Expedient Route to Access Rare Deoxy Amino l-Sugar Building Blocks for the Assembly of Bacterial Glycoconjugates

Article abstract of DOI:10.1021/jacs.6b01823

Bacterial glycoproteins and oligosaccharides contain several rare deoxy amino l-sugars which are virtually absent in the human cells. This structural difference between the bacterial and host cell surface glycans can be exploited for the development of carbohydrate based vaccines and target specific drugs. However, the unusual deoxy amino l-sugars present in the bacterial glycoconjugates are not available from natural sources. Thus, procurement of orthogonally protected rare l-sugar building blocks through efficient chemical synthesis is a crucial step toward the synthesis of structurally well-defined and homogeneous complex glycans. Herein, we report a general and expedient methodology to access a variety of unusual deoxy amino l-sugars starting from readily available l-rhamnose and l-fucose via highly regioselective, one-pot double serial and double parallel displacements of the corresponding 2,4-bistriflates using azide and nitrite anions as nucleophiles. Alternatively, regioselective monotriflation at O2, O3, and O4 of l-rhamnose/l-fucose allowed selective inversions at respective positions leading to diverse rare sugars. The orthogonally protected deoxy amino l-sugar building blocks could be stereoselectively assembled to obtain biologically relevant bacterial O-glycans, as exemplified by the first total synthesis of the amino linker-attached, conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica O:50 strain 3229 and the trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens strain M71.

Full text of DOI:10.1021/jacs.6b01823

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Article
Expedient Route to Access Rare Deoxy Amino L-Sugar
Building Blocks for the Assembly of Bacterial Glycoconjugates
Someswara Rao Sanapala, and Suvarn S. Kulkarni
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Mar 2016
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Expedient Route to Access Rare Deoxy Amino L-Sugar Building Blocks for
the Assembly of Bacterial Glycoconjugates
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Someswara Rao Sanapala and Suvarn S. Kulkarni*
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Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India.
suvarn@chem.iitb.ac.in
ABSTRACT
Bacterial glycoproteins and oligosaccharides contain several rare deoxy amino L-sugars
which are virtually absent in the human cells. This structural difference between the bacterial
and host cell surface glycans can be exploited for the development of carbohydrate based
vaccines and target specific drugs. However, the unusual deoxy amino L-sugars present in
the bacterial glycoconjugates are not available from natural sources. Thus, procurement of
orthogonally protected rare L-sugar building blocks through efficient chemical synthesis is a
crucial step towards the synthesis of structurally well defined and homogeneous complex
glycans. Herein we report a general and expedient methodology to access a variety of
unusual deoxy amino L-sugars starting from readily available L-rhamnose and L-fucose via
highly regioselective, one-pot double serial and double parallel displacements of the
corresponding 2,4-bistriflates using azide and nitrite anions as nucleophiles. Alternatively,
regioselective monotriflation at O2, O3 and O4 of L-rhamnose/L-fucose allowed selective
inversions at respective positions leading to diverse rare sugars. The orthogonally protected
deoxy amino L-sugar building blocks could be stereoselectively assembled to obtain
biologically relevant bacterial O-glycans, as exemplified by the first total synthesis of the
amino linker-attached, conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica
O:50 strain 3229 and the trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens
strain M71.
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INTRODUCTION
Bacteria have unique glycan structures on their surface which differ from their
eukaryotic counterparts.1 This difference between the bacterial and human cell surfaces can
be exploited for target specific drug discovery and vaccine development.2 Unfortunately, the
bacterial glycoproteins cannot be isolated from natural sources in pure form and acceptable
amounts. Chemical synthesis of the complex bacterial glycoconjugates is therefore a crucial
step towards realizing this goal.
