Synthesis of L-vancosamine derivatives from methyl α-D- mannopyranoside

Article abstract of DOI:10.1055/s-2006-926231

Concise synthesis of L-vancosamine, the amino sugar constituent of vancomycin and other antibiotics, has been achieved. The key steps include (1) stereoselective addition of methylcerium reagent to oximino ether, and (2) stereoselective hydrogenation of 5

Full text of DOI:10.1055/s-2006-926231

LETTER
469
Synthesis of L-Vancosamine Derivatives from Methyl a-D-Mannopyranoside
Synthesis of
L
-Van
a
cosamine
D
y
erivatives -Shin Hsu, Takashi Matsumoto, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and SORST-JST Agency, 2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551,
Japan
Fax +81(3)57342788; E-mail: ksuzuki@chem.titech.ac.jp
Received 18 October 2005
OMe
OH
O
O
O
O
Abstract: Concise synthesis of L-vancosamine, the amino sugar
constituent of vancomycin and other antibiotics, has been achieved.
The key steps include (1) stereoselective addition of methylcerium
reagent to oximino ether, and (2) stereoselective hydrogenation of
5,6-unsaturated glycoside with C(5) inversion to give L-vancos-
amine derivative. C-Glycosidation of vancosaminyl acetate with
iodoresorcinol proceeded in the presence of Sc(OTf)3 in high yield.
Me
OH
OH
Me
O
Me
OMe
NH2
OH
Me
O
HO
Me
L-vancosamine (1)
NMe2
RO
nocardicyclins
Key words: vancosamine, oximino ether, organocerium reagent,
stereoselectivity, branched amino sugar, aryl C-glycoside
R1
OH
O
O
O
L-Vancosamine (1) and N,N-dimethyl-L-vancosamine (2)
are the sugar constituents of antibiotics of diverse struc-
tural types. For example, L-vancosamine1 is installed in
the glycopeptide antibiotic vancomycin, which is an im-
portant drug used for the treatment of methicillin-resistant
Staphylococcus aureus (MRSA),2 while N,N-dimethyl
analogue 2 occurs as an O-glycoside in the nocardicyclin
antibiotics3 and as a C-glycoside in the pluramycin anti-
biotics 3 (Figure 1).4
Me Me
O
OH
Me
O
O
Me
N
R2O
Me
Me
Me
NMe2
HO
O
N,N-dimethyl-
Me
L-vancosamine (2)
NMe2
HO
O
We have been interested in the synthesis of aryl C-glyco-
side antibiotics5 involving the pluramycins 3, in which we
required a reliable synthetic route to such L-vancosamine
derivatives. Among numerous preceding syntheses of
R1
=
=
R2 = Ac; pluramycin A (3a)
vancosamine
derivatives
starting
either
from
R1
R2 = H; kidamycin (3b)
carbohydrates6 or non-carbohydrate materials,7 several
are elegantly achieved, but less practical due to the use of
toxic reagents or expensive starting materials, and few are
applicable to a high-yielding, large-scale preparation.
Figure 1
et al. reported that five equivalents of methylcerium
chloride was needed for completion of the reaction of the
corresponding benzyl imino ether.11 However, we found
that the cerium reagent could be reduced to two equiva-
lents, if the reaction was carried out at 0 °C or warmed to
15 °C for three hours. The stereostructure of 8 was
Herein, we describe a steady, stereoselective route to L-
vancosamine derivatives. A preliminary study on the aryl
C-glycosidation will be also described.
The synthesis started with the known conversion of meth-
yl a-D-mannopyranoside (4) into ketone 6 (Scheme 1).8
For introduction of the C(3) methyl-branched amino
group, we took the strategy of adding a methyl anion to
the oximino ether.9 Treatment of ketone 6 with O-methyl-
hydroxylamine hydrochloride and NaOAc (MeOH, r.t.,
12 h) afforded the oximino ether 7 in 83% yield, which
was treated with methylcerium chloride10 at –78 °C. Dur-
ing gradual warming to 0 °C and further stirring at this
temperature for three hours, the addition occurred
smoothly to give the isomer 8 as a single product. Greven
1
assigned by H NMR nuclear Overhauser enhancement
difference (NOED) experiment (Figure 2). Highly stereo-
selective addition of the methyl anion to the oximino ether
could be ascribed to the steric effect of the anomeric
methoxy group, retarding attack of the bulky cerium
reagent from the a-face.
The next stage was the amidation and the reductive cleav-
age of the N–O bond. Although the cleavage of N–O bond
by catalytic hydrogenolysis is one of the most useful
method, we reasoned that not only the N–O bond, but also
the benzylidene acetal would undergo hydrogenolysis.
Thus, we centered our attention to samarium diiodide,
which was known to cleave N–O bonds.12 Thus, after
SYNLETT 2006, No. 3, pp 0469–0471
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926231; Art ID: U29105ST
© Georg Thieme Verlag Stuttgart · New York

