A new and improved method for deglycosidation of glycopeptide antibiotics exemplified with vancomycin, ristocetin, and ramoplanin

Article abstract of DOI:10.1016/S0960-894X(03)00051-9

A general method for the deglycosidation of glycopeptide antibiotics has been developed. Treatment of vancomycin, ristocetin, and ramoplanin with anhydrous HF results in efficient cleavage of the sugars to provide the corresponding aglycons in high yield.

Full text of DOI:10.1016/S0960-894X(03)00051-9

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1169–1173
A New and Improved Method for Deglycosidation of
Glycopeptide Antibiotics Exemplified with
Vancomycin, Ristocetin, and Ramoplanin
Jutta Wanner, Datong Tang, Casey C. McComas, Brendan M. Crowley, Wanlong Jiang,
Jason Moss and Dale L. Boger*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA
Received 18 October 2002; accepted 5 December 2002
Abstract—A general method for the deglycosidation of glycopeptide antibiotics has been developed. Treatment of vancomycin,
ristocetin, and ramoplanin with anhydrous HF results in efficient cleavage of the sugars to provide the corresponding aglycons in
high yield.
# 2003 Elsevier Science Ltd. All rights reserved.
In the course of several studies addressing the synthesis
of glycopeptide antibiotics that act by inhibiting bac-
terial cell wall biosynthesis, we had the occasion to
access their peptide aglycons. To date in our efforts, this
has provided correlation samples for comparison with
synthetic material confirming the intended structure1À4
or has provided access to intermediates on which we
could examine structural features5,6 or properties.7
Beyond these immediate interests of ours, the aglycons
have served as antibiotic templates from which new
semisynthetic derivatives or hybrids may be prepared in
efforts to improve the antimicrobial properties (i.e.,
potency, efficacy), expand the antimicrobial spectrum
including addressing resistant bacterial strains, reduce
toxicity, or otherwise enhance their properties (i.e., half-
life).8 In addition, the aglycons have found use as chiral
stationary phases for chromatographic resolutions and
separations.9 Thus, there is considerable interest in
developing effective deglycosidation conditions for con-
verting the readily available glycopeptides into their
corresponding aglycons. Despite this interest, no single
procedure appears to work across a range of the glyco-
peptide antibiotics and we have found that many of the
reported and specialized procedures provide dis-
appointingly low conversions or require subsequent
tedious purifications. Herein, we report the development
of a series of closely related deglycosidation procedures
based on the use of HF which represent considerable
improvements over existing protocols.
Not only has anhydrous HF been effectively used in
solid-phase peptide synthesis to remove protecting
groups and provide resin release of the product, but it is
known to effectively cleave the glycosyl linkages of
neutral and acidic sugars (0 ꢀC, 1 h), O-linked amino-
sugars (23 ꢀC, 3 h), and to effect O-glycoprotein degly-
cosidation.10 We have used it in prior studies to effect
both such conversions on sensitive substrates3,11,12 and
now report its use for deglycosidation of the proto-
typical glycopeptide antibiotics vancomycin, ristocetin,
and ramoplanin.
Vancomycin
Since the disclosure of vancomycin (1) in 1956,13 it has
emerged as the leading member of the clinically impor-
tant glycopeptide antibiotics.8 Vancomycin is the drug
of last resort for treatment of resistant bacterial infec-
tions or for use in patients allergic to b-lactam anti-
biotics. The emergence of bacterial strains resistant to
vancomycin highlights the need to develop new anti-
biotics with improved activity. The vancomycin aglycon
(2) has been shown to possess antimicrobial activity
*Corresponding author. Tel.: +1-858-784-7522; fax: +1-858-784-
7550; e-mail:
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00051-9

