starting material, as shown in Scheme 4. To differentiate
between all of the hydroxyl groups, the C2 and C3 hydroxyl groups (syn orientation) were protected
by an isopropylidine group, thus leaving the primary (C5) hydroxyl group available for further
manipulation. The conditions for this reaction involved reacting the starting material with acetone in
the presence of conc. H2SO4 to give compound 1.11 Protecting carbonyl group using a Wittig
phosphonium salt (Ph3PMeBr) and potassium tert-butoxide (KOt-Bu) afforded the acyclic compound
2.11 Selective bromination of the primary hydroxyl group using p-toluenesulfonyl chloride (TsCl) and
a catalytic amount of dibutyltin oxide (Bu2SnO),12 followed by treatment with tetrabutylammonium
bromide (TBAB)13 smoothly generated compound 4. The remaining hydroxyl group was protected by
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5
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7
8
a benzoyl group (Bz) to give compound 5. Ozonolysis then afforded the radical precursor 6 in only
six steps, which is a far more efficient than a previous synthesis in which a D-hexoitol was used as the
starting material.10c This radical precursor 6 was directly used, without further purification, in the
following radical reactions.
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HO
OH
HO
O
OH
HO
a
b
O
O
OH
O
O
O
HO OH
D-ribose
1
2
OH
OH
TsO
Br
c
d
O
O
O
O
3
4
O
OBz
OBz
e
Br
f
Br
O
O
O
O
5
6
Scheme 4 Reagents and Conditions: (a) conc. H2SO4, acetone, rt, 2 h, 71%; (b) Ph3PMeBr, KOt-Bu,
THF, reflux, 1 h, 78%; (c) p-TsCl, Bu2SnO, Et3N, CH2Cl2, 0 oC~rt, 5.5 h, 95%; (d) Bu4N+Br, DMF,
7080 oC, 1 h, 88%; (e) BzCl, Et3N, DMAP, CH2Cl2, 0 oC~rt, 7 h, 90%; (f) O3, CH2Cl2, 78 oC, then
Me2S, 78 oC to rt, 4 h, 99%.
A series of radical reactions involving radical cyclization followed by the fragmentation of molecule
6 bearing an isopropylidine protecting group were studied. The product ratios as a function of slow
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addition and reaction time are shown in Table 1. Standard radical reaction conditions using two
different hydrogen sources, i.e., tributyltin hydride (entry 14) and tristrimethylsilylsilane (TTMSS,
entry 58) were tested. The first attempt involved the use of previously developed conditions (entry
1; Bu3SnH/AIBN = 1.5/0.2 equiv).10c The 1H spectrum of the crude reaction mixtures indicated that
the desired product 7 was formed along with the unexpected over-reduction product 8 and the
elimination product 9 in a ratio of 7:8:9 =1:1.09:0.16. This result indicates that the isopropylidine
protecting group covering the syn-diol groups on the molecules 6 may enhance the reaction efficiency
of carbonyl translocation processes.14 However, it was not possible to isolate the desired product 7
bearing a -leaving group (OBz).15 The side reaction product 8 was formed by the further reduction
of compound 7 with an excess amount of Bu3SnH reagent. The side reaction product 9 was generated
by an elimination reaction of compound 7. Other attempts (entry 23) to decrease the reagent
equivalents provided the best results (entry 3 table 1) in the products ratios of (7:8:9 =1:0.15:0.01).
A further reduction in the reagent equivalents and a decrease in the reaction time (entry 4) failed to
afford better product ratios. Oxidation of alcohol 8 back to the desired compound 7 is difficult due to
the instability of these reaction products.
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Table 1 Radical cyclization/fragmentation reactions of the precursor 6.
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O
OBz
OBz
OBz
1
2
3
4
reagents
toluene
Br
HO
+
O
O
O
O
O
O
O
O
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6
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6
7
8
OBz
O
O
9
+
+
O
10
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O
9
10
products ratioa
7 8:9
entry AIBN/Bu3SnH concentration slow addition reaction time
(equivalents)
(M)
(mins)
(mins)
( :
)
1:1.09:0.16b
1:1.04:0.14
1:0.15:0.01c
1:0.23:0.06
1
2
3
4
0.03
0.03
0.03
0.03
0
0
0
0
10
10
7
(0.2/1.5)
(0.2/1.2)
(0.1/1.05)
(0.05/1.0)
5
products ratioa
concentration slow addition reaction time
entry AIBN/TTMSS
(equivalents)
(M)
(mins)
(mins)
7 10
( :
)
1:1.64d
1:1.16
5
0.03
0.03
120
30
120
120
(0.2/1.5)
6
(0.2/1.5)
7
8
(0.2/1.5)
(0.2/1.5)
0.03
0.03
15
7
120
120
1:1.28
1:1.29
a Product ratios were determined by 1H NMR integrations.
b
7
8
Compound was unable to isolated; compound was isolated in 29%.
c The best result in this table
d
10
Compound
was isolated in 25%.
Tristrimethylsilylsilane (TTMSS) is an alternative reagent16 for decreasing the reduction products in
the hydrogen abstraction step because the SiH bond of TTMSS is relatively stronger than the SnH
bond of Bu3SnH.17 Under standard slow addition conditions (entry 5, addition time of 2h), the desired
product 7 along with a byproduct 10 were formed in a ratio of 7:10 =1:1.64. The byproduct 10 was
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produced as a result of the intramolecular hydrogen abstraction from the aldehyde CH bond, followed
by the elimination of a molecule of carbon monoxide (CO). To reduce the amount of byproduct 10
that is formed in the reaction, the addition time was gradually decreased from 120 mins to 7 mins.
However, no improvements in product ratios were detected from this technique (entry 6-8). The use
of TTMSS as the hydrogen source resulted in a decrease in the amount of reduction product 8, but the
rate for the intermolecular hydrogen abstraction step was also lowered. Therefore, the fragmentation
product 10 was produced when TTMSS was used as the hydrogen source (entry 5-8, Table 1).
