Total Synthesis of the All-Rare Sugar-Containing Pentasaccharide Repeating Unit of the O-Polysaccharide of Plesiomonas shigelloides Strain 302-73 (Serotype O1)

Strain 302-73 (Serotype O1)

Letter

Total Synthesis of the All-Rare Sugar-Containing Pentasaccharide

Repeating Unit of the O‑Polysaccharide of Plesiomonas shigelloides

†

Sayantan Biswas, Balasaheb K. Ghotekar, and Suvarn S. Kulkarni *

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sı Supporting Information

ABSTRACT: First total synthesis of the conjugation-ready pentasaccharide

repeating unit of Plesiomonas shigelloides strain 302-73 (serotype O1) is reported.

The complex target pentasaccharide is composed of all-rare amino sugars such as

orthogonally functionalized D-bacillosamine, L-fucosamine, and L-pneumosamine

linked through four consecutive α-linkages. The poor nucleophilicity of axial 4-OH of

L-fucosamine and stereoselective glycosylations are the key challenges in the total

synthesis, which was completed via a longest linear sequence of 27 steps in 3% overall

yield.

iarrhea is a leading cause of death in young children

attached to a variety of functional groups at speciﬁc positions.

The D-bacillosamine unit bears a 3S-hydroxybutyryl (Hb)

amide linker at the C4 position, whereas the L-pneumosamine

moiety has an OAc group at the C4 position. The presence of

unusual sugars and the rare side chain which are virtually

absent in host cells makes this pentasacccharide O-antigen a

below age ﬁve. According to the WHO fact sheet, every

year 525,000 children die due to diarrheal diseases.

Plesiomonas shigelloides is one of the signiﬁcant causative

agents of severe travelers’ diarrhea worldwide with a high rate

of morbidity and mortality. Along with this, it also causes

several other gastrointestinal infections like acute secretory

potential candidate for vaccine development. The key

gastroenteritis, meningitis, bacteremia, and invasive shigello-

challenges in the total synthesis of the pentasaccharide RU

involves installation of four consecutive α-glycosidic linkages

and synthesis of orthogonally protected rare sugar building

blocks. Furthermore, the presence of seven nitrogen atoms

dispensed over ﬁve sugar rings and the poor nucleophilicity of

the 4-OH group of L-fucosamine makes the oligosaccharide

sis-like diseases. There are reports on the association of this

pathogen with central nervous system disease, eye infections,

and a variety of miscellaneous ailments. The bacterial

infection also leads to cholera-like illness, pseudoappendici-

tis, and even apoptotic cell death by entering in the human

10,11

colon carcinoma Caco-2 cells.

With the gradual increase in

13,16

antibiotic-resistant strains of P. shigelloides and due to the

severity of the bacterium, eﬀective treatments are urgently

required. The development of vaccine therapy for the

assembly more challenging.

Our lab has developed an

eﬃcient protocol for the synthesis of rare D- and L-deoxyamino

sugars via a one-pot regioselective S 2 displacements of 2,4

7,18

subtropical travelers is highly desirable. The carbohydrate

bis-triﬂates derived from D-rhamnose

and L-rhamnose/L-

antigens expressed on the surfaces of these strains are

attractive synthetic targets for the development of a multi-

fucose, respectively. The methodology has been also applied

16−20

by us

and others for synthesizing a variety of bacterial

component glycoconjugate vaccine.

O-glycans. Herein, we report the ﬁrst total synthesis of the all-

rare sugar containing conjugation-ready pentasaccharide RU 1.

