Synthesis of methyl α-L-vancosaminide

Article abstract of DOI:10.1016/S0008-6215(99)00259-1

The synthesis of methyl α-L-vancosaminide from di-O-acetyl-L-rhamnal is described. The allylic alcohol methyl 2,3,6-trideoxy-3-C-methyl-α-L-threo- hex-2-enopyranoside was prepared from the glycal, 1,5-anhydro-1,2,6-trideoxy- 3-C-methyl-L-ribo-hex-1-enitol

Full text of DOI:10.1016/S0008-6215(99)00259-1

www.elsevier.nl/locate/carres
Carbohydrate Research 323 (2000) 208–212
Note
Synthesis of methyl a-L-vancosaminide
Garry R. Smith, Robert M. Giuliano *
Department of Chemistry, Villano6a Uni6ersity, 800 Lancaster A6enue, Villano6a, PA 19085, USA
Received 21 June 1999; accepted 15 September 1999
Abstract
The synthesis of methyl a-
2,3,6-trideoxy-3-C-methyl-a-
3-C-methyl- -ribo-hex-1-enitol, and converted to its N,N-dimethylisourea derivative. The cis amino alcohol function-
L
-vancosaminide from di-O-acetyl-L-rhamnal is described. The allylic alcohol methyl
L
-threo-hex-2-enopyranoside was prepared from the glycal, 1,5-anhydro-1,2,6-trideoxy-
L
ality in vancosamine was introduced by the electrophilic cyclization of the isourea, followed by hydrolysis of the
resulting oxazoline. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Vancosamine; Methyl a-L-vancosaminide; Isourea cyclization
and that carbohydrate modification by synthe-
sis can be pursued as a means of developing
useful vancomycin analogs [8,9].
The amino sugar -vancosamine [1], its C-3
L
epimer [2], and its 4-keto derivative [3] are
found in the glycopeptide antibiotics van-
comycin, A35512B, and balhimycin, respec-
tively, while N,N-dimethylvancosamine [4]
occurs in kidamycin and related C-glycoside
antibiotics. Vancomycin is an important drug
used to treat antibiotic-resistant infections
caused by Gram-positive bacteria [5]. The
emergence of vancomycin-resistant strains of
Staphylococcus aureus and Enterococcus fae-
calis has resulted in renewed interest in the
chemistry and biology of this valuable antibi-
otic [6]. Of particular interest to our labora-
tory was the recent discovery that carbo-
hydrate-modified derivatives of vancomycin
are active against these resistant strains [7], a
finding that clearly demonstrates that the glu-
cose–vancosamine disaccharide of vanco-
mycin is involved in the mechanism of action,
The key problem in the synthesis of van-
cosamine and related 3-methyl branched
amino and nitro sugars is the introduction of
the functionality at the 3-position with the
correct stereochemistry [10]. Several syntheses
of vancosamine have been described from car-
bohydrate and non-carbohydrate precursors
[11], the first being that reported in 1979 by
Thang, Lukacs, and co-workers, which was
based on the addition of HCN to a 3-keto
sugar [12] and subsequent transformation of
the cyanomesylate derivative to a spiroa-
ziridine. In vancosamine and in other amino
and nitro sugars in which the nitro or amino
group is cis to an adjacent hydroxyl group,
the electrophilic cyclization of allylic imidates
[13], carbamates [14], or isoureas [15] has been
an effective method for controlling the stereo-
chemistry at the critical C-3 position (Eq. (1))
[16]. Hydrolysis of the resulting oxazoline pro-
vides the cis amino alcohol functionality.
* Corresponding author. Tel.: +1-215-645-4868; fax: +1-
215-645-7167.
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00259-1

G.R. Smith, R.M. Giuliano / Carbohydrate Research 323 (2000) 208–212
209
tively, 2 was prepared by the addition of
methyllithium to enone 3, as reported by
Thiem and Elvers [21]. Enone 3 was prepared
from di-O-acetyl- -rhamnal by deacetylation
L
and oxidation with silver carbonate-on-Celite
[22]. These two routes afforded 2 in overall
yields of 44 and 34%, respectively. While the
route from 1 is more efficient in terms of
overall yield, we prefer the alternative synthe-
sis of 2 from the enone, as it is more conve-
nient to carry out.