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1
2
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5
O
O
O
BzOH
AIBN, Bu3SnH
or (TMS)3SiH
9
6
7
8
9
O
OBz
OBz
Bu3Sn
Br
O
O
10
11
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O
Bu3SnH
O
O
6
7
OBz
Bu3Sn
(TMS)3Si
Bu3SnH
HO
Bu3SnBr
O
(TMS)3SiH
O
(TMS)3SiBr
8
O
O
OBz
OBz
O
O
O
O
13
11
O
aldehyde
sp2 CH
aldehyde
sp2 CH
BzO
O
O
12
O
OBz
OBz
OBz
CO
CO
O
O
O
O
then Bu3SnH
or (TMS)3SiH
then Bu3SnH
or (TMS)3SiH
O
O
O
10
14
15
Scheme 5 Proposed mechanism.
A proposed mechanism for this radical reaction is shown in Scheme 5. Tributyltin radical or
tris(trimethylsilyl)silyl (TTMSS) radical were generated respectively by reaction with Bu3SnH or
TTMSS with AIBN. In the cases of tributyltin-mediated reactions (entry 1-4, Table 1), the tributyltin
radical reacts with compound 6 to give an alkyl radical 11. Radical cyclization affords the cyclic
alkoxy radical 12. In our systems, -fragmentation occurs to generate the -oxy radical 13 upon
regeneration of a carbonyl -bond, resulting in the carbonyl translocation process. The -oxy radical
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13 abstracts a hydrogen atom from Bu3SnH to afford the desired product 7 with regeneration of the
tributyltin radical, which could participate in radical chain reactions. When an excess amount (1.5
equiv) of Bu3SnH was used (entry 1, table 1), the over-reduction product 8 was obtained from the
reactions of the product 7 with an excess amount of tributyltin radical/tributyltin hydride (Bu3SnH).
The byproduct 9 is generated via elimination reactions of the product 7, assisted by the Lewis acidity
of tributyltin bromide (Bu3SnBr).18 The formation of compound 8 and 9 could be suppressed
efficiently by reducing the amount of Bu3SnH used in the reaction (entry3, table 1).
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In the cases of tris(trimethylsilyl)silyl (TTMSS) radical-mediated reactions (entry 5-8, Table 1), the
product 7 could be generated in a similar manner, through radical cyclization followed by a
fragmentation process. However, the different results were observed. The byproduct 10 is formed
through TTMSS-mediated reactions. Two mechanisms are possible for the formation of compound
10. The first possibility is from the alkyl radical 11. If the cyclization (11 12) is not an efficient
process, intramolecular hydrogen abstraction from the aldehyde CH bond (11 15) proceeds to give
the acyl radical 15.19 Compound 10 is obtained upon the release of a CO molecule from the radical 15.
The second possibility is from the -oxy radical 13. Because the SiH bond is relatively stronger than
the SnH bond, hydrogen abstraction from TTMSS would be relatively slower than an abstraction
from Bu3SnH. The -oxy radical 13 abstracts a hydrogen atom from TTMSS to give the product 7,
which is not an efficient process. Therefore, the intramolecular abstraction of hydrogen from its
aldehyde CH bond (13 14) occurs, in part, to give the acyl radical 14.19 Followed by the elimination
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of a CO molecule, the product 10 could also be produced through this process. However, the
concentration effect (entries 68, Table 1) indicates that adjustments in a slow addition time (from
120 mins to 7 mins) had almost no influence on the product ratios. It can therefore be concluded that
compound 10 may be formed from the alkyl radical 11 through the acyl radical 15 upon releasing a
CO molecule.19
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In general, the compound 6 bearing an isopropylidine protecting group on the syn-diol moieties
showed an enhanced cyclization rate to give the desired product 7 through cyclization followed by a
fragmentation process. However, an excess amount of Bu3SnH reagent would result in the formation
of the over-reduction product 8 and the elimination product 9. But this could be suppressed by lowing
the amount of Bu3SnH reagent used in the reaction. In the TTMSS-mediated reactions, neither the
cyclization reaction (11  12) nor hydrogen abstraction (13  7) are efficient processes. Hence, both
radicals 11 and 13 are involved in partial elimination reactions to give the compound 10 upon releasing
a molecule of CO.
Concerning the synthesis of the mirror image deoxyribonucleoside, the radical reaction product 7
needed to be isolated and its stereochemistry indirectly confirmed. The crude reaction mixture from
the radical reaction (entry 3, Table 1) was directly treated with 1,3-propanedithiol in the presence of
.
borontrifluoride-diethyletherate (BF3 OEt2)20 to give the dithiane 16 with partial deprotection of the
isopropylidine group, as shown in Scheme 6. Therefore, direct quenching with aqueous hydrochloride
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(0.1 N) furnished compound 16 in 51% (over four steps, 5  16). At this stage, we confirmed that we
developed a unique methodology for transforming D-ribose to a 2-deoxy-L-ribose derivative 16 in 7
steps.21 The dithiane 16 is a convenient synthon for many syntheses in which dithioacetal 2-deoxy-L-
ribose is used.22 Direct protection of the two other hydroxyl groups of compound 16 produced
compound 17 as a while solid. The stereochemistry and configuration of compound 17 was confirmed
by an X-ray crystal structure analysis, which showed that it is indeed a derivative of 2-deoxy-L-ribose
with a (3R,4S) configuration, as shown in Figure 1. Compared to previously reported methods, 21 this
is one of the practical method for transforming D-ribose to 2-deoxy-L-ribose.
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O
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S
OBz
g
h
Br
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R
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OH
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OH
OBz
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o
Scheme 6 Reagents and Conditions: (g) 1) AIBN, Bu3SnH, toluene, 88 C, 7 min; 2) 1,3-
propanedithiol, BF3 OEt2, CH2Cl2, 10 oC, 30 min; 3) 0.1 N HCl, 0 oC, 1 h, 51% (over four steps); (h)
.