Bacterial glycoconjugates are comprised of several atypical amino 6-deoxy-L-sugars.3
Some representative structures are shown in Figure 1. For example, 2-acetamido-2,6-
dideoxy-L-galactose (N-acetyl L-fucosamine, L-FucNAc) is present in Yersinia enterocolitica
serotype O:50 strain 3229,4 Staphylococcus aureus,5 Pseudomonas chlororaphis,6
Plesiomonas shigelloides serotope O17 and Pseudomonas aeruginosa serotype O12.8
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Figure 1. Representative structures of bacterial glycans containing rare deoxy amino L-
sugars
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Likewise, 2-acetamido-2,6-dideoxy-L-talose (N-acetyl 6-deoxy-L-talosamine), commonly
known as N-acetyl L-pneumosamine (L-PneNAc), is a constituent of Plesiomonas
shigelloides serotope O17 and Alteromonas nigrifaciens IAM 13010T.9 The 2-acetamido-2,6-
dideoxy-L-glucose (N-acetyl L-quinovosamine, L-QuiNAc) is present in Vibrio vulnificus
BO62316,10 Pseudomonas chlororaphis,6 Proteus vulgaris TG 155,11 Vibrio vulnificus MO6-
2412 and Shewanella putrefaciens strain S29.13 The 2-acetamido-2,6-dideoxy-L-rhamnose (N-
acetyl L-rhamnosamine, L-RhaNAc) forms a key component of the surface glycans of Vibrio
vulnificus BO6231610 and Proteus vulgaris TG 155 from a new Proteus serogroup O55.11
These glycans being virtually absent on the human cell surfaces are expected to induce
specific immune response in human hosts and are thus regarded as potential vaccine
candidates against a variety of infectious diseases. On the other hand, derivatives of 4-
amino-4,6-dideoxy L-sugars are present in potent antibiotics such as tallysomycin and
kansosamine.14 The 2,4-diamino-2,4,6-trideoxy-hexoses have also attracted attention due to
their direct involvement in microbial pathogenecity.15 Moreover, the 3-amino-3,6-dideoxy-L-
talose or 3-amino-3,6-dideoxy-L-mannose (L-mycosamine) are components of structurally
related antiviral antibiotics fluvirucins A1, A2, B1, B2, B3, B4 and B5, which are active
against influenza A virus.16
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Given their biological importance, these glycoconjugates are attractive synthetic
targets. However, the rare deoxy amino L-sugars are not available from natural sources.
Thus, procurement of the suitably protected rare deoxy amino L-sugar building blocks
through chemical synthesis is a major impediment limiting the biological evaluation of the
complex bacterial cell surface glycans. Although there are efficient methods reported in
literature for the syntheses of deoxy amino D-sugars,17 attempts towards the syntheses of their
L-counterparts are rare. Several methods are available for the synthesis of L-hexoses and 6-
deoxy L-hexoses.18 However, only a few reports are there on chemical synthesis of L-
fucosamine,19 L-quinovosamine,20 L-rhamnosamine,20,21 L-pneumosamine,22 4-amino-4,6-
dideoxy-L-sugars23 as well as 2,4-diamino-2,4,6-dideoxy-L-sugars24 and 3-amino-3,6-
dideoxy-L-sugars,25 which mostly involve lengthy routes starting from carbohydrate
precursors leading to low yields of products or diastereomeric mixtures. For this reason, the
de novo approaches have been looked upon as viable alternatives in recent years. O’Doherty
and co-workers employed their de novo methodology to construct 4-amino-4,6-dideoxy-L-
rhamnose moiety of methymycin analogs starting from furan via postglycosylational
transformations.26 Very recently, Seeberger and co-workers extended their elegant de novo
approach to the synthesis of L-FucNAc starting from D-Garner aldehyde.27 Still, there is no
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general and divergent protocol to access differentially protected rare deoxy amino L-sugar
building blocks that can be used as glycosyl donors or acceptors in the assembly of complex
bacterial glycans. Therefore, we planned to develop a general and expedient methodology to
synthesize a variety of rare amino deoxy L-sugars as thioglycosides or p-methoxyphenyl
glycoside building blocks starting from the readily available L-rhamnose and L-fucose.
Our approach involved a one-pot double serial or double parallel displacements of
2,4-bis-trifluoromethanesulfonates (OTf, triflate) of L-rhamnoside and L-fucoside by azide
and /or nitrite anions as nucleophiles. We have recently established an efficient protocol to
access rare deoxy amino D-sugars via the displacement of 2,4-bistriflates derived from D-
mannose.28,17 It was envisioned that such nucleophilic displacements on L-rhamnose or L-
fucose scaffolds would provide a facile entry to diverse rare amino deoxy L-sugars. In
conjunction with this, regioselective monotriflations at O2, O3 and O4 of L-rhamnose/L-
fucose were expected to allow selective inversions at respective positions leading to a variety
of rare sugars.