1170
J. Wanner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1169–1173
essentially equal to natural vancomycin (1)14 and semi-
synthetic derivatives of 2 containing alternative sugars
or hydrophobic substituents are emerging as a promis-
ing strategy for the discovery and development of
improved antibiotics in the fight against bacterial resis-
tance.15,16
(Table 1), but required purification of 2 by HPLC.
Thus, a new deglycosidation protocol for vancomycin
that provides 2 in higher conversions (91%), permits
access to the pure aglycon in quantity, and does not
require arduous purification was developed employing
AHF (Fig. 1).
Early attempts to cleave the sugars of vancomycin were
carried out with refluxing 4 N HCl (Table 1).17 These
conditions resulted in the formation of many degrada-
tion products and produced the aglycon in low yield. A
deglycosidation procedure utilizing TFA was disclosed
in 1988 and has remained the standard method for
aglycon synthesis despite the fact that HPLC purifica-
tion is necessary to obtain pure 2.18,5 In the course of
our studies, we found that anhydrous HF (AHF) is an
exceptional reagent for the removal of glycopeptide
sugars. When vancomycin is treated with AHF at 25 ꢀC
for 2 h (Table 1), the glycosyl linkage is cleaved, result-
ing in clean conversion to the aglycon and free sugars.
The sugars are readily removed by simple trituration to
provide the pure aglycon 2 (91%). Lower reaction tem-
peratures were nearly as effective but the reaction was
not always complete (0 ꢀC, 2 h). Other HF reagents
including HF/pyridine resulted in incomplete deglycosi-
dation, longer reaction times, or the appearance of
reaction byproducts if driven to completion. None-
theless, competitive conversions could be obtained
Representative experimental procedures
Anhydrous HF. A Kel-F reaction vessel was charged
with vancomycin (1, 50 mg, 34 mmol) and anisole (0.5
mL) and attached to an HF distillation apparatus.
Anhydrous HF (10 mL) was distilled into the vessel and
the mixture was stirred at 25 ꢀC for 2 h. After this time,
the HF and anisole were removed under vacuum to give
a light pink solid. The crude product was washed with
10 mL of 4:1 EtOAc–MeOH followed by decanting the
solvent and this was repeated three times. The product
was dried under vacuum to give 35 mg (91%) of pure
vancomycin aglycon (2) as a white solid.
HF/pyridine. A polypropylene reaction vial was charged
with vancomycin (1, 50 mg, 34 mmol) and HF/pyridine
(1.5 mL) and the mixture was stirred at 25 ꢀC for 24 h.
The mixture was diluted with 5 mL of MeOH and con-
centrated under a stream of nitrogen. The residue was
washed with 10 mL of 4:1 EtOAc–MeOH followed by
decanting the solvent and this was repeated three times.
The crude product was further purified by HPLC
(Waters semi-preparative LC 25 mm column, CH3CN–
0.07% TFA/H2O17:83, 10 mL/min, Rt=31 min) to
provide 23 mg (60%) of pure vancomycin aglycon (2) as
a white solid.
Table 1.
Ristocetin A
Ristocetin A (3) is a member of the glycopeptide family
of antibiotics related to vancomycin and it was origin-
ally isolated from Nocardia lurida.19 Although it was
clinically employed to treat bacterial infections in the
late 1950s, undesirable platelet aggregation led to its
discontinuation. However, the aglycon of ristocetin A
(4) has been found to be slightly more active than its
parent and, more interestingly, is free of the undesirable
side effects.20 In the past, the ristocetin aglycon has been
prepared in two steps. Acid hydrolysis of ristocetin A
produces the intermediate ristocetin -aglycon (5), and
a second triethylsilane reductive cleavage provides the
Entry
Reagent
Conditions
Yield of 2 (%)
1
2
3
4
5
6
4 N HCl (aq)
TFA
HF/Pyr
Et3N(HF)3
AHF
2 h, reflux
7.5 h, 50 ꢀC
24 h, 25 ꢀC
24 h, 25 ꢀC
2 h, 0 ꢀC
Decomp17
55a,18
60a
No reaction
87b
AHF
2 h, 25 ꢀC
91b
aRequires purification by semi-preparative HPLC.
bPurified by trituration of crude mixture with 4:1 EtOAc–MeOH.
Figure 1. HPLC traces of vancomycin (1) and vancomycin aglycon (2)
obtained from AHF (CH3CN–0.07% TFA/H2O17:83).

