TBAF Effects 3,6-Anhydro Formation from 6-O-Tosyl Pyranosides

Article abstract of DOI:10.1021/acs.orglett.0c00045

3,6-Anhydro sugars are common structures in algal polysaccharides and occur in the furanodictine and sauropunol natural products. We have found that treatment of 6-O-tosylpyranosides with tetrabutylammonium fluoride provides a mild, high-yielding synthesis of 3,6-anhydro sugars. Using O-glycoside substrates, 3,6-anhydropyranosides are isolated and the use of N,O-dimethyl hydroxylamine glycosides yields 3,6-anhydrofuranosides. Applying this approach, concise synthetic routes to several 3,6-anhydro sugar natural products are reported, including furanodictine A and sauropunols A-D.

Full text of DOI:10.1021/acs.orglett.0c00045

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Letter
TBAF Effects 3,6-Anhydro Formation from 6‑O‑Tosyl Pyranosides
Zachary A. Morrison and Mark Nitz*
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ABSTRACT: 3,6-Anhydro sugars are common structures in algal polysaccharides and occur in the furanodictine and sauropunol
natural products. We have found that treatment of 6-O-tosylpyranosides with tetrabutylammonium fluoride provides a mild, high-
yielding synthesis of 3,6-anhydro sugars. Using O-glycoside substrates, 3,6-anhydropyranosides are isolated and the use of N,O-
dimethyl hydroxylamine glycosides yields 3,6-anhydrofuranosides. Applying this approach, concise synthetic routes to several 3,6-
anhydro sugar natural products are reported, including furanodictine A and sauropunols A−D.
3,6-Anhydro sugars contain an intramolecular ether bridging
the C-3 hydroxyl and C-6. This feature dramatically alters the
sugar’s conformation and reactivity by locking the pyranosides
into the C4 chair. 3,6-anhydro sugars are found in red algae
polysaccharides, including agarose and many of the carra-
geenans (Figure 1), where their conformation is important in
to have anti-inflammatory activity.6 In addition, 3,6-anhydro-
galactose has been identified as a potential anticariogenic
agent, inhibiting the growth of Streptococcus mutans at lower
concentrations than xylitol.7 The properties of these
compounds have attracted significant interest in their efficient
preparation.
1
1
3,6-Anhydro sugars are usually synthesized by activating the
sugar’s C-6 hydroxyl as a leaving group followed by treatment
with base.8 Most commonly, 6-O-tosyl derivatives have been
generated and treated under strongly basic conditions such as
sodium hydroxide in refluxing ethanol9−11 or sodium
methoxide in refluxing methanol.3 Alternative chemistries
using different leaving groups, including a mesylate,12
phosphinium,13−15 cyclic sulfite and sulfate,16 5,6-carbonate,17
or triflate and similar basic cyclization conditions have been
reported.18 The reaction of selectively benzylated sugars with
DAST sometimes gives 3,6-anhydro side products, though the
scope of this is limited and hard to rationalize.19−21 A single
report of a Lewis acid promoted 3,6-anhydro cyclization of
diacetone glucose has been documented in low yield.22
Overall, the existing procedures suffer limitations including
low to moderate yields, limited scope, or the requirement of
multiple protecting group manipulations.
Figure 1. Bioactive, naturally occurring 3,6-anhydrohexosides.
Tetrabutylammonium fluoride (TBAF) has proven to be a
versatile reagent for organic synthesis. Though more
commonly employed as an organic soluble fluoride source, it
has also been useful as a base for promoting a variety of
mediating the helical character of the polysaccharide and its
gelation.2 The first nonalgal 3,6-anhydro sugar containing
natural products discovered were the amino sugar analogues
furanodictines A and B.3 These were isolated from the slime
mold Dictyostelium discoideum and found to induce neuronal
differentiation in rat PC-12 cells.3 More recently, a series of
3,6-anhydro-2-deoxyglucose derivatives were discovered, sau-
ropunols A−D.4,5 These natural products were isolated from
the Chinese medicinal plant Sauropus rostratus and were found
Received: January 5, 2020
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© XXXX American Chemical Society
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A

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transformations.23 The basicity of fluoride is highly variable,
depending on its counterion, the nature of the solvent, and the
amount of water present.24 TBAF often has greater reactivity
than alkali metal fluorides due to the weakly coordinating
nature of its tetrabutylammonium counterion and its high
organic solubility. However, though further drying is possible,
TBAF is only commercially available in its hydrated form.25
Fluoride forms strong hydrogen bonds, so this water content
greatly attenuates the reagent’s nucleophilicity and basicity.
