Reagent-Controlled α-Selective Dehydrative Glycosylation of 2,6-Dideoxy Sugars: Construction of the Arugomycin Tetrasaccharide

Article abstract of DOI:10.1021/acs.orglett.0c01153

The first synthesis of the tetrasaccharide fragment of the anthracycline natural product Arugomycin is described. A reagent controlled dehydrative glycosylation method involving cyclopropenium activation was utilized to synthesize the α-linkages with complete anomeric selectivity. The synthesis was completed in 20 total steps, and in 2.5% overall yield with a longest linear sequence of 15 steps.

Full text of DOI:10.1021/acs.orglett.0c01153

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Letter
Reagent-Controlled α‑Selective Dehydrative Glycosylation of 2,6-
Dideoxy Sugars: Construction of the Arugomycin Tetrasaccharide
Joseph R. Romeo, Luca McDermott, and Clay S. Bennett*
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ABSTRACT: The first synthesis of the tetrasaccharide fragment of the anthracycline natural product Arugomycin is described. A
reagent controlled dehydrative glycosylation method involving cyclopropenium activation was utilized to synthesize the α-linkages
with complete anomeric selectivity. The synthesis was completed in 20 total steps, and in 2.5% overall yield with a longest linear
sequence of 15 steps.
2,6-Dideoxy sugars are often found in natural products of
therapeutic significance,1,2 and alterations of the sugar
composition of these natural products have been shown to
significantly impact their biological activity.3−7 While this
approach holds promise for new avenues for therapeutic
development, it is impeded by the inherent difficulties in
deoxy-sugar oligosaccharide synthesis.2,8 Conducting α-selec-
tive glycosylations of 2,6-dideoxy sugars is a synthetic
challenge, primarily due to the lack of chemical handles at
both the C-6 position to promote conformational bias9,10 and
at the C-2 position for the use of a chiral auxiliary.11−13 Deoxy
sugar donor intermediates are also more sensitive to hydrolysis
than their fully substituted sugar counterparts,14 and species
such as halides and trichloroacetimidates have to be either
freshly prepared and used immediately or generated in situ to
function as effective donors in direct glycosylations.15−20
A
variety of novel direct,21−30 indirect,31−39 and de novo40−46
glycosylation methods have emerged in recent years to address
these drawbacks, but the extension of these methods to
complex oligosaccharide synthesis remains at the frontier of
carbohydrate synthesis.
of a cyclopropene-1-thione and oxalyl bromide affording α-
linked compounds.49−51 Both our lab and other groups have
applied the former approach to complex β-linked 2-deoxy
Received: March 30, 2020
Our group has had an enduring interest in developing
methods for reagent-controlled direct dehydrative glycosyla-
tion using shelf-stable 2-deoxy hemiacetal donors. In these
approaches, the stereochemical outcome of the reaction is
controlled by the promoter system, with sulfonyl chloride
promoters affording β-linked structures47,48 and a combination
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oligosaccharide synthesis,52−56 but the utility of the latter
method in α-linked oligosaccharide synthesis has yet to be
established. In order to determine if this chemistry would be
useful in oligosaccharide synthesis, we decided to apply it to
the synthesis of the tetrasaccharide fragment of Arugomycin
(Scheme 1).
Scheme 2. Synthesis of the Starting Monosaccharides:
Common Core Fucal 9 (A), Oliose Donors 7 and 8 (B), and
Oliose Acceptor 6 (C)
Scheme 1. Retrosynthesis of Arugomycin Tetrasaccharide
yield.61 Compound 10 was then deacetylated with catalytic
sodium methoxide, silylated at the C3 position with tert-
butyldimethylsilyl chloride (TBSCl), and then C-4 was
protected as a 2-naphthylmethyl (Nap) ether using 2-
naphthylmethyl bromide (NapBr) and sodium hydride to
afford common core fucal 11 in 68% yield over three steps.62
With the requisite fucal in hand, we turned our attention to
the synthesis of the monosaccharide coupling partners.