J. Wanner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1169–1173
1171
ristocetin aglycon (4), in an overall yield of 8%.21,22 It
was ristocetin A and the difficulties in securing its agly-
con that first forced us to examine new methods of
deglycosidation. Thus, we examined a wide range of
alternatives (Table 2) ultimately establishing that AHF
or HF/pyridine provide very effective one-step proce-
dures (92–85%) which also avoid the tedious chroma-
tographic purifications.
noticeably change the product distribution. The use of
aqueous HCl, HBr, and TFA all generated complex
reaction mixtures at 80 ꢀC (entries 3 and 5–9), and no
reaction was observed at room temperature (entry 4).
Anhydrous HF (AHF) containing anisole (5% v/v) as
the cation scavenger provided remarkable results.
Treatment of ristocetin A with AHF/anisole at À18 ꢀC
for 80 min. provided ristocetin aglycon (4) in 92% yield
(entry 17). Moreover, the pure aglycon could be isolated
by simple trituration of the reaction mixture with
EtOAc. A comparable result was obtained when the
reaction was run at À30 ꢀC for 2.5 h (entry 16). Shorter
reaction times result in partial deglycosidation and
higher reaction temperatures (0–25 ꢀC) provide an as yet
unidentified product (entries 14 and 15). Other HF
reagents including HF/Py also provided good conver-
sions affording 4 in yields as high as 85% (entry 13), but
the isolation of ristocetin aglycon in its pure form
required chromatography. Treatment of ristocetin A
with aqueous HF also provided ristocetin aglycon but a
substantial amount of ristocetin aglycon acid (7) was
also generated (entry 10).
Treatment of ristocetin A with 80% aqueous sulfuric acid
in DMSO(1:50) afforded ristocetin -aglycon (5) in 60%
yield (entry 2). Ristocetin aglycon (4) was found only in
very small amounts and prolonged reaction times did not
Table 2.
Representative experimental procedure
Following evacuation and cooling to À18 ꢀC, a 50 mL
Kel-F reaction vessel was charged with ristocetin A (3,
52 mg, 25 mmol) and anisole (0.5 mL) and attached to
an HF distillation apparatus. Anhydrous HF (10 mL)
was distilled into the reaction vessel and the mixture was
stirred at À18ꢀC for 80 min. After this time, the HF and
anisole were removed under vacuum to give a tan solid.
The crude product was triturated with 5 mL of EtOAc
three times and the product was dried under vacuum to
give 27 mg (92%) of ristocetin aglycon (4) as a white solid.
Ramoplanin
Ramoplanin, a novel lipoglycodepsipeptide with potent
antibacterial activity, was isolated from the fermenta-
tion broth of Actinoplanes sp. ATCC 33076 as a mixture
of three closely related compounds 8–10 (Table 3).23
The structure was disclosed in 1989, and it was estab-
lished that the three compounds differ only in the acyl
group attached to the Asn1 N-terminus.24 The ramo-
planin complex was shown to be 2–10 times more active
than vancomycin against Gram-positive bacteria, and
the ramoplanin A2 aglycon (12) was reported to be
equally active or more potent than the natural product
in antimicrobial assays.25,26 Shortly after its disclosure,
ramoplanin was shown to disrupt bacterial cell wall
biosynthesis where it inhibits the action of intracellular
UDP-glcNAc transferase (MurG) and the conversion of
lipid intermediate I to lipid intermediate II.26 This inhib-
ition was proposed to arise by ramoplanin complexation
of lipid intermediate I preventing its utilization as a
substrate.27 More recently, Walker has shown that
ramoplanin also inhibits the subsequent and more
accessible transglycosylase-catalyzed extracellular poly-
merization of lipid intermediate II and forms self-asso-
ciating 1:1 complexes with close analogues of the
substrate, lipid intermediate II, suggesting this may
Entry
Reagent
Conditions
48 h, 25 ꢀC
Product distributiona
1
2
3
4
5
6
7
8
Et3SiH, TFA
80% H2SO4, DMSO7–48 h, 85
4 (8%)22
5 (60%), 4 (<5%)21
Trace of 4b
ꢀC
5 N HCl
5 N HCl
1 N HCl
1.2 N HCl, HOAc
TFA
1–24 h, 80 ꢀC
24 h, 25 ꢀC
1–24 h, 80 ꢀC
1 h, 85 ꢀC
No reaction
Trace of 4b
7 presentb
2.5 h, 80 ꢀC
19 h, 80 ꢀC
1 h, 80 ꢀC
5 presentb
TFA
4 presentb
9
5 N HBr
48% HF (aq)
HF/Py
Trace of 4b
10
11
12
13
14
15
16
17
24 h, 45 ꢀC
30 min, 25 ꢀC
1 h, 25 ꢀC
4 (40%), 7 (35%)
4 (60%), 6 (30%)
4 (75%), 6 (15%)
4 (85%)
HF/Py
HF/Py
AHF
AHF
AHF
AHF
2 h, 25 ꢀC
1 h, 25 ꢀC
4 not formedc
4 (55%)c
4 (90%)
1 h, 0 ꢀC
2.5 h, À30 ꢀC
80 min, À18 ꢀC
4 (92%)d
aUnless noted otherwise, yields were determined by LC–MS of reac-
tion mixture.
bComplex mixture.
cAn unidentified side product was formed.
dIsolated yield.