Both routes provide glycal 2 as a mixture of
epimers, with the arabino isomer being the
major product in each case. This is of no
consequence as both alcohols smoothly un-
dergo acylation and Ferrier rearrangement in
the presence of methanol to give allylic ester 4,
as described by Parker and Meschwitz [23]
(Scheme 1). The b anomer of 4 is also ob-
tained (a:b=1:1); however, equilibration of
the mixture in the presence of acid, as re-
ported, provides a anomer 5 as the major
product in 49% overall yield from glycal 2.
(1)
We have utilized this method with allylic
N,N-dimethylisoureas (R=NMe2) in the syn-
thesis of the nitro sugars rubranitrose [15],
decilonitrose [17], and kijanose [18]. For the
synthesis of vancosamine, cyclization of allylic
isourea 8 would be expected to produce the
desired lyxo stereochemistry. In this paper, we
report the stereoselective synthesis of methyl
a- -vancosaminide by the electrophilic cycliza-
tion of 8, which was prepared from the 3-C-
methyl glycal 1,5-anhydro-1,2,6-trideoxy-3-C-
L
methyl- -ribo-hex-1-enitol 2.
L
Glycal 2 was synthesized by two different
routes in this study. In one sequence, benzyli-
dene acetal 1 [19] was prepared from methyl
a- -rhamnopyranoside and converted to 2 by
the addition of excess methyllithium, as de-
scribed by Jung and Klemer [20]. Alterna-
L
Scheme 1. Synthesis of methyl a-L-vancosaminide.

210
G.R. Smith, R.M. Giuliano / Carbohydrate Research 323 (2000) 208–212
Deacylation of 4 with ion-exchange resin gave
the key allylic alcohol 5, which is epimeric at
C-4 with vancosamine. Inversion of configura-
tion at C-4 in 5 was previously carried out by
the Mitsunobu reaction by Dyong et al. [24].
Use of the Martin-modified Mitsunobu reac-
tion [25], in which 4-nitrobenzoic acid in te-
trahydrofuran was substituted for benzoic
acid in benzene, gave 6 in similar yield, and
enabled the labile nitrobenzoyl group to be
cleaved by treatment with basic ion-exchange
resin.
analyses were conducted on silica gel
(Kieselgel 60 F254, E. Merck) glass plates and
visualized by W 254 nm or with ammonium
molybdate–ceric sulfate reagent. Flash chro-
matography [26] was carried out with J.T.
Baker silica gel. Optical rotations were
recorded on a Perkin–Elmer 241 polarimeter
as [h]D values at 23 °C. Elemental analyses
were carried out at Merck Research Laborato-
ries. High-resolution mass spectra were mea-
sured at Merck Research Laboratories using
ES-FT/ICR/MS with propylene glycol as in-
ternal standard on a Bruker ES-FT mass
spectrometer.
Treatment of allylic alcohol 7 with sodium
hydride in neat dimethylcyanamide gave
isourea 8 in 90% yield after purification by
column chromatography on Florisil. The
isourea was not stable, so the purified product
was immediately subjected to the conditions
for electrophilic cyclization. Treatment of 8
with mercuric trifluoroacetate followed by
sodium borohydride gave oxazoline 9. The
complete regio- and stereoselectivity of this
cyclization was consistent with that observed
in previous studies with structurally related
carbohydrate isoureas, and 9 was obtained as
the single product in high yield. Hydrolysis of
the oxazoline in refluxing saturated barium
Methyl 2,3,6-trideoxy-3-C-methyl-4-O-(4-