Corsaro and co-workers isolated and characterized the O-

chain of lipopolysaccharide (LPS) from Plesiomonas shigelloides

strain 302-73 (serotype O1). The polysaccharide was shown

to be composed of an exclusively rare sugar-based

pentasaccharide repeating unit (RU) as follows →3)-α-L-

PneNAc4OAc(1→4)-α-L-FucNAc(1→4)-α-L-FucNAc(1→4)-

α-L-FucNAc(1→3)-β-D-QuiNAc4NHb(1→. The three rare

deoxy amino sugars L-pneumosamine, L-fucosamine, and 4-

amino-D-quinosamine (also called as D-bacillosamine) are

Received: July 6, 2021

Published: July 22, 2021

2021 American Chemical Society

137

Org. Lett. 2021, 23, 6137−6142

Organic Letters

Letter

Scheme 1. Retrosynthetic Analysis

Retrosynthetically (Scheme 1), target molecule 1 can be

synthesized by FGI and global deprotection of fully protected

pentasaccharide 2, which can be assembled by stereoselective

glycosylation of L-pneumosamine donor derived from 4 and

tetrasaccharide acceptor 3 in a [4 + 1] manner. Incidentally,

the pneumosamine unit in the target molecule bears an OAc

group at the C4 position. It was anticipated that the placement

of 4-OAc group in L-pneumosamine donor 4 would assist α-

stereoselectivity in glycosylation through anchimeric assis-

provide anchimeric assistance in favor of α-stereoselective

glycosylation and later for the generation of a 4-OH acceptor

in di-, tri-, and tetrasaccharide, respectively. L-Fucosamine

donor 7 can be made from L-rhamnosyl 2,4-diol 8 via

sequential S 2 displacement of the corresponding L-rhamnosyl

bis-triﬂate. The poor nucleophilicity of the L-fucosamine 4-OH

acceptor was alleviated by placement of an electron-donating

benzyl group at O3. The D-bacillosamine acceptor 6 could be

synthesized by reduction of the C4-azide in compound 9

followed by coupling of the so-formed C4 amino group with

tance, especially in lieu of neighboring group participation

from C2 functionality. Thus, a nonparticipating azide group

could be used at the C2 position of L-pneumosamine building

block 4, which can be synthesized from L-fucose derivative 5 by

a regioselective C2 triﬂation followed by azide inversion. The

corresponding L-fucosyl thioglycoside gives O4 selectivity in

the known 3S-hydroxybutyryl acid derivative 10. D-Bacillos-

amine derivative 9 can be synthesized from the known D-

17,18

fucosamine derivative 11

by conversion of C2-azide to

NHTCA group followed by C4 inversion via azide displace-

ment of C4-triﬂate and stereoselective coupling of thioglyco-

side donor with the linker acceptor 3-benzyloxycarbonylamino

(NHCbz) propanol.

With this retrosynthetic plan, we began with the synthesis of

the diﬀerentially functionalized D-bacillosamine acceptor 6.

controlled triﬂation and hence cannot be used here.

Compound 5 in turn can be obtained by a regioselective

Nap protection of 3-OH of the corresponding L-fucosyl triol.

The Nap group was placed at the O3 of L-pneumosamine, the

connecting point of the RU, as a temporary protecting group

owing to its selective removal from fully protected

Recently, Codee and co-workers have reported a synthesis of

orthogonally protected D-bacillosamine derivatives via azido-

pentasaccharide 2 using DDQ during chain elongation of

the RU. The tetrasaccharide acceptor 3 can be assembled in a

stepwise manner from the reducing end by the stereo-

controlled installation of 1,2-cis-glycosidic linkages, ﬁrst

between 3-OH of orthogonally functionalized D-bacillosamine

acceptor 6 and L-fucosamine donor 7, followed by

deacetylation and reiteration of glycosylation with donor 7

and deacetylation sequence, two times. Donor 7 was designed

with a 4-O-acyl group as a temporary protecting group to

selenation of D-fucal through a stepwise process. For the

synthesis of D-bacillosamine acceptor 6, which bears three

diﬀerentially protected amino groups, we started with the

17,18

known D-fucosamine derivative 11,

which could be readily

prepared from D-rhamnose thioglycoside via our one-pot

double-displacement methodology. As shown in Scheme 2a,

compound 11 was subjected to azide reduction using Zn,

AcOH conditions followed by selective protection of amine

using trichloroacetyl chloride to obtain D-fucosamine derivative

138

Org. Lett. 2021, 23, 6137−6142

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Letter

Scheme 2. Synthesis of Orthogonally Protected Rare Sugar Building Blocks

3 in 79% yield over two steps. In comparison, Staudinger

steps, after a single chromatographic puriﬁcation. The C4-OH

group of compound 17 was acylated by using AcCl or BzCl in

pyridine, DMAP (cat.) conditions to furnish the L-fucosamine

thioglycoside donors 7a and 7b in 94% and 85% yields,

respectively.