1172
J. Wanner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1169–1173
Table 3.
byproducts. Reverse-phase HPLC purification of the
mixture which serves to separate the A1–A3 aglycons
[20–50% CH3CN–HCOONH4 (aq, 0.05 M)] provides
pure A1 (3%), A2 (46%), A3 (3%), albeit with a recov-
ery loss due to the physical properties of the natural
product aglycons.3 Enlisting pure ramoplanin A2 (9),
the HF deglycosidation followed by a simple EtOAc
trituration to remove the deglycosidation byproducts
provides the pure A2 aglycon (12) in 92% yield avoiding
the material loss that accompanies HPLC purification
(entry 3). Thus, the use of anhydrous HF for deglycosi-
dation of ramoplanin A1–A3 is exceptionally effective
providing the corresponding aglycons in conversions as
high as 92% and offers a superb improvement over
existing methods.
Representative Experimental Procedures
Ramoplanin A1, A2, and A3 Aglycons (11–13) from
Ramoplanin Complex (8–10). Anhydrous HF (4–5 mL)
was condensed in a Kel-F reaction vessel charged with
the ramoplanin complex (8–10, 97 mg, 36 mmol) and
anisole (0.5 mL) at À78 ꢀC. The reaction mixture was
warmed to 0 ꢀC and stirred for 1.5 h. The HF was
removed at 0 ꢀC under a stream of N2 over 90 min.
EtOH was added (1 mL), and the solvent was removed
in vacuo. The residue was dissolved in 0.1 N aqueous
HCl and lyophilized. HPLC purification [Waters semi-
preparative LC 25 mm column, 8 mL/min, 30 min gra-
dient of 20–50% CH3CN–HCOONH4 (aq, 0.05 M,
tR=17.4 min (A1); 19.2 min (A2); 21.3 min (A3))] pro-
vided pure ramoplanin A2 aglycon, and mixtures of
ramoplanin A1/A2, and A2/A3 aglycons. A second
HPLC purification (same conditions as above) of the
recovered aglycon mixtures provided pure ramoplanin
A1, A2, and A3 aglycons, as mixtures with HCOONH4.
The mixtures were lyophilized until they reached a con-
stant weight and then lyophilized with 0.1 N HCl (1 mL)
to give 11 (2.5 mg, 3%), 12 (40 mg, 46%), and 13 (2.3
mg, 3%) as white solids.
Entry
Reagent
Conditions
7 h, 70 ꢀC
Product distribution
1
2
3b
5% HCl/DMF
AHF
AHF
12 (20%)26
1.5 h, 0 ꢀC 11 (3%), 12 (46%), 13 (3%)a
1.5 h, 0 ꢀC
12 (92%)c
aRequires purification by semi-preparative HPLC.
bReaction run with pure ramoplanin A2 (9).
cPurified by trituration with EtOAc.
represent the more relevant biological site of action.28
These two steps immediately precede the transpepti-
dase-catalyzed cross-linking reaction and the site of
action of vancomycin. Thus, mechanism-based cross-
resistance between ramoplanin and vancomycin is not
observed and ramoplanin represents an excellent candi-
date for more expansive clinical use beyond its intro-
duction for topical infections.29 Ramoplanin is presently
in Phase III clinical trials for the oral treatment of
intestinal vancomycin-resistant Enterococcus faecium
(VREF) and Phase II trials for nasal MRSA.25
Ramoplanin A2 Aglycon (12) from Ramoplanin A2 (9).
Anhydrous HF (2–3 mL) was condensed in a Kel-F
reaction vessel charged with pure ramoplanin A2 (9, 4.6
mg, 1.8 mmol) and anisole (0.5 mL) at À78 ꢀC. The
reaction mixture was warmed to 0 ꢀC and stirred for 1.5
h. The HF was removed at 0 ꢀC under a stream of N2
over 90 min. EtOH was added (0.5 mL), and the solvent
was removed in vacuo. The residue was dissolved in
0.1 N aqueous HCl and lyophilized. EtOAc was added to
the light brown solid, and the slurry was sonicated and
then centrifuged. The solid was collected to give pure
ramoplanin A2 aglycon (3.8 mg, 92%) as a white solid.
Past protocols for the deglycosidation of ramoplanin
have relied on the treatment of ramoplanin complex
with either: (1) trimethylsilyl iodide or trimethylsilyl
chloride in the presence of sodium iodide followed by
hydrolysis or (2) a strong mineral acid (HCl) in the
presence of a lower alcohol (e.g., BuOH) under anhy-
drous conditions (entry 1).26 Typically, pure ramoplanin
A2 aglycon is obtained in 20–30% yield using optimized
conditions for these methods. In addition to low conver-
sions, the isolation of pure ramoplanin aglycon requires a
tedious HPLC purification that results in some loss of
material and contributes to the low conversions. We have
found that the use of anhydrous HF cleanly cleaves the
dimannose sugar moiety of ramoplanin, without affecting
the sensitive ester linkage or acyl side chains.
Acknowledgements
We gratefully acknowledge the financial support of the
National Institutes of Health (CA41101) and The
Skaggs Institute for Chemical Biology. We wish to
thank Abbott Labs and Advanced Separation Technol-
ogies for the supply of ristocetin A and Dr. Ciabatti
(Biosearch Italia S.p.A.) for a supply of the natural
Treatment of the ramoplanin complex with anhydrous
HF (entry 2) cleanly provided the A1–A3 aglycons (11–
13) contaminated only with mannose-derived reaction

J. Wanner et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1169–1173
1173
ramoplanin complex and a sample of the ramoplanin
A2 aglycon. We wish to especially thank Professor K.
D. Janda for the use of the anhydrous HF apparatus.
B.M.C. is a Skaggs Fellow.
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