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RESULTS AND DISCUSSION
Synthesis of Rare Deoxy Amino L-Sugar Building Blocks. Readily available β-L-
thiorhamnoside 129 was selected as a suitable starting material for our initial studies (Scheme
1a). A highly regioselective monobenzoylation of 1 using 5.0 mol% dimethyltin dichloride
(Me2SnCl2),30 benzoyl chloride (1.2 equiv) and DIPEA in THF cleanly generated the 3-OBz
derivative 2 (95%). For the synthesis of L-quinovosamine, the 2,4-diol 2 was treated with
tert-butyldimethyl silyl chloride (TBSCl) in the presence of imidazole to obtain 4-OTBS
derivative 3 in 66% yield along with ~10% of the corresponding 2-OTBS derivative. The
remaining 2-OH in 3 was converted to O-triflate, which was subsequently displaced by
sodium azide (NaN3) in DMF to give orthogonally protected 2-azido-2,6-dideoxy-L-glucose 4
(L-quinovosamine) in 78% yield over 2 steps, in a one-pot manner.
The 2,4-diol 2 served as a common precursor for accessing various rare sugar
derivatives of L-fucosamine and L-fucose via double serial and double parallel inversions of
the corresponding L-rhamnosyl 2,4-bis-triflates using azide, and/or nitrite anions as
nucleophiles (Scheme 1b). Throughout the studies, we carried out a brief aqueous work up
after triflation to obtain a crude triflate derivative which was used as such in the subsequent
steps. Column chromatography was performed only once at the end of each sequence of
displacements. For the synthesis of L-fucosamine derivative 5, compound 2 was treated with
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Scheme 1. Synthesis of L-quinovosamine, L-fucosamine, L-fucose, L-Fuc4N3, and L-
FucN34N3 derivatives via double parallel and double serial inversions
triflic anhydride (Tf2O) in pyridine to afford the corresponding 2,4-bis-triflate, which upon
treatment with a stoichiometric amount of tetrabutyl ammonium azide (TBAN3) in
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acetonitrile at 0 C for 1 h, underwent a facile, regioselective displacement of the C2-OTf.
Subsequent addition of 3 equiv of tetrabutyl ammonium nitrite (TBANO2) in the same pot
displaced the remaining C4-OTf, via a Lattrel-Dax reaction,31 to afford 4-OH L-fucosamine
derivative 5 in 57% yield over 3 steps. The double serial inversion also worked well upon
reversing the order of the addition of nucleophiles. Accordingly, the 4-azido-4,6-dideoxy-L-
galactose (L-Fuc4N3) 6 was obtained via a highly regioselective displacement of C2-OTf
with 3 equiv of TBANO2 in acetonitrile at 0 oC for 2 h, and concomitant displacement of the
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C4-OTf by using 3 equiv of TBAN3 in 52% yield over 3 steps. For the synthesis of 3-OH
derivative of L-fucosamine 7, compound 2 was converted to the corresponding 2,4-bistriflate,
which was treated with 1 equiv of TBAN3 in acetonitrile for 1 h at 0 oC followed by heating at
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80 C in a 9:1 CH2Cl2:H2O solvent mixture to afford 7 (59% over 3 steps). In this water
mediated transformation, the 3-OBz group displaces the C4-OTf from the bottom face to
form a transient orthoester which concomitantly opens up selectively under the conditions to
give axial 4-OBz group.32 The reaction worked very well on a gram scale. Finally, the
double parallel inversion of the 2,4-bistriflates with excess of sodium azide in
dimethylformamide afforded 2,4-diazido-2,4,6-trideoxy-L-galactose derivative 8 in 74% yield
over 2 steps. Similarly, treatment of the 2,4-bistriflates with 4 equiv of TBANO2 in
acetonitrile furnished L-fucose derivative 9 in 50% yield over 2 steps. In this way, we were
able to rapidly transform L-rhamnose into various differentially protected derivatives of L-
fucosamine and L-fucose in an efficient manner by involving one-pot transformations.
It should be however noted that the displacement of 2/4-O-triflates or 2,4-bistriflates
of 3-O-benzoyl thio-α-L-rhamnoside and p-methoxyphenyl-α-L-rhamnosides did not work
well and led to either decomposition or elimination products. These results are in congruence
with the Richardson-Hogue rules33 for nucleophilic displacement of pyranoside triflates
which are recently updated by Hale and coworkers.34
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In the case of a α-L-rhamnoside, there is a strong unfavorable interaction between the
anomeric p-methoxyphenyl group (or thiophenyl group) and the approaching nucleophile
(Pyranoside Vicinal Axial Effect34) (Fig 2a) in the SN2 transition state which leads to either
E2 elimination35 (in the case of OMP) or decomposition (for thioglycoside through
participation of sulfur29,36). A mere change in the anomeric configuration from α- to β-
alleviated such unfavorable repulsions facilitating successful displacement reactions (Fig 2b).
