A divergent route to 3-amino-2,3,6-trideoxysugars including branched sugar: Synthesis of vancosamine, daunosamine, saccharosamine, and ristosamine

Article abstract of DOI:10.1246/cl.2007.1372

Four 3-amino-2,3,6-trideoxysugars were synthesized by a divergent route from a single enone 9a. The Migita-Stille coupling introduced a methyl group at the 3-position. Stereoselective reduction of enone and the Mitsunobu reaction provided both β- and α-hy

Full text of DOI:10.1246/cl.2007.1372

1372
Chemistry Letters Vol.36, No.11 (2007)
A Divergent Route to 3-Amino-2,3,6-trideoxysugars Including Branched Sugar:
Synthesis of Vancosamine, Daunosamine, Saccharosamine, and Ristosamine
Takayuki Doi, Kazuaki Shibata, Atsushi Kinbara, and Takashi TakahashiÃ
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552
(Received August 9, 2007; CL-070854; E-mail: ttak@apc.titech.ac.jp)
Four 3-amino-2,3,6-trideoxysugars were synthesized by a
trideoxysugars 1–4 including C3 methyl branch from a single
starting compound.
divergent route from a single enone 9a. The Migita–Stille cou-
pling introduced a methyl group at the 3-position. Stereoselec-
tive reduction of enone and the Mitsunobu reaction provided
both ꢀ- and ꢁ-hydroxy groups at the 4-position. Stereospecific
radical cyclization of the C4 carbamoyl moiety furnished the de-
sired 5a, 5b and 6a, 6b, respectively.
Our strategy is illustrated in Scheme 1. We envisaged four
3-amino-2,3,6-trideoxysugars 5a, 5b, 6a, and 6b to be available
from stereospecific radical cyclization of carbamates 7a, 7b, 8a,
and 8b, recently reported by Nicolaou et al.9 The carbamates
would be synthesized from a single synthetic intermediate 9a
(R = H) by introducing the C3 methyl group in case R = Me,
followed by stereoselective reduction of the enones 9a and 9b
and inversion of the resulting hydroxy group by the Mitsunobu
reaction. The enone 9a is readily available from furfuryl alcohol
(S)-10. This synthetic method can be available to the synthesis of
their enantiomers from (R)-10.
Enone 11 was prepared from commercially available furfur-
yl alcohol (S)-10 by the Achmatowicz reaction followed by pro-
tection of the resulting hemiacetal with (Boc)2O according to the
reported procedure.10 The enone 11 was obtained as a 2:1 mix-
ture of diastereomers with its anomeric epimer and was easily
separated by silica-gel column chromatography. The Boc group
was converted to a 4-methoxyphenylmethyl (MPM) group by
Pd-catalyzed glycosidation reaction.10 The reaction smoothly
proceeded with excellent stereoselectivity via a double inversion
process leading to 9a (R = H) in 92% yield. Next, we examined
introduction of a methyl group at the 3-position. Iodination of
enone 9a with I2–DMAP gave an ꢁ-iodo enone 12 in quantita-
tive yield. The labile 12 was immediately subjected to the
Migita–Stille coupling with Me4Sn to avoid decomposition.
After optimization of the reaction conditions, it was found that
a POPd,11 CuI, and DMF system is very effective for the cou-
pling reaction to provide enone 9b without addition of arsenic
ligands (Scheme 2).
3-Amino-2,3,6-trideoxysugars were found in nature as
structural components of glycosidic and oligosaccharide antibi-
otics.1 These have various configurational isomers and substitu-
ents such as a methyl group (Figure 1). L-Vancosamine (1) is
known as a C3-branched sugar found in vancomycin antibiotics.
It has been known that the sugar moieties play an important role
in biological activity of these antibiotics. For instance, in doxo-
rubicin, an anthracycline antibiotic, displacement of L-daunosa-
mine (2) to its 4-epimer, L-acosamine, or its 3,4-epimer, L-risto-
samine (4), suppresses the undesired toxic side effects while
maintaining similar antitumor activity.2,3 Recently, it has been
reported that displacement of L-vancosamine in a vancomycin
derivative to its demethyl sugar, L-daunosamine, exhibits signif-
icant activity against methicillin-resistant staphylococcal
strains.4 Therefore, 3-amino-2,3,6-trideoxysugars and its
branched-sugars are in high demand although these are rare
and not commercially available.
Several syntheses of 3-amino-2,3,6-trideoxysugars have
been reported from both sugars and non-sugar precursors.5 How-
ever, most of them were prepared one by one. Recently, Riera et
al. reported a stereodivergent approach to four 3-amino-2,3,6-tri-
deoxysugars using reagent-controlled stereoselective epoxida-
tion and organometallic addition as key steps.6 Zhang et al. also
reported a divergent approach to 3-azido-2,3,6-trideoxysugars
from rhamnal using stereoselective epoxidation followed by
azidation.7
Enones 9a and 9b in our hand were steroselectively reduced
O
OMPM
O
OMPM
4
We have demonstrated a semi-synthesis of vancomycin and
its glucose-modified derivatives by solid-phase glycosidation of
glucose with vancomycin aglycon, followed by glycosylation
with vancosamine, and then nucleophilic cleavage at the 6-posi-