BzCl, Et3N, CH2Cl2, 0 oC~rt, 10 h, 63%.
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Figure 1. X-ray crystal structure of compound 17 with a (3R,4S) configuration.
To extend this synthetic methodology to the synthesis of the mirror image deoxyribonucleoside or L-
DNA, an acyclic dithiane (diethylthio acetal) derivative was employed to prepare an alkyl S-2-deoxy-
L-riboside, which is a 2-deoxy-L-ribosyl sugar synthon for glycosylation reactions with a nucleobase,
as shown in Scheme 7. Direct treatment of the crude radical products with ethanethiol (EtSH) in the
.
presence of BF3 OEt2 and followed by quenching with an aqueous HCl solution completed the
formation of the diethylthio acetal 18 with a 2-deoxy-L-ribose configuration.23 Regioselective
benzoylation in the presence of a catalytic amount of dimethyltin dichloride (Me2SnCl2) gave
compound 19.24 A NIS-promoted cyclization reaction25 furnished ethyl S-2-deoxy-L-riboside 20,
which can be used as a 2-deoxy-L-ribosyl sugar synthon for the synthesis of various L-
deoxyribonucleosides. Compared to other syntheses,21 We could use this synthetic methodology for
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converting D-ribose to a 2-deoxy-L-ribosyl sugar synthon 20 in nine steps and to L-
deoxyribonucleosides in ten steps. Formal total synthesis of L-dT could be completed by treating S-2-
deoxy-L-riboside 20 with silylated Thymine, as reported in the literature.26
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O
OBz
EtS
EtS
OBz
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EtS
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i
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OH
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OH
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OBz
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OBz
EtS
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Scheme 7 Reagents and Conditions: (i) 1) AIBN, Bu3SnH, toluene, 88 oC, 7 min; 2) EtSH, BF3 OEt2,
CH2Cl2, 10 oC, 30 min; 3) 0.1 N HCl, 0 oC, 1 h, 43% (over four steps); (j) BzCl, Me2SnCl2, K2CO3,
THF, 0 oC~rt, 1.5 h, 63%; (k) NIS, CH2Cl2, 0 oC, 15 min, 62%; (l) Silylated Thymine, NBS, DCM, rt.
10 h, 99 %, (/ = 1/0.3).
Conclusions
A synthetic approach for preparing mirror image deoxyribonucleosides (L-deoxyribonucleoside) from
D-ribose is reported. Starting from inexpensive D-ribose, an acyclic D-form carbohydrate precursor
was synthesized and then used in a unique radical reaction involving a carbonyl translocation process.
In this novel radical reaction, not only was the configuration of the sugar transformed from D to L, but
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deoxygenation at the C(2) position of the sugar could be achieved. This is one of the most practical
methods for converting a D-sugar to a 2-deoxy-L-sugar in a single organic reaction. To further identify
the reaction product, radical reactions followed by treatment with 1,3-propanedithiol and further
benzoylation afforded a dithioacetal derivative. The stereochemistry and configuration of the L-2-
deoxyribose derivative were confirmed by an X-ray crystal structure. To further apply this
methodology to the synthesis of L-deoxyribonucleosides, diethyl thioacetal formation, followed by
selective benzoyl protection, and an NIS-initiated cyclization reaction gave the desired ethyl S-2-
deoxy-L-riboside, which can be used as a 2-deoxy-L-ribosyl sugar synthon for the synthesis of various
L-deoxyribonucleosides. This synthetic methodology represents another method for preparing mirror
image deoxynucelosides, such as L-dT, starting from an inexpensive D-sugar. The overall conversion
was completed within ten steps. Since some L-deoxyribonucleosides are antitumor or antiviral agents,
the development of potential L-deoxyribonucleosides with chemotherapeutic activities using these
methods are currently underway. Meanwhile, a combination of the methods here and phosphorylation
methods27 developed in our laboratory for the synthesis of various L-deoxynucleotides or L-DNA are
also ongoing.
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Experimental Section
General. 1H NMR (300 MHz),13C{1H}-DEPT-NMR (75 MHz) for proton-decoupled carbon data, 2D
spectra were recorded on a 300 MHz. The NMR spectra were recorded in CDCl3 or CD3OD.
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Chloroform (δ = 7.26 ppm in 1H NMR; δ = 77.0 ppm in 13C NMR) and methanol (δ = 3.31 ppm in 1H
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NMR; δ = 49.00 ppm in C NMR) were used as internal standard, respectively. Splitting patterns
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were reported as following: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet. Coupling constant
(J) was reported in Hz. IR were recorded on a FT-IR spectrometer and reported in cm1. High
resolution mass spectrometry (HRMS) were recorded on a LCMS-IT-TOF spectrometer (ESI-MS) or
a magnetic sector spectrometer (EI-MS). Optical rotations were measured on a Digital polarimeter.
Crystallographic data were obtained from a Single Crystal XRD. Elementary analysis (EA) were
recorded on a cube spectrometer. TLC (0.25 mm) precoated sheet was used. The reaction products
were isolated by flash chromatography performed on (0.0400.063 mm) silica gel. Yields of products
refer to chromatographically purified products unless otherwise stated. THF were distilled by refluxing
them over traces of sodium metal using benzophenone as indicator under N2. Toluene were distilled
by refluxing them over traces of sodium metal under N2. Dichloromethane, pyridine, triethylamine,
and dimethylformamide were dried over CaH2 and then distilled. Methanol and ethanol was dried over
magnesium/iodine and then distilled. Benzoyl chloride were distilled before use. The toluene used for
radical cyclizations was deoxygenated by passing a gentle stream of argon through for 30 min before
use. All reactions were performed under a blanket of N2 or Ar.
