Synthetic avenues towards a tetrasaccharide related to Streptococcus pneumonia of serotype 6A

Full text of DOI:10.3762/bjoc.14.95

Synthetic avenues towards a tetrasaccharide related to
Streptococcus pneumonia of serotype 6A
Aritra Chaudhury1,2, Mana Mohan Mukherjee1,3 and Rina Ghosh*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1095–1102.
1Department of Chemistry, Jadavpur University, 188, Raja S. C.
Mullick Rd., Kolkata 700032, India, 2Department of Chemical
Sciences, Indian Institute of Science Education and Research,
Kolkata, Mohanpur, 741246, West Bengal, India and 3present
addrress: Laboratory of Bioorganic Chemistry, NIH, NIDDK,
Bethesda, MD, USA
doi:10.3762/bjoc.14.95
Received: 26 February 2018
Accepted: 26 April 2018
Published: 17 May 2018
Associate Editor: S. Flitsch
Email:
Rina Ghosh* - ghoshrina@yahoo.com
© 2018 Chaudhury et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
carbohydrates; glycosylation; oligosaccharides; stereoselectivity; total
synthesis
Abstract
Streptococcus pneumonia (SPn) is a Gram-positive bacterium which causes life threatening diseases. The bacteria protect them-
selves against non-specific host defence by an external polysaccharide (PS) capsule which bears a repeating unit, α-D-Galp(1->3)-
α-D-Glcp(1->3)-α-L-Rhap(1->3)-D-Rib (SPn 6A). A closer look at the structure reveals the presence of α-linked galactose and
glucose residues. The synthesis of these 1,2-cis glycosidic linkages are considered challenging particularly in the context of a one-
pot oligosaccharide synthesis. We have synthesized the aforesaid tetrasaccharide (SPn 6A) based on both stepwise and sequential
one-pot glycosylation reactions using easily accessible common building blocks; eventually similar overall yields were obtained in
both cases.
Introduction
Complex glycans serve as attractive targets for carbohydrate- most important causes of invasive pneumonococcal diseases
based vaccines and therapeutics [1-3]. Streptococcus pneu- [7]. These facts have led to extensive research towards the
monia (SPn) has been posing a serious threat in recent times. It establishment of polysaccharide structures associated with the
is a major cause of pneumonia, bacteraemia, and meningitis in SPn serogroup 6 [8,9] (Figure 1).
immune-compromised patients, elderly and children. A
UNICEF/WHO survey has estimated that 920136 children died Initially, it was thought that due to their similar carbohydrate
of pneumonia in 2015 accounting for 16% of all fatalities under core structures the antibodies elicited by SPn 6A would be
the age of five [4]. Out of over 90 serotypes that have been re- effective against SPn 6B as well [10-13]. But recent studies
ported for SPn [5,6], serogroup 6 has been ranked among the have shown that serotype specific immune responses are
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Figure 1: The tetrasaccharides associated with the pneumonicoccal serogroup 6.
elicited by the antibodies and that they cross react slowly [14]. Herein, we wish to report synthetic routes to the SPn 6A tetra-
As a result the importance of the presence of the capsular poly- saccharide via stepwise as well as one-pot sequential glycosyla-
saccharide of SPn 6A in multicomponent vaccines like Pneu- tion strategies.
movax® has been recognized [15]. The low hydrolytic stability
of the phosphodiester linkages in the clinical isolates of the SPn Results and Discussion
6A polysaccharides poses a major drawback as it leads to low Keeping in mind our objective to synthesize the SPn 6A tetra-
bioavailability [16]. Hence, the requirements of pure SPn 6A saccharide following stepwise as well as one-pot synthetic
conjugate in proper amounts for future vaccine development strategies based on common building blocks, a retrosynthetic
can only be met via chemical synthesis. Therefore, a number of analysis was made which led us to galactose-based donor 2
syntheses targeting the SPn 6A tetrasaccharide has been re- [26], ribitol-based acceptor 7 [22] and a gluco-rhamno-based
ported in literature. Initial reports of a linear synthesis were disaccharide (3a/3b) to contemplate the synthesis of the tetra-
made by Vliegenthart et al. in the nineties [17-21]. After this, saccharide derivative 1 (Figure 2).
the Demchenko group improved these early reports with a
convergent approach using glycosyl thioimidates as comple- The disaccharides (3a/3b) can be synthesized from their parent
mentary glycosyl donors with respect to thioglycosides [22-25]. monomeric units 6a/6b/6c and 5 [27]. To ensure high α-selec-
Figure 2: Retrosynthetic analysis.
