Formal synthesis of furanodictine B from D-glucose

Article abstract of DOI:10.1016/j.tetasy.2004.09.012

Formal synthesis of furanodictine B is described starting from d-glucose. An efficient formal synthesis of furanodictine B 1b is described starting from d-glucose. The synthetic protocol is based on deriving the bicyclic intermediate 2 from d-glucose by a

Full text of DOI:10.1016/j.tetasy.2004.09.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3457–3460
Formal synthesis of furanodictine B from D-glucose
*
Hari Babu Mereyala, Mohd Baseeruddin and Sreenivasulu Reddy Koduru
Speciality, Gas-Based Chemicals and Processes Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 August 2004; accepted 10 September 2004
Available online 18 October 2004
Abstract—An efficient formal synthesis of furanodictine B 1b is described starting from D-glucose. The synthetic protocol is based
on deriving the bicyclic intermediate 2 from D-glucose by a modified method and its further manipulations to obtain the advanced
intermediate 8. Methanolysis of compound 2 to the 2-hydroxy derivative 3 followed by its conversion to the corresponding 2-O-tri-
flate 4 is described. Inversion of configuration at C(2) of compound 4 by nucleophilic displacement with NaN gives the azido deriv-
3
ative 5. Straightforward reactions of azide derivative 5 to the corresponding amine 6, N-acetyl derivative 7 and to the required
template 8 are described. Conversion of 8 to the natural product 1b has previously been reported.
ꢀ
2004 Published by Elsevier Ltd.
1
. Introduction
prepare 1a and 1b was reported starting from D-arabi-
7
nose. Synthesis of the bicyclic bis-tetrahydrofurofuran
structures, such as those present in 1a and 1b, has been
Isolation of biologically active substances from natural
sources with the potential for development as new drugs
continues to be explored. In this pursuit, Oshima and
co-workers have explored secondary metabolites pro-
duced by cellular slime moulds for their pharmacologi-
8
the subject of our interest as they constitute an integral
9
part of several other natural products. In spite of the
above reported methods, there is still a need to prepare
large quantities of such pharmacophore containing
compounds from easily available raw materials by sim-
ple methods. Accordingly, a synthetic strategy starting
from easily available raw material D-glucose was
designed and executed.
1
–4
cal activities
and isolated two novel aminosugar
5
analogues, furanodictine A 1a and B 1b from the meth-
anolic extract of the multicellular fruit body of Dictyo-
stelium discoideum and shown that they exhibited
6
neuronal differentiation activity (Fig. 1). Compounds
1a and 1b are the first examples of amino sugars with
a 3,6-anhydrohexofuranose carbon skeleton. The abso-
lute configurations of 1a and 1b were established as
2. Results and discussion
(
2R,3R,4S,5R), and (2S,3R,4S,5R) by total synthesis
from N-acetyl-D-glucosamine and N-acetyl-D-mannos-
The retrosynthetic analysis of 1b has indicated that the
absolute configurations at C(4), C(5) and C(6) are the
same as those present in D-glucose at C(3), C(4) and
C(5), respectively. The stereocentre at C(3) of 1b can
5
amine, respectively. A second synthetic route to
Me
O
be derived by nucleophilic inversion (S 2) of configura-
N
H
tion at C(2) of D-glucose by azide. The bicyclic 3,6-anhy-
dro sugar
O
Me
O
3
can be constructed through the
OH
intramolecular cyclization of the C(3) hydroxyl group
with C(6) by a simple protocol developed earlier by us
(Fig. 2). Execution of the retrosynthetic plan is summa-
rized in Scheme 1.
O
Y
H
X
1
a) Furanodictine A (X=NHAc, Y=H)
1b) Furanodictine B (X=H, Y=NHAc)
D-Glucose was converted to the 3,6-anhydro sugar
derivative 2 by reaction of 1,2-O-isopropylidene gluco-
furanose with diethylcarbonate/NaH/THF by the modi-
fied method earlier described by us for the synthesis of
Figure 1.
*
Corresponding author. Tel.: +91 40 27193137; fax: +91 40 27160387/
7160757; e-mail: mereyalahb@rediffmail.com
8
2
bicyclo nucleosides (Scheme 1).
