A Convergent Synthetic Strategy towards Oligosaccharides containing 2,3,6-Trideoxypyranoglycosides

Article abstract of DOI:10.1002/anie.201812222

A de novo synthetic strategy for the production of oligosaccharides containing 2,3,6-trideoxypyranoglycoside is reported. The key event is the Pd-catalyzed asymmetric diastereoselective hydroalkoxylation of ene-alkoxyallene-linked glycosidic fragments. The utility of this approach was demonstrated by the activation-free, stereodivergent, and convergent synthesis of various 2-deoxyoligosaccharides, as well as their aglycon conjugates.

Full text of DOI:10.1002/anie.201812222

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Accepted Article
Title: A Convergent Synthetic Strategy towards Oligosaccharides
Containing 2,3,6-Trideoxypyranoglycosides
Authors: Juyeol Lee, Soyeong Kang, Jungjoon Kim, Dohyun Moon,
and Young Ho Rhee
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812222
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10.1002/anie.201812222
Angewandte Chemie International Edition
COMMUNICATION
A Convergent Synthetic Strategy towards Oligosaccharides
Containing 2,3,6-Trideoxypyranoglycosides
Juyeol Lee,[a] Soyeong Kang, [a] Jungjoon Kim, [a] Dohyun Moon[b] and Young Ho Rhee*[a]
Dedication ((optional))
For example, repeating patterns (such as found in
Langkocycline congeners) are reported[6] while heterogeneous
patterns (such as found in Landomycin Y) are also known.[7] Due
to this diverse nature, oligosaccharides containing 2,3,6-
trideoxypyranoglycosides have been considered as attractive
synthetic targets.[8] Yet, access to these structures has been very
limited.[9] This is mainly because of the problems associated with
the controlled synthesis of 2-deoxyglycosides. The absence of a
directing group at the 2-position makes the stereoselective
glycosidic bond formation a particularly difficult task.[10] In addition,
anomeric centers in the 2-deoxyoligosaccharides becomes less
stable and thus more prone to epimerization/decomposition.
These problems become most pronounced with 2,3,6-
trideoxypyranoglycosides. In fact, many of the stereoselective
(substrate-controlled) methods recently developed for 2,6-
dideoxyglycoside showed poorer outcome for 2,3,6-
trideoxyglycosides.[11] Due to these problems, classical syntheses
of 2-deoxyoligosaccharides rely heavily on the use of removable
electron-withdrawing groups at the 2-position.[12] Thus, general
and flexible approaches that can provide various 2-
deoxyoligosaccharides particularly those possessing 2,3,6-
trideoxyglycosides remain underdeveloped. Here, we wish to
report a de novo synthetic method that allows rapid assembly of
complex 2-deoxyglycosides in a convergent and stereodivergent
manner based on chemoselective metal catalysis.
Abstract: A de novo synthetic strategy towards oligosaccharides
containing 2,3,6-trideoxypyranoglycoside is reported. A signature
event
is
highlighted
by the
Pd-catalyzed
asymmetric
diastereoselective hydroalkoxylation of ene-alkoxyallene linked to
glycosidic fragments. The utility of this unique approach was
demonstrated by the activation-free, stereodivergent and convergent
synthesis of various 2-deoxyoligosaccharides as well as their aglycon
conjugates.
2-Deoxyoligosaccharides represent key components found in
numerous bioactive natural products.[1] As illustrated by some
examples
shown
in
Figure
1,
many
of
these
deoxyoligosaccharides contain 2,3,6-trideoxypyranoglycosides
(amicetose and rhodinose).[2-5] These moieties are linked to
various aglycons as well as to other 2-deoxyglycosides with
divergence in sequence and stereochemistry.
Figure 1. Natural products containing 2-deoxyoligosaccharides
Scheme 1. Basic Concept of the Proposed Study
[a]
[b]
J. Lee, S. Kang, J. Kim, Prof. Y. H. Rhee
Department of Chemistry
Pohang University of Science and Technology (POSTECH)
Pohang, 37673, Republic of Korea
E-mail: yhrhee@postech.ac.kr
Dr. D. Moon
Department of Beamline
Pohang Accelerator Laboratory
Pohang, 37673, Republic of Korea
Over the past decades, transition metal catalysis has emerged
as a new technique for the oligosaccharide assembly.[13-15] In this
context, we recently reported a de novo synthesis of mono- and
disaccharide form of pyranose glycosides using Pd-catalyzed
asymmetric hydroalkoxylation of alkoxyallene as the key strategy,
in combination with the ring-closing-metathesis (RCM).[16-18]
A
salient feature of this method is highlighted by the chiral ligand-
driven stereocontrol in the glycosidic bond formation. Also, the
chemoselective metal catalysis avoids the need of highly reactive
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201812222
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activating groups, which is common in conventional
glycochemistry. Based upon these features, we envisioned that
the method should be also desirable for the synthesis of
oligosaccharides possessing 2,3,6-trideoxyglycosides. At the
outset of the study, we reasoned that a new strategy combining
ene-alkoxyallene and alcohol nucleophiles should be better suited
for the proposed study in many regards (Scheme 1). First, the
revised strategy allows for the direct use of the alcohol
nucleophiles without conversion into the corresponding
alkoxyallenes. This new feature can ease the difficulty in forming
the glycon-aglycon conjugates. In addition, employing the
alkoxyallene moiety linked to a glycosidic unit will enable a unique
convergent synthesis.[19] The complexity and diversity of the
glycon portion can rapidly increase by the iterative use of
diversely substituted ene-alkoxyallenes. In combination with the
ligand-driven stereocontrol discussed previously,[16b] the
proposed method can give rise to various oligosaccharides
containing 2,3,6-trideoxyglycosides and the related natural
products in a highly efficient and well-controlled manner.
