A neighboring group participation strategy: Facile synthesis of 3,5-di-O-benzoyl-2-C-methyl-d-arabino-γ-lactone

Article abstract of DOI:10.1016/j.tetlet.2015.05.085

A simple and efficient approach for the synthesis of 3,5-di-O-benzoyl-2-C-methyl-d-arabino-γ-lactone through a neighboring group participation mechanism is reported. This compound could be a useful precursor for the synthesis of nucleoside antiviral agents.

Full text of DOI:10.1016/j.tetlet.2015.05.085

Tetrahedron Letters 56 (2015) 4345–4348
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A neighboring group participation strategy: facile synthesis
of 3,5-di-O-benzoyl-2-C-methyl-D-arabino-c-lactone
Yuanchao Xie a, Jian Zhang b, Guanghui Tian b, Mingshuo Xu a, Tianwen Hu a, Xiangrui Jiang a,
Jingshan Shen a,
⇑
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zuchongzhi Road, Shanghai 201203, PR China
b Topharman Shanghai Co., Ltd, 1088 Chuansha Road, Pudong, Shanghai 201209, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient approach for the synthesis of 3,5-di-O-benzoyl-2-C-methyl-D-arabino-c-lactone
through a neighboring group participation mechanism is reported. This compound could be a useful pre-
cursor for the synthesis of nucleoside antiviral agents.
Received 23 March 2015
Revised 20 May 2015
Accepted 22 May 2015
Available online 28 May 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Fluorinating agent
Neighboring group participation
Stereoselectivity
2-C-Methyl-D-ribono-c-lactone
3,5-Di-O-benzoyl-2-deoxy-2-fluoro-2-C-methyl-
D
-ribono-
c
-
material is also available, but also hardly applied to the synthesis
lactone 1 is an important intermediate for the preparation of sofos-
buvir 2, a highly effective drug recently approved for treating
chronic hepatitis C.1 Some other nucleoside HCV NS5B polymerase
inhibitors currently under preclinical or clinical studies are also
synthesized through this intermediate.2–6 By now, there have been
several routes reported for preparing 1 (Fig. 1), but most of them
are not industrially acceptable.7–11
of 1.13
2-C-Methyl-
intermediate in the synthesis of bioactive 20-C-methyl nucleo-
sides,14,15 and could be easily prepared from -glucose.13 The only
D-ribono-c-lactone 5 is a useful pharmaceutical
D
difference between lactones 3 and 5 is the steric configuration of
the C2 hydroxyl or methyl group. We considered that if the config-
uration of the hydroxyl group was able to be changed from
a to b, 4
Scheme 1 describes a route for the industrial production of 1,
characterized by two common starting materials, 2,3-O-isopropyli-
would be obtained from 5. To our knowledge, there is no relevant
study about the conversion. Being interested in this new idea, we
devoted ourselves to make the synthesis of 4 from 5, and also
exploit efficient methods for preparing 1 without using DAST.
The three hydroxyl groups of 5 present varied reactivity, which
is as follows: C5-OH P C3-OH > C2-OH. Accordingly, selective ben-
zoylation of C5 and C3 hydroxyl groups with benzoyl chloride effi-
ciently gave 6 in a yield of 80%, Scheme 2. The following
sulfonylation of 6 was performed with trifluoromethanesulfonic
anhydride (Tf2O), and the reaction went smoothly to afford 7.
When 7 was treated with N,N-dimethylformamide (DMF), a new
product was rapidly generated, and subsequently identified as 9
by the 1H NMR, 13C NMR, and HRMS spectrum. This intermediate
was stable in air or neutral water, but in the presence of bases, such
as Et3N, it could be easily converted to 4.
dene-D-glyceraldehyde L1 and 2-(triphenyl-phosphanylidene)-
propionic acid ethyl ester L2.8 In this route, there usually
exist two byproducts, 3,5-di-O-benzoyl-2-deoxy-2-fluoro-2-C-
methyl-
D
-arabino-c-lactone 12 and 3,5-di-O-benzoyl-2-deoxy-2-
chloro-2-C-methyl-
D
-ribono- -lactone 13 (their structures are
c
shown in Scheme 6), which are difficult to be removed and have
a great influence on the product quality.12 3,5-Di-O-benzoyl-2-C-
methyl-D-arabino-c-lactone 4, prepared with the same starting
materials can also be used to synthesize 1. However, due to the