0
957-4166/$ - see front matter ꢀ 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2004.09.012

3458
H. B. Mereyala et al. / Tetrahedron: Asymmetry 15 (2004) 3457–3460
5
Me
the literature. Compound 8 exhibited a specific rotation
O
H
H
RO
H
25
D
+
of ½aꢀ ¼ þ148 (c 0.8, MeOH) and mass of M 218,
O
O
Me
O
which is in agreement with the structure. The advanced
intermediate 8 was obtained in 13.2% overall yield from
D-glucose. Conversion of compound 8 to the natural
OH
NHAc
OMe
OR1
O
O
5
H
H
product 1b has been reported earlier there by complet-
ing the formal synthesis of 1b.
Furanodictine B 1b
3
HO
H
HO
O
O
3. Conclusion
HO
HO
O
OH
HO
HO
In conclusion, a simple and efficient route for the formal
total synthesis of furanodictine B 1b has been developed
starting from D-glucose. The synthetic protocol devel-
oped offers advantages to synthesize the analogues re-
quired for the development of new drugs.
O
H
H
OH
1
,2-O-isopropylideneglucose
D-glucose
Figure 2.
4
. Experimental
RO
RO
H
H
H
O
O
4.1. General
ref.8
i
D
-Glucose
O
OMe
OR
O
Me
Me
O
1
H NMR spectra were recorded on a Bruker Avance
(300MHz) and Varian Gemini (200MHz) instruments
with tetramethyl silane as the internal standard for solu-
H
O
1
2) R = Bn
3) R = H
1
4
ii
iii
a) R = Tf
1
4
b) R1 = Ms
tions in CDCl . Optical rotations were measured in a
3
RO
HO
H
H
H
1dm cell of 1mL capacity using a JASCO DIP-370 pola-
rimeter. Melting points were determined by using
Fischer–JohnÕs melting point apparatus and are
uncorrected. IR spectra were taken with a Perkin–
Elmer 1310 spectrometer.
O
O
iv
vii
1b
OMe
OM-
O
O
X
H
8
NHAc
v
5) X = N3
6
7
) X = NH2
) X = NHAc
vi
4.2. Methyl 3,6-anhydro-5-O-benzyl-D-glucofuranoside 3
+
Scheme 1. Reagents and conditions: (i) IR120-H , MeOH, reflux, 2h,
5%; (ii) Tf N, 0ꢁC; (iv)
O, pyridine, 0ꢁC to rt, 1h, 87%; (iii) MsCl, Et
NaN P, THF–CH Cl , rt, 3h, 81%; (vi)
, DMF, 60ꢁC, 6h, 87%; (v) Ph
Ac O, pyridine, CH Cl , rt, 2h, 95%; (vii) Pd(OH) /C/H , MeOH,
atm, 2h, 95%.
To a solution of compound 2 (4.0g, 13.66mmol) in
methanol was added IR120-H+ (2.0g) and refluxed for
8
2
3
3
3
2
2
2
h. When TLC revealed the absence of starting mate-
2
2
2
2
2
rial, the solution was decanted from the resin, concen-
trated and purified by column chromatography to
afford the title compound 3 (3.12g, 85%) as a syrup;
1
2
5
1
The bicyclic compound 2 on methanolysis catalyzed by
ion exchange resin gave the 2-hydroxy derivative 3 in
½aꢀ ¼ þ143 (c 0.1, CHCl ); H NMR (300MHz,
D
3
CDCl ) d (ppm, J Hz) (diastereomeric mixture): 7.40–
3
8
5% yield as a diastereomeric mixture (anomeric ratio
7.20 (m, 5H, Ar-H); 5.05 (d, 0.3H, 2.1, H-1); 4.90 (s,
0.7H, 2.1, H-1); 4.82–3.60 (m, 7H, H2–H6, PhCH2);
3.45, 3.40 (2s, OMe). Anal. Calcd for C H O : C,
a/b = 2:3). Compound 3, on reaction with triflic anhy-
dride/pyridine gave the corresponding 2-O-triflate deriv-
ative 4a, which on nucleophilic displacement (S 2)
1
4
18
5
63.14; H, 6.81. Found: C, 63.38; H, 6.65.