Hemiacetal donor 7 was produced by hydration of fucal 11
with catalytic triphenylphosphine hydrobromide (Scheme
2B).44 To obtain 8, fucal 11 was desilylated with
tetrabutylammonium fluoride (TBAF) to afford fucal 12 in
84% yield, followed by methylation at the C3 position with
methyl iodide in 91% yield.63 Finally, hydration of the glycal
with catalytic triphenyl phosphine hydrobromide provided 8 in
73% yield.64
Synthesis of monosaccharide acceptor 6 commenced with
dehydrative glycosylation of donor 8 using a coactivation-
based variant of our published methodology for secondary
alcohol acceptors.62 To this end, thione 14 was activated with
oxalyl bromide in (5.5:1) TCE/CH2Cl2, followed by the
sequential addition of para-methoxyphenol (PMP) at −10 °C,
and donor 8. This order of activation minimized the formation
of trehalose byproducts and afforded 13 in 93% yield
exclusively as the α-anomer (Scheme 2C). Subsequent
deprotection of the Nap group at C4 with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) produced monosaccharide
acceptor 6 in 89% yield. With the necessary monosaccharides
in hand, we turned our attention to disaccharide synthesis.
Arugomycin, first isolated from the bacteria Streptomyces
violaceochromogenes in 1983, was shown to have moderate
activity against Gram-Positive bacteria (S. aureus, B. subtilis, M.
luteus, MIC = 12.5 μg/mL),57−59 and it also has potential as an
antitumor agent from its ability to intercalate DNA similar to
other anthracyclines.60 Notably, this compound possesses
tetrasaccharide and trisaccharide deoxy-sugar chains, which
represent challenging synthetic targets for reasons outlined
above. We particularly viewed the tetrasaccharide chain, which
consists of α-linked L-oliose configured residues with a fumaric
acid moiety at the nonreducing end, as an ideal model system
to test our method. Here we report the first synthesis of this
tetrasaccharide, complete with fumarate attachment, starting
from L-fucose.
From our retrosynthetic analysis of target compound 1, we
considered an approach where the fumarate moiety could be
appended to tetrasaccharide 3 at the later stage. Tetrasacchar-
ide 3 could then arise from a [2 + 2] coupling of disaccharide
donor 5 and acceptor 4. Both disaccharides could originate
from monosaccharide coupling partners 6, 7, and 8, which
would in turn be derived from L-fucal.
We began our synthesis with the construction of L-fucal
derivative 11 as a precursor to the monosaccharide coupling
partners (Scheme 2A). Commercially available L-fucose was
peracetylated with acetic anhydride and DMAP to afford
compound 9 in 96% yield. Compound 9 was then halogenated
at the anomeric position with PBr3 and subsequently subjected
to a modified Fischer−Zach protocol to afford fucal 10 in 70%
B
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We initially investigated coupling of 8 and 6 using our
previously optimized conditions for secondary alcohol accept-
ors at rt.51 These conditions afforded α-linked disaccharide 15
in a low yield of 14% (Table 1, entry 1). The major byproducts
Table 2. Optimization of Disaccharide 16
Table 1. Optimization of Disaccharide 15
a
entry
donor/acceptor
scavenger
temp
0 °C
rt
0 °C
0 °C
yield (α-only)
b
1
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
TTBP
TTBP
TTBP
DTBMP
ADB
TTBP
TTBP
TTBP
55%
11%
53%
38%
2%
87%
74%
65%
b
2
c
3
b
4
b
entry
donor/acceptor
scavenger
temp
rt
0 °C
0 °C
0 °C
0 °C
0 °C
−10 °C
−10 °C
yield (α-only)
5
0 °C
a
b
b
1
2
3
4
5
6
7
8
2:1
2:1
2:1
2:1
1:2
1:3
1:3
1:3
TTBP
TTBP
DTBMP
TTBP
TTBP
TTBP
TTBP
TTBP
14%
44%
11%
18%
47%
64%
74%
6
−10 °C
−10 °C
−10 °C
a
b
bd
,
7
8
a
b
be
,
c
b
a
NMR yield, product identified in a complex with p-methoxyphenol.
d
b
b
c
d
TCE/CH2Cl2 (1.6:1). TCE/CH2Cl2/THF (9.5:1:4.5). 400 mg
d
b
e
scale 7. 1 g scale 7.
d
e
df
,
e
scavenger,66 but the use of this scavenger led to a complex
mixture (Table 2, entry 5). Inspired by our last optimization,
we then lowered the temperature of the system to −10 °C and
we were pleased to observe an increase in yield of 16 to 87%
with no decrease in α-selectivity (Table 2, entry 6). These
latter conditions were used for scale-up with minimal impact
on the yield (Table 2, entries 7 and 8).