nitrobenzoyl)-h- -threo-hex-2-enopyranoside
L
(6).—To a stirring soln of methyl 2,3,6-
trideoxy-3-C-methyl-a- -erythro-hex-2-enopy-
L
ranoside 5 (1.3 g, 8.16 mmol) in anhyd THF
(40 mL) under nitrogen was added PPh3 (4.3
g, 16.3 mmol) and 4-nitrobenzoic acid (2.73 g,
16.3 mmol). To the resulting soln was added
diethyl azodicarboxylate (2.6 mL, 16.3 mmol)
over 15 min, and the reaction mixture was
stirred for 18 h at room temperature (rt). The
solvent was removed by concn at reduced
pressure, and the resulting oil was diluted with
diethyl ether (150 mL) and washed with satd
aq NaHCO3 (70 mL), then with satd aq NaCl
(50 mL). The organic layer was dried
(MgSO4), filtered, and concd at reduced pres-
sure. The resulting oil was purified by flash
column chromatography over silica gel with
3:1 hexanes–EtOAc to yield 1.54 g of a white
solid (61%): mp 122–124 °C; [h]D +173° (c
1.02, CHCl3); Rf 0.49 (1:3 EtOAc–hexanes);
1H NMR (300 MHz): l 8.28 (bd, 4 H, Ar),
5.80 (m, 1 H, H-2), 5.27 (d, J4,5 2.5 Hz, 1 H,
H-4), 4.96 (bs, 1 H, H-1), 4.31 (dq, J5,6 6.6 Hz,
1 H, H-5), 3.45 (s, 3 H, OCH3), 1.78 (bs, 3 H,
3-CH3), 1.22 (d, 3 H, H-6); 13C NMR (75
MHz): l 164.6 (CꢀO), 134.9 (ipso), 133.8 (C-
3), 130.9, 123.5 (Ar), 125.5 (C-2), 95.5 (C-1),
69.8 (C-4), 64.8 (C-5), 55.5 (OCH3), 20.1 (3-
CH3), 15.9 (C-6). Anal. Calcd for C15H17NO6:
C, 58.63; H, 5.58; N, 4.56. Found: C, 58.80;
H, 5.69; N, 4.40.
hydroxide solution provided methyl a- -van-
L
cosaminide 10 in 93% yield. Conversion of 10
to the known dibenzoyl derivative 11 was
carried out with benzoyl chloride in pyridine,
1
and gave a product for which the H NMR
spectrum matched that reported [1a]. The syn-
thesis of 10 from di-O-acetyl- -rhamnal re-
L
quired a total of nine steps, with an overall
yield of 6.5%. Synthetic transformations of 10
at the anomeric position and the amino group
will be investigated in due course.
1. Experimental
General methods.—1H NMR spectra were
recorded on a Varian XL-300 MHz spectrom-
eter with Me4Si as an internal reference in
CDCl3 unless otherwise noted. 13C NMR
spectra were recorded on a Varian XL-300
MHz spectrometer at 75 MHz and referenced
with CDCl3. Melting points were determined
in an open capillary tube with a Thomas–
Hoover apparatus and are uncorrected. TLC
Methyl 2,3,6-trideoxy-3-C-methyl-h- -threo-
L
hex-2-enopyranoside (7).—A soln of nitroben-
zoate 6 (2.0 g, 6.5 mmol) in MeOH (60 mL)
was stirred with Amberlite IRA 400 (OH)

G.R. Smith, R.M. Giuliano / Carbohydrate Research 323 (2000) 208–212
211
resin (1.4 g) for 30 h at rt. The resulting slurry
was then filtered through Celite, and the re-
sulting clear soln was concd at reduced pres-
sure to yield 0.87 g of a white solid (85%): mp
84–86 °C; [h]D +110° (c 1.03, MeOH); Rf
1 H, H-1), 3.98 (d, 1 H, H-4), 3.91 (dq, J5,4 1.5
Hz, 1 H, H-5), 3.37 (s, 3 H, OCH3), 2.91 (s, 6
H, N(CH3)2), 2.22 (dd, J2a,1 5.7 Hz, 1 H,
H-2a), 1.58 (dd, J2e,1 7.9 Hz, J2e,2a 14.7 Hz, 1
H, H-2e), 1.29 (s, 3 H, 3-CH3), 1.25 (d, J6,5 6.6
Hz, 3 H, H-6); 13C NMR (75 MHz): l 160.6
(CꢀN), 98.5 (C-1), 85.8 (C-4), 64.6 (C-3), 64.3
(C-5), 54.6 (OCH3), 37.4 (C-2), 36.9
(N(CH3)2), 29.7 (3-CH3), 16.0 (C-6). HRMS
Calcd for C11H20N2O3 [M+1]+: 229.1547.
Found: 229.1554.