bulkier than cyclohexanol, afforded the β-glycosides (compounds
7a, 9a and 11a) in considerably higher yield (entries 2-4).
Preparation of the corresponding α-glycosides proceeded much
smoother, generating the products in high yield with 5 mol%
catalyst loading. Notably, allene 3 also worked well with
galactose-derived alcohol 12 to produce the disaccharide 13 in a
stereodivergent manner (entry 5). This example verifies the
potential utility of the proposed method for future studies involving
fully oxygenated oligosaccharides synthesis.
Table 1. Ligand-driven Stereodivergent Synthesis
Entry
1
Alcohol (ROH)
Product
Scheme 2. Preliminary studies for Pd-catalyzed hydroalkoxylation of ene-
alkoxyallenes
2
3
4
5
In order to test the plausibility of the revised strategy, we first
examined the reaction of readily available allene
1 and
cyclohexylmethyl alcohol (Scheme 2). Using the previously
optimized condition[16b] for the asymmetric hydroalkoxylation (2 eq
allene 1/ 1 eq alcohol/ 1.5 eq Et3N/ 2.5 mol% Pd2(dba)3/ 5.0 mol%
ligand L1) in toluene (0.5 M) proceeded very slowly, producing
the target compound 2a in poor yield after the subsequent ring-
closing-metathesis (RCM) reaction. After extensive further
optimization, the yield was significantly improved (to 84% over two
steps) when excess amount of alcohol (2 eq) was reacted with 1
(1 eq) in the presence of catalytic Et3N (0.1 eq) at 40oC.[20] Simply
switching the chiral ligand to the enantiomeric form ent-L1
produced diastereomeric product 2b in a comparable manner.
Following a similar two-step protocol, the monosaccharide
glycosides 4a and 4b were also obtained from more densely
substituted alkoxyallene 3 in high yield and selectivity.
[a] RCM reaction showed 90~98% yield. [b] Diasteromeric ratio was determined
by crude NMR after RCM. [c] The reaction was performed on ~1 mmol scale.
[d] 10 mol% Grubbs catalyst in CH2Cl2 was used. [e] Alkoxyallene 3 was used.
Having firmly established the generality of this second-
generation strategy in the mono- and disaccharide formation, we
turned our attention to the convergent synthesis of various
oligosaccharides shown in Figure 1. The structural features of
these compounds consisting of olivose-rhodinose or olivose-
amicetose moiety led us to consider the use of olivose-derived
allenes 14 and 15 as a key structural motif. These compounds
were readily prepared by using the SN2 glycosylation method
Then, we explored the stereodivergent reaction of various
alcohol nucleophiles with allene 1 or 3 using the optimized
condition in Scheme 2. As can be seen from Table 1, formation of
β-glycosides was in general slower than that of the corresponding
α-anomers. Nevertheless, increasing the catalyst loading (to 10
mol%) considerably improved the yield (>80%) without
significantly harming the stereoselectiviy. In case when
structurally simple cyclohexanol was used, the β-glycoside 5a
was obtained in low 54% yield even with 10 mol% catalyst loading
(entry 1). Gratifyingly, monosaccharide alcohol substrates
(compounds 6 and 8) and cholesterol 10, which are apparently
reported by Bennett (For the detailed procedure, see the SI).[21]
A
preliminary reaction of the cholesterol 10 as the aglycon moiety
with alkoxyallene 14 gave the steryl disaccharides 16a and 16b
in 87 and 92% yield over two steps, respectively (Example A).[22]
In addition, coupling of the diastereomeric allene 15 with
cyclohexanol proceeded in the presence of ligand ent-L1 to
produce β-disaccharide 17a in 68% yield, which represents the
glycosidic framework of kigamicin C (Example B). Again, simply
changing the ligand to the enantiomeric form L1 generated the
anomeric α-disaccharide 17b exclusively in 77% yield. Additional
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10.1002/anie.201812222
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example using unprotected C-glycoside 18 also provided the
corresponding α-disaccharide 19 in 63% isolated yield along with
its C-4 reigoisomer in 18% yield (Example C). For the
determination of the regioselecivity, see below). Thus, the current
method can be applied for the synthesis of angucycline natural
products such as Quanolirones and Galtamycin without the
protection of the C4-OH group.