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tion during the formation of the central gluco-rhamno disaccha-
ride the benzylidene protected glucosyl donor (Figure 2) was
selected, because the induction of the 1,2-cis selectivity in
benzylidene-protected substrates via torsional/electronic effects
have already been recognized [28].
The galactosyl trichloroacetimidate donor 2 was prepared
following literature procedures [26]. On the other hand the
D-glucosyl thioglycoside 8 was converted to the known benzyl-
idene derivative 9 [29,30] according to our previously reported
procedure. Benzylation of 9 under phase-transfer conditions led
to 10 [31] in 49% yield (Scheme 1). Subsequently, 10 was sub-
jected to naphthylmethylation/p-methoxybenzylation [32] with
2-(bromomethyl)naphthalene (NapBr)/p-methoxybenzyl chlo-
ride in DMF to afford 6a/11 [32] in 90% and 80% yields, re-
spectively.
Scheme 2: Preparation of L-rhamnosyl acceptor 5. Reaction condi-
tions: a) Py, BzCl, rt, 12 h, 99%; b) DDQ, DCM/H2O (19:1), rt, 2 h,
83%.
dimethoxypropane and pTSA in acetone. Treatment with NapBr
and NaH in DMF gave compound 19 in 93% yield. Subsequent
These derivatives were next subjected to thioglycoside hydroly- deprotection of isopropylidene ketal with pTSA/MeOH (aq) and
sis using trichloroisocyanuric acid (TCCA) [33] in wet acetone then benzylation furnished 20 in 95% yield over two steps.
which provided 12a/12b [34] in 85% and 89% yields, respec- Deprotection of the naphthylmethyl group in the presence of
tively. These were finally converted to their corresponding tri- DDQ in aqueous dichloromethane (19:1) gave the glycosyl
chloroacetimidate 6b/6c [34] (Scheme 1) with yields of 93% acceptor 7 [22] in 85% yield (Scheme 3).
and 90%, respectively.
In order to construct the central disaccharide fragment 3 in high
The L-rhamnosyl thioglycoside 14 [29,30], prepared from yield with 1,2-cis selectivity, several glycosylation reactions
L-rhamnose (13), was deacetylated quantitatively in the pres- using glucosyl donors 6a/6b/6c/12a and rhamnosyl acceptor 5
ence of Et3N/MeOH/H2O [35], and then stannylene-mediated were contemplated. None of the conditions, based on the use of
selective naphthylmethylation at the O-3 position was carried thioglycoside 6a as the glycosyl donor and separately, BSP/
out to give the known derivative 15 in 82% yield [36]. This was Tf2O (Table 1, entry 1) or Ph2SO/Tf2O (Table 1, entry 2) as the
next benzoylated almost quantitatively to give 16. Finally corresponding activators, or based on 1-hydroxy donor 12a and
DDQ-mediated deprotection of the naphthylmethyl group gave Ph2SO/Tf2O (Table 1, entry 3), could furnish any desired result.
the acceptor 5 [27] in 83% yield (Scheme 2).
After trying with the mentioned donors, and reagent combina-
tions (Table 1), we switched over to utilize trichloroacetimidate
For acceptor 7 (Figure 2) ribitol 17 was converted to its corre- donors (6b, Table 1, entries 5 and 6, and 6c, entry 4); the
sponding diisopropylidene derivative 18 [37] in the presence of TMSOTf mediated glycosylation in DCM/Et2O solvent
Scheme 1: Preparation of D-glucosyl donor 6. Reaction conditions: a) NapBr/PMBCl, NaH, DMF, rt, 12 h, 90% (6a), 80% (11); b) TCCA, CH3COCH3/
H2O (4:1), rt, 85% (12a), 89% (12b); c) CCl3CN, DBU, DCM, 0 °C, 93% (6b), 90% (6c).
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Beilstein J. Org. Chem. 2018, 14, 1095–1102.