470
D.-S. Hsu et al.
LETTER
NBS, BaCO3,
CCl4, reflux
22–71%
Ph
O
Br
BzO
Me
Ph
O
OH
O
O
O
O
HO
HO
HO
Ph
O
O
PhCH(OMe)2, TsOH
O
Me
O
or NBS, pyridine,
CCl4, reflux, 2.5 h
73%
CF3CONH
OMe
CF3CONH
OMe
DMF, 70 °C, 3 h
95%
OMe
OMe
11
10
4
5
MeONH2·HCl,
Ph
O
H2, Pd/C
DBU
O
O
BzO
n-BuLi, THF
O
NaOAc
Me
MeOH, r.t., 12 h
67%
DMF, 90 °C, 4 h
76%
–50 °C to –30 °C
84%
MeOH, r.t., 12 h
83%
CF3CONH
OMe
O
OMe
12
6
Ph
O
Ph
O
OH
Me
O
Me
O
MeCeCl2, THF
O
O
O
O
Me
OMe
Me
Me
–78 °C to 0 °C
or –78 °C to 15 °C
MeON
NHCOCF3
NH2
OMe
MeONH
OMe
BzO
HO
7
8
13
L-vancosamine (1)
Ph
O
(CF3CO)2O, Et3N
O
SmI2, MeOH
O
Scheme 2
Me
CH2Cl2, 0 °C, 20 min
88% (2 steps)
THF, r.t., 10 min
94%
MeON
OMe
CCF3
resulting hydroxy group gave glycosyl acetate 15 (b:a =
>20:1),19 ready for the C-glycosidation (Scheme 3). In-
deed, upon treatment of glycosyl acetate 15 with phenol
16 in the presence of 50 mol% amount of Sc(OTf)3 and
powdered Drierite® in 1,2-dichloroethane at –30 °C fol-
lowed by gradual warming to 10 °C, the C-glycoside 17
was obtained in 93% yield.20 The stereostructures of 15
O
Ph
O
9
O
O
Me
CF3CONH
10
OMe
Scheme 1
1
and 17 were assigned by H NMR NOE experiments
hydroxyamino sugar 8 was protected as a trifluoroacet-
amide 9, which was treated with samarium diiodide,
where the cleavage of the N–O bond completed in 10
minutes, giving amide 10 in 94% yield.
(Figure 3).
OH
Me
O
Me
20% HOAc
Me
Me
O
OMe
100 °C, 12 h
NHCOCF3
NHCOCF3
Opening of the benzylidene acetal in 10 was attempted by
treatment with N-bromosuccinimide (NBS) and BaCO3 in
refluxing CCl4.13 This process, however, turned to be ca-
pricious, and the yield fluctuated in the range of 22–71%
(Scheme 2). Careful drying of the reaction flask, reagents
and the solvent, or control experiments with/without room
light illumination, were all incapable of solving the poor
reproducibility. However, the situation was solved by
adding one equivalent of pyridine,14 instead of BaCO3, in
refluxing CCl4 under normal room light illumination to
produce bromide 11 in 73% yield.9 Dehydrobromination
was effected by using DBU in hot DMF (90 °C, 4 h).15
Finally, catalytic hydrogenation of the resulting enol ether
furnished the L-vancosamine derivative 13.16
BzO
BzO
13
14 (α:β = 1:1)
50 mol% Sc(OTf)3
Me
O
Ac2O, pyridine
Me
OAc
16
®
CH2Cl2, r.t., 12 h
88% (2 steps)
Drierite
NHCOCF3
BzO
1,2-dichloroethane
15
–30→10 °C
OH
OH
I
Me
I
Me
O
NHCOCF3
OBn
OBn
BzO
17 93%
16
For the glycoside formation, we needed a better leaving
group at the C(1) position rather than a methoxy group.17
Thus, methyl glycoside 13 was hydrolyzed in 20%
aqueous AcOH (100 °C, 12 h),18 and acetylation of the
Scheme 3
9.7%
9.6%
δΗ = 5.96
δΗ = 4.89
(dd, J = 2.7, 10.3 Hz)
(dd, J = 2.7, 12.2 Hz)
5.6%
9.5%
3.1%
OH
I
H
H
H
H
H
Me
O
Me
O
Ph
O
Me
OAc
O
Me
O
Me
NHCOCF3
NHCOCF3
OBn
BzO
BzO
MeONH OMe
15
17
8
Figure 3 Selected data of 1H NMR and NOE for 15 and 17.
Figure 2 1H NMR study of NOE for 8.
Synlett 2006, No. 3, 469–471 © Thieme Stuttgart · New York

