Efficient synthetic route to ravidosamine derivatives

Article abstract of DOI:10.1055/s-2005-864792

Concise synthesis of ravidosamine, the amino sugar constituent of ravidomycin and other antibiotics, has been achieved. The key steps include (1) regioselective reduction of benzylidene acetal with DIBAL, and (2) stereoselective reduction of oxime to the

Full text of DOI:10.1055/s-2005-864792

LETTER
801
Efficient Synthetic Route to Ravidosamine Derivatives
S
ynthetic Route to
a
R
avidosam
y
ine Derivati
-ves Shin Hsu, Takashi Matsumoto, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology and SORST-JST Agency, 2-12-1, Ookayama, Meguro-ku, Tokyo 152-8551,
Japan
Fax +81(3)57342788; E-mail: ksuzuki@chem.titech.ac.jp
Received 17 December 2004
O
O
OH
OH OMe
Abstracts: Concise synthesis of ravidosamine, the amino sugar
constituent of ravidomycin and other antibiotics, has been achieved.
The key steps include (1) regioselective reduction of benzylidene
acetal with DIBAL, and (2) stereoselective reduction of oxime to
the corresponding amine by using samarium diiodide in the
presence of methanol.
Me
OH
OMe
O
OH OH
O
O
R
OH
Me
O
Me
R'O
OH
O
Key words: ravidosamine, regioselectivity, boron trifluoride ether-
ate, stereoselectivity, samarium diiodide, amino sugar
NMe2
Me2N
HO
komodoquinone A
ravidomycin (1)
(R = -CH=CH2, R' = Ac)
deacetylravidomycin M
(R = -CH3, R' = H)
Amino sugars are involved as an important partial struc-
ture of many antibiotics or cytotoxic natural products, and
play essential roles in their biological activities.1 There-
fore, considerable attention has been focused on develop-
ment of their efficient and highly stereoselective synthetic
methods.2
HO
OH
OH
O
Me
Me
O
HO
NMe2
HO
Me2N
OH
D-ravidosamine
L-ravidosamine (2)
Figure 1
Ravidomycin (1), an amino sugar antibiotics, exhibits
strong inhibitory effect on Gram positive microorganisms
and potent antitumor activity.3 We previously accom-
plished the total synthesis of 1, albeit long synthetic se-
quence remained to be improved.4 Recently, we found a
viable protocol for the C-glycoside formation of a 3-azi-
do-3-deoxy sugar as the amino sugar surrogate,5 which
will enable the improved synthesis of 1. Herein, we wish
to describe an efficient entry to the constituent amino
sugar, ravidosamine (2), and the corresponding azido de-
rivative. This amino sugar is included also in deacetyl-
ravidomycin M6 and komodoquinone A7 (Figure 1).
cleaved under mild acidic conditions to give alcohol 6 in
98% isolated yield.
A shorter route from methyl a-L-fucoside (3) to the inter-
mediate 6 was also opened by adopting the method origi-
nated by Guo et al.10 Protection of 3,4-diol with
benzylidene acetal11 produced a diastereomeric mixture 7
in 76% yield, and subsequent masking of the remaining
hydroxyl group as benzyl ether gave the isomeric acetals
8 (50%) and 9 (48%), which were easily separable by sil-
ica gel chromatography (Scheme 2). The structures of 8
and 9 were assigned by 1H NMR nuclear Overhauser en-
hancement difference (NOED) experiments (Figure 2).
Although the natural ravidosamine is a D-series sugar, ex-
ploratory studies were carried out by using its L-enantio-
mer, just because we sought for a synthesis starting from
fucose, in which the L-antipode is much cheaper than D-
counterpart. Once an optimized synthetic pathway was
established, it should be applied to the D-series sequence
as well.
Methyl a-L-fucoside (3)8 was converted to alcohol 4 in
80% overall yield by the reported method (Scheme 1).9
The C(3) hydroxyl group in 4 was temporarily protected
as an ethoxyethyl ether, and the acetate and benzoate pro-
tecting groups were removed by barium oxide in metha-
nol. After the resulting hydroxyl groups in 5 were
protected as benzyl ethers, the ethoxyethyl ether was
1. MeC(OEt)3,
TsOH
OMe CH2Cl2,
r.t., 1 h
OEt, PPTS
CH2Cl2, r.t., 12 h
OMe
1.
Me
O
OBz
Me
O
OH
2. BaO, MeOH
r.t., 18 h
OH
2. BzCl, pyridine
CH2Cl2,
r.t., 3 h
OH
AcO
HO
4
3
96% (2 steps)
3. 80% AcOH,
r.t., 2 h
80% (3 steps)
1. NaH, BnBr, DMF
r.t., 12 h (95%)
OMe
OH
OMe
Me
Me
O
O
OBn
2. PPTS, MeOH
r.t., 12 h (98%)
OEE
OH
HO
BnO
5
6
SYNLETT 2005, No. 5, pp 0801–0804
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-864792; Art ID: U35004ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