Figure 2. Explanation for the observed regioselectivity
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The regioselectivity attained in the triflate displacement reactions can be attributed to the
differences in the steric crowding and stereoelectronic factors (β-trans axial effect33,34 and
1,3-diaxial repulsions) at C2-OTf and C4-OTf of L-rhamnoside (Figure 2b). The equatorial
C4-OTf on the β-L-rhamnoside scaffold (Fig. 2b) is less accessible due to the presence of the
axial C2-OTf which imparts a severe 1,3-diaxial repulsion as well as steric repulsion on the
approaching nucleophile for a bottom face approach. Moreover, for the equatorial triflates to
react the pyranoses would have to undergo a ring flip and therefore much higher temperatures
are required to achieve these transformations. In comparison, the axial C2-OTf is freely
accessible for the nucleophile from the top face of the β-configured L-rhamnoside.
Strategically, as soon as the axial C2-OTf is displaced, the C4-OTf becomes freely accessible
for the incoming nucleophile. This set up may potentially lead to a double serial
displacement of 2,4-bistriflates, which could be arrested at 0 oC using stoichiometric amount
of TBAN3 or controlled amount of TBANO2. The C-4OTf could then be displaced
concomitantly by another nucleophile (azide, nitrite, OBz) in a tandem one-pot manner. By
extending the same logic, it was envisioned that, on the α-L-fucoside scaffold (Fig 2c), the
axial C4-OTf would preferentially get displaced over the equatorial 2-OTf. In this case, the
axial C4-OTf is expected to hinder the approaching nucleophile from the bottom face owing
to steric and electronic repulsions. We anticipated that a very similar relative arrangement of
substituents should allow us to carry out one-pot, regioselective displacements of L-fucosyl
2,4-bistriflates.
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With these considerations, we began experimenting with L-fucose. The p-
methoxyphenyl-α-L-fucoside 10 was first prepared from L-fucose following the reported
procedure.37
Accordingly, per-O-acetylation of L-fucose followed by nucleophilic
displacement of the anomeric acetate with p-methoxyphenol using BF3·Et2O in CH2Cl2 and
subsequent deacetylation provided triol 10 (Scheme 2). Regioselective 3-O-benzoylation of
2,3,4-triol 10 was achieved by using 5 mol% Me2SnCl2 and benzoyl chloride to afford 11 in
86% yield. The L-fucosyl 2,4-diol 11 was then treated with Tf2O and pyridine to form the
corresponding 2,4-bistriflate, which upon a brief work up was as such subjected to double
serial and double parallel inversions to access the rare deoxy amino L-rhamno and L-talo
derivatives. As anticipated, the 2,4-bistriflate, upon treatment with 3 equiv of TBANO2 in
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acetonitrile at 0 C for 1 h, underwent a highly regioselective displacement of the more
accessible C4-OTf group; subsequent addition of NaN3 in HMPA at 110 oC displaced the C2-
OTf to afford L-rhamnosamine derivative 12 in 58% yield over 3 steps, after a single column
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OMP
OH
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4
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OMP
OH
OH
1. Ac2O, Py
Me2SnCl2 (5 mol%),
O
O
O
OH
2. PMPOH, BF3·OEt2
CH2Cl2
3. NaOMe, MeOH
76% over 3 steps
BzCl, DIPEA, THF
10 min, 86%
OBz
HO
OH
HO
L-fucose
OH
HO
10
11
OMP
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4-azido-4,6-
dideoxy-L-mannose
O
N3
BzO
OH
13
52% over
3 steps
1. Tf2O, Py, CH2Cl2
2. TBAN3 (1 equiv),
1. Tf2O (3.0 equiv),
CH3CN, 0 C, 2 h
3. TBANO2, 60 C, 5 h
Me2SnCl2, 2,6-Lutidine,
CH2Cl2, 0 C, 0.5 h
2. Ac2O, 2 h
1. Tf2O, Py, CH2Cl2
OMP
1
OMP
OMP
5
2. TBANO2 (3 equiv),
CH3CN, 0 C, 1 h
3. NaN3, HMPA,
3
O
OBz 2
O
4
O
OH
110 C, 10 h
HO
OBz
HO
OBz