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2,3-O-Isopropylidene-β-D-ribofuranose (1)
To a solution of D-ribose (4.00 g, 26.64 mmol) in 40 mL of reagent grade acetone was slowly
added con. H2SO4 (0.12 mL). The reaction mixture was stirred at rt for 1.5 h. The reaction mixture
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was added solid NaHCO3 to neutralize the solution until the pH value was 7 and then directly
concentrated to give a crude product, which was purified by flash chromatography with the eluent of
EtOAc/hexanes = 60/40 to give the desired product 1 (3.56 g, 70%) as a colorless oil. [α]23D 39.05 (c
= 1.68, acetone); IR (neat) 3373 (OH), 1265 (CO) cm1; 1H NMR (300 MHz, CDCl3) δ 5.39 (d, J =
6.0 Hz, 1H, H1), 5.19 (br s,1H, OH), 4.81 (d, J = 6.0 Hz, 1H, H3), 4.56 (d, J = 6.0 Hz, 1H, H2), 4.38
(br s, 1H, H4), 3.93 (br s, 1H, OH), 3.773.62 (m, 2H, H5, H5'),1.47 (s, 3H), 1.31 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 112.1 (C), 102.8 (CH), 87.7 (CH), 86.7 (CH), 81.6 (CH), 63.5 (CH2), 26.3 (CH3),
24.7 (CH3); HRMS (ESI): m/z calcd. for C8H13O5 [MH]: 189.0762; found: 189.0759.
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5,6-Dideoxy-3,4-O-isopropylidene-D-ribo-hex-5-enitol (2)
To a refluxing solution of methyltriphenylphosphonium bromide (2.94 g, 8,23 mmol) in 8 mL of
tetrahydrofuran was added potassium tert-butoxide (0.74 g, 6.58 mmol). The mixture was refluxed for
30 mins, and then was added a solution of compound 1 (0.63 g, 3.29 mmol) in 8.5 mL of
tetrahydrofuran. The mixture was refluxed for another 1 h. The reaction was quenched with water (30
mL) and then concentrated to dryness under vacuum. The residue was dissolved in EtOAc (150 mL),
washed with saturated NaHCO3(aq) (50 mL), and brine (50 mL). The organic layer was dried over
MgSO4 and concentrated to give a crude product, which was purified by flash chromatography with
the eluent of EtOAc/hexanes = 7/3 to 1/5 to give the desired product 2 (0.48 g, 77%) as a colorless oil.
[α]20D 5.86 (c = 2.71, CHCl3); IR (neat) 3407 (OH) cm1 ; 1H NMR (300 MHz, CDCl3) δ 6.01 (ddd,
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J = 17.1, 10.2, 7.0 Hz, 1H, H5), 5.46 (d, J = 17.1 Hz, 1H, H6), 5.33 (d, J = 10.5 Hz, 1H, H6'), 4.70 (t,
J = 6.6 Hz, 1H, H4), 4.10 (t, J = 7.1 Hz, 1H, H3), 3.863.77 (m, 1H, H1), 3.773.66 (m, 2H, H1', H2),
2.37 (br s,2H, OH), 1.47 (s, 3H), 1.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 133.7 (C), 118.5 (CH2),
109.0 (C), 78.5 (CH), 78.1 (CH), 69.8 (CH), 64.3 (CH2), 27.7 (CH3), 25.2 (CH3); HRMS (ESI) :
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m/z calcd. for C9H17O4 [MH]: 189.1121; found: 189.1122.
5,6-Dideoxy-3,4-O-isopropylidene-1-O-toluenesulfonate-D-ribo-hex-5-enitol (3)
To a solution of compound 2 (3.71 g, 19.71 mmol) in 66 mL of dry CH2Cl2 was added dibutyltin
oxide (0.10 g, 0.39 mmol). This solution was then cooled to 0 °C before triethylamine (4.10 mL, 29.57
mmol) was added. Then, the reaction solution was added p-toluenesulfonyl chloride (4.13 g, 21.68
mmol) under Ar. The resulting mixture was stirred at rt for 5.5 h. The reaction was then quenched with
water (80 mL) and concentrated to dryness under vacuum. The residue was dissolved in EtOAc (240
mL), washed with saturated NaHCO3(aq) (80 mL), and brine (80 mL). The organic layer was dried over
MgSO4 and concentrated to give a crude product, which was purified by flash chromatography with
the eluent of EtOAc/hexanes = 30/70 to give the desired product 3 (6.42 g, 95%) as a colorless oil.
[α]24D 29.20 (c = 2.12, CHCl3); IR (neat) 3579 (OH) cm1 ; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J
= 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.93 (ddd, J = 17.1, 10.5, 6.5 Hz, 1H, H5), 5.42 (d, J = 17.1
Hz, 1H, H6), 5.28 (d, J = 10.5 Hz, 1H, H6'), 4.68 (t, J = 6.3 Hz, 1H, H4), 4.31 (dd, J = 10.5, 2.3 Hz,
1H, H1), 4.07 (dd, J = 10.5, 6.6 Hz, 1H, H1'), 4.00 (dd, J = 9.0, 6.3 Hz, 1H, H3), 3.84 (t, J = 6.8 Hz,
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1H, H2), 2.45 (s, 3H, PhCH3), 1.39 (s, 3H), 1.31 (s, 3H); C NMR (75 MHz, CDCl3) δ 145.1 (C),
133.1 (CH), 132.6 (C), 129.9 (CH), 128.1 (CH), 118.4 (CH2), 109.1 (C), 78.2 (CH), 77.5 (CH), 72.2
(CH2), 68.3 (CH), 27.6 (CH3), 25.2 (CH3), 21.7 (CH3) ； HRMS (ESI) : m/z calcd. for
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C16H22O6SNa [MNa]: 365.1029; found: 365.1031.