We then pursued preparation of more complex 2-
deoxyoligosaccharides. On the basis of the structural pattern
found in the Langkocyclines (Figure 1), we reasoned that an
iterative use of the allene 14 would pave the road for the collective
synthesis of the glycosidic portion of Langkocycline A1 and A2
(Figure 1).[23] As depicted in Example D, the iterative cycle is
composed of three-step sequential metal catalysis involving (i)
Pd-catalyzed asymmetric hydroalkoxylation followed by (ii) Ru-
catalyzed RCM and (iii) Pd-catalyzed hydrogenation (and the
concomitant removal of the benzyl group). Remarkably, two
glycosidic residues can be introduced by each iteration. Initial
subjection of 14 and cyclohexanol to this cycle using ligand ent-
L1 as a stereocontrol element led to the formation of Lankocycline
A1 cyclohexyl glycoside 20 in 75% yield (over three steps).
Additional cycle employing sequential Pd-Ru catalysis and allene
14 in the presence of ent-L1 produced the tetrasaccharides 21a
in 60% yield. (In this case, C4-regioisomer was also obtained in
~20% yield). X-ray crystalographic analysis of this compound
unambiguously confirmed the stereo- and regioselectivity of the
reaction (For detailed information, see the SI). Furthermore,
switching to enantiomeric ligand L1 gave an unnatural derivative
of the tetrasaccharide (compound 21b) in comparable 61% yield.
As a final example, we explored the synthesis of a tetrasaccharide
moiety in Landomycin Y (compound 25), which is highly
heterogeneous in terms of the sequence and stereochemistry
(Example E). For this purpose, the disaccharides 24 was first
prepared from allene 22 and β-D-olivose derivative 23 via the
three-step protocol in 61% overall yield. Then, synthesis of
tetrasaccharide 25 was pursued by the coupling of 24 and the
repeating unit 15. As described in Scheme 3, Pd-catalyzed
asymmetric hydroalkoxylation in this case needed higher loading
of Pd2(dba)3 (15 mol%) to provide the acyclic acetal in 67% yield.
After the RCM reaction, the target tetrasaccharide 25 was
obtained in 92% yield (62% over two steps). As illustrated by
Scheme 3. Convergent synthesis of various 2-deoxy oligosaccharides.[a,b]
these examples,
a
number of natural and non-natural
oligosaccharides can arise by simply conjugating diverse ene-
alkoxyallene fragments. It should be also noted that the proposed
method can be easily expanded to the convergent synthesis of
natural
products
possessing
(such as
oligomeric
Amicenomycins
2,3,6-
and
trideoxysaccharides
Cervimycins[24]).
In conclusion, we developed a Pd-catalyzed asymmetric
diastereoselective hydroalkoxylation of highly substituted ene-
alkoxyallenes. This reaction opens up a new paradigm in the
synthesis of oligosaccharides containing 2,3,6-trideoxyglycosides.
The future direction of the work is directed to examining
automation of the process and to studying the relationship
between the stereochemistry of the various monomeric units and
the potential bioactivities. The results of these future studies will
be reported in a due course.
Acknowledgements
Financial support for this work was provided by the Samsung
Science and Technology Foundation. (STF-BA-1502-08).
Keywords: Oligosaccharides • Carbohydrates • Palladium •
Diastereoselectivity • Asymmetric synthesis
[a] Method A: 5 mol% Pd2(dba)3, 10 mol% of L1. Method B: 2.5 mol% Pd2(dba)3,
5 mol% of ent-L1. Method C: 5.0 mol% Pd2(dba)3, 10 mol% of ent-L1. Method
D: 2.5 mol% Pd2(dba)3, 5 mol% of ligand L1. [b] The yield of RCM reaction in
all cases was higher than 90%. [c] Isolated yield of the pure compound. [d] The
dr could not be measured because of the complex patterns of the crude NMR.
[e] 15 mol% Pd2(dba)3, 30 mol% of ligand L1.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
A new synthetic strategy towards
2,3,6-trideoxyoligosaccharide is
described. The key event is the use of
ene-alkoxyallene moiety possessing a
glycosidic unit. The utility of the
reaction was demonstrated by a
number of well-controlled synthesis of
2,3,6-trideoxyoligosaccharides,
including a tetrasaccharide moiety
found in Landomycin Y.
Juyeol Lee, Soyeong Kang, Jungjoon
Kim, Dohyun Moon, Young Ho Rhee*
Page No. – Page No.
A Convergent Synthetic Strategy
towards Oligosaccharides Containing
2,3,6-Trideoxypyranoglycosides
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