11
AcO
N3
52% over 3 steps
3. NaN3, HMPA,
110 °C 10 h
58% over 3 steps
N3
12
14
L-pneumosamine
L-rhamnosamine
1. Tf2O (3 equiv), Me2SnCl2,
2,6-Lutidine, CH2Cl2, 0 C
2. NaN3, HMPA,
1. Tf2O, Py, CH2Cl2
2. NaN3, HMPA, 110 C
ps
ste
2
er
ov
%
69
110 C, 10 h
s
tep
2 s
er
ov
%
49
OMP
OMP
O
O
N3
OH
15
OBz
16
BzO
N3
N3
L-pneumosamine acceptor
(2,6-dideoxy-L-talosamine)
2,4-diazido-2,4,6-trideoxy
L-mannose
Scheme 2. Synthesis of L-rhamnosamine, L-pneumosamine, 4-azido-L-mannoside, 2,4-
diazido-L-mannoside via double parallel and double serial inversions
chromatographic purification. Likewise, addition of a stoichiometric amount of TBAN3 to
the so formed 2,4-bistriflate in acetonitrile led to azide displacement of C4-OTf. Subsequent
o
addition of TBANO2 in the same pot and heating at 60 C for 5 h generated 4-azido-2,6-
dideoxy-L-mannose derivative 13 (52%, 3 steps). In order to synthesize 2-azido-2,6-dideoxy-
L-talose (L-pneumosamine), we examined the catalytic Me2SnCl2 mediated regioselective 2-
O-triflation of the 2,4-diol, capitalizing on the higher reactivity of the equatorial hydroxyl
group and strong coordination ability of the 1,2-cis oriented oxygens with tin. Indeed, the
2,4-diol 11 upon treatment with 3 equiv of triflic anhydride in the presence of catalytic
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Me2SnCl2 and 2,6-lutidine in CH2Cl2 generated the corresponding 2-OTf derivative,
1
exclusively (as judged by H NMR). Sequential addition of acetic anhydride, to mask the
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remaining 4-OH, in the same pot and displacement of the C2-OTf by NaN3 in HMPA as a
solvent afforded the differentially protected L-pneumosamine derivative 14 in 52% yield over
3 steps. On the other hand, a regioselective C2-OTf formation of diol 11, followed by its
nucleophilic displacement with NaN3 in HMPA at 110 oC for 10 h led to the formation of the
3-OH derivative of L-pneumosamine 15 in 49% over 2 steps, via a migration of the benzoyl
group from 3-OH to 4-OH under the prevailing conditions. Thus differentially protected L-
pneumosamine derivatives could be obtained simply by capping the 4-OH by acetylation or
by leaving it free to participate in the reaction. The double parallel displacement of the 2,4-
bistriflate of L-fucoside 11 with sodium azide in HMPA at 110 oC generated the 2,4-diazido-
2,4,6-trideoxy-L-mannoside 16 in 69% yield over 2 steps, uneventfully. In this way, we were
able to rapidly access various differentially protected derivatives of L-rhamnosamine and L-
pneumosamine from L-fucoside 11.
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To access the C3-functionalized rare L-sugars, we resorted to a regioselective
triflation of the 2,3,4-triol. Synthesis of 3-azido-3,6-dideoxy-L-altroside was achieved via
inversion of 3-OH of L-rhamnoside 1 by using regioselective 3-O-triflation and its sequential
displacement (Scheme 3). Thus, regioselective 3-O-triflation using 3.5 equiv of Tf2O,
catalytic Me2SnCl2 and 2,6-lutidine in CH2Cl2 followed by acetylation of the 2,4-OH groups
by addition of acetic anhydride in the same pot afforded the corresponding 3-O-triflyl-2,4-di-
Scheme 3. Synthesis of 3-azido-3,6-dideoxy-L-altroside 17, L-mycosamine 19
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O-acetyl-L-rhamnoside derivative, which upon subsequent displacement of the C3-OTf by
NaN3 offered 3-azido-3,6-dideoxy-L-altroside 17 in 56% yield over 3 steps. Likewise, a
regioselective 3-O-triflation of L-rhamnoside 1, followed by acetylation of 2,4-hydroxyl
groups and subsequent displacement of C3-OTf by TBANO2 gave 6-deoxy-L-altroside 18
(40% yield over 3 steps). Triflation of 3-OH of 18 and concomitant displacement of the so
formed C3-OTf with NaN3 in HMPA fashioned L-mycosamine derivative 19 (47% yield over
2 steps).