802
D.-S. Hsu et al.
LETTER
OMe
OMe
OMe
OMe
OH
PhCH(OMe)2, TsOH
MeCN, r.t., 18 h
DIBAL, CH2Cl2
Me
Me
Me
Me
O
O
Me
HO
O
Me
O
OBn
OBn
OH
O
OH
OH
O
0 °C, 0.5 h
96%
O
O
O
BnO
O
76%
3
7
8
6
Ph
Ph
H
OMe
OMe
OMe
OMe
OMe
Me
Me
O
O
NaH, BnBr
Me
O
DIBAL, CH2Cl2 Me
0 °C, 2 h
O
O
OBn
OBn
OBn
OBn
OBn
+
+
O
O
DMF, r.t., 18 h
O
OH
OBn
HO
O
O
BnO
Ph
H
94%
9
6
1.3
10
H
H
Ph
Ph
:
1
8
9
50%
48%
OMe
OMe
BF3·OEt2, CH2Cl2
0 °C, 5 min;
Scheme 2
O
Me
O
OBn
OBn
then DIBAL, 0.5 h
85%
O
OH
BnO
OMe
1
OBn
OMe
1
9
6
H
Ph
Me
O
Me
H
O
OBn
2
4
Scheme 3
O
O
O
H
O
11.7%
H
Ph
Ph
H
5.3%
OMe
8
9
OMe
Me
O
fast
OBn
Figure 2 1H NMR studies of NOE (%) for 8 and 9
Me
O
OBn
O
O
AlH(i-Bu)2
OH
BnO
Ph
As previously noted by Guo, the isomers, 8 and 9 showed
significant difference in the reactivity for reductive acetal
cleavage (Scheme 3).10 Endo-isomer 8 rapidly reacted
with diisobutylaluminum hydride (DIBAL, 3 equiv) in
dichloromethane within 30 minutes, affording the desired
product 6 as single product in 96% yield. On the other
hand, the corresponding reaction of exo-isomer 9 reacted
much slower under the same conditions, and two hours
was needed for the complete consumption of 9, giving a
mixture of regioisomers 6 and 10 (1.3:1). We reasoned
that the lower reactivity of 9 was due to the presence of the
exo-phenyl group, retarding the coordination of DIBAL to
the acetal oxygen(s) (Scheme 4).12 This issue was nicely
solved by using DIBAL in combination with BF3·OEt2.
Upon exposure of exo-acetal 9 with BF3·OEt2 (2 equiv)
for 5 minutes (0 °C, CH2Cl2), followed by the addition of
DIBAL (3 equiv), the reaction was complete within 0.5
hours to furnish the desired product 6 as a single isomer in
85% yield.
H
8 (endo)
6
OMe
O
OMe
OMe
OBn
Me
slow
OBn
Me
Me
O
OBn
+
O
O
OH
OBn
BnO
HO
H
AlH(i-Bu)2
(i-Bu)2AlH
Ph
9 (exo)
6
10
Scheme 4
OMe
OBn
OMe
BF3·OEt2
Me
Me
O
O
OBn
CH2Cl2, 0 °C
O
O
O
O
Ph
H
H
Ph
8
9
Concerning this highly favorable result, a typical Curtin–
Hammett system was relevant (Scheme 5). Upon treat-
ment with BF3·OEt2, the isomers 8 and 9 became quickly
equilibrated, although the ratio was only 2:1.13 However,
as a consequence of the rapid equilibrium and also the fact
that 8 reacts with DIBAL much faster than 9 (vide supra),
the entity that undergoes reduction is 8, only giving the
product 6. The exo-isomer 9 could serve as an in situ
source of the reactive isomer 8. Indeed, we can also use a
mixture of 8 and 9 by prior treatment with BF3·OEt2 fol-
lowed by exposure to DIBAL under the same conditions
to afford product 6, although the yield was less than ex-
pected (Scheme 6).
DIBAL
k1
DIBAL
k2
k1 > k2
OMe
OMe
OMe
Me
Me
Me
O
O
O
OBn
OBn
OBn
+
OH
OBn
OH
BnO
BnO
HO
6
10
6
Scheme 5
Synlett 2005, No. 5, 801–804 © Thieme Stuttgart · New York