1
0.45 in 1:1 EtOAc–hexanes; H NMR (300
MHz): l 5.52 (m, 1 H, H-2), 4.82 (bs, 1 H,
H-1), 4.06 (dq, J4,5, J5,6 2.0, 6.6 Hz, 1 H, H-5),
3.36 (s, 3 H, OCH3), 3.34 (dd, J4,OH 10.8 Hz, 1
H, H-4), 1.93 (d, 1 H, OH), 1.88 (bs, 3 H,
3-CH3), 1.32 (d, 3 H, H-6); 13C NMR (75
MHz): l 139.2 (C-3), 121.7 (C-2), 95.7 (C-1),
68.2 (C-4), 66.3 (C-5), 55.3 (OCH3), 20.3 (3-
CH3), 15.8 (C-6). HRMS Calcd for C8H14O3
[M+Na]+: 181.0835. Found: 181.0842.
Methyl 3-amino-2,3,6-trideoxy-3-C-methyl-
h-L
-lyxo-hexopyranoside (methyl h- -6an-
L
cosaminide) (10).—A soln of oxazoline 9 (280
mg, 1.23 mmol) in aq BaOH (2 N, 1.5 mL)
was stirred for 22 h under reflux. The reaction
mixture was then cooled to rt, diluted with
water, and extracted with CHCl3 until no
more product was removed (8×5 mL). The
combined extracts were dried (Na2SO4), de-
canted, and concd at reduced pressure to yield
200 mg of a waxy solid (93%): [h]D −132° (c
1.4, MeOH); lit. [h]D −118° (c 0.09, MeOH)
Methyl
4-O-(N,N-dimethyl-1-oxa-3-azo-
prop-2-eno)-2,3,6-trideoxy-3-C-methyl-h-
L
-
threo-hexopyranoside (9).—To a stirring soln
of allylic alcohol 7 (230 mg, 1.46 mmol) in
N,N-dimethylcyanamide (1.8 mL, 22 mmol)
under nitrogen was added NaH (60% disper-
sion in mineral oil, 70 mg, 1.76 mmol) at rt.
After 0.5 h, MeOH (0.5 mL) in hexanes (10
mL) was added, followed by water (3 mL).
The aq phase was extracted with CHCl3 (5×
15 mL), and the combined organic extracts
were dried (Na2SO4), filtered and concd at
reduced pressure. The resulting oil was then
purified by flash column chromatography over
Florisil (35 g) with EtOAc to yield unstable
isourea 8 as a colorless oil (300 mg, 90%),
which was used without further purification.
To a soln of 8 (300 mg, 1.31 mmol) in anhyd
THF (5 mL) under nitrogen was added mer-
cury(II) trifluoroacetate (673 mg, 1.58 mmol),
and the reaction mixture was stirred for 20 h
at ambient temperature. The reaction mixture
was cooled to 0 °C, and aq NaOH (2 N) was
added until a pH of 12 was reached. A soln of
NaBH4 in 2 N aq NaOH (4 N, 2 mL) was
added slowly, resulting in the precipitation of
mercury. After stirring for 2 h, the slurry was
washed with diethyl ether (4×25 mL), and
the combined extracts were dried (MgSO4),
filtered and concd at reduced pressure. The
residual mercury was removed by dissolving
the oil in diethyl ether and filtering by gravity
through a short column of Celite. Concentra-
tion of the clear, colorless filtrate gave 290 mg
of oil (96%): [h]D −0.8° (c 1.2, CHCl3); Rf
0.57 (MeOH); 1H NMR (300 MHz): l 4.72 (d,
1
[1a]; H NMR (300 MHz): l 4.74 (d, J1,2a 4.4
Hz, 1 H, H-1), 4.01 (q, J6,5 6.6 Hz, 1 H, H-5),
3.32 (s, 3 H, OCH3), 3.02 (bs, 1 H, H-4), 1.78
(dd, J2e,2a 13.6 Hz, 1 H, H-2a), 1.54 (d, 1 H,
H-2e), 1.32 (s, 3 H, 3-CH3), 1.29 (d, 3 H, H-6);
13C NMR (75 MHz): l 98.3 (C-1), 74.9 (C-4),
63.5 (C-5), 54.7 (OCH3), 49.8 (C-3), 37.5 (C-
2), 27.5 (3-CH3), 17.3 (C-6).