1-Bromo-5,6-dideoxy-3,4-O-isopropylidene-D-ribo-hex-5-enitol (4)
To a flask containing solid tetrabutylammonium bromide (7.50 g, 23.15 mmol) was dried under
reduced pressure at 5060 °C for 3 h, and then it was added a solution of compound 3 (3.17 g, 9.26
mmol) in 46 mL of dry dimethylformamide. The resulting mixture was stirred at 7080 °C for 1 h.
The reaction was concentrated to dryness under vacuum. The residue was dissolved in EtOAc (230
mL), washed with water (45 mL), saturated NaHCO3(aq) (45 mL), and brine (45 mL). The organic layer
was dried over MgSO4 and concentrated to give a crude product, which was purified by flash
chromatography with the eluent of EtOAc/hexanes = 10/90 to 30/70 to give the desired product 4 (2.05
g, 88%) as a colorless oil. [α]25D 12.80 (c = 2.13, CHCl3); IR (neat) 1217 (C-O) cm1 ; 1H NMR (300
MHz, CDCl3) δ 6.00 (ddd, J = 17.1, 10.5, 6.6 Hz, 1H, H5), 5.46 (dt, J = 17.1, 1.5 Hz, 1H, H6), 5.32
(dt, J = 10.5, 1.5 Hz, 1H, H6'), 4.72 (t, J = 6.5 Hz, 1H, H4), 4.06 (dd, J = 8.7, 6.3 Hz, 1H, H3), 3.813.71
(m, 2H, H1,H2), 3.58 (dd, J = 10.5, 7.1 Hz, 1H, H1'), 2.21 (d, J = 5.4 Hz, 1H, OH), 1.47 (s, 3H), 1.37
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 133.4 (C), 118.3 (CH2), 109.1 (C), 78.6 (CH), 78.3 (CH), 69.2
(CH), 38.5 (CH2), 27.7 (CH3), 25.3 (CH3); Note: this is a special case. Due to the molecular ion (M+)
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is not stable in the ion channel, several attempts to obtain the molecular peak (M+) were not successful.
Eventually, we found a peak of (M+CH3), which could be referred to the elimination of a [CH3]
fragment from the isopropylidine group. HRMS (EI): m/z calcd. for C8H12O379Br [MCH3]:
234.9969; found: 234.9967; m/z calcd. for C8H12O381Br [MCH3]: 236.9949; found:
236.9956.
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2-Benzoyl-1-bromo-5,6-dideoxy-3,4-O-isopropylidene-D-ribo-hex-5-enitol (5)
To a solution of compound 4 (3.98 g, 15.85 mmol) in 53 mL of dry CH2Cl2 was added 4-
dimethylaminopyridine (0.02 g, 0.16 mmol). This solution was then cooled to 0 °C before
trimethylamine (3.30 mL, 23.77 mmol) and benzoyl chloride (2.20 mL, 19.02 mmol) were added. The
resulting mixture was stirred at rt for 7 h. The reaction was quenched with water (10 mL) and then
concentrated to dryness under vacuum. The residue was dissolved in EtOAc (240 mL), washed with
saturated NaHCO3(aq) (80 mL), and brine (80 mL). The organic layer was dried over MgSO4 and
concentrated to give a crude product, which was purified by flash chromatography with the eluent of
EtOAc/hexanes = 1/20 to give the desired product 5 (5.63 g, 90%) as a colorless oil. [α]25D 24.28 (c
= 2.07, CHCl3); IR (neat) 1723 (C=O) cm1; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H),
7.59 (tt, J = 7.5, 1.5 Hz, 1H), 7.45 (t, J = 6.9 Hz, 2H), 5.77 (ddd, J = 17.1, 10.2, 6.8 Hz, 1H, H5), 5.32
(dt, J = 17.1, 1.3 Hz, 1H, H6), 5.135.04 (m, 2H, H6', H2), 4.76 (t, J = 6.5 Hz, 1H, H4), 4.57 (dd, J =
8.4, 6.3 Hz, 1H, H3), 3.83 (dd, J = 3.3, 1.1 Hz, 2H, H1), 1.52 (s, 3H), 1.43 (s, 3H); 13C NMR (75 MHz,
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CDCl3) δ 165.1 (C), 133.4 (CH), 132.0 (CH), 129.7 (CH×2), 129.5 (C), 128.4 (CH×2), 118.5 (CH2),
109.3 (C), 78.1 (CH), 76.3 (CH), 69.8 (CH), 33.3 (CH2), 27.7 (CH3), 25.3 (CH3)； HRMS (ESI) :
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m/z calcd. for C16H20O479Br [MH]: 355.0539; found: 355.0540; m/z calcd. for
C16H20O481Br [MH]: 357.0519; found: 357.0514.
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2-Benzoyl-1-bromo-3,4-O-isopropylidene-D-ribose (6)
The compound 5 (0.62 g, 1.74 mmol) was dissolved in 17 mL of dry CH2Cl2 in a round-bottomed
flask with the concentration of 0.1 M. The solution was cooled to 78 °C, and then a stream of ozone
(O3) was bubbled into the reaction solution through a pipet for about 20 min. Once the color of the
solution turned blue, oxygen (O2) was continuously bubbled into the reaction for another 5 min in
order to disperse the ozone remained in the reaction solution. While the color of solution turned from
blue to colorless, excess of Me2S (3.5 mL) was added at 78 °C. The reaction temperature was allowed
to warm up gradually to the room temperature and the reaction mixture was stirred at rt for 4 h. The
resulting solution was directly concentrated to give the desired aldehyde product 6 (0.62 g, >99%) as
a colorless viscous liquid. [α]23D 32.16 (c = 1.83, CHCl3); IR (neat) 1728 (C=O) cm1 ; 1H NMR (300
MHz, CDCl3) δ 9.65 (d, J = 3.0 Hz, 1H, H1), 8.00 (d, J = 7.2 Hz, 2H), 7.60 (tt, J = 7.4, 1.6 Hz, 1H),
7.47 (t, J = 7.7 Hz, 2H), 5.27 (dt, J = 7.8,3.9 Hz, 1H, H4), 4.87 (t, J = 7.4 Hz, 1H, H3), 4.59 (dd, J =
6.9, 2.9 Hz, 1H, H2), 3.84 (dd, J = 11.4, 4.2 Hz, 1H, H5), 3.76 (dd, J = 11.4, 3.6 Hz, 1H, H5'), 1.58 (s,
3H), 1.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 198.4 (CH), 164.9 (C), 133.7 (CH), 129.9 (CH×2),
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128.9 (C), 128.6 (CH×2), 111.6 (C), 80.7 (CH), 76.8 (CH), 69.4 (CH), 31.8 (CH2), 27.4 (CH3), 25.3
(CH3); HRMS (ESI): m/z calcd. for C15H18O579Br [MH]: 357.0332; found: 357.0334;
m/z calcd. for C15H18O591Br [MH]: 359.0312; found: 359.0308.