LETTER
Synthetic Route to Ravidosamine Derivatives
803
OMe
a
OMe
BF3·OEt2,
CH2Cl2
0 °C, 5 min
H–
Me
OMe
OMe
OMe
OMe
NH2
O
H
Me
O
Me
O
OBn
OBn
Me
Me
O
O
Me
O
OBn
+
OBn
OBn
+
OBn
O
O
then DIBAL,
0.5 h
O
O
H
NOH
NH2
OH
BnO
BnO
H–
BnO
BnO
H
Ph
81%
Ph
H
b
8
9
6
12
13
14
Scheme 6
Scheme 8
The stage was now set for introduction of the C(3) amino Having limited success with metal hydrides, we turned
group, for which we took the strategy of the oxime reduc- our attention to the use of an electron transfer reagent.
tion. Oxidation of 6 was achieved by using pyridinium When oxime 12 was treated with zinc powder and glacial
dichromate (PDC) or preferably o-iodoxybenzoic acid acetic acid at room temperature15 or even at 100 °C, only
(IBX),14 giving a better yield of ketone 11, which was recovery of the starting material was observed (entry 4).
converted to oxime 12 (Scheme 7).
After some experimentation, we were pleased to find that
oxime 12 could be reduced in high stereoselectivity
(13:14 = 19:1) by using samarium diiodide and
methanol16 in 78% yield (entry 5).
OMe
OMe
PDC, CH2Cl2, r.t., 24 h, 79%
or IBX, DMSO, r.t., 24 h, 96%
Me
Me
O
O
OBn
OBn
OH
O
BnO
BnO
OMe
OMe
11
6
2 SmI2, MeOH
Me
Me
O
O
OBn
OBn
OMe
NOH
NH
BnO
BnO
NH2OH·HCl, NaOAc
Me
O
12
OBn
15
MeOH, r.t., 12 h
94%
NOH
BnO
2 SmI2
12
favored
disfavored
OMe
Scheme 7
OMe
(III)Sm
NH
Me
– O
Me
O
C-
C-
–
However, initial attempts to reduce oxime 12 with hydride
reducing agents gave a poor stereoselectivity, giving the
mixture of isomeric amines 13 and 14 (Table 1, entries
1–3). The reduction with LiAlH4 gave the corresponding
amines 13 and 14 in moderate selectivity (entry 1). When
a bulky hydride reducing agent (e.g. Red-Al) was used,
the axial approach became less favorable, presumably due
to the hindrance by the C(1) methoxy group (Scheme 8),
giving preferentially the undesired amine 14 as a major
product.
OBn
OBn
NH
BnO
BnO
Sm(III)
16
17
MeOH
OMe
MeOH
OMe
NH2
O
Me
Me
O
OBn
OBn
NH2
BnO
BnO
13
14
Scheme 9
Table 1 Reduction of Oxime 12 with Hydride Reducing Agents
OMe
OMe
OMe
NH2
O
H
Scheme 9 shows our rationale for this electron transfer re-
duction.17 The oxime is first reduced to imine 15, and its
further reduction generates the isomeric intermediates 16
and 17. Among these, equatorial disposition of the amino
substituent is preferred to avoid the unfavorable 1,3-diax-
ial interactions, and protonation by the coexisting MeOH
gives the desired amine 13 as the major product.
reagents
Me
Me
Me
O
O
OBn
OBn
OBn
+
conditions
H
NOH
NH2
BnO
BnO
BnO
14
12
13
Entry
Reagents
LiAlH4
Red-Al
Conditions
THF, 0 °C
THF, 0 °C
Et2O, 0 °C
Yield (%, ratio)a
72 (4:1)
1
2
3
4
5
Finally, primary amine 13 was converted to dimethylami-
no sugar 18 by reductive dimethylation (Scheme 10). This
sugar 18 contained the required stereochemistry and func-
tionality of L-ravidosamine (2).18 Azide 20 was also pre-
pared from amine 13, when treated with triflyl azide and
a catalytic amount of cupric sulfate.19 Acetolysis of 19
gave azide 20, which is ready for use in the glycoside
formation.
57 (1:2)
LiAlH4, AlCl3
Zn, HOAc
63 (1:2)
b
r.t. to 100 °C
THF, r.t.
–
SmI2, MeOH
87 (>19:1)
a Determined by 1H NMR.
b Recovery of the starting material.
Synlett 2005, No. 5, 801–804 © Thieme Stuttgart · New York

