Stereodirecting Effect of C3-Ester Groups on the Glycosylation Stereochemistry of L-Rhamnopyranose Thioglycoside Donors: Stereoselective Synthesis of α- and β-L-Rhamnopyranosides

Article abstract of DOI:10.1002/ejoc.201901186

The tuning effect of C3-ester groups on the glycosylation stereochemistry of L-rhamnopyranose (L-Rha) ethyl thioglycoside donors is described. On one hand, the L-Rha thioglycoside donors carrying 3-O-arylcarbonyl or levulinoyl group undergo highly α-selec

Full text of DOI:10.1002/ejoc.201901186

DOI: 10.1002/ejoc.201901186
Full Paper
Glycosylation
Stereodirecting Effect of C3-Ester Groups on the Glycosylation
Stereochemistry of L-Rhamnopyranose Thioglycoside Donors:
Stereoselective Synthesis of α- and ꢀ-L-Rhamnopyranosides
Jin-Cai Lei,[a] Yu-Xiong Ruan,[a] Sheng Luo,[a] and Jin-Song Yang*[a]
Abstract: The tuning effect of C3-ester groups on the glycosyl- ucts are obtained when these L-Rha donors couple with the
ation stereochemistry of L-rhamnopyranose (L-Rha) ethyl thio- primary or reactive secondary acceptors, while the ꢀ-selectivity
glycoside donors is described. On one hand, the L-Rha thioglyc- may decrease significantly when these donors react with less
oside donors carrying 3-O-arylcarbonyl or levulinoyl group un- reactive secondary alcohols. The synthetic utility of the newly
dergo highly α-selective glycosylation to afford a wide variety developed α- and ꢀ-directing L-Rha donors 1h and 1e has been
of α-L-rhamnoside products in high chemical yields. On the demonstrated by the efficient synthesis of a structurally unique
other hand, the glycosylation of the 3-O-4-nitropicoloyl and 2- trisaccharide 9, which is derived from the cell wall polysacchar-
pyrazinecarbonyl group substituted L-Rha thioglycosides dis- ide of Sphaerotilus natans.
plays ꢀ-stereoselectivity. Only or predominant ꢀ anomeric prod-
Introduction
aglycon delivery (IAD) strategy reported by Ito et al.[4a] was ef-
fective in the synthesis of ꢀ-L-rhamnosides, but the mixed
acetal intermediates need further converting to the desired
glycoside products, which lowered the total synthetic efficiency.
Recently, an elegant ꢀ-L-rhamnosylation protocol using 1,2-an-
hydro-L-rhamnosyl donors and mono-ol or diol acceptors in the
presence of borinic/boronic acid promoters was reported by
the Toshima group.[5] Although stereospecific ꢀ-selectivity was
obtained, the chemical yields in the glycosylations of the sec-
ondary glycosyl acceptors were strongly affected by the steric
effects of the acceptors. Therefore, there has been a continuous
pursuit of a more practical approach for the preparation of
ꢀ-L-rhamnoside.