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(3R,4S)-3-Benzoyl-4,5-O-isopropylidene-1,3,4,5-pentanetetrol (8)
To a refluxed solution of the radical precursor 6 (85.90 mg, 0.24 mmol) in 4 mL of toluene at 88
°C was added a solution of AIBN (8.00 mg, 0.05 mmol) and tributyltin hydride (0.10 mL, 0.36 mmol)
in 4 mL of toluene. The resulting solution was continuously stirred at the same temperature for 10
min. The solution was then cooled down and directly concentrated to give a crude product, which was
purified by flash chromatography with the eluent of EtOAc/hexanes = 40/60 to give the desired
product 8 (19.2 mg, 29%) as a colorless oil. [α]26D 119.48 (c = 0.12, CHCl3); IR (neat) 3437 (OH),
1718 (C=O) cm1 ; 1H NMR (300 MHz, CDCl3) δ 8.05 (d,J = 7.9 Hz, 2H), 7.59 (tt, J = 7.5, 1.5 Hz,
1H), 7.45 (t, J = 7.5 Hz, 2H), 5.32 (ddd, J = 9.3, 5.7, 3.6 Hz, 1H, H3), 4.32 (q, J = 6 Hz, 1H, H4), 4.13
(dd, J = 8.4, 6.6 Hz, 1H, H5), 3.94 (dd, J = 8.4, 1.6 Hz, 1H, H5'), 3.75 (ddd, J = 11.7, 5.6, 4.4 Hz, 1H,
H1), 3.63 (ddd, J = 11.7, 9.8, 3.8 Hz, 1H, H1'), 2.152.02 (m, 1H, H2), 1.881.76 (m, 1H, H2'), 1.39 (s,
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3H), 1.37 (s, 3H); C NMR (75 MHz, CDCl3) δ 166.8 (C), 133.4 (CH), 129.8 (CH×2), 129.5 (C),
128.5 (CH×2), 109.9 (C), 77.0 (CH), 72.0 (CH), 66.2 (CH2), 58.2 (CH2), 34.2 (CH2), 26.4 (CH3), 25.1
(CH3); HRMS (ESI): m/z calcd. for C15H21O5 [MH]: 281.1384; found: 281.1387.
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(2S,3R)-2-Benzoyl-3,4-O-isopropylidenebutane (10)
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To a refluxed solution of the radical precursor 6 (0.20 g, 0.57 mmol) in 9.5 mL of toluene at 88
°C was added a solution of AIBN (0.02 g, 0.11mmol) and TTMSS (0.26 mL, 0.86 mmol) in 9.5 mL
of toluene over 1h via a syringe pump. The resulting solution was continuously stirred at the same
temperature for another 2h. The solution was then cooled and directly concentrated to give a crude
product, which was purified by flash chromatography with the eluent of EtOAc/hexanes = 1/12 to give
the desired product 10 (39.40 mg, 25%) as a colorless oil. [α]23D 34.16 (c = 0.57, CHCl3); IR (neat)
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1718 (C=O) cm1; H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 7.8Hz, 2H), 7.55 (tt, J = 7.2, 1.5 Hz,
1H), 7.43 (t, J = 7.5 Hz, 2H), 5.255.14 (m, 1H, H2), 4.23 (q, J = 5.9 Hz, 1H, H3), 4.11 (dd, J = 8.4,
6.8 Hz, 1H, H4), 3.92 (dd, J = 8.4, 6 Hz, 1H, H4'), 1.38 (d, J = 6.6 Hz, 3H, H1, overlapping with two s
at 1.40 and at 1.37, CH3×2, 9H); 13C NMR (75 MHz, CDCl3) δ 165.7 (C), 133.0 (CH), 130.2 (C),
129.6 (CH×2), 128.3 (CH×2), 109.7 (C), 77.7 (CH), 71.1 (CH), 66.1 (CH2), 26.4 (CH3), 25.2 (CH3),
16.3 (CH3); HRMS (ESI) : m/z calcd. for C14H19O4 [MH]: 251.1278; found: 251.1279.