804
D.-S. Hsu et al.
LETTER
(6) Arai, M.; Tomoda, H.; Matsumoto, M.; Takahashi, Y.;
OMe
OMe
HCHO,
OH
OH
Woodruff, B. H.; Ishiguro, N.; Kobayashi, S.; Omura, S. J.
Antibiot. 2001, 54, 554.
NaBH3CN
Me
Me
Me
O
O
O
OBn
OBn
MeCN,
r.t., 24 h
NH2
NMe2
NMe2
(7) (a) Itoh, T.; Kinoshita, M.; Aoki, S.; Kobayashi, M. J. Nat.
Prod. 2003, 66, 1373. (b) The absolute stereostructure of the
sugar portion of komodoquinone A has not been established.
(8) Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J. Org.
Chem. 1984, 49, 992.
BnO
BnO
HO
13
18
L-ravidosamine (2)
91%
TfN3, CuSO4, MeOH,
pyridine, CH2Cl2, r.t., 6 h
82%
(9) Lindhorst, T. K.; Thiem, J. Liebigs Ann. Chem. 1990, 1237.
(10) Guo and coworkers studied exactly the same system, noting
qualitatively the difference in the reactivities of 8 and 9 for
DIBAL reduction and also suggested the solution by
employing BF3·OEt2. Unfortunately, the exact conclusion
could not be drawn from their data, because they used the
a/b-anomeric mixture of methyl glycoside. See: Guo, Z.-W.;
Deng, S.-T.; Hui, Y.-Z. J. Carbohydr. Chem.; 1996, 15, 965.
(11) Bundle, D. R.; Josephson, S. Can. J. Chem. 1978, 56, 2686.
(12) Gauthier, D. R. Jr.; Szumigala, R. H. Jr.; Armstrong, J. D.
III; Volante, R. P. Tetrahedron Lett. 2001, 42, 7011.
(13) To a stirred solution of 9 (356 mg, 1 mmol) in CH2Cl2 (5 mL)
at 0 °C was added BF3·OEt2 (0.25 mL, 2 mmol). After
stirring for 5 min, the reaction was quenched with sat. aq
NaHCO3 solution. The mixture was extracted with CH2Cl2,
and the combined organic extracts were washed with brine,
dried over Na2SO4, filtered, and concentrated. The 1H NMR
indicated that the ratio of 8 and 9 was about 2:1.
OMe
OAc
Ac2O, H2SO4
Me
Me
O
O
OBn
OBn
0 °C, 25 min
89%
N3
N3
BnO
BnO
19
20
Scheme 10
In conclusion, we have developed an efficient synthetic
route to ravidosamine derivatives. Total synthesis of
ravidomycin and the related natural products is now in
progress, and the results will be reported shortly.
Acknowledgment
D.S.H. thanks CREST for a postdoctoral fellowship. Thanks are due
to Mr. Tomoo Matsuura for his contribution to the early phase of
this work.
(14) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8019.
(15) Brünker, H.-G.; Adam, W. J. Am. Chem. Soc. 1995, 117,
3976.
(16) Yamaura, M.; Noguchi, M.; Umemura, K.; Yoshimura, J.
Kidorui 1993, 22, 54.
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H), 4.64–4.56 (m, 3 H), 4.07 (dd, J = 3.7, 11.2 Hz, 1 H), 3.85
(br q, J = 6.6 Hz, 1 H), 3.62 (br d, J = 2.9 Hz, 1 H), 3.33 (s,
3 H), 3.00 (dd, J = 2.9, 11.2 Hz, 1 H), 2.59 (s, 6 H), 1.13 (d,
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Synlett 2005, No. 5, 801–804 © Thieme Stuttgart · New York