tion of glucose from the solid-support.8 To synthesize vancosa-
mine-modified vancomycin derivatives, we need an efficient
synthetic method for a variety of 3-amino-2,3,6-trideoxysugars.
Herein, we report a divergent synthesis of four 3-amino-2,3,6-
4
O
3
3
O
O
O
OMPM
R
R
N
NH
PMP
7a (R = H)
7b (R = Me)
O
4
PMP
O
3
5a (R = H)
5b (R = Me)
R
9a (R = H)
9b (R = Me)
O
OMPM
O
N
OMPM
O
OH
O
OH
OH
O
O
OH
O
OH
O
O
O
R
R
NH
PMP
HO
H2N
HO
HO
H2N
HO
O
PMP
NH2
NH2
L-Vancosamine (1) L-Daunosamine (2) L-Saccharosamine (3) L-Ristosamine (4)
6a (R = H)
6b (R = Me)
8a (R = H)
8b (R = Me)
(S)-10
Figure 1. Structures of naturally occurring 3-amino-2,3,6-tri-
deoxysugars.
Scheme 1. Retrosynthesis of 3-amino-2,3,6-trideoxysugars.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.11 (2007)
1373
1H NMR spectra with coupling constants of the vicinal protons
and NOE obervation.13,14 Removal of the MPM and p-methoxyl-
phenyl (PMP) groups [Ce(NH4)2(NO3)6/MeCN–H2O/rt], fol-
lowed by saponification [Ba(OH)2/H2O/125 ꢀC; CO2(s)] pro-
vided 3-amino-2,3,6-trideoxysugars 1–4 (80–90%).5,9 Since the
MPM group at the anomeric position in 5 and 6 was selectively
removed by treatment with TFA–H2O–CH2Cl2 at room temper-
ature (85–90%), the products can also be utilized for glycosyla-
tion.5
In summary, we have demonstrated a novel divergent syn-
thesis of 3-amino-2,3,6-trideoxysugars 5a, 5b, 6a, and 6b from
(S)-10 with control of the stereochemistry of the three contigu-
ous stereogenic centers (C3, C4, and C5). The configuration at
the 4-position is controlled by stereoselective reduction and
the Mitsunobu reaction. The methyl group at the 3-position
was introduced by the palladium-catalyzed Migita–Stille cou-
pling. The amino group at the 3-position is exclusively intro-
duced by IBX-mediated radical cyclization from the C4 carba-
moyl moiety. This method can be easily applied to the synthesis
of their enantiomers from (R)-10.
O
OBoc
O
OMPM
c
a, b
(S)-10
O
O
92%
3
54%
R
(Ref. 10)
11
9a (R = H)
12 (R = I)
9b (R = Me)
d
e
2 steps 80%
Scheme 2. Synthtesis of enones 9a and 9b. Reagents and con-
ditions: (a) NBS, NaHCO3, NaOAc, THF–H2O, 0 ꢀC; (b)
(Boc)2O, DMAP, CH2Cl2, À78 ꢀC; (c) 4-methoxybenzyl alco-
ꢀ
.
hol, Pd2(dba)3 CHCl3, PPh3, CH2Cl2, 0 C; (d) I2, DMAP,
CH2Cl2; (e) Me4Sn, POPd, CuI, DMF, 80 ꢀC. MPM = 4-
methoxyphenylmethyl. POPd = PdCl2(Pt-Bu2OH)2.
O
OMPM
O
R
OMPM
a
b, c
9a (R = H)
9b (R = Me)
HO
HO
R
13a (R = H)
94% (dr = 95:5)
13b (R = Me)
84% (dr = 95:5)
14a (R = H) 86%
14b (R = Me) 39%
References and Notes
1
2
F. M. Hauser, S. R. Ellenberger, Chem. Rev. 1986, 86, 35.
F. Arcamone, S. Penco, A. Vigevani, S. Redaelli, G. Franchi,
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Scheme 3. Synthtesis of allylic alcohols 13a, 13b and 14a, 14b.
Reagents and conditions: (a) NaBH4, CH2Cl2, MeOH, À78 to
0 ꢀC; (b) p-nitrobenzoic acid, DEAD, PPh3, THF, rt for 13a,
70 ꢀC for 13b; (c) NaOMe, THF, MeOH.
3
4
5
with NaBH4 via axial attack of hydride to provide allylic alcohol
13a and 13b, respectively. The Mitsunobu reaction of alcohol
13a smoothly proceeded under conventional conditions using
p-nitrobenzoic acid as a nucleophile.12 The reaction of 13b did
not proceed under the same reaction conditions owing to steric
hindrance by the methyl group at the 3-position. However, under
heating to 70 ꢀC the desired alcohol 14b was provided in 39%
yield after methanolysis (Scheme 3).
M. T. Mendlik, P. Tao, C. M. Hadad, R. S. Coleman, T. L.
Lowary, J. Org. Chem. 2006, 71, 8059 and references
therein.
The four allylic alcohols 13a, 13b, 14a, and 14b were re-
spectively converted to carbamates 7a, 7b, 8a, and 8b by treat-
ment with (p-methoxyphenyl)isocyante and DBU in CH2Cl2
(71–83%). IBX-mediated radical cyclization9 of the four carba-
mates was investigated. 7a was initially treated with IBX (2.1
equiv.)–NaHCO3 in THF–DMSO (10:1) in a sealed tube at
90 ꢀC for 12 h. The reaction mixture was further heated with
an additional amount of IBX (2.1 equiv.) for another 12 h. After
silica-gel chromatography, the desired protected L-ristosamine
5a was obtained in 56% yield and the starting material was also
recovered. Although we optimized the reaction conditions such
as temperature, time, molar, and equivalent of the reagent, the
reaction was not complete. The reactions of 7b, 8a, and 8b also
proceeded under the same reaction conditions leading to the pro-
tected L-saccharosamine 5b (62%), L-daunosamine 6a (68%)
and L-vancosamine 6b (63%), respectively, with exclusive
stero- and regioselection. Their structures were determined by
6
7
8
9
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11 G. Y. Li, Angew. Chem. Int. Ed. 2001, 40, 1513.
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13 The reaction of its epimer of 6b was demonstrated. See
Ref. 9.
14 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/.
Published on the web (Advance View) October 20, 2007; doi:10.1246/cl.2007.1372