(3R,4S)-1-(1,3-Dithian-2-yl)-4,5-dihydroxypentan-2-yl benzoate (16)
To a refluxed solution of the radical precursor 6 (0.44 g, 1.22 mmol) in 20.4 mL of toluene at 88
°C was added a solution of AIBN (0.02 g, 0.12 mmol) and tributyltin hydride (0.34 mL,1.28 mmol)
in 20.3 mL of toluene. The resulting solution was continuously stirred at the same temperature for 7
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min. The solution was then cooled and directly concentrated to give a crude residue, which was directly
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To a solution of the previous crude residue (0.34 g, 1.22 mmol) in 2.4 mL of CH2Cl2 were added
1,3-propanedithiol (0.25 mL, 2.44 mmol) and BF3·OEt2 (1.30 mL, 9.77 mmol) at −10 °C. The reaction
mixture was stirred at the same temperature for 30 min then was added 0.1 N HCl (2.4 mL) at the
same temperature. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was worked
up by addition of saturated NaHCO3(aq) and then concentrated to dryness under vacuum. The residue
was dissolved in EtOAc (100 mL) washed with saturated NaHCO3(aq) (20 mL× 2) and brine (20 mL),
dried over MgSO4, filtered, and concentrated to give a crude product, which was purified by flash
chromatography with the eluent of EtOAc/hexanes =30/70 to 50/50 to give the desired product 16
(0.21 g, 51%, over four steps) as a coloress oil. [α]23D 47.19 (c = 1.04, CHCl3); IR (neat) 3045 (OH),
1716 (C=O) cm1; 1H NMR (300 MHz, CDCl3) 8.07 (d, J = 8.1 Hz, 2H), 7.60 (tt, J = 7.4, 1.6 Hz, 1H),
7.46 (t, J = 7.5 Hz, 2H), 5.32 (ddd, J = 9.3, 7.1, 2.6 Hz, 1H, H3), 4.13 (dd, J = 9.0, 5.3 Hz, 1H, H1),
3.763.55 (m, 3H, H4,H5, H5') 2.902.70 (m, 6H, SCH2×2, OH×2), 2.49 (ddd, J = 15.0, 9.3, 2.7 Hz,
1H, H2'), 2.29 (ddd, J = 15.0, 9.5, 5.6 Hz, 1H, H2), 2.132.00 (m, 1H, SCH2CH2) 1.941.80 (m, 1H,
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SCH2CH2); C NMR (75 MHz, CDCl3) δ 167.1 (C), 133.6 (CH), 130.0 (CH×2), 129.3 (C), 128.5
(CH×2), 72.9 (CH), 71.9 (CH), 62.1 (CH2), 43.6 (CH), 36.8 (CH2), 29.9 (CH2), 29.6 (CH2), 25.6 (CH2)；
HRMS (ESI): m/z calcd. for C15H20O4S2Na [MNa]: 351.0695; found: 351.0698.
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(3R,4S)-1-(1,3-Dithian-2-yl)pentane-3,4,5-triyl tribenzoate (17)
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To a solution of compound 16 (0.02 g, 0.07 mmol) in 0.33 mL of dry CH2Cl2. This solution was
then cooled to 0 °C before trimethylamine (0.03 mL, 0.23 mmol) and benzoyl chloride (0.02 mL, 0.16
mmol) was added. The resulting mixture was stirred at rt for 10 h. The reaction was quenched with
water (6 mL). The residue was dissolved in CH2Cl2 (20 mL), washed with saturated NaHCO3(aq) (6
mL), and brine (6 mL). The organic layer was dried over MgSO4 and concentrated to give a crude
product, which was purified by flash chromatography with the eluent of EtOAc/hexanes = 15/85 to
25/75 to give the desired product 17 (0.02 g, 63%) as a white solid.mp 116118 ℃; [α]25D 3.68 (c =
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2.15, CHCl3); IR (neat) 1722 (C=O) cm1 ; H NMR (300 MHz, CDCl3) δ 8.087.96 (m, 6H),
7.627.50 (m, 3H), 7.487.36 (m, 6H), 5.89 (dt, J = 9.3, 3.8 Hz, 1H, H3), 5.80 (dt, J = 6.6, 4.2 Hz, 1H,
H4), 4.74 (dd, J = 12.0, 4.2 Hz, 1H, H5), 4.60 (dd, J = 12.0, 6.9 Hz, 1H, H5'), 4.15 (dd, J = 9.0, 5.4 Hz,
1H, H1), 2.922.72 (m, 4H, SCH2×2), 2.512.29 (m, 2H, H2,H2'), 2.142.01 (m, 1H, SCH2CH2),
1.941.77 (m, 1H, SCH2CH2); 13C NMR (75 MHz, CDCl3) δ 166.1 (C), 165.6 (C), 165.5 (C), 133.3
(CH2×2), 133.1 (CH), 129.9 (CH), 129.8 (CH), 129.7 (CH), 129.6 (C), 129.4 (C×2), 128.5 (CH×2),
128.4 (CH), 72.2 (CH), 70.2 (CH), 62.6 (CH2), 43.1 (CH), 36.3 (CH2), 30.0 (CH2), 29.7 (CH2), 25.6
(CH2); HRMS (ESI): m/z calcd. for C29H29O6S2 [MH]: 537.1400; found: 537.1412.
(3R,4S)-1,1-Bis(ethylthio)-4,5-dihydroxypentan-3-yl benzoate (18)
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To a refluxed solution of the radical precursor 6 (0.11 g, 0.31 mmol) in 5.1 mL of toluene at 88
°C was added a solution of AIBN (5.10 mg, 0.03mmol) and tributyltin hydride (0.09 mL, 0.32 mmol)
in 5.1 mL of toluene. The resulting solution was continuously stirred at the same temperature for 7
min. The solution was then cooled and directly concentrated to give a crude residue, which was directly
used for the next step without further purification.