With disaccharides 15 and 16 in hand, we turned our
attention to converting them to the requisite disaccharide
coupling partners 5 and 4 (Scheme 3). To this end, DDQ
69%
a
b
TCE/CH2Cl2 (2.7:1). NMR yield, product identified in a complex
with α,α-trehalose. TCE/CH2Cl2/THF (6.5:1:3.2). TCE/CH2Cl2
(1.6:1). Isolated yield. 300 mg scale of 8.
c
d
e
f
of the reaction were an α,α-trehalose derivative of 8, and a α-
PMP glycoside derivative of 8, which we posit arose from
aglycone elimination/transfer from acceptor 6.65 Lowering the
temperature to 0 °C led to a slight increase in yield (Table 1,
entry 2). Switching to a more basic proton scavenger 2,6-di-
tert-butyl-4-methylpyridine (DTBMP) negatively impacted the
yield and led to increased formation of PMP transfer
byproduct (Table 1, entry 3). The use of THF as a cosolvent,
a beneficial practice in our prior study with thione promoter
reagent 14,51 also led to aglycone transfer and decreased our
yield relative to the TCE/CH2Cl2 solvent condition (Table 1,
entry 4). Unable to limit the formation of byproducts by
solvent or scavenger adjustments, we elected to switch the
stoichiometry of the glycosylation to make the donor the
limiting reagent, which led to a slight drop in byproduct
formation (Table 1, entry 5). Further increasing the
stoichiometry of the acceptor resulted in a marked increase
in yield to 64% (Table 1, entry 6). Reducing the temperature
to −10 °C led to a further increase in yield to 74% (Table 1,
entry 7). These latter conditions were used to scale up the
reaction (Table 1, entry 8).
We applied a similar optimization strategy to the coupling of
donor 7 and acceptor 6. Applying a 1:3 donor/acceptor ratio at
0 °C afforded α-linked disaccharide 16 in 55% yield by NMR
integration (Table 2, entry 1). Again α,α-trehalose and
derivatives of the donor 7 arising from intramolecular aglycone
transfer were the major byproducts of the reaction.
Furthermore, free p-methoxyphenol coeluted with 16 and
could not be separated. Running the reaction at room
temperature increased byproduct formation, and the use of
THF as a cosolvent did not improve the yield (Table 2, entries
2 and 3). Rationalizing that byproduct formation was the result
of inefficient proton scavenging, we again tried DTBMP, but
this was again detrimental to the yield (Table 2, entry 4).
Seeing the detrimental effect of increasingly Lewis basic
scavengers on our substrates, we then investigated the alkene
4-allyl-1,2-dimethoxybenzene (ADB) as an alternate type of
Scheme 3. Disaccharide Deprotections
deprotection of the Nap group of 16 gave disaccharide
acceptor 4 in 89% yield, and we gratifyingly did not observe
anomerization of the PMP group in the absence of a proton
scavenger for this reaction.64 Disaccharide donor 5 was then
generated with ceric ammonium nitrate in 64% yield. In this
latter reaction we found that addition of sodium bicarbonate to
this reaction was essential to limit the acid-catalyzed hydrolysis
of the disaccharide.67
With the stage set for tetrasaccharide formation, we initially
examined the [2 + 2] glycosylation using the optimal
conditions for disaccharide 16 formation. Using our
preactivation protocol, we reacted donor 5 and acceptor 4 in
a 1:3 ratio at −10 °C and obtained tetrasaccharide 3 as a single
α-anomer in 28% yield (Table 3, entry 1). Under these
conditions donor 5 was not fully consumed, and we identified
the major byproduct of this reaction as the α,α-trehalose
derivative of donor 5. We additionally could quantitatively
recover and reuse excess acceptor 4 through flash chromatog-
C
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Table 3. Tetrasaccharide Optimization
Scheme 4. Synthesis of Tetrasaccharide Ester 1
activation
yield
d
a
entry
method
scavenger
temp
−10 °C
−10 °C
−30 °C → −10 °C
−10 °C
−10 °C
(α-only)
1
2
3
preactivation
coactivation
preactivation
preactivation
preactivation
TTBP
TTBP
TTBP
TTBP
IBO
28%
trace
31%
30%
trace
trace
b
c
4
5
6
preactivation
β-Pinene −10 °C
a
b
c
d
Isolated yield. 4 added at −30 °C. rxn time 23 h, 1:3 donor/
acceptor ratio for all reactions.