Attempted preparation of 6-fluoro-6-deoxy-GlcNAc by
treating tosylate 1 with undried commercial TBAF in DMF/
THF (Scheme 1) led to an excellent yield (87%) of the
Table 1. Screen of Reaction Conditions To Promote 3,6-
Anhydro Cyclization of Tosylate 1
a
base or additive
solvent
temp (°C) time (h)
yield (%)
e
b
b c
,
TBAF
DMF/THF
THF
THF
55
55
55
55
55
55
55
50
50
80
50
50
50
65
16
16
16
16
16
16
16
24
22
24
24
24
24
3
83 (87)
e
b
TBAF
69
e
f
d
TBAF , H2O
trace
e
g
TBAF , AcOH
THF
trace
trace
0
e
CsF
DMF/THF
DMF/THF
DMF/THF
DMF
Pyr
Pyr
Pyr/THF
Pyr/THF
Pyr/THF
MeOH
e
f
CsF , H2O
e
Et3N
Pyr
0
0
e
trace
0
Scheme 1. Unexpected 3,6-Anhydro Cyclization of C6-Tosyl
GlcNAc 1 Promoted by TBAF
e
TBABr
trace
trace
e
CsF
e
b
TBAF
65
0
h
NaOMe
a
All reactions were performed on 0.1 mmol scale unless otherwise
b
c
d
stated. Isolated yield. Reaction at 1 mmol scale. Yield <10% by
TLC. Using 7.5 equiv. Using 20 equiv. Using 3.75 equiv. At 0.3 M.
e
f
g
h
Furthermore, substituting CsF for TBAF gave poor conversion.
We noted that the CsF fully dissolved upon heating, so
reduced solubility was unlikely the source of the reduced
conversion. We hypothesized that the water content of
commercial TBAF may be beneficial for the transformation
but, to the contrary, adding water (20 equiv) to the CsF
reaction reduced the yield to zero. Other mild bases including
triethylamine and pyridine also failed to give appreciable
product formation. Similarly, employing TBABr or CsF as
additives in a pyridine/THF solvent system failed to enhance
the yield of product, though TBAF gave a dramatic
improvement. Taken together, these results suggest that both
components of the fluoride/tetrabutylammonium ion pair are
required for efficient 3,6 anhydro sugar formation.
unexpected 3,6-anhydrofuranoside 2. The structure of 2 was
verified by acetylation which resulted in a large downfield shift
in the H-5 absorbance in the 1H NMR spectrum of product 3,
consistent with acetylation of the C-5 hydroxyl and a furanose
ring configuration. An X-ray crystal structure of 3 was acquired
to unambiguously confirm its identity (Figure 2). Surprised by
the simplicity, high yield, and mild conditions for 3,6 anhydro
sugar formation in comparison with reported methods,9−22 the
scope of the reaction was explored.
Previous reports of 3,6-anhydro GlcNAc formation treated
methyl 2-acetamido-2-deoxy-6-O-tosyl-α-D-glucopyranoside
with sodium methoxide in refluxing methanol.3 For compar-
ison, we subjected tosylate 1 to these conditions. Substantial
decomposition was observed and the desired 3,6-anhydro
product could not be isolated, supporting the mild TBAF
promoted condition as a useful alternative to the reported
synthetic strategy.
We next explored the scope of this transformation to
determine if tosylate 1 was unusually susceptible to 3,6-
anhydro cyclization or if TBAF was a general reagent for
formation of these fused ring systems. We found that the
TBAF-based conditions gave a range of the 3,6-anhydrohexo-
ses in high yield, including glucose, N-acetyl-glucosamine, 2-
deoxyglucose, mannose, and galactose configurations (Table
2). Both α- and β-O-glycoside substrates consistently gave
pyranose products with retention of anomeric configuration.
