Synthesis of mycinose from 1,2:5,6-Di-O-isopropylidene-α-D- glucofuranose

Article abstract of DOI:10.2174/157017811797249290

A facile synthesis of mycinose from commercially available 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose was developed. A selective and direct reductive debromination of α-hydroxy bromides in a simple NaBH₄/EtOH/H₂O system was found.

Full text of DOI:10.2174/157017811797249290

592
Letters in Organic Chemistry, 2011, 8, 592-595
Synthesis of Mycinose from 1,2:5,6-Di-O-Isopropylidene-ꢀ-D-glucofur-
anose
Kai Bao#,1,2, Hao Gao#,1, Zhibin Zhu2, Jinhong Wang2, Guoning Zhang2, Jun Sun2, Weige Zhang*,2
and Xinsheng Yao*,1,3
1Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510632, P. R. China
2Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical
University, Shenyang 110016, P. R. China
3School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China
Received February 08, 2011: Revised April 25, 2011: Accepted April 25, 2011
Abstract: A facile synthesis of mycinose from commercially available 1,2:5,6-Di-O-isopropylidene-ꢀ-D-glucofuranose
was developed. A selective and direct reductive debromination of ꢀ-hydroxy bromides in a simple NaBH4/EtOH/H2O sys-
tem was found.
Keywords: 1,2:5,6-Di-O-Isopropylidene-ꢀ-D-glucofuranose, debromination, mycinose, synthesis.
INTRODUCTION
isopropylidene-ꢀ-D-glucofura- nose 1, in the presence of
chromium trioxide to give the corresponding keton , which
was reduced to furnish 2 in 78% yield. O-Methylation of 2
was achieved by treating with sodium hydride and methyl
iodide in THF. Microwave assisted deprotection of the 5,6-
diol of 3 with aqueous acetic acid at 40°C afforded 4 in 87%
yield. Compared with the conventional hydrolysis at room
temperature, microwave irradiation could accelerate the reac-
tion rate significantly (3h:20h).
Mycinose (6-deoxy-2,3-di-O-methyl-D-allose) is a struc-
tural component of many macrolide antibiotics such as ty-
losin, chalcomycin, and angolamycin [1-3]. In the past few
decades, a number of macrolides from both natural and syn-
thetic sources were found to contain mycinose [4-6]. How-
ever, there have only been a few synthetic approaches estab-
lished for the preparation of mycinose after its structure de-
termination [7,8]. In addition, a number of drawbacks of
these methods were revealed, such as the unsatisfactory
overall yields and not readily available starting material.
1,2:5,6-Di-O-isopropylidene-ꢀ-D-glucofuranose is a com-
mercially available and versatile synthon in carbohydrate
chemistry. It has been used in a variety of applications in the
construction of many bioactive substances. As part of our
study of the structure activity relationships and chemistry of
new antibiotics agents, we sought to develop a reliable and
efficient synthetic route from cheap, commercial sources that
would allow ready access to mycinose. In this letter, we de-
scribe a new and efficient synthesis of mycinose from
1,2:5,6-Di-O-isopropylidene-ꢀ-D-glucofuranose, which could
be a useful addition to the synthesis of mycinose and its ana-
logs.
In the course of the synthesis of the C6 bromo derivative
5, CBr4/PPh3 and N-bromosuccinimide/PPh3 bromination
systems at room temperature were tested [9,10], and the lat-
ter was found to be a more efficient agent. Furthermore, the
influences of stoichiometry and solvent on the yields were
also examined (Table 1). Thus the selective bromination of
the primary hydroxyl group in 4 was achieved by using NBS
and PPh3 in pyridine to give 5 in 91% yield (entry 6).
Since LiAlH4 and H2/Pd systems had been proved to be
efficient and convenient methods for the reduction of organic
bromine compounds [8,11], we treated 5 under the above
mentioned conditions, respectively. However, the rates of
reaction and yields of 6 were not satisfied (less than 60%).
To our surprise, 5 was reduced smoothly to give 6 in 88%
yield by the use of sodium borohydride (3.0 equiv) in
EtOH/H2O at room temperature.
RESULTS AND DISCUSSION
Then the secondary hydroxy function of 6 was protected
with a benzyl group and the resulting benzyl ether 7 was
treated with trifluoroacetic acid to give 8 in a 1.5:1 ratio of
ꢀ:ꢁ anomers, respectively. Conversion of 8 into the corre-
sponding benzyl ether by the treatment of benzyl alcohol and
p-toluene sulfonic acid under reflux yielded 9 in 79% yield
[12]. The ꢁ-stereochemistry at the anomeric position was
The synthetic route to mycinose is outlined in Scheme 1.
Our synthesis started with oxidation of 1,2:5,6-Di-O-
*Address correspondence to these authors at the Key Laboratory of Struc-
ture-Based Drug Design & Discovery, Ministry of Education, Shenyang
Pharmaceutical University, Shenyang, 110016, P. R. China; Tel: +86-24-
23986422; Fax: +86-24-23986393; E-mail: zhangweige2000@sina.com
1
determined by H NMR (5.06 ppm, J = 0.9 Hz). Treatment
Institute of Traditional Chinese Medicine & Natural Products, Jinan Univer-
sity, Guangzhou, 510632, P. R. China; Tel: +86-20-85225849; Fax: +86-20-
85221559; E-mail: yaoxinsheng@vip.tom.com
#These authors contributed equally to this work.
of 9 with sodium hydride and methyl iodide in THF afforded
compound 10. Deprotection of the benzyl protecting groups
via hydrogenolysis under ultrasound irradiation afforded an
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