low yield, the high cost and risk of diethylaminosulfurtrifluoride
(DAST), its application is only restricted to small scale preparation
in the lab.7 For the synthesis of 2-C-methyl-
D
-arabino-c-lactone 3,
an alternative method with
S-erythronolactone as the starting
We proposed a possible mechanism for the conversion of 7 to 4,
shown in Figure 2. In DMF, the C2-OTf of 7 should first leave to
generate an
a-carbonyl carbocation, which facilitated the occur-
⇑
Corresponding author. Tel.: +86 21 20231962.
E-mail address: shenjingshan@simm.ac.cn (J. Shen).
rence of an atypical neighboring group participation. The C3
http://dx.doi.org/10.1016/j.tetlet.2015.05.085
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4346
Y. Xie et al. / Tetrahedron Letters 56 (2015) 4345–4348
O
result, the following neighboring group participation did not hap-
pen too. In order to validate that DMF served as a reactant in the
reaction, N,N-dimethylacetamide (DMAC) was used to replace
DMF (Scheme 3). As expected, intermediate 10 was produced.
To further explore the mechanism, we discovered that com-
pound 4 could be also converted to intermediate 9 using the sim-
ilar method, Scheme 4. Differently, reaction of compound 4 with
Tf2O or MsCl did not give any new product, but with acetyl chloride
produced the corresponding ester. We supposed that the b hydro-
xyl group at C2 position of compound 4 could be sulfonated with
Tf2O, but the neighboring group participation happened fast due
to the favorable steric configuration. Therefore, we added DMF in
the reaction to ‘catch’ the active intermediate. When DMF was pre-
sent in the reaction solvent, we successfully obtained intermediate
9 in a high yield. Following the previous procedure, compound 4
was also obtained.
Even though 4 could be easily synthesized, the complicated pro-
cedure in Scheme 2 was not suitable for a large-scale preparation.
The reaction conditions still needed to be optimized. Similar to
DMF, dimethyl sulfoxide (DMSO) is another polar aprotic solvent.
When DMSO was chosen as the solvent, surprisingly, 7 was found
to be fast converted to 4 in less than ten minutes without using any
base. Importantly, 4 could be prepared in large quantities. The
reaction was exothermic, and also gave a small amount of 11. 11
was the elimination product which could be minimized within
1% by lowering the reaction temperature and diluting DMSO with
dichloromethane.
NH
O
N
O
O
P
OPh
O
O
CH3
O
BzO
BzO
N
H
O
CH3
O
F
HO
F
1
2
sofosbuvir
Figure 1. Structures of 1 and 2.
benzoate carbonyl attack on the
a-carbonyl carbocation led to the
formation of an active intermediate 7-I. DMF served as
a
nucleophilic reagent to attack the benzyl cation of 7-I. The derived
intermediate 7-II was very unstable in the presence of water, and
quickly hydrolyzed to afford 9. An extension of the Vilsmeier–
Haack reaction for the synthesis of formic acid esters was also
achieved through the imidate ester.16 The last step from 9 to 4
was hard to proceed without the addition of bases. The base, such
as Et3N would consume the produced formic acid, therefore pro-
moting the reaction.
The participation of the C3 benzoate carbonyl group should take
place after the departure of the C2 leaving group. In Scheme 2, we
had found that stirring of 8 in a solution of DMF and water did not
give any product, even under high temperature conditions.
Since –OMs is a much weaker leaving group than –OTf, the depar-
ture of –OMs at the C2 position of 8 would not easily happen. As a
O
O
sharpless AD
or KMnO4
O
O
CH3
CH3
CO2Et
Wittig
CH3
O
+
CHO
Ph3P
O
CO2Et
OH
OH
L4
CO2Et
H
H
L1
L2
L3
H
O
t
E
/
l
C
H
O
3
O
O
OH
CH3
O
OH
CH3
O
BzCl HO
DAST
O
CH3
BzO
BzO
1. SOCl2/Et3N
2. NaClO/TEMPO
BzO
BzO
HO
F
1
4
O
O
BzCl
O
O
CH3
F
TEAF
HCl
O
CH3
CO2Et
O
O
HO
O
H
CH2O2Et
S
H
OSO3H
O
HO
L7
F
O
L5
L6
Scheme 1. Industrial route for the synthesis of 1.
O
O
CH3
OMs
DMF
BzO
l
C
s
BzO
M
8
O
O
CH3
OH
O
O
CH3
OH
HO
BzCl
80%
T
BzO
BzO
f
2O
O
DMF
>80%
O
CH3
OTf
HO
9
BzO
BzO
9
%
5
6
7
O
O
CH3
O
4
BzO
O
OH
CH3
H2O, Et3N
82%
BzO
BzO
O
O
O
O
H
9
Scheme 2. Synthesis of 3 from 15.

