Novel and stereoselective asymmetric synthesis of an amino sugar analogue, furanodictine A

Article abstract of DOI:10.1016/j.tetlet.2003.12.135

A novel and efficient strategy is described for the asymmetric synthesis of the first 3,6-anhydrosugar to be isolated from natural sources, furanodictine A. The synthetic process is based on requisite stereodefined manipulation of the functionalized amino

Full text of DOI:10.1016/j.tetlet.2003.12.135

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1599–1601
Novel and stereoselective asymmetric synthesis of an amino
sugar analogue, furanodictine A
Hidemi Yoda,* Yuji Suzuki and Kunihiko Takabe
Department of Molecular Science, Faculty of Engineering, Shizuoka University, Johoku 3-5-1, Hamamatsu 432-8561, Japan
Received 9 December 2003; revised 23 December 2003; accepted 25 December 2003
Abstract—A novel and efficient strategy is described for the asymmetric synthesis of the first 3,6-anhydrosugar to be isolated from
natural sources, furanodictine A. The synthetic process is based on requisite stereodefined manipulation of the functionalized amino
alcohol obtained through nucleophilic addition of vinyl Grignard reagent to the aminal incorporating the
derived skeleton in a complete stereoselective manner.
D-arabinofuranose-
Ó 2004 Elsevier Ltd. All rights reserved.
Furanodictine A (1) and B (2) were first isolated in 2001
by Oshima and co-workers from a methanol extract of
the multicellular fruit body of Dictyostelium discoideum1
in a research to clarify the diversity of secondary
metabolites of Dictyostelium cellular slime molds and to
explore biologically active substances that could be
useful in the development of novel drugs (Fig. 1). These
natural products are unambiguously known to possess
the ability to cause neuronal differentiation of rat
pheochromocytoma (PC-12) cells and revealed to be the
first 3,6-anhydrosugars to be isolated from natural
sources after structural characterization by the same
group based on comprehensive spectral analysis.1 Their
structural complexity coupled with diverse and poten-
tially useful characteristics as an antitumor agent
described above would make them inviting targets for
synthesis. In spite of these attractive features, to the best
of our knowledge, only one approach concerning the
total synthesis of these compounds has appeared to
date,1 since the synthesis of this type of compounds
poses interesting and often unsolved problems of ste-
reocontrol. With these considerations in mind, the cen-
tral feature of this communication is to disclose the
details of a novel and convenient route for the stereo-
selective construction of furanodictine A (1) possessing
real and potential pharmacological properties and the
attractive 3,6-anhydrosugar structure.
O
H
H
O
O
OH
O
Y
X
X=H, Y=NHAc: Furanodictine A (1)
X=NHAc, Y=H: Furanodictine B (2)
Figure 1.
In formulating the synthetic plan for 1, we recognized
that the absolute configurations at C(3), C(4), and C(5)
are the same as the configurations at the corresponding
centers C(2), C(3), and C(4) of D-arabinofuranose (I) as
shown in Figure 2. Particularly the furanyl part in 1
would be constructed through nucleophilic intramole-
cular cyclization of the hydroxyl group of C(2) in the
acyclic form of D-arabinose. Further we envisioned that
the stereogenic center of C(2) a to the nitrogen would
originate from the nucleophilic addition to the aminal
derivative of (I), allowing the synthesis of amino alcohol
(II). Meanwhile, construction of the bicyclic furano-
lactol structure in furanodictine A (1) would have to be
independently set in a chemo- and regioselective cycli-
zation reaction of the corresponding a-amino aldehyde
intermediate (III).
The results from our survey are summarized in Scheme
1. To begin with, the functionalized amino alcohol 5
with desired contiguous stereogenic centers was pre-
pared from commercially available 2,3,5-tri-O-benzyl-b-
Keywords: Furanodictine; 3,6-Anhydrosugar; Amino alcohol; Arabino-
furanose.
* Corresponding author. Tel./fax: +81-53-478-1150; e-mail: tchyoda@
ipc.shizuoka.ac.jp
D
-arabinofuranose (3) through successive amination
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.135