Scheme 3: Preparation of ribitol acceptor 7. Reaction conditions: a) Me2C(OMe)2, pTSA, CH3COCH3, rt, 81%; b) NapBr, NaH, DMF, rt, 8 h, 93%;
c) (i) pTSA, MeOH, 40 °C, 4 h, (ii) BnBr, NaH, DMF, rt, 12 h, 95% over 2 steps; d) DDQ, DCM/H2O (19:1), rt, 2 h, 85%.
Table 1: Optimization of protocol for the synthesis of disaccharide 3.
Entry
1
Donor
Acceptor
Conditions
Yielda
N.R.d
BSPb, Tf2O, DCM,
−60 °C→rt (A)c
6a
6a
5
5
5
Ph2SO, TTBP, Tf2O, DCM,
−60 °C→−40 °C (B)c
2
3
N.R.e
N.R.d
Ph2SO, TTBP, Tf2O, DCM,
−60 °C→−40 °C (B)c
12a
TMSOTf, DCM,
−30 °C (C)c
4
5
6
N.R.f
5
5
5
6c
6b
6b
3a,
54%
(α only)
TMSOTf, DCM,
−10 °C (C)c
3a,
75%
(α only)
TMSOTf, DCM/Et2O (5:1),
−30 °C (C)c
aIsolated yields of products; bBSP = benzenesulfinylpiperidine; ccorresponding glycosylation procedure (see Supporting Information File 1); dstarting
material was decomposed; edonor was decomposed but acceptor was recovered; fa complex mixture was formed from which the desired disaccha-
ride could not be purified by column chromatography.
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(Table 1, entry 6) was found to be effective in case of donor 6b one-pot protocol to achieve the same derivative. The one-pot
and acceptor 5 which generated the desired disaccharide 3a in synthesis of this target is particularly challenging because of the
high yield and exclusive α-anomeric selectivity (evidenced from presence of the two 1,2-cis glycosidic linkages which are likely
NMR). We presume that this near exclusivity in α-selection to make product isolation particularly difficult at the end of the
may be due to the synergistic effect from the 4,6-O-benzyl- glycosylative protocol. Assuming equal preference of forma-
idene group, which is a good promoter for 1,2-cis glycosylation tion for each and every possible diastereomer across the three
in galactose-based systems [38], as well as the steric crowding glycosylation steps a mixture of 8 different diastereomers may
caused by the bulky 3-O-naphthylmethyl group at the β-side of be formed if the four monomers are sequentially added in a
the ring. Having obtained the central disaccharide 3a in requi- (1 + 1 + 1 + 1) one-pot strategy. However, the number of possi-
site yield and excellent stereochemical purity we now bilities may be reduced to 4 isomers by using a participating
proceeded towards the synthesis of the trisaccharide fragment group on the rhamnose residue to induce near exclusive α-selec-
21 (Scheme 4).
tivity in the last step. Further reduction can be ensured by incor-
porating a (1 + 2 + 1) approach where the number of possible
Compound 3a was treated with DDQ in dichloromethane to diastereomers becomes 2. So, we selected this (1 + 2 + 1) glyco-
remove the 3-O-Nap protection group generating acceptor 4 in sylation for our synthesis.
93% yield. Glycosylation between donor 2 and acceptor 4 was
achieved uneventfully in the presence of TMSOTf in dichloro- Two different strategies were attempted in this direction.
methane/Et2O (4:1) to give the trisaccharide 21 in 70% yield. Recently, Mong et al. have reported high α-selectivity in the
Successful glycosylation was also carried out between trisac- formation of glucan and galactan under non-participating condi-
charide 21 and ribitol acceptor 7 in the presence of NIS and tions from the O-2 protecting group [39,40]. With this method,
TMSOTf in dichloromethane at −20 °C to give the tetrasaccha- we tried to couple donor p-tolyl 2,3,4,6-tetra-O-benzyl-1-thio-β-
ride derivative 1 in 89% yield, thereby finishing the stepwise D-galactopyranoside (22) with acceptor 4 using a NIS/TMSOTf
synthesis of SPn 6A tetrasaccharide 1 in the protected form combination in the presence of DMF acting as a modulating sol-
(Scheme 4).
vent (inset, Scheme 5). Unfortunately, when this strategy was
applied to our case it could not produce a viable result. So we
Having standardized a stepwise synthesis of the tetrasaccharide switch to the conventional orthogonal strategy for a one-pot
1 in the protected form we then turned our attention to devise a synthesis of the targeted tetrasaccharide (Scheme 5).