LETTER
Synthesis of L-Vancosamine Derivatives
471
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In summary, we have developed an efficient and prepara-
tive synthetic route of L-vancosamine derivatives, which
was accomplished in 9 steps from methyl a-D-mannopyr-
anoside (4) with an overall yield of 20%. In addition, no
chromatographic purification procedures are required
from the intermediate 5 to 8. Total synthesis of the
pluramycins and the related natural products is now in
progress, and the results will be reported in due course.
Acknowledgment
D.S.H. thanks SORST-JST for a postdoctoral fellowship.
References and Notes
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28
(19) Compound 15: mp 168–169 °C (CH2Cl2–hexane); [a]D
+10 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.16–
8.13 (m, 2 H), 7.67–7.48 (m, 3 H), 6.99 (br s, 1 H), 5.96 (dd,
J = 2.7, 10.3 Hz, 1 H), 5.07 (br s, 1 H), 4.17 (dq, J = 1.0, 6.6
Hz, 1 H), 2.61 (dd, J = 2.7, 12.6 Hz, 1 H), 2.15 (s, 3 H), 2.10
(dd, J = 10.3, 12.6 Hz, 1 H), 1.77 (s, 3 H), 1.29 (d, J = 6.6
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 169.1 (C), 167.7
(C), 156.3 (q, J = 37 Hz, C), 134.1 (CH), 130.0 (CH), 128.7
(CH), 128.3 (C), 115.2 (q, J = 290 Hz, C), 90.6 (CH), 73.4
(CH), 69.1 (CH), 57.2 (C), 35.3 (CH2), 21.2 (CH3), 21.0
(CH3), 17.2 (CH3). IR (neat): 3334, 3076, 2989, 1728, 1556,
1452, 1273, 1161, 1049, 908, 758, 715 cm–1. Anal. Calcd: C,
53.60; H, 5.00; N, 3.47. Found: C, 53.39; H, 5.25; N, 3.37.
(20) Compound 17: mp 89–90 °C (Et2O–hexane); [a]D29 –0.3 (c
0.98, CHCl3). 1H NMR (400 MHz, CDCl3): d = 8.38 (s, 1 H),
8.19–8.16 (m, 2 H), 7.68–7.28 (m, 8 H), 7.01 (d, J = 8.5 Hz,
1 H), 6.88 (br s, 1 H), 6.42 (d, J = 8.5 Hz, 1 H), 5.22 (br s, 1
H), 5.16 (s, 2 H), 4.89 (dd, J = 2.7, 12.2 Hz, 1 H), 4.20 (q,
J = 6.6 Hz, 1 H), 2.49 (dd, J = 2.7, 12.4 Hz, 1 H), 2.28 (dd,
J = 12.2, 12.4 Hz, 1 H), 1.84 (s, 3 H), 1.31 (d, J = 6.6 Hz, 3
H). 13C NMR (100 MHz, CDCl3): d = 167.6 (C), 158.3 (C),
156.3 (q, J = 37 Hz, C), 155.3 (C), 136.5 (C), 134.1 (CH),
130.1 (CH), 128.9 (CH), 128.5 (CH), 128.2 (C), 127.8 (CH),
127.5 (CH), 126.9 (CH), 118.6 (C), 115.2 (q, J = 290 Hz, C),
104.2 (CH), 79.0 (C), 75.5 (CH), 73.7 (CH), 71.0 (CH), 70.9
(CH2), 56.7 (C), 37.1 (CH2), 20.4 (CH3), 17.8 (CH3). IR
(neat): 3340, 3064, 2985, 1728, 1614, 1452, 1269, 1063,
908, 735, 714 cm–1. Anal. Calcd: C, 52.03; H, 4.07; N, 2.09.
Found: C, 52.18; H, 4.33; N, 2.14.
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Synlett 2006, No. 3, 469–471 © Thieme Stuttgart · New York