L-Rhamnopyranose (L-Rha) is widespread in nature and is a very
common component of numerous natural carbohydrates.[1]
Synthesis of α-L-rhamnopyranoside can be achieved in a
straightforward manner through classic neighboring group par-
ticipating (NGP) approach. But highly stereoselective construc-
tion of ꢀ-L-rhamnoside, usually found in the cell wall polysac-
charides of pathogenic bacteria, poses a great challenge.[2] This
is because, in the L-Rha system with a standard 1C4 chair confor-
mation, the steric hindrance between the ꢀ-rhamnosidic bond
and the axial C2-hydroxy group disfavors formation of ꢀ-ano-
mer. Up to now, a variety of L-rhamnosyl donors,[3] such as the
3,4-O-carbonate or 2-O-sulfonate substituted thioglycoside or
bromide derivatives discovered by Crich[3d,3e] as well as the 2-
alkynyl-4-nitro-benzoate donor reported by Yu,[3g] have been
developed to achieve the direct ꢀ-L-rhamnosylation. But some
of them suffer from disadvantages such as limited ꢀ-selectivity,
low stability or harsh conditions for the cleavage of the stereo-
directing groups. Meanwhile, among the indirect methods,[4]
the 2-naphthylmethyl (Nap) ether-mediated intramolecular
Recently, based on the hydrogen-bond-mediated aglycon
delivery (HAD) concept first put forward by Demchenko,[6] our
laboratory developed a novel 2-quinolinecarbonyl (Quin)-
assisted glycosylation approach for stereocontrolled synthesis
of various difficult-to-obtain glycosidic linkages including ꢀ-ara-
bino-[7a] and α-galactofuranosides[7b] and ꢀ-3-deoxy-
D-manno-
oct-2-ulosonic acid (Kdo) glycoside.[7c] The Quin group, serving
as a hydrogen-bond acceptor, exhibits powerful stereodirecting
ability in the condensation of furanosyl or Kdo thioglycoside
donors with a wide range of alcohols. In this paper, we planned
to apply the Quin-directed stereoselective glycosylation
method to the preparation of the ꢀ-L-rhamnoside. As shown by
Scheme 1, we considered that, in a typical glycosylation reac-
tion of a 3-O-Quin substituted Rha donor, the temporary
hydrogen bond tether formed between the Quin group and the
acceptor is capable of guiding the nucleophilic attack of the
acceptor from the ꢀ-side of the pyranose ring, which would be
likely to form a ꢀ-glycoside product.
[a] Key Laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced
Drug and Sichuan Research Center for Drug Precision Industrial
Technology, West China School of Pharmacy, and State Key Laboratory of
Biotherapy, West China Hospital, Sichuan University,
Chengdu 610041, China
E-mail: yjs@scu.edu.cn (J.-S. Yang)
http://pharmacy.scu.edu.cn/news.aspx?id=1390
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901186.
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Scheme 1. 2-Quinolinecarbonyl-directed synthesis of ꢀ-L-rhamnopyranoside.
Results and Discussion
the acceptor in the presence of the N-iodosuccinimide (NIS)/
trifluoromethanesulfonic acid (TfOH) system in dry dichloro-
methane (CH2Cl2). The anomeric configuration of the product
We first examined the effectiveness of hydrogen bond as a
stereocontrolling factor on the formation of ꢀ-L-rhamnopyran-
oside. A series of L-rhamnosyl thioglycosides 1a–f bearing Quin,
2-pyridinecarbonyl (Pico), 4-nitropicoloyl, and 2-pyrazine-
carbonyl group, respectively, on the C3 position (Table 1) were
prepared (see the Supporting Information) and their glycosyl-
ation behaviors were evaluated by reaction with model galact-
ose (Gal) derivative 2a.[8] We conducted all the reactions by
1
was assigned on the basis of the anomeric JCH coupling con-
stants.[9] For the α-anomer, 1JCH is 167.2–172.3 Hz, while, for the
1
ꢀ-anomer, JCH is 152.3–159.8 Hz.
As summarized in Table 1, entries 1–6, the couplings of all
the donors 1a–f with acceptor 2a furnished the corresponding
glycosides 3a-d in good 72–85 % yields but with varying de-
gree of anomeric selectivity. The reaction of 3-O-Quin substi-
employing 1.5 equiv. of the donor (50 mM) and 1 equiv. of
Table 1. ꢀ-Selective glycosylation between donors 1a–f and acceptor 2a.[a]
[a] Glycosylations were carried out with L-Rha thioglycoside donor (1.5 equiv.), acceptor (1 equiv.), NIS (1.5 equiv.)/TfOH (0.1 equiv.), 4 Å MS in anhydrous
CH2Cl2. [b] Isolated yield based on the acceptor. [c] Determined by 1H NMR of the corresponding isomer mixture.
