New insight on 2-naphthylmethyl (NAP) ether as a protecting group in carbohydrate synthesis: A divergent approach towards a high-mannose type oligosaccharide library

Article abstract of DOI:10.1039/c1cc13264d

A new method for selective cleavage of 2-naphthylmethyl (NAP) ether utilizing 10-20 molar excess of HF/pyridine in toluene was revealed and strategically applied to a divergent approach towards generation of a high-mannose type oligosaccharide library.

Full text of DOI:10.1039/c1cc13264d

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New insight on 2-naphthylmethyl (NAP) ether as a protecting group in
carbohydrate synthesis: a divergent approach towards a high-mannose
type oligosaccharide librarywz
Yao Li, Bimalendu Roy and Xinyu Liu*
Received 2nd June 2011, Accepted 22nd June 2011
DOI: 10.1039/c1cc13264d
A new method for selective cleavage of 2-naphthylmethyl (NAP)
ether utilizing 10–20 molar excess of HF/pyridine in toluene was
revealed and strategically applied to a divergent approach
towards generation of a high-mannose type oligosaccharide
library.
in an effort to generate a high-mannose type oligosaccharide
library.
ð1Þ
The emergence of glycobiology as a major research field demands
the rapid access of structurally defined oligosaccharides.1
Chemical synthesis of complex carbohydrates and glyco-
conjugates relies on novel glycosylating agents, but also
robust protecting group chemistry that can be strategically
applied to differentiate a collection of hydroxyl and amino
groups during and at the end of the synthetic processes.2 Thus,
there is a continuous need for inventing novel and reliable
protective groups for oligosaccharide synthesis.3 2-Naphthyl-
methyl (NAP) ether has recently emerged as a new type of
protecting group for hydroxyl functionality.4 NAP ether
retains the ease of installation as benzyl ether and can be
readily cleaved under either oxidative or hydrogenolytic
conditions.4,5 The acid-stable nature of NAP ether, in
comparison with analogously oxidant-labile p-methoxylbenzyl
(PMB) ether, popularized its application as a temporary
hydroxyl protecting group in complex natural product and
carbohydrate syntheses.6
The stoichiometry of HF/Py required to cleave NAP ether
in compound 1 was readily optimized to be 10–20 molar
equivalents to afford 2 in 2–4 hours at room temperature.
Mechanistically, we postulated the generation of a NAP cation
(eqn (2)) upon the acidic activation of NAP ether, which can
be subsequently trapped by the solvent. This hypothesis was
supported by the clean isolation of adduct 2a where the NAP
cation was trapped when using p-xylene as a solvent (eqn (2)).
ð2Þ
With this mechanistic support in hand, we used compound 3
to investigate whether other solvent and/or acid combinations
might be more suitable for the cleavage of NAP ether
(Table 1). Strong Lewis acids such as TMSOTf or BF3ꢀEt2O
were not effective under identical conditions, nor TFA and
HF/H2O. When employing HF/Py as the acid, neither
During our recent effort to develop new chemical and
enzymatic glycosylation methods, we discovered that 3-O-NAP
ether in glucose tetraacetate 1 was cleanly removed by the
treatment of HF/pyridine (Olah’s reagent) in toluene with
simultaneous generation of glucosyl fluoride 2 in good yield
(eqn (1)). We captured this serendipitous discovery and herein
report the details of selective cleavage of NAP ether using
gentle the acidic condition that involves 10–20 molar excess
of HF/Py in toluene in the context of carbohydrate synthesis.
We further demonstrated the versatility of this new approach
Table 1 Screening acids and solvents for selective cleavage of NAP
ether in the presence of benzyl ether
Entry
Acid
Solvent
Conversion (%)
1
2
3
4
5
6
7
HF–Py
HF–Py
HF–Py
TMSOTf
BF3ꢀOEt2
TFA
Toluene
CH2Cl2
THF
Toluene
Toluene
Toluene
Toluene
100
ND
ND
o5
o5
NR
NR
Department of Chemistry, University of Pittsburgh,
219 Parkman Avenue, Pittsburgh, PA 15260, USA.
E-mail: xinyuliu@pitt.edu; Fax: +1-412-624-8611;
Tel: +1-412-624-6932
w This article is part of the ‘Glycochemistry and glycobiology’
web-theme issue for ChemComm.
z Electronic supplementary information (ESI) available: Details of
synthetic procedures and spectral data of newly synthesized
compounds. See DOI: 10.1039/c1cc13264d
HF/H2O
ND = not determined, NR = no reaction.
c
8952 Chem. Commun., 2011, 47, 8952–8954
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Scheme 1 Selective differentiation of NAP, PMB and silyl ethers
using amine-buffered HF/Py. (a) HF–Py (20 eq.), Et3N (3 eq.),
toluene, rt, 12 h; (b) HF–Py (40 eq.), pyridine, rt, 24 h.
dichloromethane nor THF is suitable as a solvent, even in the
presence of a cation scavenger such as anisole, suggesting that
HF/Py exhibits maximal efficiency in toluene that serves as a
non-Lewis-basic cation scavenger.7
Fig. 1 Structure of HMT oligosaccharide and
a
retrosynthetic