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In the course of our studies directed towards the synthesis of L-pneumosamine
derivative, we observed an unexpected regioselectivity in triflation of L-thiofucoside 9
(Scheme 4). When compound 9 was treated with 1.1 equiv of Tf2O and pyridine we obtained
the corresponding C4-OTf, exclusively, which could be concomitantly displaced with NaN3
in the same pot to furnish 4-azido-L-glucose derivative 20 in 54% yield over 2 steps. The
reason behind the observed unusual selectivity (4-OH axial over 2-OH equatorial) in triflation
of 2,4-diol 9, could be attributed to the steric and electronic effects. Due to the equatorial
disposition of the anomeric SPh group, as well as C3-OBz group, perhaps there is a steric
hindrance for a bulky group such as a triflate to approach the C2-OH, in comparison with the
freely accessible C4-OH. In addition to this, the SPh group being not a powerful electron
withdrawing group does not cause appreciable difference in the acidity of C4-OH and C2-OH
protons. Synthesis of 2,3-diazido-2,3,6-trideoxy-L-guloside 21 was achieved by inversion of
3-OH of L-fucosamine derivative 7, via 3-O-triflation followed by displacement with NaN3 in
DMF in 77% yield over 2 steps. The rare sugar 2,3,4-triazido-2,3,4,6-tetradeoxy-L-guloside
23 was obtained from diazido compound 8. Its debenzoylation gave 2-OH derivative 22,
Scheme 4. Synthesis of 4-azido-4,6-dideoxy-L-glucose 20, 2,3-diazido 2,3,6-trideoxy-L-
guloside 21, 2,3,4-triazido-2,3,4,6-tetradeoxy-L-guloside 23.
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which upon triflation and subsequent displacement by NaN3 offered 23 in 71% yield over 2
steps in a one-pot manner. It should be noted that direct displacement of the corresponding
L-rhamnosyl 2,3,4-tristriflate, derived from triol 1, with NaN3 failed to give 23 and led to the
elimination of the axial C2-OTf instead.
In this way, an expedient protocol has been established for the synthesis of
differentially protected phenylthio or p-methoxyphenyl glycosides of rare amino deoxy-L-
sugars from readily available L-rhamnose or L-fucose via one-pot tandem nucleophilic
displacements of O-triflates. We have also optimized reaction conditions for one pot double
serial and double parallel inversions of L-rhamnosyl 2,4-bistriflates to access L-fucosamine,
L-fucose, L-Fuc4N3, L-FucN34N3 derivatives in good overall yields. An azide displacement of
orthogonally protected L-rhamnosyl C2-OTf afforded L-quinovosamine derivative.
Similarly, L-rhamnosamine, 4-azido-4,6-dideoxy-L-mannoside, 2,4-diazido-2,4,6-trideoxy-L-
mannosides were obtained from L-fucoside. Alternatively, regioselective monotriflation at
O2, O3 and O4 of L-rhamnose/L-fucose allowed facile entry to L-pneumosamine (6-deoxy-L-
talosamine), L-mycosamine and other rare sugars through inversion of respective positions.
All the rare sugar building blocks synthesized in this study are either thioglycosides or
methoxyphenyl glycosides which can be employed in glycosylation reactions as stable donors
and acceptors. Ready availability of the rare deoxy amino L-sugar building blocks will
expedite the synthesis of complex, rare sugar containing bacterial glycans, thereby allowing
us to study their role in pathogenesis and their immunological properties for further
development of vaccines.
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Application to Total Synthesis of Bacterial O-Glycans. As an application of our
methodology, we report herein the first total synthesis of the amino linker-attached,
conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica O:50 strain 3229
(Figure 3, 24) and the trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens strain
M71 (Figure 3, 25) respectively. O-specific polysaccharide (O-PS) biological repeating unit
of Yersinia enterocolitica serotype O:50 strain 3229 was isolated in 20124 and the structure
was elucidates as →2)-α-L-Rhap-(1→3)-α-L-FucpNAc-(1→3)-α-L-FucpNAc-(1→3)-β-D-
GlcpNAc-(1. Y. enterocolitica is clinically important among 17 Gram-negative species of
Yersinia genus.38 Y. enterocolitica most often causes enterocolitis, acute diarrhea, mesenteric
lymphadentis, and pseudoappendicitis.39 A structurally related O-specific trisaccharide →2)-
α-L-Rhap-(1→3)-α-L-FucpNAc-(1→3)-β-L-QuipNAc-(1→ was isolated from the root of a
tomato plant by the mild acid hydrolysis of the lipopolysaccharide from P. chlororaphis
subsp. aureofaciens strain M71.6 This compound was able to inhibit the in vitro growth of S.