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tuted α- and ꢀ-thioglycosides 1a, b showed poor ꢀ-selectivity 4d as a disappointing anomeric mixture (α/ꢀ 1:1.3, entry 4) but
(α/ꢀ 1:4, entries 1 and 2). In the cases of the 3-O-Pico substi- the rhamnosylation with 2,3-di-O-benzyl (Bn) protected Rha al-
tuted donors, the α-anomer 1c showed a lower ꢀ-selectivity cohol 2f[14] showed excellent ꢀ-stereoselectivity (α/ꢀ 1:15, entry
than its ꢀ-counterpart 1d (α/ꢀ 1:6, entry 3 vs. α/ꢀ 1:10, entry 4). 5). We also assessed the electronic effect of the acceptor on the
Gratifyingly, the 3-O-4-nitropicoloyl donor 1e displayed a strong glycosylation selectivity. The condensation between 1e and the
stereocontrolling ability in the reaction with 2a and excellent 2-O-benzoyl (Bz)-4,6-O-benzylidene substituted D-glucose (Glc)
ꢀ-selectivity was obtained for the product 3c (75 % yield, α/ꢀ acceptor 2g[15] was non-stereoselective, whereas the coupling
1:14, entry 5). Moreover, the glycosylation between the 3-O-2- between 1e and the 2-O-Bn-4,6-O-benzylidene blocked Glc al-
pyrazinecarbonyl donor 1f and 2a also proceeded in high yield cohol 2h[16] was highly ꢀ-selective (α/ꢀ 1:1, entry 6 vs. α/ꢀ 1:15,
with good ꢀ-selectivity (83 % yield, α/ꢀ 1:8, entry 6).
entry 7). A similar dramatic change in selectivity was also ob-
served between the glycosylation of 1e with the 2,3,6-tri-O-Bz
protected Glc 4-OH substrate 2i[17] and the glycosylation of 1e
with the 2,3,6-tri-O-Bn protected Glc alcohol 2j[18] (α/ꢀ 1:2, en-
try 8 vs. α/ꢀ 1:15, entry 9). These results reveal that the electron-
donating substituent on the acceptor is beneficial to the ꢀ-
anomeric product formation. Other secondary acceptors such
In order to broaden the substrate scope, we further investi-
gated the glycosylations between Rha donors 1e,f and a series
of acceptors 2b-l (Table 2). The reactions of 1e with the primary
alcohols including the linear molecule 2b,[10] the disarmed and
armed carbohydrate alcohols 2c,[11] d[12] gave the correspond-
ing glycoside products 4a–c in high chemical yields and with
good ꢀ-stereoselectivity (Table 2, entries 1–3). Nevertheless, for
the reactions of 1e with the secondary glycosyl acceptors, the
yields were good but the stereochemical outcome was mark-
edly influenced by the protecting group pattern of the acceptor
as the N-acetyl-D-glucosamine (GlcNAc, 2k[19]) and
D-mannose
(Man, 2l) alcohols were examined as well. As a result, the reac-
tion of the former 2k containing an electron-withdrawing acetyl
(Ac) group at C2 position brought a moderate ꢀ-stereoselecti-
(Table 2, entries 4–12). For instance, rhamnosylation of 1e with vity (Table 2, entry 10) while the reaction of the latter 2l,[20]
Rha 4-OH alcohol 2e[13] bearing a cyclic 2,3-O-isopropylidene having an axial 2-OH group, gave poor ꢀ-selectivity (entry 11)
acetal protection yielded the ꢀ-L-Rha-(1→4)-L-Rha disaccharide and no significant enhancement in ꢀ-selectivity was detected
Table 2. Glycosylation of donors 1e,f with various acceptors.[a]
[a] Glycosylations were carried out with L-rhamnosyl thioglycoside donor (1.5 equiv.), acceptor (1 equiv.), NIS (1.5 equiv.)/TfOH (0.1 equiv.), 4 Å MS in anhydrous
CH2Cl2. [b] Isolated yield based on the acceptor. [c] Determined by 1H NMR of the corresponding isomer mixture.
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upon switching the donor to the 3-O-2-pyrazinecarbonylated
1f (entry 12).