N
reaction with NaN /DMF/60ꢁC smoothly afforded the
3
azido derivative 5. A similar nucleophilic displacement
reaction of the 2-O-mesylate derivative 4b with NaN3/
DMF/80ꢁC was unsuccessful. Reduction of the azido
derivative 5 was achieved with Ph P/H O/CH Cl to
4.3. Methyl 3,6-anhydro-5-O-benzyl-2-O-trifluoro-
methanesulfonyl-D-glucofuranoside 4a
To a solution of compound 3 (3.0g, 11.1mmol) in
CH Cl was added pyridine (2.6mL, 33.5mmol) and
3
2
2
2
afford amine 6 contaminated with phosphorus by-prod-
ucts. Compound 6 was purified as the hydrochloride
salt. Compound 6 was acetylated (Ac O/Py) to give
2
2
triflic anhydride (2mL, 11.9mmol) at 0ꢁC after
which it was stirred at room temperature for 1h.
When TLC revealed no starting material, the solution
was diluted with dichloromethane (200mL), washed
with dil HCl (2 · 50mL), water (2 · 80mL), brine solu-
tion (2 · 50mL) and then dried over Na SO . Removal
2
compound 7 (mp 94–97ꢁC), which was subjected to
hydrogenolysis [Pd(OH) /C/H /1atm/MeOH] to isolate
the required methyl 3,6-anhydro-N-acetylamino-
2
2
b-D-mannofuranoside 8 as a crystalline solid (mp 174–
2
4
1
1
(
75ꢁC). Compound 8 was characterized by H NMR
of the solvent gave the title compound 4a (3.8g,
25
D
1
300MHz, CDCl ) spectrum from the appearance of
87%) as a syrup; ½aꢀ ¼ þ160 (c 1.0, CHCl );
H
3
3
H-1 at d 4.97 as a doublet (J = 2.3Hz), methoxy group
NMR (300MHz, CDCl ) d (ppm, J Hz) (diastereomeric
3
1
at d 3.36 and acetyl group at d 2.01. H NMR data of
compound 8 was in agreement with that reported in
mixture): 7.40–7.20 (m, 5H, Ar-H); 5.21 (d, 0.3H,
H-1); 5.14 (s, 0.7H, H-1); 5.04 (s, 0.7H, H-2);

H. B. Mereyala et al. / Tetrahedron: Asymmetry 15 (2004) 3457–3460
3459
4
.95–4.50 (m, 4.7H, H-1,3,4,5, PhCH ); 4.10–3.60 (m,
2
for C H O N: C, 63.38; H, 7.22; N, 5.28. Found: C,
14 19 4
2
C H F O S: C, 45.23; H, 4.30. Found: C, 45.34; H,
H, H-6,6); 3.48, 3.43 (2s, OMe). Anal. Calcd for
63.54; H, 7.15; N, 5.29.
1
5
17
3
7
4
.45.
4.7. Methyl 2-acetamido-3,6-anhydro-5-O-benzyl-2-
deoxy mannofuranoside 7
4
.4. Methyl 3,6-anhydro-5-O-benzyl-2-O-methanesulfon-
yl-D-glucofuranoside 4b
To a solution of compound 6 (1.4g, 5.2mmol) in
CH Cl (5mL) and pyridine (1.2mL, 15.2mmol) was
2
2
To a solution of compound 3 (25g, 9.2mmol) in CH Cl
2
added acetic anhydride (8mL, 7.8mmol) at 0ꢁC. The
reaction mixture was stirred at room temperature for
2h. When TLC revealed the absence of starting material
the reaction mixture was diluted with CH Cl (50mL),
2
was added triethylamine (38mL, 27.3mmol) and meth-
anesulfonyl chloride (11mL, 13.7mmol) at 0ꢁC and stir-
red at room temperature for 1h. When TLC revealed no
starting material, the solution was diluted with dichloro-
methane (150mL), washed with water (2 · 50mL),
2
2
washed with 5% aq CuSO (2 · 50mL), water (50mL),
4
dried over Na SO , concentrated and purified using
column chromatography to give the title compound 7
2
4
NaHCO solution (2.2g in 100mL water), brine solution
3
25
(1.54g, 95%) as a solid. Mp 94–97ꢁC; ½aꢀ ¼ þ143 (c
(
vent gave the title compound 4b (3.6g, 90% yield) as a
50mL) and then dried over Na SO . Removal of sol-
2
4
D
1
1.0, CHCl ); H NMR (300MHz, CDCl) d (ppm, J
3
1
syrup. H NMR (300MHz, CDCl ) d (ppm, J Hz) (dia-
Hz) (diastereomeric mixture): 7.20–7.30 (m, 5H,
Ar-H); 4.90 (d, 1H, 1.8); 4.72–4.70 (2s, 1H); 4.65 (d,
2H, 6.2); 4.52–4.50 (2s, 1H); 4.18–4.28, 4.0–4.10 (2dd,
2H, 8.9, 5.2); 3.90 (d, 2H, 3.2); 3.20–3.30 (2s, OMe);
2.10– 1.80 (2s, OAc). Anal. Calcd for C H O N: C,
3
stereomeric mixture): 7.38–7.20 (m, 5H, Ar-H); 5.31 (s,
0
4
3
.3H, H-1); 5.31–5.11 (m, 1.3H, H-1,2); 4.90–4.50 (m,
.7H, H-1,3,4,5, PhCH ); 4.10–3.60 (m, 2H, H-6,6);
.48, 3.43 (2s, OMe); 3.08, 3.03 (2s, SO Me). Anal.