approach from the differentially protected core dimannoside 10.
Recognizing that the acidity of HF/Py in toluene is essential
for the cleavage of NAP ether, we envisioned that buffering
HF/Py with a suitable amine base should allow for efficient
differentiation of NAP ether from more acid-labile PMB ether
and/or fluoride-sensitive silyl ether, thus making HF/Py a
versatile reagent for selective or tandem removal of single or
multiple protecting groups in a complex molecule. This approach
was validated using NAP, PMB and/or tert-butyldiphenylsilyl
(TBDPS) protected glycerols (Scheme 1). Selective removal of
PMB ether in 5a in the presence of NAP ether was readily
achieved by buffering HF/Py in toluene with triethylamine
(Scheme 1, eqn (1)), while selective removal of TBDPS ether
in 5b was effective with HF/Py in pyridine where PMB ether
remains intact (Scheme 1, eqn (2)).
10 with three hydroxyl groups at each branch point, masked
with triisopropylsilyl (TIPS), NAP and PMB groups, should
allow for the facile generation of five mono-, di-, and tri-hydroxyl
unmasked dimannosides using the HF/Py-mediated deblocking
protocols developed here.
Sequential exposure of 10 with HF/Py in toluene,
Et3N-supplemented toluene and pyridine led to dimannosides
10a, 10b and 10c in excellent yields with a varied degree of
hydroxyls unmasked (Scheme 3), while leaving all glycosidic
linkages and reducing-end p-methoxylphenol (MP) group
intact. The TIPS group was readily installed to the primary
hydroxyls in 10a and 10b to further give 10d and 10e. Thus,
five dimannosides (10a–e) are ready for further diversification
with mannosylations. Exemplary glycosylation of 10c with
mannosyl imidate 11 and dimannosyl thioglycoside 12
afforded tri- and tetra-mannoside 13 and 14 in excellent yields.
The details of the library synthesis and its application in
addressing glycobiology problems will be reported in due
course.
We further examined the suitability of HF/Py-mediated
NAP ether cleavage in complex carbohydrate building block
preparations (Scheme 2). As shown with di- and mono-glucosides
6 and 8, this approach worked very well with allyl, benzyl
ethers and esters. It is noteworthy to mention that in both
occasions, the glycosidic linkages remained intact, while
anhydrous HF, a known agent that can cleave benzyl ether,8
would simultaneously cleave any glycosidic linkage.9
In summary, we have disclosed an unprecedented strategy
that utilizes 10–20 molar excess of HF/Py in toluene for
To fully explore the versatility of HF/Py-mediated
deprotection of NAP, PMB and silyl ethers, we set out to
use it for a strategic assembly of a high-mannose type (HMT)
oligosaccharide library. HMT oligosaccharide is the major
component of eukaryotic glycoprotein.10 Moreover, its
presence in HIV-1 glycoprotein gp120 rendered it a viable
antigen for HIV vaccine development.11 Structurally, HMT
oligosaccharide has three oligomannoside branches, stemming
from a core dimannoside (Fig. 1). Previous syntheses including
those by the groups of Ito,12 Wong,13 Danishefsky14 and
Seeberger15 relied on either a co-block or a linear assembly
strategy that limits the number of possible oligomannosides
generated. We envisioned that a dimannoside building block
Scheme 3 Divergent approach towards an HMT oligosaccharide
library using HF/Py-mediated selective removal of NAP, PMB and
silyl ethers in dimmanoside 10. (a) HF–Py (20 eq.), toluene, rt, 2 h;
(b) HF–Py (20 eq.), Et3N (3 eq.), toluene, rt, 12 h; (c) HF–Py (40 eq.),
Scheme 2 Functional group compatibility of HF/Py-mediated NAP
ether cleavage. (a) HF–Py (20 eq.), toluene, rt, 2 h; (b) HF–Py (40 eq.),
pyridine, rt, 24 h.
pyridine, rt, 24 h; (d) TIPSCl, Imid, CH2Cl2, rt, 16 h; (e) TBSOTf (cat.)
,
CH2Cl2, 0 1C, 20 min; (f) NIS, TMSOTf (cat.), CH2Cl2, 0 1C, 45 min.
c
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selective removal of NAP ether in the context of complex
carbohydrate synthesis. With proper buffering, HF/Py is
shown to be a versatile reagent for selective differentiation of
NAP, PMB and silyl ethers, as exemplified in a straight-
forward generation of five dimannoside structures for a
divergent HMT oligosaccharide library synthesis. The unique
reactivity of NAP ether towards acids, as shown here, is
expected to have this protecting group strategy find more
applications in complex molecule synthesis. Exploring the
NAP group as well as related analogues in complex carbo-
hydrate assembly is currently undergoing in our laboratory.
This research was supported by University of Pittsburgh.
The authors thank Prof. Scott Nelson for accessing the
anhydrous solvent system in his laboratory and Prof. Dennis
Curran, Peter Wipf and Kaz Koide for sharing their groups’
chemicals.
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c
8954 Chem. Commun., 2011, 47, 8952–8954
This journal is The Royal Society of Chemistry 2011