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cardinale and other cypress pathogenic fungi as Diplodia cupressi, Seridium cupressi and
Seridium unicorne.40
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7
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9
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Figure 3. Structures of tetrasaccharide and trisaccharide repeating units of O-PS of Yersinia
enterocolitica and Pseudomonas chlororaphis subsp. aureofaciens strain M71, respectively.
The major challenges in the synthesis of the tetrasaccharide 24 are synthesis of
appropriately protected L-fucosamine building block and installation of consecutive 1,2-cis
linkages. For a convergent synthesis of tetrasaccharide 24, we envisaged that a [2+2]
glycosylation would be a better option (Figure 3). This would entail formation of two α-
linked disaccharides, both containing the rare L-fucosamine unit, and their α-stereoselective
assembly. Advantageously, the same non-reducing end disaccharide could be utilized for the
synthesis of the trisaccharide 25 by coupling with appropriately protected L-quinovosamine
derivative. As shown in Scheme 5, we began with the synthesis of the reducing end
disaccharide 29. A regioselective coupling between known 2641 and the amino linker
HO(CH2)3NHCbz using NIS and TMSOTf as activator in CH2Cl2 furnished the β-linked
product 27 in 87% yield (β-linkage, δ 4.39, J = 7.5 Hz, 1JC,H = 158.8 Hz). The 3-OH of 7 was
capped using chloroacetyl chloride and pyridine to afford the fully protected β-thio-L-
fucoside donor 28 (94% yield), which was subsequently glycosylated with the 3-OH D-
glucosamine acceptor 27 under NIS and TfOH promotion in CH2Cl2 to afford the desired α-
1
linked disaccharide 29 in 70% yield (α-linkage, δ 4.90, J = 2.4 Hz JC,H = 172.5). The
observed exclusive α-selectivity can be attributed to the stabilization of the glycosyl cation
intermediate through the anchimeric assistance of the strategically positioned 4-O-ester
group.42 Removal of the chloro acetyl group by treating 29 with thiourea gave 3′-OH 30
(93%), a suitable acceptor for the key [2+2] glycosylation. In order to synthesize the non-
reducing end disaccharide 32, trichloroacetimidate donor 3143 and acceptor 7 were coupled in
the presence of TMSOTf to afford the α-linked disaccharide 32 in 73% yield (α-linkage, δ
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Ph
O
O
SPh
N3
OTCA
O
O
SPh
HO
O
BnO
OR
BzO
NHTroc
26
BnO
31
OBn
NIS, TMSOTf,
MS 3Å, CH2Cl2,
0 C, 30 min
87%
7, R = H
ClAcCl,
Py, 94%
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24
25
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NIS, TMSOTf,
HO(CH2)3NHCbz
28, R = ClAc
SPh
N3
O
MS 3Å, CH2Cl2,
OH
0 C, 30 min
BzO
7
73%
O
Ph
O
O
O
O
SPh
N3
NHCbz
HO
NHTroc
O
BzO
27
NIS, MS 3Å
O
BnO
TfOH (0.4 equiv),
BnO
OBn
CH2Cl2, -20 C
2 h, 70%
32
Ph
O
O
Ph
O
O
O
O
O
O
O
NHCbz
NIS, TMSOTf,
NHCbz
O
O
NHTroc
NHTroc
O
MS 3Å, CH2Cl2,
0 C, 30 min
65%
O
N3
N3
OAcCl
BzO
BzO
29, R = ClAc
30, R = H
1. Zn, AcOH, Ac2O
O
Thiourea
Py, 90 C
93%
24
N3
2. NaOMe, MeOH
3. H2, Pd(OH)2/C,
O
BzO
O
50% AcOH, rt, 24 h
62% over 3 steps
BnO
33
OBn
OBn
Scheme 5. Synthesis of tetrasaccharide 24
5.21, J = 1.6 Hz. 1JC,H = 167.6 Hz). The crucial coupling between disaccharide donor 32 and
the reducing end disaccharide acceptor 30 in the presence of NIS and TMSOTf in CH2Cl2
1
afforded tetrasaccharide 33 in 65% yield (α-linkage, δ 5.36, J = 4.0 Hz. JC,H = 172.5 Hz).