Methyl 3 - benzamido - O - benzoyl - 2,3,6-tri-
deoxy-3-C-methyl-h-
(11).—To a soln of methyl a-
L
-lyxo-hexopyranoside
-vancosaminide
L
10 (28 mg, 0.16 mmol) in pyridine (0.5 mL)
under nitrogen was added BzCl (70 mL), and
the reaction mixture was stirred for 20 h at
ambient temperature. Ethyl acetate was
added, and the soln was washed with 1 M
HCl, then satd aq NaHCO3. The organic layer
was dried (MgSO4), filtered, and concd at
reduced pressure to an oil that was purified by
flash column chromatography over silica gel
with 3:1 hexanes–EtOAc to yield 38 mg of a
white solid (62%), which was not crystallized:
[h]D −179° (c 0.16, MeOH); lit. [h]D −191°
(c 0.1, MeOH) [1a]; Rf 0.24 in 3:1 hexanes–
1
EtOAc; H NMR (300 MHz): l 6.70 (s, 1 H,
NH), 5.15 (bs, 1 H, H-4), 4.92 (d, J1,2a 4.4 Hz,
1 H, H-1), 4.29 (dq, J4,5 0.9 Hz, J5,6 6.5 Hz, 1
H, H-5), 3.40 (s, 3 H, OCH3), 2.83 (d, J2e,2a

212
G.R. Smith, R.M. Giuliano / Carbohydrate Research 323 (2000) 208–212
[9] For a synthesis of vancomycin from the aglycone, see: C.
Thompson, M. Ge, D. Kahne, J. Am. Chem. Soc., 121
(1999) 1237–1244.
[10] (a) P.A. Wade, R.M. Giuliano, H. Feuer, A.T. Nelsen
(Eds.), in Nitro Compounds: Recent Ad6ances in Synthesis
and Chemistry, VCH, New York, 1993, pp. 137–265. (b)
F.M. Hauser, S.R. Ellenberger, Chem. Re6., 86 (1988)
35–67.
[11] (a) T.T. Thang, F. Winternitz, A. Lagrange, A. Olesker,
G. Lukacs, J. Chem. Soc., Chem. Commun., (1979) 153–
154. (b) H.I. Ahmad, J.S. Brimacombe, A.S. Mengech,
L.C.N. Tucker, Carbohydr. Res., 93 (1981) 288–293. (c)
I. Dyong, H. Friege, H. Luftman, H. Merten, Chem.
Ber., 114 (1981) 2669–2680. (d) G. Fronza, C. Fuganti,
P. Grasselli, G. Pedrocchi-Fantoni, Tetrahedron Lett., 22
(1981) 5073–5076. (e) Y. Hamada, A. Kawai, T. Shioiri,
Tetrahedron Lett., 25 (1984) 5413–5414. (f) F.M. Hauser,
S.R. Ellengerger, J. Org. Chem., 51 (1986) 50–57. (g) A.
Klemer, H. Wilbers, Liebigs Ann. Chem., (1987) 815–
823. (h) R. Greven, P. Ju¨tten, H.-D. Scharf, Carbohydr.
Res., 275 (1995) 83–93. (i) K.C. Nicolaou, H.J. Mitchell,
F.L. van Delft, F. Rusbaum, R.M. Rodriguez, Angew.
Chem., Int. Ed. Engl., 37 (1998) 1871–1874.
[12] J.M. Bourgeouis, Hel6. Chim. Acta, 57 (1974) 2553–
2557.
14.0 Hz, 1 H, H-2e), 2.21 (dd, 1 H, H-2a),
1.90 (s, 3 H, 3-CH3), 1.26 (d, 3 H, H-6); 13C
NMR (75 MHz): l 167.9, 166.6 (OCꢀO,
NCꢀO), 133.2, 135.0 (Ar ipso), 133.6, 131.0,
129.9, 128.5, 128.3, 128.3, 126.6 (Ar), 98.5
(C-1), 75.8 (C-4), 62.6 (C-5), 55.1 (C-3), 55.0
(OCH3), 35.1 (C-2), 23.6 (3-CH3), 17.4 (C-6).