Y. Xie et al. / Tetrahedron Letters 56 (2015) 4345–4348
4347
O
O
O
O
O
O
O
O
O
CH3
BzO
BzO
H2O
BzO
O
4
BzO
CH3
CH3
CH3
O
OH
O
b
path a
O
BzO
BzO
BzO
H
H
O
O
O
O
O
O
O
O
O
CH3
OTf
CH3
N
a
O
Ph
O
S+
OTf
O
-OTf
H
N
p
a
t
h
7
7-II
b
7-I
7
O
O
CH3
BzO
BzO
O
O
H2O
O
O
BzO
BzO
OH
CH3
CH3
11
Et3N
H2O
O
O
O
O
H
O
O
Figure 3. A proposed mechanism of DMSO-mediated reaction.
4
9
O
3
O
O
O
OH
CH3
O
CH3
OTf
DMSO
O
OH
CH3
1. K2CO3
2. HCl
HO
BzO
BzO
BzO
Figure 2. A proposed mechanism of DMF-mediated reaction.
HO
BzO
4
7
TBAF, acetone
SOCl2, pyridine
O
O
BzO
O
CH3
, H2O
N
O
O
O
O
O
O
O
BzO
BzO
O
O
CH3
O
BzO
BzO
12
BzO
BzO
F
CH3
OTf
CH3
Cl
CH3
13
7
10
Scheme 6. Synthesis of 3, 12, and 13.
Scheme 3. Synthesis of 20.
the elimination. Different from the role of DMF in the above mech-
anism, DMSO served as a catalyst in the reaction. H2O was an
important nucleophile, attacking on the a-carbon to generate the
O
O
CH3
BzO
O
O
OH
CH3
Tf2O, Pyridine
CH2Cl2, DMF
BzO
BzO
b-OH of 4 at the C2 position.
O
O
O
Another three compounds were also conveniently synthesized
from 7 for the first time, shown in Scheme 6. In previous studies,
3 was mainly prepared by the Kiliani reaction of sodiumcyanide
Ph
O
H
4
9
H2O, Et3N
with 2,3-O-isopropylidene-D-erythronolactone. Though the route
is feasible, indeed it is hard to be carried out.19 Our method
enabled the efficient synthesis of 4, which was an excellent mate-
rial for the preparation of 3 by removing the benzoyl protecting
groups with K2CO3, and 13 by chloridization with sulfoxide chlo-
ride. With respect to the stereoselective synthesis of diastereomer
12, at present no pleasurable method is available. We successfully
obtained 12 by reaction of 7 with tetrabutylammonium fluoride
(TBAF) in a yield of 85%. The reaction not only proceeded fast
and but only produced the single diastereomer.
In conclusion, we discovered a simple and efficient method for
the synthesis of 4 from 5 by an atypical neighboring-group partic-
ipation mechanism. DMSO was the preferred solvent and H2O
played an important role in the reaction. Using SO2F2 as the fluo-
rating agent, we successfully synthesized 1 in a high yield from
4. This route held a great potential in industrial application.
Besides, several other important intermediates were also conve-
niently prepared for the first time. The methods in the study would
Scheme 4. Synthesis of 9 from 4.
Sulfuryl fluoride (SO2F2) is a common gas used for insect control
and has been reported as an efficient dehydroxylating fluorinating
agent of alcoholic compounds.17,18 Previously, 4 was not conve-
niently prepared which restricted the application of this fluorinat-
ing agent. Our study enabled the synthesis of 1 using 4 and SO2F2
in the presence of triethylamine trihydrofluoride (Et3Nꢀ3HF) and
Et3N, Scheme 5. The method was highly practicable and also appli-
cable to large-scale production of the key medicinal intermediate.
Because 11 was an inevitable byproduct in the DMSO-mediated
reaction, we thought that the synthesis of 4 was achieved via a
similar mechanism (Fig. 3). In the presence of DMSO, the –OTf of
7 had a high ability to leave. With its departure, the participation
of both C3 benzoate carbonyl and E2 elimination occurred, but
the intramolecular participation was much more dominant than
SO2F2,
O
O
O
CH3
O
OH
CH3
BzO
Et3N.3HF,Et3N
BzO
BzO
BzO
F
O
4
90%
O
CH3
OTf
1
DMSO, H2O
fast
BzO
BzO
O
O
7
BzO
BzO
CH3
11
Scheme 5. Synthesis of 1 and 3 with improved methods.

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Y. Xie et al. / Tetrahedron Letters 56 (2015) 4345–4348
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