Synthesis of Mycinose from 1,2:5,6-Di-O-Isopropylidene
Letters in Organic Chemistry, 2011, Vol. 8, No. 8
593
O
O
O
O
O
O
HO
O
O
O
HO
BnO
HO
O
b
c
a
O
O
O
O
HO
O
HO
O
O
O
O
O
1
2
3
4
Br
HO
BnO
O
O
HO
O
O
g
d
e
f
O
OH
O
O
O
O
O
O
O
O
OH
O
O
8
7
5
6
OH
O
BnO
O
BnO
O
j
i
h
O
OBn
OBn
HO
OH
O
O
O
OH
O
O
O
11
10
9
12
O
O
OAc
O
k
AcO
13
Scheme 1. Synthesis of mycinose. Reagents and conditions: (a) i) CrO3, Ac2O, py, CH2Cl2, r.t.; ii) NaBH4, EtOH/H2O (2.5:1), 0°C to r.t.,
78%; (b) NaH, CH3I, THF, r.t., 82%; (c) AcOH/H2O (2:1), MW, 800W, 40°C, 87%; (d) NBS, PPh3, py, r.t., 91%; (e) NaBH4, EtOH/H2O
(2.5:1), r.t., 88%; (f) NaH, BnBr, THF, r.t., 76%; (g) TFA, H2O, r.t., 83%; (h) TsOH, Benzyl alcohol, CH2Cl2, reflux, 79%; (i) NaH, CH3I,
THF, r.t., 84%; (j) Pd/C, H2, AcOH, ultrasound, r.t., 91%; (k) Ac2O, py, r.t., 80%.
Table 1. Selective Bromination of 4
Entry
Bromination Systems
Molar Ratio a
Solvent
Yield(%)
1
2
3
4
5
6
7
THF
DMF
Py
40
25
35
28
31
91
74
CBr4, PPh3
1:2:2
THF
DMF
Py
1:2:2
1:1:2
NBS, PPh3
Py
aThe molar ratio of 4 to CBr4/NBS to PPh3.
equilibrium mixture of pyranose 11 (75%) and furanose 12
(25%) in 91% yield.
During the process from 5 to 6, an uncommon reductive
debromination of 5 using 3.0 equiv NaBH4 in EtOH/H2O
(volume ratio 2.5:1) at room temperature was found. It is
known that reduction of organic bromine compounds could
be achieved by using NaBH4 in dimethyl sulfoxide [13,14].
To the best our knowledge, however, direct reductive de-
bromination of ꢁ-hydroxy bromides only using NaBH4 in
alcohol, has never been documented to date.
Acetylation of compound 11 and 12, with acetic anhy-
dride in pyridine, gave diacetate 13 as the major product
(80% yield), which was assigned to the ꢀ-configuration at C1
on the basis of NMR spectroscopy. In addition, 7% of
furanose diacetate was yielded in this reaction. Synthetic 13
(11 steps in 14% overall yield) was identical in all respects
(1H NMR, 13C NMR, MS) to synthetic product reported pre-
viously [8].
We believed that the ꢁ-hydroxyl group of 5 played a key
role in the reduction and an epoxy intermediate might be
involved. To test our speculation, we designed the following

594 Letters in Organic Chemistry, 2011, Vol. 8, No. 8
Bao et al.
Table 2. Reductive Debromination of Bromine Compounds Under NaBH4, EtOH/H2O Conditions
Substrate
Product
Entry
NaBH4 (eqiuv)
Yield (%)
HO
O
1
1:3
88
Br
O
O
O
HO
O
O
O
O
O
O
2
3
1:1
1:3
65
O
O
O
OH
O
62
17
Br
OH
OH
O
O
O
39
46
4
5
O
1:3
1:3
Br
OH
OH
O2N
O2N
O
50
41
O2N
Br
OH
O
Br
--
6
7
1:3
1:3
--
--
Br
O
--
reactions. As indicated in Table 2 (entry 1 and 2), the use of
3.0 equiv NaBH4 in this reaction could generate 6 in 88%
yield; by decreasing the quantity of NaBH4 from 3.0 to 1.0
equiv, 65% of 5 was converted to the epoxy product.
EtOH/H2O), afforded a selective and direct reductive debro-
mination of ꢀ-hydroxy bromides under mild conditions.
CONCLUSION
We further investigated the reactions of several ꢀ-
bromoketones (entry 3-5) under the standard conditions. It is
known that the treatment of ꢀ-bromoketones with NaBH4
resulted in reduction of the carbonyl bond [15,16]. Thus the
resulting ꢀ-hydroxy bromides were epoxidized and then re-
duced by the residual NaBH4 to give the expected mixture of
primary and secondary alcohols, respectively. Attempts to
reduce 2-bromoethyl benzyl ether and 2-bromoethyl phenyl
ether under certain condition were failed, and only the unre-
acted starting materials were recovered. These results clearly
indicated that the ꢀ-hydroxyl was necessary and an epoxy
intermediate was generated during the reduction. Thus, the
simple reduction system reported here (NaBH4 in
In conclusion, we have developed a new and efficient
synthesis of mycinose using commercially available 1,2:5,6-
diisopropyl-idene-ꢀ-D-glucose as the starting material under
mild conditions. Furthermore, a selective and direct reduc-
tive debromination of ꢀ-hydroxy bromides in a simple
NaBH4/EtOH/H2O system was found. Mechanism research
revealed that the ꢀ-hydroxyl was necessary and an epoxy
intermediate was generated during the reduction.
ACKNOWLEDGEMENTS
This work was supported by grants from the National
Science Foundation for Post-doctoral Scientists of China

Synthesis of Mycinose from 1,2:5,6-Di-O-Isopropylidene
Letters in Organic Chemistry, 2011, Vol. 8, No. 8
595
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SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
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