Acknowledgements
The authors thank Merck Research Labo-
ratories and Villanova University for financial
support, including a research fellowship for
G.R.S. from the Merck Medicinal Chemistry
Department. We also thank Patrice Ciecko
and C.W. Ross III of Merck for the elemental
analyses and HRMS measurements, respec-
tively.
[13] H. Pauls, B. Fraser-Reid, J. Chem. Soc., Chem. Com-
mun., (1983) 1031–1032.
[14] (a) K.A. Parker, R. O’Fee, J. Am. Chem. Soc., 105
(1983) 654–655. (b) S. Knapp, M.J. Sebastian, H. Ra-
mathan, J. Org. Chem., 48 (1983) 4786–4788.
[15] R.M. Giuliano, T.W. Deisenroth, W.C. Frank, J. Org.
Chem., 51 (1986) 2304–2307.
[16] G. Cardillo, M. Orena, Tetrahedron, 46 (1990) 3321–
3401.
[17] R.M. Giuliano, T.W. Deisenroth, Carbohydr. Res., 158
(1986) 249–252.
[18] R.M. Giuliano, T.W. Deisenroth, J. Carbohydr. Chem., 6
(1987) 295–299.
[19] D.M. Clode, D. Horton, W. Weckerle, Carbohydr. Res.,
49 (1976) 305–314.
[20] G. Jung, A. Klemer, Chem. Ber., 114 (1981) 740–
745.
[21] J. Thiem, J. Elvers, Chem. Ber., 112 (1979) 818–
822.
[22] (a) H. Paulsen, H. Bu¨nsch, Chem. Ber., 111 (1978) 3484–
3496. (b) J.M.J. Tronchet, J. Tronchet, A. Birkha¨user,
Hel6. Chim. Acta, 53 (1970) 1489–1490.
[23] K.A. Parker, S.M. Meschwitz, Carbohydr. Res., 172
(1988) 319–326.
[24] I. Dyong, H. Merten, J. Thiem, Justus Liebigs Ann.
Chem., (1986) 600–612.
[25] S.F. Martin, J.A. Dodge, Tetrahedron Lett., 32 (1991)
3017–3020.
[26] W.C. Still, J. Kahn, A. Mitra, J. Org. Chem., 43 (1978)
2923–2925.
References
[1] (a) A.W. Johnson, R.M. Smith, R.D. Guthrie, J. Chem.
Soc., Perkin Trans. 1, (1972) 2153–2159. (b) W.D.
Weringa, D.H. Williams, J. Feeney, J.P. Brown, R.W.
King, J. Chem. Soc., Perkin Trans. 1, (1972) 443–446.
[2] M. Debono, R.M. Malloy, J. Org. Chem., 45 (1980)
4685–4687.
[3] S. Nadkarni, M.V. Patel, S. Chatterjee, E.K.S. Vijayaku-
mar, K.R. Desikan, J. Blumbach, B.N. Ganguli, J. An-
tibiot., 47 (1994) 334–341.
[4] (a) M. Furukawa, I. Hayama, G. Ohta, Y. Iitaka, Tetra-
hedron, 31 (1975) 2989–2995. (b) S. Kondo, M.
Miyamoto, H. Naganawa, T. Takeuchi, H. Umezawa, J.
Antibiot., 30 (1977) 1143–1145. (c) U. Sequin, Tetrahe-
dron, 34 (1978) 761–767.
[5] D.H. Williams, B. Bardsley, Angew. Chem., Int. Ed.
Engl., 28 (1999) 1172–1193.
[6] C. Walsh, Science, 284 (1999) 442–443.
[7] M. Ge, Z. Chen, H.R. Onishi, J. Kohler, L.L. Silver, R.
Kerns, S. FuLuzawa, C. Thompson, D. Kahne, Science,
284 (1999) 507–511.
[8] For vancomycin total synthesis, see: (a) K.C. Nicolaou,
H.J. Mitchell, N.F. Jain, N. Winssinger, R. Hughes, T.
Bando, Angew. Chem., Int. Ed. Engl., 38 (1999) 240–244.
(b) D.A. Evans, M.R. Wood, B.R. Trotter, T.I. Richard-
son, J.C. Barrow, J.L. Katz, Angew. Chem., Int. Ed.
Engl., 37 (1998) 2700–2704.
.