Intriguingly, N,O-dimethyl hydroxylamine glycoside substrates
(1 and 5) rearranged to the 3,6-anhydrofuranose sugars. It is
known that the methyl glycosides of 3,6-anhydroglucose, 2-
deoxyglucose, and mannose undergo a rapid pyranose to
furanose rearrangement upon treatment with strong acids.9−11
It is likely that the lower energy barrier for ring opening N,O-
dimethyl hydroxylamine N-glycosides relative to O-glycosides
allows the facile rearrangement of these substrates. Consistent
with low barrier ring opening, we observed that N,O-dimethyl
Figure 2. X-ray crystal structure of α-anomer 3 (CCDC deposition
no. 1972383).
To understand the requirements for high yielding intra-
molecular ether formation, we examined the reaction
conditions (Table 1). Using DMF as a cosolvent was found
to be beneficial, giving a slight improvement over THF alone.
Attenuating the reactivity of TBAF by buffering it with acetic
acid or adding additional water (20 equiv) gave inferior yields.
B
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Table 2. Substrate Scope for TBAF-Promoted 3,6-Anhydro
Cyclization
Scheme 2. Proposed Mechanism for 3,6-Anhydro
Cyclization and Furanose Rearrangement of Tosylate 1
a
Conveniently, this strategy for 3,6-anhydro sugar formation
minimizes protecting group manipulations as selective
tosylation of the C-6 hydroxyl can be accomplished in
moderate to high yields. To demonstrate the utility of the
strategy, the total synthesis of several 3,6-anhydro sugar natural
products were completed.
In previous reports, furanodictine A has been synthesized
from methyl 2-acetamido-2-deoxy-α-D-glucopyranoside.3 Se-
lective 6-O-tosyl formation and intramolecular ether formation
proceeded in a combined 38% yield. Though the methyl
glycoside survives the 3,6-anhydro cyclization, the hydrolysis of
the methyl glycoside requires protecting group manipulations
later in the synthesis. Another total synthesis of furanodictine
A generated the 3,6-anhydro cycle via degrading GlcNAc in
boiling borate buffer, but this gave a low yield and required a
complex purification.26 Finally, other routes have been
developed from alternative starting materials including 2,3,5-
tri-O-benzyl-β-D-arabinofuranose27 and D-glucuronolactone.28
However, these methods required 17 and 18 steps,
respectively.
We found that furanodictine A could be accessed from
GlcNAc in five steps with an overall yield of 49%. N-Acetyl
glucosamine was protected as the N,O-dimethyl hydroxylamine
glycoside under aqueous conditions, giving 18.29 Next,
selective tosylation of the C-6 hydroxyl in cold pyridine gave
1. Treating the tosyl ester 1 with TBAF in DMF/THF afforded
3,6-anhydrofuranoside 2 in 59% yield over two steps. With the
C-5 hydroxyl unprotected acylation proceeded smoothly with
isovaleric anhydride in pyridine, giving 19. The N,O-dimethyl
hydroxylamine glycoside was selectively cleaved in 4:1 AcOH/
H2O at room temperature, yielding furanodictine A (20)
(Scheme 3).
We also applied our synthetic approach toward the total
synthesis of sauropunols A−D. In previously reported routes to
sauropunols A and B, the furanoside ring was set via the
isolation of butyl 2-deoxy-D-glucofuranoside in low yield from
a Fischer glycosidation.18 The 3,6-anhydro cyclization was
furnished via an interesting concomitant loss of a 3-O-p-
methoxybenzyl ether and intramolecular cyclization of butyl 2-
deoxy-6-O-trifluorosulfonyl-3,5-di-O-p-methoxybenzyl-α-D-glu-
cofuranoside. An improved synthesis of sauropunols A−D was
more recently reported which proceeds through 1,2-
isopropylidene-α-D-glucofuranose to overcome the low-yield-
ing Fischer glycosidation.6 Lastly, a short six-step asymmetric
synthesis from divinyl carbinol was reported.30
a
Conditions: 7.5 equiv of TBAF, 2:1 DMF/THF, 55 °C, 16−20 h.
hydroxylamine glycoside 3 undergoes mutarotation in neutral
MeOD at rt over several days (Figure S1).