So, we further probed the possible remote participating ef-
fect of the C3-carbonyl functionality of thiorhamnosides on the
stereoselectivity of glycosylation. Several 3-O-levulinoyl (Lev) or
arylcarbonyl-substituted Rha thioglycoside substrates 1g–j
were synthesized and glycosylated with model compounds 2a
and 2e under the activation of NIS/TfOH (cat.) in CH2Cl2
(Table 3). These donors showed good-to-excellent α-selectivity
in all reactions with both primary (2a) and secondary (2e) sugar
alcohols, giving predominantly or solely the corresponding α-
linked disaccharide glycosides 5a–h in satisfactory yields
(Table 3, entries 1–8). These results obviously indicate the
strong stereocontrolling ability of the C3-acyl substitution of
thiorhamnosides to promote the α-glycosylation reaction. In
the condensations of the 3-O-arylcarbonylated donors 1h–j
with the primary acceptor 2a, the electron density of the carb-
onyl function affects the stereochemical outcome. For instance,
compared to the Bz (1h) and the more electron-rich p-methoxy-
Overall, the experimental outcomes above indicate that (1)
in the couplings of 1e with the primary or reactive secondary
sugar alcohols, the hydrogen bond interaction between the 4-
nitropicoloyl group and the acceptors is strong enough to
achieve high ꢀ-selectivity; but (2) in the condensation between
1e and the secondary alcohols with relatively low nucleophilic-
ity, there is no or little hydrogen bond interaction, which leads
to the dramatic loss of ꢀ-selectivity. Conversely, in these glycos-
ylations, the increase in α-linked product was probably caused
by the remote participating effect of the carbonyl of the 3-O-
4-nitropicoloyl moiety on the anomeric center. Indeed, the re-
mote participating phenomenon of a carbonyl protection has
been reported in the literatures. For examples, Boons et al. de-
scribed that the remote participation of the axial C4-carboxyl-
ate ester group in Gal donors was able to enforce facile α-galac-
tosylation reaction. Recently, our group also reported a highly benzoyl (1i) moieties, the electron-deficient p-nitrobenzoyl (1j)
α-stereoselective glycosylation of Kdo thioglycoside donors en- substituent led to a relatively lower stereocontrol (α only, en-
abled by the remote participation of 5-O-carbonyl function.
tries 2 and 3 vs. α/ꢀ 8.5:1, entry 4).
Table 3. α-Selective glycosylation of 3-O-acylated L-Rha donors (1g–j).[a]
[a] Glycosylations were carried out with L-rhamnosyl thioglycoside donor (1.5 equiv.), acceptor (1 equiv.), NIS (1.5 equiv.)/TfOH (0.1 equiv.), 4 Å MS in anhydrous
CH2Cl2. [b] Isolated yield based on the acceptor. [c] Determined by 1H NMR of the corresponding isomer mixture.
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The reaction scope of the 3-O-Bz substituted thiorhamnoside
donor 1h was further studied. The couplings of this donor with
the primary alcohols 2b and 2d proceeded in an α-selective
and high-yielding manner, affording exclusively the α-linked
glycoside products 6a,b in good yield (Table 4, entries 1–2).
Moreover, in the NIS/TfOH (cat.)-catalyzed condensation with
sterically demanding secondary Glc 2-OH (2m[21]), Rha 2-, 3-,
and 4-OH (2n[22]–o[23], and 2f) acceptors, 1h was also observed
to be an efficient glycosyl donor and both the yields and
α-selectivity in these coupling reactions were generally high
(Table 4, entries 3–6).
Table 4. α-Selective glycosylation of 3-O-benzoylated L-Rha donor 1h with
various acceptors.[a]
To demonstrate the usefulness of these approaches in the
synthesis of α- and ꢀ-L-Rha-containing oligosaccharides, we tar-
geted the production of trisaccharide glycoside 9 (Scheme 2).