Scheme 4: Stepwise synthesis of tetrasaccharide 1. Reaction conditions: a) TMSOTf, DCM/Et2O (5:1), 4 Å MS, −30 °C, 75%; b) DDQ, DCM/H2O
(9:1), rt, 93%; c) TMSOTf, DCM/Et2O (4:1), 4 Å MS, −15 °C, 70%; d) NIS, TMSOTf, DCM, 4 Å MS, −20 °C, (procedure D, see Supporting Information
File 1), 89%.
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Beilstein J. Org. Chem. 2018, 14, 1095–1102.
Scheme 5: One-pot synthesis of tetrasaccharide 1. Reaction conditions: a) TMSOTf, 4 Å MS, DCM/Et2O (4:1), N2, −15 °C, 1 h; b) NIS, TMSOTf,
−10 °C, 45 min; c) NaOMe, MeOH, rt; d) H2, Pd/C, EtOH/EtOAc/AcOH, rt.
The disaccharide acceptor 4 was glycosylated with galactosyl reported C-1 chemical shifts at δ 99.5, 95.6, and 100.3, exhib-
trichloroacetimidate donor 2 at −15 °C using 30 mol % of ited in D2O corresponding to the anomeric centers of com-
TMSOTf. After full consumption of the starting materials pound 23 [22].
(TLC), into the same pot the second acceptor 7 followed by NIS
were added. The reaction mixture was allowed to reach −10 °C Conclusion
before another 30 mol % of TMSOTf were added; TLC after Summarizing our work we have achieved stepwise and sequen-
45 minutes showed complete consumption of the starting mate- tial one-pot syntheses of the tetrasaccharide repeating unit of
rials. Thus the targeted tetrasaccharide derivative was prepared SPn 6A via an orthogonal glycosylation strategy using com-
via a three component, one-pot sequential glycosylation tech- monly used trichloroacetimidate and thioglycoside donors. The
nique in 52% yield (Scheme 5). It is to be noted that the temper- challenging 1,2-cis linkages could be prepared with a yield and
ature had to be raised to −10 °C from −20 °C in the second step a selectivity which were high enough to allow the one-pot syn-
of the one-pot protocol. This was necessary to improve the thesis.
overall yield of the final product. The tetrasaccharide derivative
1 was next deprotected under Zemplén conditions [41], fol-
Supporting Information
lowed by hydrogenation with H2/Pd-C in EtOH/EtOAc/AcOH
solvent to give the deprotected tetrasaccharide 23 in 85% yield
Supporting Information File 1
over two steps.
Experimental details for the preparation of compounds 1,
3a, 4, 5, 6a, 6b, 7, 12a, 19, 20, 21, and 23 and the
corresponding characterization data.
1H NMR in D2O of the target tetrasaccharide 23 showed the
anomeric protons of the galactose, glucose, and rhamnose
residues from the non-reducing end appearing at δ 5.32
(d, J = 3.5 Hz), δ 5.02 (d, J = 3 Hz), and δ 4.93 (bs), respective-
ly. 13C NMR along with the HSQC in the same solvent
revealed that the chemical shifts of the anomeric carbons
of the same units from the non-reducing end are at δ 99.2
(1JC1-H1 = 167.7 Hz), 95.4 (1JC1-H1 = 169.3 Hz) and 100.1
(1JC1-H1 = 169.2 Hz), respectively. The values are indicative of
α-stereochemistry at all the anomeric centers [42]. Moreover,
the chemical shifts were found to be in fair agreement with the
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-95-S1.pdf]
Supporting Information File 2
1H and 13C NMR of compounds 1, 3a, 4, 5, 6a, 6b, 7, 12a,
19, 20, 21, and 23 and 2D NMR (COSY, HSQC and
HMBC) of compound 23.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-95-S2.pdf]
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Beilstein J. Org. Chem. 2018, 14, 1095–1102.
20.Thijssen, M. J. L.; Bijkerk, M. H. G.; Kamerling, J. P.;
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RG acknowledges the SERB, DST (Scheme No. SR/S1/OC-61/
2012), India for financial support. AC and MMM are thankful
to the CSIR and UGC, India, respectively, for providing senior
research fellowships.
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ORCID® iDs
Rina Ghosh - https://orcid.org/0000-0002-6506-5089
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