1600
H. Yoda et al. / Tetrahedron Letters 45 (2004) 1599–1601
to find that the use of NaIO4 as an oxidative cleavage
O
H
HO
O
OH
CHO
reagent to the aldehyde intermediate could effect the
reaction smoothly to lead to the corresponding desired
bicyclic product 11 in satisfactory yield.6 After protec-
tion of the hydroxyl group in 11 with benzyl bromide to
resist changes in pH, replacement of the MOM group by
the desired isovaleric acid ester function in the presence
of EDCI {1-ethyl-3-(3-dimethylaminopropyl)carbodi-
imide hydrochloride} was subsequently effected to pro-
duce O-benzyl furanodictine A (12) in high yield.
Finally, 12 was subjected to deprotection under mild
5
4
O
OH
3
2
O
O
H
NHAc
H
NHR
1
Furanodictine A (1)
(III)
OR OH
OH
2
HO
OR
2
R HN
1
OR
(II)
HO
2
OH
OH OH
2
3
OH
OHC
conditions with H2 on Pd/C again to compete the total
OH
27
D
4
HO
O
synthesis of the natural type of 1, ½aꢀ +132.6° (c 0.72,
OH
25
CHCl3) {natural 1, ½aꢀ +100.4° (c 0.233, CHCl3)1 and
D-arabinofuranose (I)
D
25
D
synthetic 1, ½aꢀ +118.5° (c 0.437, CHCl3)1},7 in 87%
Figure 2.
yield.
and extremely stereoselective addition of vinyl magne-
sium bromide2 (>99% de, determined by HPLC) at low
temperature in good yield. Then, N-acetylation was
performed with acetyl chloride under acidic conditions
to avoid racemization of the vinyl group a to the
nitrogen3 and the product was in turn submitted to
hydrolysis to provide the corresponding alcohol 6. Due
to the lability of the final bicyclic furano-lactol structure
under acidic deprotection conditions,4 the MPM (p-
In summary, this process involves no separation of ste-
reoisomers and was substantially performed under
ambient conditions through entire sequence until fur-
anodictine A was synthesized. Further it constitutes a
new synthetic strategy and, in addition, represents a
short and easily accessible pathway to furanodictine
natural product.
methoxybenzyl) group in 6 was in advance removed at
28
D
Acknowledgements
this stage to give the acetoamide 7, ½aꢀ )22.4° (c 1.17,
CHCl3). This was then subsequently effected by reac-
tions of dihydroxylation with OsO4, chemoselective
acetonide formation, and MOM-protection, leading to
the benzylether 8 in 84% yield (three steps). Three benzyl
protecting groups in 8 were easily removed under mild
conditions such as treatment with H2 on Pd/C in almost
quantitative yield, followed by the regioselective mono-
tosylation in the presence of cat. Bu2SnO5 to afford the
tosylate 9. Treatment of 9 with K2CO3 in methanol
brought about the regioselectively cyclized tetrahydro-
furan derivative 10 in 96% yield. We were then delighted
This work was supported in part by a Grant-in-Aid (No.
15550031) for Scientific Research from the Japan Soci-
ety for the Promotion of Science.
References and notes
1. Kikuchi, H.; Saito, Y.; Komiya, J.; Takaya, Y.; Honma, S.;
Nakahata, N.; Ito, A.; Oshima, Y. J. Org. Chem. 2001, 66,
6982–6987.
OBn OH
OBn OH
OBn
OBn OH
OBn
BnO
X
OBn
a
b
c
OBn
OBn
OBn
OBn
X=OH: (3)
X=NHMPM: (4)
O
MPM(Ac)N
MPMHN
OBn
AcHN
OH
5
6
7
MOMO
OBn OMOM
OBn
OH OMOM
O
O
d
e
f
O
O
O
O
OTs
O
AcHN
OH
AcHN
OBn
8
9
H
H
NHAc
10
MOMO
H
H
O
O
H
O
i
g
h
O
O
OH
O
O
OBn
OH
NHAc
O
O
O
NHAc
H
H
11
NHAc
12
Furanodictine A (1)
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide, THF, )78 to )40 °C; 62%; (b) 1, CH3COCl, CH2Cl2; 2, K2CO3, MeOH; 50% (two
steps); (c) CAN (diammmonium cerium(IV) nitrate), MeOH; 49%; (d) 1, cat. OsO4, NMO, acetone–H2O (1:1); 99%; 2, 2,2-dimethoxypropane, cat.
p-TsOH, acetone; 90%; 3, MOMCl, (i-Pr)2NEt, CH2Cl2; 94%; (e) 1, H2, Pd/C, MeOH; 97%; 2, TsCl, Bu2SnO, Et3N, CH2Cl2; 79%; (f) K2CO3,
MeOH; 96%; (g) 1, cat. concd HCl, MeOH; 82%; 2, NaIO4, ether–H2O (1:1); 92%; (h) 1, BnBr, Ag2O, CH3COOEt; 77%; 2, cat. concd HCl, MeOH;
78%; 3, isovaleric acid, EDCI, DMAP, CH2Cl2; 94%; (i) H2, Pd/C, CH3COOEt; 87%.

H. Yoda et al. / Tetrahedron Letters 45 (2004) 1599–1601
1601
2. (a) Lay, L.; Nicotra, F.; Paganini, A.; Pangrazio, C.;
Panza, L. Tetrahedron Lett. 1993, 34, 4555–4558; (b)
Yoda, H.; Yamazaki, H.; Kawauchi, M.; Takabe, K.
Tetrahedron: Asymmetry 1995, 6, 2669–2672; (c) Yoda, H.;
Uemura, T.; Takabe, K. Tetrahedron Lett. 2003, 44, 977–
979.
and, instead, the reaction resulted in the production of an
inseparable mixture.
5. (a) Martinelli, M. J.; Vaidyanathan, R.; Khau, V. V.
Tetrahedron Lett. 2000, 41, 3773–3776; (b) Martinelli, M. J.;
Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.; Pawlak, J. M.;
Vaidyanathan, R. Org. Lett. 1999, 1, 447–450.
3. Partial racemization at this center was observed under basic
acetylation conditions employing Ac2O, Et3N, and cat.
DMAP in CH2Cl2.
4. Initial experiments have been performed on the synthesis of
the target compound 1 without removal of the MPM
group, however, in this case the desired product could not
be isolated at the final MPM-deprotection reaction stage
6. The ratio of the two anomers (a:b ¼ 6.2:1) was easily
determined by 1H NMR, since the observed coupling
constant corresponding to the a-anomer was 4.8 Hz,
indicating the cis-relationship and the other b-one has no
coupling constant.
7. Synthesized furanodictine A in this report was a mixture
{a:b ¼ 3.9:1 (natural; a:b ¼ 7:1)1} of the two anomers.