2
2
16 21
5
Calcd for C H O : C, 63.14; H, 6.81. Found: C,
1
62.52; H, 6.88; N, 4.56. Found: C, 62.75; H, 6.97; N,
4.53.
4
18
5
6
3.38; H, 6.65.
4.5. Methyl 3,6-anhydro-2-azido-5-O-benzyl-2-deoxy-D-
mannofuranoside 5
4.8. Methyl 2-acetamido-3,6-anhydro-2-deoxy-b-D-
mannofuranoside 8
To a solution of compound 4a (3.7g, 9.25mmol) in
DMF was added NaN (1.8g, 27.8mmol) and heated
To a solution of compound 7 (1.1g, 3.5mmol) in MeOH
(10mL) was added Pd(OH) (100mg) and stirred under
3
2
to 60ꢁC for 3h. When TLC revealed the absence of
starting material, the reaction mixture was diluted with
water and extracted into ether. The ether layer was
washed with water, dried over Na SO and concentrated
hydrogen atmosphere (1atm). When TLC revealed the
absence of starting material, the catalyst was filtered
off and washed with MeOH. The combined filtrates were
concentrated and purified by column chromatography
to give the title compound 8 (0.71g, 95%) as a colourless
2
4
to gave the title compound 5 (2.3g, 87%) as a
2
D
5
1
25
1
syrup; ½aꢀ ¼ þ93 (c 1.0, CHCl ); H NMR (300MHz,
solid. Mp 174–175ꢁC, ½aꢀ ¼ þ142 (c 0.8, MeOH); H
3
D
CDCl ) d (ppm, J Hz) (diastereomeric mixture):
NMR (300MHz, CDCl ) d (ppm, J Hz): 6.30 (br s,
3
3
7
2
2
5
1
.4–7.30 (m, 5H, Ar-H); 4.91 (d, 1H); 4.85–4.65 (m,
H); 4.10–3.55 (m, 4H); 3.48–3.41 (2s, OMe). IR:
1H, NH); 4.97 (d, 1-H, 2.3, H-1); 4.64–4.78 (m, 2H,
H-2,3); 4.17–4.27 (m, 2H, H-4,5); 3.81–3.92 (m, 2H,
ꢁ
1
130cm (CHCl ). Anal. Calcd for C H O N : C,
+
H-6,6); 3.36 (OMe). FAB MS (m/z) 218 (M ). Anal.
3
14 17
4
3
7.72; H, 5.88; N, 14.43. Found: C, 57.98; H, 5.79; N,
4.29.
Calcd for C H O N: C, 49.76; H, 6.96; N, 6.45. Found:
5
9
15
C, 49.89; H, 6.99; N, 6.37.
4.6. Methyl 2-amino-3,6-anhydro-5-O-benzyl-2-deoxy
mannofuranoside 6
Acknowledgements
M.B. and K.S.R. thank CSIR, New Delhi for financial
support in the form of a research fellowship.
To a solution of compound 5 (2.2g, 7.5mmol) in THF/
CH Cl (20mL/5mL) was added triphenylphosphine
2
2
(
2
4.4g, 16.8mmol), two drops of water and stirred for
h. When TLC revealed no starting material, the reac-
tion mixture was concentrated, dissolved in CH Cl
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