conditions gave 13 in 54% yield. Subsequent triﬂation of 4-OH

in 13 using triﬂic anhydride in pyridine and concomitant

nucleophilic displacement of the formed C4-triﬂate with

sodium azide aﬀorded 14 in 86% yield over two steps.

Glycosylation of thioglycoside donor 14 with Cbz protected

amino propanol linker acceptor, at 0 °C under NIS/TMSOTf

activation conditions furnished the desired β-linked glycoside 9

in 88% yield. The C3-OBz group in compound 9 was removed

Only a few methods are reported for the synthesis of rare

amino L-pneumosamine derivatives in low yields. Seeberger

and co-workers tactically employed azidoselenation of L-fucal

to generate a mixture of both L-fucosamine (52%) and L-

under Zemplen

conditions to obtain alcohol 15 (96%). Using

pneumosamine (<25%). We recently reported synthesis of 3-

OBz derivative of L-pneumosamine from L-fucose via a

regioselective C-2 triﬂation followed by azide inversion as a

Staudinger reduction, the azide group was reduced to amine

and subjected to coupling with acid 10 (EDC-HCl, HOBt,

NaHCO ) to give C4-amide acceptor 6 in 73% yield over two

steps.

L-Fucosamine building blocks 7a and 7b were synthesized by

a modiﬁcation of our established protocol involving a highly

key step. Synthesis of 3-O-Nap-protected L-pneumosamine

building block 20 from the L-fucose derivative 18 is shown in

Scheme 2c. Triol 18 was regioselectively protected at the O3

position as a 2-naphthylmethyl (Nap) ether by using Bu SnO

regioselective one-pot S 2 displacements of 3-OBz-protected

in toluene at 110 °C followed by treatment with 2-

naphthylmethyl bromide and TBAB to furnish 2,4-diol 5 in

83% yield over two steps. Diol 5 upon regioselective triﬂation

by using 1.5 equiv of Tf O and pyridine in CH Cl solvent at 0

°C gave exclusively C2-OTf, which on treatment with NaN₃

(portionwise addition over 6 h) in HMPA at 110 °C aﬀorded

the desired L-pneumosamine compound 19 in 61% yield over

two steps. Use of DMF in place of HMPA gave 19 in 52%

yield. Compound 19 on acetylation using AcCl and pyridine

gave fully protected L-pneumosamine derivative 4 (95%). The

structure of compound 4 was further conﬁrmed by X-ray

16,19

L-rhamnosyl 2,4-bistriﬂates (Scheme 2b).

Previously, we

had used the corresponding 3-OBz derivative as the substrate

and the 4-OTf was either displaced by TBANO₂or by

intramolecular attack of C3-OBz group followed by water

mediated ring opening of the so formed cyclic orthoester to

form 3-OBz and 4-OBz derivatives of L-fucosamine,

respectively. Here, we explored 3-OBn derivative of L-

rhamnose and found that it works well in the sequential one-

pot S 2 protocol using cheaply available KNO as the

nucleophile. Accordingly, the known L-rhamnosyl diol 16

upon triﬂation was subjected to selective C-2 OTf displace-

ment by azide using TBAN (1 equiv) in CH CN at 0 °C

single-crystal analysis (Scheme 2) which showed that 4 is

present in C conformation. Compound 4 was subjected to

followed by treatment with KNO for C-4 OTf displacement

the cleavage of p-methoxyphenyl group using CAN/CH CN

to aﬀord L-fucosamine compound 17 in 62% yield over three

condition (86%), which on further treatment with CCl CN,

139

Org. Lett. 2021, 23, 6137−6142

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Letter

DBU in CH Cl furnished L-pneumosamine imidate donor 20

in 71% yield.