The C NMR spectrum displayed peaks at 98.8 (1JC,H = 175.0 Hz), 94.4 (1JC,H = 168.7 Hz),
94.1 ppm (1JC,H = 172.5 Hz) for α and 100.8 ppm (1JC,H = 162.0 Hz) for β-anomeric carbons,
13
respectively.
Global deprotection of tetrasaccharide 33 was achieved in 3 steps. Conversion of the
azide and NHTroc to the corresponding acetamido group in a one pot conversion was
achieved by treatment with Zn/AcOH and Ac2O. Debenzoylation with 2 N NaOMe in
methanol followed by debenzylation and benzylidene deprotection was carried out under
hydrogenation conditions using H2/Pd(OH)2 in 50% acetic acid to afford the target
tetrasaccharide 24 in 62% over 3 steps, after purification over Sephadex G25 column. In this
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way, we have successfully completed the first total synthesis of a conjugation ready
tetrasaccharide 24 of the O-PS from Y. enterocolitica. The installation of consecutive 1,2-cis
linkages of L-fucosamine residues were achieved by exploiting the neighboring group
participation of 4-OBz group.
The disaccharide 32 was also utilized in the assembly of trisaccharide 25 belonging to
Pseudomonas chlororaphis subsp. aureofaciens strain M71, as shown in Scheme 6. Diol 34
could be easily prepared from triol 1 following the procedure reported by Crich and
coworkers.29 Catalytic Me2SnCl2 mediated regioselective 3-O-benzoylation of 2,3-diol 34
provided 2-OH derivative 35 in 91% yield. The remaining 2-OH was triflated and displaced
with azide to furnish L-quinovosamine derivative 36 (66% over 2 steps). Reduction of azide
by using zinc in acetic acid and ethyl acetate gave the corresponding amine, which was
capped as a trichloroacetate to obtain 37 (69% over 2 steps). Glycosylation of thioglycoside
donor 37 with OH(CH2)3NHCbz linker as an acceptor in the presence of NIS and TMSOTf
afforded 38 in 83% yield (β-linkage, δ 4.41, J = 8.5 Hz. 1JC,H = 160.0 Hz). Debenzoylation of
38 using NaOMe in methanol provided 39 (65%), which was employed as an acceptor in the
ensuing glycosylation. Finally, the disaccharide donor 32 was coupled with L-quinovosamine
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Scheme 6. Synthesis of trisaccharide 25
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acceptor 39 in the presence of NIS and TMSOTf in CH2Cl2 at 0 C to furnish α-linked
1
trisaccharide 40 in 65% yield (α-linkage, δ 5.61, J = 4.0 Hz. JC,H = 171.5 Hz). Global
6
7
8
9
deprotection of trisaccharide 40 was accomplished in 3 steps, in a similar manner.
Conversion of azide and NHTCA to the corresponding acetamido group in a one pot
conversion (Zn/AcOH and Ac2O) followed by debenzoylation using 2 N NaOMe in methanol
and subsequent debenzylation under hydrogenation conditions using H2/Pd(OH)2 in 50%
acetic acid smoothly delivered the target trisaccharide 25 in 60% yield over 3 steps.
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CONCLUSION
In conclusion, we have established an expedient and facile protocol to synthesize
differentially protected rare deoxy amino L-sugars of bacterial origin from readily available
L-rhamnose and L-fucose in good overall yields. We employed one pot double serial and
double parallel inversions of O-triflates or regioslective triflation as powerful method to
access most of the rare deoxy amino L-sugars present in bacteria. We extended this
methodology to the total synthesis of O-PS repeating units of Yersinia enterocolitica and
Pseudomonas chlororaphis subsp. aureofaciens strain M71. The methodology will expedite
assembly of bacterial glycoconjugates and speed up the vaccine development. The azide
bearing rare sugars can be also utilized for metabolic incorporation of glycans to discover
new bacterial glycoproteins and for target specific drugs.44 The rare L-sugar building blocks
will also serve as valuable tools to delineate the biosynthetic pathways of various infectious
bacteria. This would further open up avenues for the development of novel antibiotics.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data for all new compounds, and copies of 1H, 13C
and 2D NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
suvarn@chem.iitb.ac.in.
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Notes
The authors declare no competing financial interests.
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ACKNOWLEDGMENT
9
This work was supported by Science and Engineering Research Board, Department of
Science and Technology (Grant No. EMR/2014/000235). S.R.S. thanks UGC-New Delhi for
a fellowship.
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Expedient Route to Access Rare Deoxy Amino L-Sugar Building Blocks for
the Assembly of Bacterial Glycoconjugates
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