We hypothesize that the pyranose to furanose rearrangement
of substrates 1 and 5 occurs rapidly after 3,6-anhydro
formation (Scheme 2) as 3,6-anhydropyranose intermediates
could not be detected in the reactions. Furthermore, the O-
glycoside and N,O-dimethyl hydroxylamine N-glycoside
substrates required similar reaction conditions for quantitative
formation of 3,6-anhydro product. If the reactions of 1 and 5
proceeded through an alternative, lower energy mechanism, we
would expect completion under milder conditions, suggesting
that ring opening preceding 3,6-anhydro cyclization for these
substrates is unlikely.
Curious if free hemiacetals would also be viable substrates
for our synthetic method, we subjected unprotected 6-O-tosyl-
D-glucopyranoside to the TBAF reaction condition. In this
case, no 3,6-anhydro product was obtained. Partial degradation
of the sugar occurred and a low yield of 1,6-anhydro product
was afforded. Thus, protection of the anomeric center is
required for 3,6-anhydro formation.
C
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furanose forms. Remarkably, treating α-pyranose 14 with trace
TFA in dry CDCl3 yielded solely α-furanose product with
complete selectivity. The β-pyranoside 15 rearranged with less
selectivity, giving only partial retention of anomeric config-
uration (2:5 α/β). This imperfect selectivity and the low
proportion of β-anomer from the Fischer glycosylation
restricted the amount of sauropunol B available. However,
Scheme 3. Synthesis of Furanodictine A from N-
Acetylglucosamine
similar to observations made by Markovic et al.,30 we find that
̌
the equilibrium ratio between sauropunols A and B in CDCl3/
TFA is roughly 3:2. Taking advantage of this, additional
amounts of sauropunol B could be afforded by treating α-
pyranose 14 with excess TFA in CDCl3 and allowing the
mixture to equilibrate.
In conclusion, we have identified TBAF as a gentle and
efficient base for cyclizing C6-O-tosyl pyranosides into 3,6-
anhydro sugars. The advantages of this approach were
demonstrated through short, high-yielding total syntheses of
furanodictine A and sauropunols A−D. We anticipate that our
methodology will expediate further synthesis and study of the
chemical and biological properties of this interesting class of
sugar derivatives.
We achieved a concise synthesis of sauropunols A−D
(Scheme 4), starting from 2-deoxyglucose, in four steps giving
58%, 25%, and 51% overall yield of sauropunols A, B, and C/
D, respectively. No protecting groups were required.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00045.
Scheme 4. Synthesis of Sauropunols A−D
Experimental details and spectroscopic and analytical
data for all compounds (PDF)
Accession Codes
CCDC 1972383 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Mark Nitz − Department of Chemistry, University of Toronto,
Toronto, Canada M5S 3H6; orcid.org/0000-0001-8078-
2265; Email: mnitz@chem.utoronto.ca
Author
Zachary A. Morrison − Department of Chemistry, University of
Toronto, Toronto, Canada M5S 3H6
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00045
Notes
A Fischer glycosylation of 2-deoxyglucose with n-butanol
gave a mixture of α and β butyl pyranosides (21). Next,
selective tosylation at the C-6 hydroxyl in cold pyridine yielded
chromatographically separable butyl glycosides 7 and 8.
Reaction of tosyl esters 7 and 8 with TBAF in DMF/THF
gave 3,6-anhydropyranose products 14 and 15 in high yield.
Sauropunols C/D 22 were prepared from 14 or 15 by
hydrolysis of the butyl glycoside in 7:3 AcOH/H2O.
Sauropunols A and B (23 and 24) were obtained by acid-
catalyzed rearrangement of 14 and 15 to their respective
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the Natural Sciences
and Engineering Research Council (NSERC) of Canada. We
thank Dr. Alan Lough (Department of Chemistry, University
of Toronto) for collecting the X-ray crystal data and
performing structure refinement.
D
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Carbohydr. Chem. 1987, 6 (3), 423−439.
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