This trisaccharide motif, possessing a linear α-L-Rha-(1→3)-ꢀ-
L-Rha-(1→4)-α-D-Glc framework, is isolated from the cell wall
polysaccharide of Sphaerotilus natans.[24] The unique structural
feature of 9 is that it comprises both α- and ꢀ-L-rhamnosyl
bonds. Previously, a trisaccharide with identical sugar sequence
was made by Ito and co-workers. In their preparation, the chal-
lenging ꢀ-L-Rha unit was constructed through the indirect
C2-Nap-mediated IAD protocol. In this study, we decided to em-
ploy our newly developed 1e and 1h as the key building blocks
for the assembly of the corresponding ꢀ- and α-L-rhamnosidic
linkages, respectively. In Scheme 2, the synthesis started with
the coupling of the effective ꢀ-L-rhamnosylating agent 1e with
methyl 2,3,6-tri-O-benzyl-α- -glucopyranoside (2j), which gen-
D
erated disaccharide 4i in a satisfactory 88 % yield with excellent
anomeric ratio (α/ꢀ 1:15). Pure ꢀ-4i was in turn selectively de-
protected by treatment with sodium methoxide (NaOMe) in
methanol to furnish the 3′-OH disaccharide alcohol 7 (93 %),
thus ready for further glycosylation. Then, this material was sub-
[a] Glycosylations were carried out with L-rhamnosyl thioglycoside donor 1h
(1.5 equiv.), acceptor (1 equiv.), NIS (1.5 equiv.)/TfOH (0.1 equiv.), 4 Å MS in
anhydrous CH2Cl2. [b] Isolated yield based on the acceptor. [c] Determined
by 1H NMR of the corresponding isomer mixture.
jected to condense with the α-directing donor 1h upon activa- benzoate ester groups with NaOMe in MeOH and then cleavage
tion with NIS/TfOH (cat.) in CH2Cl2 at –70 °C for 0.5 h, giving of all the Bn ethers by hydrogenolysis over Pd/C, which cleanly
rise to the corresponding trisaccharide glycoside 8 in 87 % yield produced the desired 9 in 86 % yield over two steps. Compared
as a single α diastereomer. Finally, the global deprotection of 8 to the existing synthetic route, our procedure is more practical
was readily carried out in the following order: removal of the for the preparation of the target molecule as it not only pro-
Scheme 2. Synthesis of α-L-Rha-(1→3)-ꢀ-L-Rha-(1→4)-α-D-Glc trisaccharide 9.
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Conclusions
In conclusion, two stereoselective L-rhamnopyranosylation
methods have been developed. One is an α-selective rhamnos-
ylation reaction in which the 3-O-arylcarbonyl or Lev carrying
L-Rha thioglycosides are used as glycosyl donors to couple with
a variety of carbohydrate alcohols, forming the α-L-rhamnos-
ides in high chemical yields with complete α-selectivity. The
other is a ꢀ-rhamnosylation means adopting the 3-O-4-nitro-
picoloyl or 2-pyrazinecarbonyl-substituted L-Rha thioglycosides
as donors. The glycosylation stereochemistry of these donors is
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acceptors. High ꢀ-stereocontrol is obtained when these donors
glycosylate with the primary or reactive secondary acceptors,
while the ꢀ-selectivity may greatly drop in the couplings with
less reactive secondary carbohydrate nucleophiles. Utility of the
present methods allowed a concise and stereocontrolled syn-
thesis of a structurally unique trisaccharide 9 having both α-
and ꢀ-L-rhamnoside substructures. Further application of the
methods for the generation of biologically active L-Rha-contain-
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promotion of NIS/TfOH: A mixture of glycosyl donor (1.5 equiv.),
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sieves in CH2Cl2 (50 mM) was stirred under nitrogen for 1 hour at
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(1.5 equiv.) and TfOH (0.1 equiv.) were added. The reaction mixture
was gradually warmed to –20 °C and stirred for 2 to 3 hours at the
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Conflicts of interest
The authors declare no competing financial interest.
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Acknowledgments
We appreciate the financial support from the National Natural
Science Foundation (21772132, 21572145), the Ministry of Sci-
ence and Technology (2017ZX09101003–005–004), and the
Fundamental Research Funds for the Central Universities of
China.
Keywords: Carbohydrates · Glycosides · Glycosylation ·
Stereoselective synthesis · Synthetic methods
Received: August 11, 2019
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