raphy, reducing the impact of these low yields. In an attempt to
improve the reaction outcome, we switched to the coactivation
protocol described above, which had limited trehalose
formation in the PMP glycosylation of monosaccharide
donor 8 (Scheme 2C). This method resulted in a complex
mixture of products and a significant amount of α-PMP
glycoside of donor 5 was produced, signifying aglycone transfer
(Table 3, entry 2). Reasoning that the majority of trehalose
would be formed during the activation of the donor in the
absence of the acceptor, we then cooled the reaction to −30
°C and then allowed the system to warm to −10 °C upon
addition of the acceptor, but this failed to increase the yield
(Table 3, entry 3), and the donor consumption was sluggish at
this lower temperature. Increasing the reaction time to 23 h
did not improve the yield (Table 3, entry 4), and we again
explored nonbasic proton scavengers as a means of controlling
byproduct formation without causing elimination of the PMP
substituent of 4. Isobutylene oxide (IBO), which was reported
to be effective in preventing halo acid formation in direct
glycosylation methods involving halide ion release,27,68 did not
benefit our system, instead affording a complex mixture of
products (Table 3, entry 5). We next examined the strained
alkene β-Pinene as an acid scavenger;69−71 however, this too
afforded a complex mixture (Table 3, entry 6). Having
established a fully selective, albeit low-yielding [2 + 2]
glycosylation method, we decided to move forward with the
synthesis.
To complete the synthesis of tetrasaccharide 1, compound 3
was first quantitatively deprotected at the nonreducing end
with DDQ in the presence of β-Pinene, which was necessary to
prevent PMP anomerization (Scheme 4).64 The alcohol
derivative of 3 was then coupled to fumarate monoester 2
using 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hy-
drochloride (EDCI·HCl) and N,N-diisopropylethylamine
(DIPEA) to give tetrasaccharide ester 17 in 74% yield.72
The sensitivity of the glycosidic linkages of 17 made removal of
the TBS masking group challenging, and several conventional
approaches failed (e.g., acid-buffered TBAF, HF·pyridine
complex). Fortunately, we were able to remove the TBS
with an excess of triethylamine trihydrofluoride to afford
alcohol-ester 1 in 64% yield.73
In conclusion, we have achieved the first synthesis of the
Arugomycin tetrasaccharide fragment by a convergent [2 + 2]
route, relying solely on our third-generation promoter system
of aryl cyclopropene-1-thione and oxalyl bromide to conduct
fully α-selective glycosylations with secondary alcohol accept-
ors. In our application of this method to more complex
glycosylations of 2,6-dideoxy mono- and disaccharides, we
addressed the formation of yield-limiting byproducts through
adjustments to temperature, stoichiometry, and addition
method to ensure good to excellent yields in our disaccharide
couplings. Our challenges in extending this method further to
tetrasaccharide glycosylation are illustrative of the sensitivity of
2-deoxy sugar linkages and the need for both effective and
innocuous proton scavengers. Taken together, the strategies
and results reported herein may inform the synthesis of other
2,6-dideoxy-sugar containing oligosaccharides.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01153.
Experimental details and characterization data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1−10 (ZIP)
FAIR data, including the primary NMR FID files, for
compounds 11−17, S3, S5, and S8 (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Clay S. Bennett − Department of Chemistry, Tufts University,
Medford, Massachusetts 02155, United States; orcid.org/
0000-0001-8070-4988; Email: clay.bennett@tufts.edu
Authors
Joseph R. Romeo − Department of Chemistry, Tufts University,
Medford, Massachusetts 02155, United States
D
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Sugars. 2. Synthesis of the Cororubicin Trisaccharide. J. Org. Chem.
1999, 64, 6275−6282.
Luca McDermott − Department of Chemistry, Tufts University,
Medford, Massachusetts 02155, United States
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Aryl-D-Glycosides via Direct Displacement of Glycosyl Iodides. Org.
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Complete contact information is available at:
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(17) Tanaka, H.; Yoshizawa, A.; Takahashi, T. Direct and
Stereoselective Synthesis of β-Linked 2,6- Deoxyoligosaccharides.
Angew. Chem., Int. Ed. 2007, 46, 2505−2507.
Notes
The authors declare no competing financial interest.
(18) Kaneko, M.; Herzon, S. B. Scope and Limitations of 2-Deoxy-
and 2,6-Dideoxyglycosyl Bromides as Donors for the Synthesis of β-2-
Deoxy- and β-2,6-Dideoxyglycosides. Org. Lett. 2014, 16, 2776−2779.
(19) Tanaka, H.; Yoshizawa, A.; Chijiwa, S.; Ueda, J. Y.; Takagi, M.;
Shin-ya, K.; Takahashi, T. Efficient Synthesis of the Deoxysugar Part
of Versipelostatin by Direct and Stereoselective Glycosylation and
Revision of the Structure of the Trisaccharide Unit. Chem. - Asian J.
2009, 4, 1114−1125.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (NSF CHE-
1566233) and National Institutes of Health (R01-GM115779
and U01-GM120414) for generous financial support
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