After having all the rare sugar building blocks in hand, we

went ahead for the glycosylation reactions (Table 1). L-

acetyl group in disaccharide 21 by using NaOMe/methanol

conditions furnished the disaccharide acceptor 22 (94%). The

concomitant glycosylation of L-fucosamine donor 7a with

disaccharide acceptor 22 required tuning of the conditions for

obtaining exclusive selectivity. The reaction conditions and

results are summarized in Table 1. First, glycosylation of 7a

and 22 using NIS/TMSOTf conditions furnished trisaccharide

Table 1. Synthesis of Trisaccharide 23

3a in 51% yield with 8.5:1.5 α/β selectivity. To improve the

yield, we changed the promoter from TMSOTf to TfOH.

Under these conditions (Table 1, entry 2) we obtained

trisaccharide 23a in 76% yield and with marginally improved

selectivity of α/β 9:1 (entry 2) at 0 °C. Further reducing the

reaction temperature to −60 °C resulted in a slightly better

yield of 79%; however, the selectivity remained the same

(

entry 4). Since it was not possible to separate the α/β isomers

by column chromatography, it was necessary to get exclusive

selectivity in this glycosylation. In order to increase the steric

crowding to discourage the approach of the acceptor from

bottom face, we replaced the 4-OAc group in L-fucosamine

donor 7a with the 4-OBz group to construct 7b. Gratifyingly,

glycosylation of donor 7b with disaccharide acceptor 22 using

NIS/TfOH, CH Cl condition furnished exclusively α-linked

trisaccharide 23b in 72% yield (entry 5).

Synthesis of target molecule 1 from trisaccharide 23b is

donor,

P =

temp

yield (%)

entry

promoter

(°C)

(α/β ratio)

NIS, TMSOTf,

CH Cl

51 (8.5:1.5)

delineated in Scheme 3. Deprotection of the benzoate group in

NIS, TfOH, CH Cl

−30

−60

76 (9:1)

73 (9:1)

79 (9:1)

72 (1:0)

3b using NaOMe/methanol conditions furnished trisacchar-

ide acceptor 24 in 96% yield. Glycosylation of thiofucoside

donor 7a under NIS/TfOH, 0 °C activation conditions with

trisaccharide acceptor 24 aﬀorded the desired α-linked

tetrasaccharide 25, exclusively, in 75% yield. Further

deacetylation of compound 25 by using NaOMe/MeOH

generated tetrasaccharide acceptor 3, which upon subsequent

glycosylation with L-pneumosamine imidate donor 20 using

TMSOTf promoter over the temperature range of −40 °C to

−20 °C aﬀorded the fully protected pentasaccharide 2 in 91%

Fucosamine thioglycoside donor 7a on glycosylation using NIS

and TMSOTf as a promoter in dry CH Cl condition with

acceptor 6 at 0 °C aﬀorded α-linked disaccharide 21 in 82%

yield, exclusively. The characteristic NMR signals ( H NMR δ

.88 (d, J = 3.3 Hz, 1H, H-1′), 4.83 (d, J = 8.2 Hz, 1H, H-1),

C NMR δ 99.1 (C-1) and 98.6 (C-1′) ppm) conﬁrmed the

yield as a single isomer. The α-stereochemistry of the newly

formation of α-linked disaccharide 21. Removal of the O4

formed glycosidic linkage was conﬁrmed by measuring J

C−H

Scheme 3. Synthesis of Target Molecule 1

140

Org. Lett. 2021, 23, 6137−6142

Organic Letters

Letter

coupling constant of the anomeric carbon of L- pneumosamine

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Corresponding Author

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Sayantan Biswas − Department of Chemistry, Indian Institute

of Technology Bombay, Mumbai 400076, India

Balasaheb K. Ghotekar − Department of Chemistry, Indian

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ACKNOWLEDGMENTS

■

(

S.S.K. thanks the Council of Scientiﬁc and Industrial Research

Grant No. 02(0413)/21/EMR-II) for ﬁnancial support.

B.K.G. and S.B. thank UGC, New Delhi, for research

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Organic Letters

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