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To a solution of the previous crude residue (0.09 g, 0.31 mmol) in 0.6 mL of CH2Cl2 were added
ethanethiol (0.11 mL, 1.54 mmol) and BF3·OEt2 (0.30 mL, 2.46 mmol) at −10 °C. The reaction mixture
was stirred at the same temperature for 30 min and then was added 0.1 N HCl (0.6 mL). The reaction
mixture was stirred at 0 °C for 1 h. The reaction was worked up by addition of saturated NaHCO3(aq)
and then concentrated to dryness under vacuum. The residue was dissolved in EtOAc (60 mL) washed
with saturated NaHCO3(aq) (10 mL), brine (10 mL), dried overMgSO4, filtered, and concentrated to
give a crude product, which was purified by flash chromatography with the eluent of EtOAc/hexanes
=40/60 to 50/50 to give the desired product 18 (0.11 g, 43%, over four steps) as a colorless oil. [α]23
D
50.80 (c = 0.62, CHCl3); IR (neat) 3406 (OH), 1740 (C=O) cm1 ; 1H NMR (300 MHz, CDCl3) 8.04
(d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 5.39 (ddd, J = 10.8, 8.7, 3.6 Hz,
1H, H3), 3.91 (dd, J = 9.6, 5.1 Hz, 1H, H1), 3.783.56 (m, overlapping with one dd at 3.60, J = 12.3,
4.1 Hz, H4,H5, H5'), 2.96 (br s, 1H, OH), 2.85 (br s, 1H, OH), 2.762.49 (m, 4H, SCH2×2), 2.492.28
(m, 2H, H2,H2'), 1.22 (t, J = 7.5 Hz, 3H, SCH2CH3), 1.17 (t, J = 7.5 Hz, 3H, SCH2CH3); 13C NMR (75
MHz, CDCl3) δ 167.1 (C), 133.6 (CH), 129.8 (CH×2), 129.3 (C), 128.5 (CH×2), 72.9 (CH), 72.6 (CH),
62.2 (CH2), 47.6 (CH), 37.5 (CH2), 24.3 (CH2), 23.6 (CH2), 14.3 (CH3×2); HRMS (ESI): m/z calcd.
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for C16H24O4S2Na [MNa]: 367.1008; found: 367.1005.
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To a solution of compound 18 (28.80 g, 0.08 mmol) in 0.42 mL of tetrahydrofuran. Then, was
added dimethyltin dichloride (0.20 mg, 0.84 μmol) under nitrogen. This solution was then cooled to 0
°C and stirred at the same temperature for 15 min before potassium carbonate (23.20 mg, 0.17 mmol)
and benzoyl chloride (12.00 μL, 0.01 mmol) was added. The resulting mixture was stirred at rt for 1.5
h. The reaction was quenched with water and then concentrated to dryness under vacuum. The residue
was dissolved in EtOAc (30 mL), washed with saturated NaHCO3(aq) (4 mL), and brine (4 mL). The
organic layer was dried over MgSO4 and concentrated to give a crude product, which was purified by
flash chromatography with the eluent of EtOAc/hexanes = 15/85 to 25/75 to give the desired product
19 (23.70 mg, 63%) as a colorless oil. [α]24 6.94 (c = 0.47, CHCl3); IR (neat) 3481 (OH), 1722
D
(C=O) cm1; 1H NMR (300 MHz, CDCl3) 8.097.99 (m, 4H), 7.617.53 (m, 2H), 7.4839 (m, 4H),
5.675.59 (m, 1H, H3), 4.53 (dd, J = 11.7, 4.1 Hz, 1H, H5), 4.42 (dd, J = 11.7, 6.6 Hz, 1H, H5'), 4.27
(br s, 1H, H4), 3.95 (dd, J = 9.6, 4.8 Hz, 1H, H1), 2.97 (br s, 1H, OH), 2.76 m, 4H, SCH2×2),
2.532.39 m, 1H, H2), 2.27 (ddd, J = 14.4, 10.2, 3.8 Hz, 1H, H2'), 1.22 (t, J = 7.5 Hz, 3H, SCH2H3),
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133.2 (CH), 129.7 (CH×4), 129.5 (C×2), 128.5 (CHx2), 128.4 (CH×2), 73.7 (CH), 71.5 (CH), 65.6
(CH2), 47.5 (CH), 37.0 (CH2), 24.3 (CH2), 23.9 (CH2),14.3 (CH3×2); HRMS (ESI): m/z calcd. for
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C23H28O5S2Na [MNa]: 471.1270; found: 471.1265.
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Ethyl 3,5-di-O-benzoyl-2-deoxy-1-thio-L-threo-pentofuranoside (20)
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To a reaction mixture of compound 19 (0.017 g, 0.039 mmol) and solid NaHCO3 (0.003 g, 0.039
mmol) in 0.2 mL of CH2Cl2, was cooled to 0 °C and N-iodosuccinimide (0.008 g, 0.035 mmol, 0.9
equiv) was added. The reaction mixture was stirred at the same temperature for 15 min. The reaction
was then quenched with saturated sodium thiosulfate (0.6 mL) and the residue was dissolved in EtOAc
(20 mL), washed with saturated NaHCO3(aq) (5 mL), brine (5 mL). The organic layer was dried over
MgSO4 and concentrated to give a crude product, which was purified by flash chromatography with
the eluent of EtOAc/hexanes = 15/85 to 3/7 give the desired product 20 (9.3 mg, 62%, α:β= 1:0.8) as
a colorless oil. IR (neat) 1718 (C=O) cm1; 1H NMR (300 MHz, CDCl3) 8.137.98 (m, 4H) 7.637.51
(m,2H), 7.517.37(m, 4H) 5.64 (dd, J = 7.8, 2.1 Hz, 1H, H1, major) 5.615.55 (m, 1H, H1, minor)
5.555.39 (m, 1H, H3) 4.724.55 (m, 3H, H4, H5, H5') 2.962.82(m, 1H, H2, major) 2.822.62 (m,
2H, SCH2CH3) 2.602.49 (m, 1H, H2, minor) 2.492.35 (m, 1H, H2', minor) 2.19 (d, J = 14.4 Hz,1H,
H2', major), 1.32 (q, J = 7.2 Hz, 3H, SCH2CH3); 13C NMR (75 MHz, CDCl3) δ 166.2 (C), 165.9 (C),
133.3 (CH×2), 133.1 (CH), 129.8 (CH×2), 129.7 (CH), 128.4 (CH×2), 84.6 (CH), 83.8 (CH), 82.9
(CH), 80.6 (CH), 76.3 (CH), 74.8 (CH), 64.7 (CH2), 64.1 (CH2), 39.5 (CH2), 39.0 (CH2), 25.9 (CH2),
25.3 (CH2), 15.1 (CH3); HRMS (ESI): m/z calcd. for C21H22O5SNa [MNa]: 409.1080;
found: 409.1076.
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